<PAGE>
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 8-K/A
AMENDMENT NUMBER 1 TO
CURRENT REPORT
PURSUANT TO SECTION 13 OR 15(D) OF
THE SECURITIES EXCHANGE ACT OF 1934
Date of Report (Date of Earliest Event Reported): August 18, 1998
Cambridge Heart, Inc.
-----------------------------------------------------
(Exact Name of Registrant as Specified in its Charter)
Delaware
-----------------------------------------------------
(State or Other Jurisdiction of Incorporation)
0-20991 13-3679946
- ------------------------ -----------------------------------
(Commission File Number) (I.R.S. Employer Identification No.)
1 Oak Park Drive
Bedford, Massachusetts 01730
- ---------------------------------------- ----------
(Address of Principal Executive Offices) (Zip Code)
(781) 271-1200
----------------------------------------------------------------------
(Registrant's Telephone Number, Including Area Code)
Not Applicable
----------------------------------------------------------------------
(Former Name or Former Address, if Changed Since Last Report)
<PAGE>
Item 7 is amended in its entirety as set forth below:
ITEM 7. FINANCIAL STATEMENTS, PRO FORMA FINANCIAL INFORMATION AND EXHIBITS.
(c) Exhibits
--------
See Exhibit Index attached hereto.
- 2 -
<PAGE>
SIGNATURE
---------
Pursuant to the requirements of the Securities Exchange Act of 1934, the
registrant has duly caused this report to be signed on its behalf by the
undersigned hereunto duly authorized.
Date: September 4, 1998 CAMBRIDGE HEART, INC.
-----------------------------------
(Registrant)
By: /s/ Robert B. Palardy
---------------------------------------
Robert B. Palardy
Chief Financial Officer and Vice
President, Finance and Administration
<PAGE>
EXHIBIT INDEX
EXHIBIT
- -------
NUMBER DESCRIPTION
- ------ -----------
99.1* Press Release dated August 19,2998.
99.2 Integrated Clinical statistical Report
99.3 Integrated Clinical Statistical Report (Interim
Report)
_________________________
* Previously filed.
<PAGE>
EXHIBIT 99.2
1. TITLE PAGE
INTEGRATED CLINICAL STATISTICAL REPORT
A PROSPECTIVE MULTI-CENTER STUDY
TO DETERMINE THE EFFECTIVENESS OF T-WAVE
ALTERNANS IN PREDICTING
SUSCEPTIBILITY TO VENTRICULAR ARRHYTHMIAS
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INDICATION: Patients referred for evaluation of known,
suspected, or risk of, cardiac arrhythmias
- -----------------------------------------------------------------------------------
METHODS: 1. Pilot study
2. Prospective, multi-center, open-label,
single-test comparison
- -----------------------------------------------------------------------------------
SPONSOR NAME AND Cambridge Heart, Inc.
ADDRESS: 1 Oak Park Drive
Bedford, MA 01730
- -----------------------------------------------------------------------------------
PROTOCOL IDENTIFICATION: Protocol 95-CH2000-3.0
- -----------------------------------------------------------------------------------
REGULATORY STATUS: Non-significant-risk device: CH 2000 510(k)
Numbers K950018 and K981697(pending);
Hi-Res electrodes K962115.
- -----------------------------------------------------------------------------------
STUDY INITIATION DATE: Pilot study: October 25, 1996
Main study: July 29, 1997
- -----------------------------------------------------------------------------------
STUDY COMPLETION DATE: June 23, 1998
- -----------------------------------------------------------------------------------
INVESTIGATORS: Refer to Section 6 for a list of
Investigators.
- -----------------------------------------------------------------------------------
SIGNATURES:
- -----------------------------------------------------------------------------------
COMPLIANCE STATEMENT: This study was performed in compliance with
Good Clinical Practices.
- -----------------------------------------------------------------------------------
DATE OF REPORT: August 20, 1998
- -----------------------------------------------------------------------------------
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ii
2. STUDY SYNOPSIS
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Title of Study: A Prospective Multi-Center Study To Determine The Effectiveness Of T-Wave
Alternans In Predicting Susceptibility To Ventricular Arrhythmias
====================================================================================================
Investigators: Refer to Section 6 for a list of Investigators.
====================================================================================================
Study Center(s): Refer to Section 6 for a list of study centers.
====================================================================================================
Publication (reference): None.
====================================================================================================
Studied period: 1 year, 3 months, Regulatory status: Non-significant-risk device, CH 2000
10 days 510(k) Numbers K950018 and K981697(pending); Hi-Res
(date of first enrollment, Main electrodes K962115
Study): March 13, 1997
(date of last completed): June 23,
1998
====================================================================================================
Objectives of Main Study: The objective of this study was to show that TWA was associated with an
increased susceptibility to ventricular tachyarrhythmia. In support of this objective the primary
hypothesis was that, in patients being evaluated for known, suspected or risk of cardiac arrhythmias,
the presence of T wave alternans (TWA) measured during an exercise stress test using the spectral
method of the CH 2000 Cardiac Diagnostic System and Hi Res(TM) ECG electrodes was predictive of
increased susceptibility to ventricular arrhythmias. An increased susceptibility to ventricular
arrhythmias was defined as sustained monomorphic ventricular tachycardia (VT) induced during
electrophysiology (EP) testing.
The secondary objective of the study was to demonstrate that, in patients being evaluated for known,
suspected or risk of cardiac arrhythmias, the presence of TWA measured during an exercise stress
test using the spectral method of the CH 2000 Cardiac Diagnostic System and Hi Res ECG electrodes
was substantially equivalent to or better than signal-averaged electrocardiography (SAECG) measured
using the ART (Arrhythmia Research Technology, Inc.), LP-Pac Q(TM) ver. 1.10q, Late Potential Analysis
Software (510(k) Number K915760) as a measure of increased susceptibility to ventricular arrhythmias.
======================================================================================================
Methodology: Pilot Study: This study collected data on the first 65 patients, after which enrollment
in the Pilot Study was closed and an analysis was performed of the Pilot Study data. The Main Study
was initiated by Amendment 5 (July 29, 1997) and included all those enrolled patients not included
in the Pilot Study. Main Study: Prospective, multi-center, open-label, single-test comparison. The
results reported here are only for the patients in the Main Study; summary tables and data listings
statistical results for the Pilot Study are in appendix 14.6.
======================================================================================================
Number of patients (planned and analyzed): Pilot Study: 65 patients enrolled. Main Study: 270 planned
for a total of 100 available for evaluation of the Secondary Hypothesis. Two-hundred-seventy-two (272)
were enrolled and included in the All Patients Sample. The Primary
======================================================================================================
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August 20, 1998
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iii
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Hypothesis Sample (determinate results for TWA and EP) included 140 patients, and the Secondary
Hypothesis Sample (determinate results for all three tests) included 103 patients.
======================================================================================================
Diagnosis and main criteria for inclusion: Patients referred for evaluation of known, suspected or
risk of cardiac arrhythmias.
======================================================================================================
Device serial numbers: 95016, 96024, 96035, 96036, 96052, 96058, 96059, 28030100, 28100146, 29010167
======================================================================================================
Criteria for evaluation:
Efficacy: Patients with determinate EP and TWA results who were not in violation of the protocol, had
- --------
short acting blockers withheld for 24 hours prior to TWA testing, with no changes in anti-arrhythmic
drugs between tests, were used in the analysis of the primary hypothesis. A fully evaluable patient
was defined as one who was not in violation of the protocol, completed a standard EP induction
protocol with a determinate outcome, had a TWA test and SAECG study with determinate results, who had
no changes in anti-arrhythmic drugs between these tests, and who had blockers held for 24 hours prior
to TWA testing. Only fully evaluable patients were used for testing of the secondary hypothesis.
Safety: Data on all patients entered in the study were tabulated and analyzed for safety.
- ------
======================================================================================================
Statistical methods: Descriptive statistics were tabulated for continuous data (mean, median, standard
- -------------------
deviation, minima, and maxima), and for categorical data (the number and percent of patients within
each category). A two-sided Fisher's Exact test was used to test the Primary Hypothesis. Confidence
intervals about the sensitivity, specificity, predictive value, and other descriptive statistics, are
also presented. A two-sided McNemar's test that the TWA and SAECG findings are in agreement with
respect to EP findings, was used to test the Secondary Hypothesis.
======================================================================================================
SUMMARY - CONCLUSIONS
EFFICACY RESULTS: Both the primary and secondary hypotheses were met.
- ----------------
With respect to the Primary Hypothesis, TWA test results were statistically significantly predictive of
EP test results (p less than 0.0001). Sensitivity was 76% and specificity was 65% for TWA test results
when compared to EP test results. The relative risk of having a positive EP finding for those patients
with a positive TWA finding was 3.93 compared with those patients with a negative TWA finding.
With respect to the Secondary Hypothesis, TWA was found to be substantially equivalent to or better than
SAECG in its ability to predict EP outcome. The desired outcome was obtained that there was no
statistically significant difference between TWA and SAECG findings in their prediction of EP findings:
McNemar's test, p-value = 0.2498 (one-sided p-value = 0.1249).
When comparing both the TWA and SAECG tests, using the Secondary Hypothesis Sample,
==========================================================================================================
</TABLE>
August 20, 1998
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iv
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<S> <C>
TWA showed a considerably greater sensitivity for predicting true positives (80%) than SAECG (50%) but a
somewhat lower specificity (70%) than SAECG (86%). The relative risk for TWA (6.05) in predicting EP
results was considerably greater than that found for SAECG (3.68) and TWA had greater statistical
significance (p less than 0.0001) than did SAECG (p less than 0.0014). Thus, there appeared to be a
stronger association between TWA findings and EP findings than between SAECG findings and EP findings, as
reflected in the measure of relative risk.
SAFETY RESULTS: The TWA procedure was safe and well tolerated. Only three adverse events were reported to
- --------------
have been possibly associated with the procedure: VT (from exercising) and two reports of a rash. One
death occurred during the study, unrelated to the TWA test or study procedures. The patient underwent
coronary artery bypass grafting (CABG) and suffered incessant VT during the postoperative period. The VT
was not relieved by cardioversion and treatment with antiarrhythmics and resulted in death.
CONCLUSION: Both the primary and secondary hypothesis were met. TWA test results were predictive of EP
test results, and were substantially equivalent to or better than SAECG findings. There was a trend
toward a greater association between TWA findings and EP outcome than between SAECG findings and EP outcome.
Date of the report: August 20, 1998
============================================================================================================
</TABLE>
August 20, 1998
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v
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3. TABLE OF CONTENTS
1. TITLE PAGE......................................................................... I
2. STUDY SYNOPSIS..................................................................... II
3. TABLE OF CONTENTS.................................................................. V
4. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................... X
5. ETHICS............................................................................. 1
5.1. Institutional Review Board (IRB)................................................... 1
5.2. Ethical review..................................................................... 2
5.3. Ethical conduct of the study....................................................... 2
5.4. Patient information and consent.................................................... 2
6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE................................... 3
6.1. Investigators...................................................................... 3
6.2. Sponsor's study personnel.......................................................... 4
6.3. Other study personnel.............................................................. 4
7. INTRODUCTION....................................................................... 4
7.1. Device information................................................................. 4
7.1.1. The CH 2000........................................................................ 4
7.1.2. The HI RES(TM) ECG Electrode....................................................... 5
7.2. Background......................................................................... 5
7.3. Prior Studies...................................................................... 6
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August 20, 1998
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vi
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7.4. Clinical Implications.............................................................. 7
8. STUDY OBJECTIVES................................................................... 7
9. INVESTIGATIONAL PLAN............................................................... 8
9.1. Overall study design............................................................... 8
9.2. Selection of study population...................................................... 10
9.2.1. Number of patients................................................................. 10
9.2.2. Inclusion criteria................................................................. 10
9.2.3. Exclusion criteria................................................................. 10
9.3. Study procedures................................................................... 11
9.3.1. Prior to testing................................................................... 11
9.3.2. T-wave alternans................................................................... 12
9.3.2.1. Recording apparatus............................................................. 12
9.3.2.2. Exercise Protocol............................................................... 12
9.3.2.3. Definitions of terms............................................................ 13
9.3.2.4. Classification Rules............................................................ 14
9.3.2.5. Classification of Results....................................................... 15
9.3.3. Electrophysiology study............................................................ 16
9.3.4. SAECG.............................................................................. 16
9.3.5. Intervening events................................................................. 17
9.3.6. Follow-up.......................................................................... 18
9.3.7. Termination........................................................................ 18
9.3.8. Withdrawal criteria................................................................ 18
9.3.9. Adverse events..................................................................... 19
9.3.9.1. Procedures for adverse event reporting.......................................... 19
</TABLE>
August 20, 1998
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vii
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9.4. EFFICACY AND SAFETY VARIABLES...................................................... 20
9.4.1. Efficacy and safety measurements assessed and flow chart........................... 20
9.4.2. Description of all efficacy variables.............................................. 20
9.4.3. Description of all safety variables................................................ 21
9.5. DATA QUALITY ASSURANCE............................................................. 21
9.5.1. Monitoring......................................................................... 21
9.5.2. Training of study personnel........................................................ 21
9.6. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE............................... 21
9.6.1. Statistical and analytical plans................................................... 21
9.6.1.1. Variables...................................................................... 21
9.6.1.2. Analytical plan................................................................ 22
9.6.1.3. Handling of dropouts........................................................... 22
9.6.1.4. Patient populations analyzed................................................... 22
9.6.1.5. Statistical methods............................................................ 23
9.6.2. Determination of sample size....................................................... 24
9.6.3. Data management.................................................................... 26
9.7. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES............................ 26
9.7.1. Amendments for the Pilot Study..................................................... 26
9.7.1.1. Amendment 1: September 23, 1996................................................ 27
9.7.1.2. Amendment 2: October 9, 1996................................................... 27
9.7.1.3. Amendment 3: February 3, 1997.................................................. 27
9.7.1.4. Amendment 4: April 24, 1997.................................................... 28
9.7.2. Amendments to Initiate the Main Study.............................................. 28
9.7.2.1. Amendment 5: July 29, 1997..................................................... 28
</TABLE>
August 20, 1998
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viii
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9.7.3. Amendments During the Main Study................................................... 29
9.7.3.1. Amendment 6: March 25, 1998..................................................... 29
9.7.4. Changes in the Conduct of the Study................................................ 29
10. STUDY PATIENTS..................................................................... 31
10.1. DISPOSITION OF PATIENTS............................................................ 31
10.2. PROTOCOL DEVIATIONS................................................................ 31
11. EFFICACY EVALUATION................................................................ 32
11.1. DATA SETS ANALYZED................................................................. 32
11.2. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS..................................... 33
11.3. EFFICACY RESULTS................................................................... 40
11.3.1. All patients analysis.............................................................. 40
11.3.2. Primary hypothesis analysis........................................................ 41
11.3.3. Secondary hypothesis analysis...................................................... 42
11.3.4. Efficacy conclusions............................................................... 44
12. SAFETY EVALUATION.................................................................. 45
12.1. ADVERSE EVENTS..................................................................... 45
12.2. DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS......... 46
12.2.1. Deaths............................................................................. 46
12.2.2. Other serious adverse events....................................................... 47
12.2.3. Other significant adverse events................................................... 47
12.2.4. Narratives of serious adverse events, and certain other significant adverse events. 47
</TABLE>
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ix
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13. DISCUSSION AND OVERALL CONCLUSIONS............................................... 48
</TABLE>
August 20, 1998
<PAGE>
x
4. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
TERM ABBREVIATION
Arrhythmia Research Technology, Inc. ART
Beats per minute BPM
Coronary artery bypass graft CABG
Congestive heart failure CHF
Electrocardiogram ECG
Electrophysiology EP
Heart rate HR
Implantable cardioverter defibrillator ICD
Institutional review board IRB
Myocardial infarct MI
New York Heart Association NYHA
Percutaneous transluminal coronary PTCA
angiography
R-wave to R-wave RR
Signal-averaged ECG SAECG
Supraventricular tachycardia SVT
T-wave alternans TWA
Ventricular fibrillation VF
Ventricular tachycardia VT
August 20, 1998
<PAGE>
1
5. ETHICS
This was a non-significant-risk study involving minimal risk to the patients
beyond the risk of the clinical testing already scheduled as part of their
clinical care. The additional procedures which the patients in this study
underwent were signal-averaged electrocardiography (SAECG), which is noninvasive
and risk free, and T wave alternans (TWA) measurement done during the course of
a submaximal exercise test. During the TWA measurement the patients exercised
moderately (to 70% of predicted maximum for age or a heart rate of 105 beats per
minute [bpm] whichever was greater) under electrocardiographic and blood
pressure monitoring. The test was terminated if the exercise precipitated
either ischemia or serious rhythm disturbances.
There was a risk that even moderate exercise could exacerbate existing
conditions such as congestive heart failure (CHF) or asthma, induce an
arrhythmia or cause ischemia, which in rare circumstances may lead to cardiac
arrest, myocardial infarction (MI) or death.
The potential side effects of the gel and adhesive used in the manufacture of
the Hi-Res ECG electrodes are those skin irritation effects noted in the device
labeling.
5.1. INSTITUTIONAL REVIEW BOARD (IRB)
This study was performed in accordance with the principals of the
Declaration of Helsinki and in accordance with 21 CFR 50 Protection of
Human Patients and 21 CFR 56 Institutional Review Boards.
Prior to initiating this study, the protocol and Informed Consent Form were
reviewed and approved by a properly constituted Institutional Review Board
(IRB). The Principal Investigator at each site submitted an application to
that site's IRB. The protocol for the study was included as part of that
application. The Principal Investigator at each site bore complete
responsibility for the conduct of the study at that site.
The opinion of the IRB were dated and given in writing. A list of those
present at the committee meeting (names and positions) was attached
whenever possible. It was the responsibility of the Investigator to
forward to Cambridge Heart before the initiation of the study a copy of the
approval from the IRB clearly identifying the protocol submitted for
review.
August 20, 1998
<PAGE>
2
5.2. ETHICAL REVIEW
The investigator was responsible for informing the IRB of any serious
adverse events, amendments to the protocol as well as notification of the
termination/completion of the study as per local requirements. All
correspondence with the committee was maintained by the Investigator.
5.3. ETHICAL CONDUCT OF THE STUDY
The conduct of the study was audited by the Sponsor for conformance with
the GCP guidance E6 released by FDA in April 1996.
Each investigator was responsible for keeping a list of all patients who
had been screened for participation in the study, including study number if
assigned, or the reason the patient was not enrolled.
The patients were informed in writing about the possibility of audits by
authorized representatives of the company and/or regulatory authorities in
which case a review of those parts of their hospital records relevant to
the study may be required.
The patients were informed in writing that the results were stored and
analyzed in a computer maintaining confidentiality in accordance with local
data laws.
5.4. PATIENT INFORMATION AND CONSENT
The Principal Investigator (or his/her designated representative) described
the study, including procedures and risks to the patient, and reviewed
consent forms with the patient. It was made clear to the patient that
his/her decision to participate or not participate in the study would not
affect the medical care he/she would otherwise receive. Written consent to
the study was obtained from each patient. A consent form meeting the
requirements of each participating institution was used. A suggested
format was included at the end of the protocol.
A copy of the Patient Information and Informed Consent Form was provided to
the patient and the Investigator kept a copy in his/her records, the signed
original was placed in the patient's hospital record.
August 20, 1998
<PAGE>
3
6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
6.1. INVESTIGATORS
The study was conducted by nine Investigators at 10 investigational sites.
---------------------------------------------------------------------------
INVESTIGATOR SITE (NUMBER)
---------------------------------------------------------------------------
Kelley P. Anderson, MD University of Pittsburgh Medical Center
200 Lothrup Street
Pittsburgh, PA 15213-2582 (21)
---------------------------------------------------------------------------
Daniel M. Bloomfield, MD Columbia Presbyterian Medical Center
Director, Syncope Center
Harkness Pavilion, Room 362
180 Ft. Washington Ave.
New York, NY 10032 (26)
---------------------------------------------------------------------------
Elizabeth S. Kaufman, MD MetroHealth Medical Center
2500 MetroHealth Dr.
Cleveland, OH 44109 (38)
---------------------------------------------------------------------------
Nabil El-Sherif, MD SUNY Health Sciences Center
Professor of Medicine and Physiology
Room B-2 325
Box 1199
450 Clarkston Ave.
Brooklyn, NY 11203 (12)
And
VA Medical Center
800 Poly Place
Brooklyn, NY 11209 (12)
---------------------------------------------------------------------------
Mark Estes, MD New England Medical Center
Director Cardiac Arrhythmia Service
NEMC 197
750 Washington St.
Boston, MA 02111 (11)
---------------------------------------------------------------------------
Michael R. Gold, MD, PhD University of Maryland Medical Center
(Principal Investigator) Director Cardiac Electrophysiology Service
Room N3W79
22 South Greene Street
Baltimore, MD 21201-1595 (22)
---------------------------------------------------------------------------
Mark L. Greenberg, MD Dartmouth Hitchcock Medical Center
Director Clinical Electrophysiology & Pacing
1 Medical Center Drive
Lebanon, NH 03756 (30)
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August 20, 1998
<PAGE>
4
---------------------------------------------------------------------------
INVESTIGATOR SITE (NUMBER)
---------------------------------------------------------------------------
William J. Groh, MD Krannert Institute of Cardiology
Assistant Professor of Medicine
1111 West 10/th/ Street, KI 316
Indianapolis, IN 46202-4800 (40)
---------------------------------------------------------------------------
David J. Wilber, MD University of Chicago Hospitals
Director, Electrophysiology
Department of Cardiology, MC09024
DCAM room 5734
Chicago, IL 60367 (27)
---------------------------------------------------------------------------
6.2. SPONSOR'S STUDY PERSONNEL
Jeffrey Arnold, CEO was the Sponsor's representative for the study.
6.3. OTHER STUDY PERSONNEL
Clinical trial monitoring was performed by Medical & Technical Research
Associates, Inc. of Two Vision Drive, Natick, MA 01760.
7. INTRODUCTION
7.1. DEVICE INFORMATION
7.1.1. The CH 2000
The CH 2000 Cardiac Diagnostic System received FDA 510(k) clearance
on February 29, 1996 (510(k) Number K950018).
The CH 2000 is a computerized platform which supports a wide range of
standard stress test protocols as well as performing TWA computation
at rest, during exercise, pacing or pharmacologic stress. TWA is
computed by the spectral method as published by J.M. Smith et al.,
Circulation 1988; 77:110-21. The CH 2000 meets the standards for
diagnostic electrocardiographic devices and where applicable, for
cardiac monitors, heart rate meters and alarms.
August 20, 1998
<PAGE>
5
7.1.2. The HI RES(TM) ECG Electrode
The Hi Res(TM) ECG Electrode is manufactured by Cambridge Heart, Inc.
It received FDA 510(k) clearance on August 29, 1996 (510(k) Number
K962115).
The Hi-Res(TM) ECG Electrode is a pregelled, single use, multi
segment, Silver/Silver Chloride electrode for short-term use to
measure ECG signals with the Cambridge Heart CH 2000 Stress Test
System.
7.2. BACKGROUND
Approximately 300,000 patients die each year of sudden cardiac death in the
United States alone. The proximate cause of death in the vast majority of
these cases is a ventricular rhythm disturbance. Patients known to be at
high risk for ventricular arrhythmias may be treated with various
modalities, including anti-arrhythmic drugs, placement of internal
defibrillators and/or ablation procedures, conducted in the catheterization
laboratory or operating room, which attempt to selectively destroy cardiac
tissue to prevent arrhythmias.
The standard clinical technique for identifying individuals at risk for
ventricular arrhythmias is electrophysiology (EP) testing, an invasive
procedure in which catheter electrodes are placed into the patient's heart
and electrical impulses are delivered in a deliberate attempt to induce the
arrhythmias. Because EP testing is an expensive, invasive procedure which
involves significant risk to the patient, a variety of clinical data are
used to determine which patients should undergo EP testing.
One of the techniques used for this purpose is the signal-averaged
electrocardiogram (SAECG). The SAECG is a technique for measuring low
amplitude potentials in the ECG, which are predictive of an individual's
susceptibility to ventricular arrhythmias/1/. Recently, measurement of low
levels of repolarization or T-wave alternans (TWA) in the electrocardiogram
(ECG), during increased heart rate, has also been
__________________
/1/ M.E. Cain, J.L. Anderson, M F. Arnsdorf, J.W. Mason, M.M. Scheinman, A.L.
Waldo. ACC Expert Consensus Document, Signal-Averaged Electrocardiography,
JACC Vol. 27, No. 1, 238-49, 1996
August 20, 1998
<PAGE>
6
shown to be predictive of an individual's susceptibility to ventricular
arrhythmias/2/.
In Rosenbaum et al., 1994, the heart rate of patients undergoing
electrophysiology study was raised by pacing the heart electrically in the
catheterization laboratory. Studies currently underway in Europe and the
US have indicated that the use of an exercise stress test as a noninvasive
means of raising the patients' heart rate is adequate to measure TWA levels
in patients scheduled to undergo EP testing. The current investigation
uses exercise as a non-invasive method of raising heart rate.
7.3. PRIOR STUDIES
A prior study was completed in the US to determine the value of TWA as a
predictor of susceptibility to ventricular arrhythmias as determined by the
results of EP testing and to compare this predictive value to that of
SAECG. TWA was recorded during sinus rhythm and with the heart rate
elevated by exercise./3/ TWA recordings were made at rest and during a
bicycle exercise protocol to maintain the heart rate at 100 beats per
minute (BPM). A total of 27 patients undergoing EP testing were included,
based on their ability to complete the exercise protocol. Results in this
patient population indicated that TWA had a sensitivity of 89% and
specificity of 75%, and an overall clinical accuracy of 80% (P less than
0.003). TWA was superior to SAECG, which was not a statistically
significant predictor in this study.
A second study compared microvolt TWA to EP testing and to other currently
used noninvasive methods with respect to prediction of future
tachyarrhythmic events in 95 patients with a history of ventricular
tachyarrhythmias scheduled to undergo implantation of a
cardioverter/defibrillator./4/ In addition to TWA and EP testing, the
patients underwent determination of left ventricular ejection fraction,
baroreflex sensitivity, SAECG, analysis of 24-hour Holter monitoring for
heart rate
___________________
/2/ D.S. Rosenbaum, L.E. Jackson, J.M. Smith, H.G. Garan, J.N. Ruskin and R.J.
Cohen. Electrical Alternans and Vulnerability to Ventricular Arrhythmias,
New England Journal of Medicine, 330:235-24 l, 1994.
/3/ N.A.M. Estes, G. Michaud, D.P. Zipes, N. El-Sherif, F.J. Venditti, D.S.
Rosenbaum, P. Albrecht, P.J. Wang, R.J. Cohen. "Electrical Alternans
During Rest and Exercise as Predictors of Vulnerability to Ventricular
Arrhythmias". Am J Cardiol 1997;80:1314-1318.
/4/ S.A. Hohnoloser, T. Klingenheben, M. Zebel, J. Peetermans, R. Cohen. "T
Wave Alternans as a Toll for Risk Stratification in Patients with Malignant
Arrhythmias: Prospective Comparison with conventional Risk Markers".
Submitted for publication.
August 20, 1998
<PAGE>
7
variability and the presence of nonsustained ventricular tachycardia (VT),
and the measurement of QT dispersion from the 12-lead ECG. The endpoint of
the study was the first appropriate firing of a cardioverter/defibrillator
for ECG-documented ventricular fibrillation (VF) or ventricular tachycardia
during follow-up. Kaplan-Meier survival analysis revealed that only TWA (P
less than 0.006) and left ventricular ejection fraction (P less than 0.04)
were statistically significant risk stratifiers. Multivariate Cox
regression analysis suggested that TWA was the only statistically
significant independent risk factor.
7.4. CLINICAL IMPLICATIONS
Patients being evaluated for anti-arrhythmic therapy, either with drugs
such as sotalol, amiodarone or quinidine, or with the placement of
implantable cardioverter defibrillators (ICDs) will most likely undergo an
EP study. Electrophysiology studies are expensive and present a
significant risk to patients. The process of determining which patients
should undergo these studies involves the evaluation of information from
many sources, including family history, the patient's medical history,
results from ECGs, tilt-table tests, exercise-tolerance tests and other
tests that might be indicated. Even with all the information currently
available, many of those patients referred for EP studies (approximately
50% according to Rosenbaum et al., 1994) will not be inducible in the
laboratory.
TWA is predictive of increased susceptibility to ventricular arrhythmias.
As such it is a valuable addition to the physicians' armamentarium to aid
in identifying those patients who will benefit from further diagnostic
tests or therapeutic interventions as well as those patients who may not
benefit from additional testing or interventions.
8. STUDY OBJECTIVES
The objective of this study was to show that TWA was associated with an
increased susceptibility to ventricular tachyarrhythmia. In support of this
objective the primary hypothesis was that, in patients being evaluated for
known, suspected or risk of cardiac arrhythmias, the presence of TWA measured
during an exercise stress test using the spectral method of the CH 2000 Cardiac
Diagnostic System and Hi Res(TM) ECG electrodes was predictive of increased
susceptibility to ventricular arrhythmias. An increased susceptibility to
ventricular arrhythmias was defined as sustained monomorphic ventricular
tachycardia (VT) induced during electrophysiology testing.
August 20, 1998
<PAGE>
8
The secondary objective of the study was to demonstrate that, in patients being
evaluated for known, suspected or risk of cardiac arrhythmias, the presence of
TWA measured during an exercise stress test using the spectral method of the CH
2000 Cardiac Diagnostic System and Hi Res(TM) ECG electrodes was substantially
equivalent to or better than the SAECG measured using the ART (Arrhythmia
Research Technology, Inc.), LP-Pac Q(TM) ver. 1.10q, Late Potential Analysis
Software (510(k) Number K915760) as a measure of increased susceptibility to
ventricular arrhythmias.
The order of the study objectives changed as a result of Amendment 6. Refer to
Section 9.7 for details of these changes.
9. INVESTIGATIONAL PLAN
9.1. OVERALL STUDY DESIGN
This study consisted of two parts, a Pilot Study and a Main Study. In the
Pilot Study data were collected on the first 65 patients, after which
enrollment in the Pilot Study was closed and an analysis was performed of
the Pilot Study data. The Main Study was initiated by Amendment 5 (July
29, 1997) and included all those enrolled patients not included in the
Pilot Study. The results reported here are only for patients in the Main
Study. Pilot Study tables and data listings are presented for reference in
Appendix 14.6.
The Main Study was a prospective, multi-center study to demonstrate that:
. Primary Hypothesis: in patients being evaluated for known, suspected
or risk of ventricular arrhythmias, the presence of TWA measured
during exercise using the CH 2000 spectral method was predictive of
increased susceptibility to ventricular arrhythmias.
and
. Secondary Hypothesis: In the same population, the presence of TWA
measured during exercise using the CH 2000 spectral method was
equivalent to the standard SAECG measure as a predictor of increased
susceptibility to ventricular arrhythmias.
Patients with bundle branch block may not have determinate SAECG results
and therefore were not used to test the Secondary Hypothesis.
August 20, 1998
<PAGE>
9
These patients were however, used to determine if TWA was predictive of
increased susceptibility to ventricular arrhythmias (Primary Hypothesis).
Males and females 18 years or older who had been referred to the EP
laboratory, who were capable of undergoing an exercise stress test (to 70%
of maximum predicted for age, [0.70(220-age)] or a target heart rate of 105
bpm, whichever was greater), who were able to have blockers withheld for
24 hours prior to the TWA test, who did not have unstable coronary artery
disease, and who did not have a history of persistent atrial fibrillation
or flutter, were enrolled by signing an informed consent.
Patients enrolled in the study had the SAECG measure made and TWA tests
performed prior to and within ten days of undergoing the scheduled EP
studies.
All tests were performed with no changes in anti-arrhythmic medications
between the tests. Short acting ? blockers (propranolol and metoprolol)
were allowed if ? blockade was required, but in order to increase the
likelihood that patients could achieve the required heart rate, blockers
must have been withheld for 24 hours prior to the TWA tests. Patients
unable to tolerate having ? blockers withheld were excluded from the study.
Demographic information, medical history (including the reason for EP
referral), and cardiac medication history were obtained. Anti-arrhythmic
and ? blocker drugs taken from the time of the first study procedure to the
time of the last study procedure were recorded.
The conduct of EP studies was guided by clinical indication. In the
original protocol, the outcome of the EP study was to be determined by an
independent electrophysiologist in accordance with a set of rules defined
in the protocol (Section 9.3.3). A decision was later made to
automatically determine this outcome in accordance with a programming
specification reviewed by the Principal Investigator to be in accordance
with these rules. Refer to Section 9.7.3 for a listing of these
programming rules.
The ECG data for the SAECG was obtained using the LP Pac Q(TM) ver. 1.10q
Late Potential Analysis Software (510(k) Number K915760). The SAECG data
were reviewed by the investigator, who determined the outcome of the test.
The ECG data for the TWA measure was made by the CH 2000 using Hi Res(TM)
ECG electrodes. For this study, the TWA reports were reviewed by two
independent third party physicians who were masked to the patient's EP and
SAECG outcome and other clinical data.
August 20, 1998
<PAGE>
10
9.2. SELECTION OF STUDY POPULATION
9.2.1. Number of patients
Approximately 270 patients were to be enrolled of which 100 were
expected to be fully evaluable patients. (A fully evaluable patient
was defined as one who completed a standard EP induction protocol
with a determinate outcome, had a TWA test and SAECG study with
determinate results, who had no changes in anti-arrhythmic drugs
between these tests, and who had beta blockers withheld for 24 hours
prior to TWA testing. Only fully evaluable patients were used for
testing of the secondary hypothesis.) Patient accrual was expected to
be completed within six months, and seven sites were to participate
in this study. In actuality, ten sites participated.
9.2.2. Inclusion criteria
Patients referred for electrophysiology studies who met the following
inclusion criteria were enrolled in the study:
1. The patient was scheduled for EP studies to evaluate known or
suspected cardiac arrhythmias
2. The patient was 18 years of age or older
3. The patient was capable of undergoing a submaximal bicycle
exercise test with a target heart rate of 70% of maximum
predicted heart rate for age, [0.70(220-age)] or 105 BPM,
whichever was greater
4. The patient had signed an Institutional Review Board (IRB)
approved informed consent form
9.2.3. Exclusion criteria
Patients meeting any of the following exclusion criteria were not
eligible for enrollment:
1. The patient was unable to give informed consent
2. The patient had unstable coronary artery disease
August 20, 1998
<PAGE>
11
3. The patient had persistent atrial fibrillation or flutter
4. The patient was less than six days post-MI
5. The patient could not tolerate the withdrawal of (B) blockers for
24 hours prior to TWA testing
6. The patient was participating in a study of another
investigational device or drug
7. The patient had any other significant medical condition that in
the opinion of the investigator precluded participation, such as:
serious ongoing cardiac dysrhythmia (such as bigeminy, trigeminy,
etc. or more than 10% ectopic beats at rest per Holter Monitor or
ECG), endocarditis, severe aortic or mitral stenosis, severe left
ventricular dysfunction, acute pulmonary embolus/infarction,
acute or serious non-cardiac disorder or severe physical
handicap.
8. The patient was known to have ventricular arrhythmias due to
reversible causes, such as severe electrolyte abnormalities, pro-
arrhythmic drug effects or active ischemia.
9.3. STUDY PROCEDURES
Eligible patients were enrolled by signing an IRB-approved informed consent
form. Only those patients who met all the inclusion and exclusion criteria
were considered eligible for the study.
9.3.1. Prior to testing
Demographic information, consisting of age, sex, height and weight,
and a cardiovascular medical history, was obtained. New York Heart
Association (NYHA) Functional Class was determined. Cardiovascular
medications taken from the time of the index event or symptoms
resulting in referral for EP studies to the time of the first study
procedure were recorded. (B)-blocker and anti-arrhythmic medications
taken from the time of the first study procedure to the time of the
last study procedure were recorded.
August 20, 1998
<PAGE>
12
9.3.2. T-wave alternans
The TWA measure was made using the spectral method employed by the CH
2000 system. The TWA test involved an ECG recording made during
sitting rest, exercise, and recovery. The TWA exercise protocol was a
submaximal exercise protocol, which had an endpoint of the greater of
70% of maximal age predicted heart rate or a heart rate of 105 BPM, or
symptoms which limited the exercise. The protocol required that the
patient exercise at workloads which increased every three minutes,
with the workload beginning at 15 watts, increasing to 30 watts and
then increasing by 30 watts in each stage.
9.3.2.1. Recording apparatus
The TWA test involved the simultaneous recording of 12-lead
ECGs and orthogonal ECGs by the Cambridge Heart CH 2000
Stress Test system using 14 electrodes, seven standard
electrodes and seven Cambridge Heart Hi Res(TM) ECG
Electrodes. The CH 2000 is a computer based ECG exercise
tolerance test system intended for the recording of
electrocardiograms and vector cardiograms. Signal processing
and ECG computations include, ST level, ST slope, ST
integral, ST index and T-wave alternans amplitude computed by
the spectral method. The Hi Res(TM) ECG Electrodes are multi-
segment electrodes developed by Cambridge Heart, Inc.
9.3.2.2. Exercise Protocol
The ECG was recorded for five minutes with the patient
sitting motionless at rest.
Immediately following the rest recordings, the patient was
exercised on a bicycle ergometer at a pedal rate determined
by the auditory and visual prompts provided by the CH 2000
which assured that the patient's pedaling relative to heart
rate was appropriate for the TWA test.
The ECG was recorded during a submaximal ergometer stress
test (with a target heart rate of 70% of maximum predicted
for age or 105 BPM whichever was greater.)
August 20, 1998
<PAGE>
13
Immediately following the exercise recording, the patient
remained motionless while four minutes of recovery ECG data were
recorded.
9.3.2.3. Definitions of terms
Sustained alternans:
--------------------
SUSTAINED ALTERNANS was defined as alternans that was
consistently present over a patient-specific heart rate (HR)
threshold (except for gaps believed to be due to obscuring
factors such as ectopic beats, noise or HR dips)
. With at least one minute of V\alt\ 1.9 (cigma)V and
alternans ratio greater than or equal to 3
. In any of leads VM, X, Y, Z or in two adjacent precordial
leads
. With some period of artifact-free data
ECG data were considered to be ARTIFACT FREE if:
. Bad Beats less than or equal to 10%
. Patient was pedaling properly at 1/3 or 2/3 of HR or not
pedaling
. Respiratory activity was not at 0.25 cycles per beat
. HR was stable or slowly changing
. There was no heart rate (RR) interval alternans (or its
level was less than or equal to 2 milliseconds)
Onset heart rate:
-----------------
The alternans ONSET HEART RATE was the rate at which the
alternans which met the requirements for sustained alternans
first appears. In determining the onset heart rate short gaps
which could be attributed to noise, ectopic beats, or HR dips
were bridged. All leads were considered.
August 20, 1998
<PAGE>
14
9.3.2.4. Classification Rules
The following classification rules were defined prospectively and
used in analyzing the results of the TWA studies. A decision flow
chart for this classification is presented in diagram 1 below:
[DIAGRAM APPEARS HERE]
Positive:
---------
A test was POSITIVE (+) if it had Sustained Alternans with an
Onset Heart Rate known to be less than or equal to 110 BPM (or at
the resting heart rate if that was greater than 110 BPM).
Negative:
---------
A test was NEGATIVE (-) if it did not have Sustained Alternans
and a HR greater than or equal to 105 BPM was achieved for at
least one minute during which noise was greater than or equal to
1.8 (cigma)V, bad beats were less than or equal to 10% and during
which significant alternans (i.e. 1.9 less than or equal to
(cigma)V) was not
August 20, 1998
<PAGE>
15
present, or if the onset of sustained alternans was known to be
greater than 110 BPM (and not at the resting HR).
Incomplete:
-----------
A test was incomplete if it was not positive and a HR 105 BPM
had not been achieved for at least one minute.
Indeterminate:
--------------
A test was INDETERMINATE if it was not positive, negative, or
incomplete.
The system of classification used for this study changed between
the Pilot Study and the Main Study as a result of Amendment 5.
Refer to Section 9.7 for details of these changes.
9.3.2.5. Classification of Results
For purposes of this study, each TWA record was read and
interpreted by two physician readers who were masked to the
patient's EP and SAECG outcome and other clinical data and who
conferred on their results to resolve differences. There were
two primary readers with experience with the CH 2000 System and a
third alternate who were trained to read TWA reports via the
Sponsor's standard training course. The primary readers read all
studies except those for which they might have knowledge of
clinical data; these were read by the alternate in conjunction
with one of the primary readers. (One primary reader was an
investigator and was barred from reading reports from his own
site; the other primary reader had previously seen the TWA
reports from the Pilot Study and was barred from reading these.).
An audit was performed of the readers' results by an independent
experienced reader who was blinded to the clinical data. This
audit uncovered a number of mistakes in the original readings.
As a result of this audit the readers were asked to repeat their
readings and then confer again while still blinded to the
clinical data and with no further instruction from the Sponsor.
The results of the repeat readings were used for the study.
August 20, 1998
<PAGE>
16
9.3.3. Electrophysiology study
The extent of ventricular stimulation and the conduct of the EP
testing were guided by the clinical indication for the EP test.
In order for patient results to be considered evaluable for this
study the EP induction protocol used must meet the following
criteria defined in the protocol for the study:
. The induction protocol involved the progressive
administration of up to three extrastimuli, at a minimum of
two ventricular sites, at a minimum of two paced-cycle
lengths.
. However, for patients with presumed supraventricular
tachycardia (SVT) a minimum of two extra-stimuli must be
delivered from at least one ventricular site.
. Standard pulses were two milliseconds and had an amplitude
of twice diastolic threshold.
The outcome of the EP testing were
. Positive if the study induced sustained monomorphic VT which
lasted at least 30 seconds or caused hypotension requiring
intervention, (providing that not more than three extra-
stimuli were used).
. Negative if the induction protocol was fully completed, and
neither sustained VT, VF, nor ventricular flutter were
induced.
Indeterminate if the above criteria for evaluability were not met
or the EP study resulted in an inducible VF or flutter only.
9.3.4. SAECG
The SAECG measure was made using the ART, LP-Pac Q(TM) ver.
1.10q, Late Potential Analysis Software. The ECG was obtained
during supine rest for a duration determined by an SAECG mean
noise less than 0.5 (cigma) (approximately 5 minutes).
ECG data acquisition was to be conducted in the Auto-Average
mode. In this mode the position of the correlation window was
automatically selected by the software. If the auto-template
August 20, 1998
<PAGE>
17
selection failed, the Manual Average function was used. In this
mode the user may have appropriately adjusted the position of the
correlation window on the QRS signal to obtain an acceptable
template. The filter corner frequencies were to be set to 40 Hz,
the width of the correlation was fixed at 40 ms.
The outcome of the SAECG/5/ was:
. Positive if two of the following three criteria were
satisfied with regard to the vector magnitude of the
filtered X, Y, Z leads:
1. The filtered QRS complex duration exceeded 114 ms
2. Root mean square voltage of the terminal 40 ms of the
filtered QRS was less than 20 (cigma) V
3. The duration of time that the terminal portion of the
filtered QRS remained less than 40 (cigma) V was greater
than 38 ms.
. Negative if at least two of the above criteria were not
satisfied.
. Indeterminate if the unfiltered QRS duration was
greater than 120 ms, if sufficient noise reduction was
not achieved, or if in the opinion of the investigator
a determinate result could not be obtained.
9.3.5. Intervening events
If during the period (10 days maximum) between the conduct
of the non-invasive studies (SAECG and TWA) and the EP study
a clinical event occurred which (in the opinion of the
investigator) could change the correlation between the non-
invasive tests and the EP study, another set of non-invasive
studies must have been performed prior to the EP studies. If
it was not possible to conduct another series of tests the
patient was terminated from the study. (There were no such
intervening events in the study.)
____________________
/5/ "Standards for Analysis of Ventricular Late Potentials Using High-
Resolution or Signal-Averaged electrocardiography: A Statement by a Task
Force Committee of the European Society of Cardiology, the American Heart
Association, and the American College of Cardiology", G. Breithhardt, M.E.
Cain, N.C. Flowers, et al, JACC, l7, l 991, 999-l 006.
August 20, 1998
<PAGE>
18
9.3.6. Follow-up
All patients enrolled in the study were followed until the
patient was discharged from the hospital following EP testing.
Patients were evaluated for the occurrence of ventricular
tachyarrhythmic events. Anti-arrhythmic and (B) blocker
medications, intervening cardiac events and ventricular
tachyarrhythmic events occurring during the follow-up period were
recorded.
9.3.7. Termination
The patient's participation in the study was completed when the
patient had completed the follow-up period or until the patient
was withdrawn from the study for any reason.
9.3.8. Withdrawal criteria
The reason for early termination was recorded on the case report
form. A patient may have withdrawn from the study for any of the
following reasons:
1. Development of an adverse event that, in the opinion of the
investigator, required protocol interruption
2. Noncompliance or uncooperativeness
3. Patient request
4. Patient required treatment with another investigational drug
or device
5. Change in anti-arrhythmic medications (Vaughn Williams class
I and III) between TWA and EP studies
6. Inability to tolerate withholding of (B) blockers for 24
hours prior to the TWA test
7. Lost to follow-up
8. Investigator's judgment that withdrawal was in the best
interest of the patient
August 20, 1998
<PAGE>
19
9. Termination of the research effort by the Sponsor
10. Significant protocol violation
11. Patient was unable to have another series of non-invasive
testing conducted prior to the EP study following an
intervening event
If withdrawal of the patient was the result of an adverse event
that was attributable to the TWA test, the patient was followed
until, in the opinion of the investigator, all parameters had
returned to baseline or were clinically stable.
9.3.9. Adverse events
The investigator closely monitored each patient for evidence of
adverse events throughout the study.
Adverse events occurring during the conduct of the SAECG or TWA
tests were recorded. An assessment of severity, relationship to
device and whether or not the event was expected, was made by the
Investigator.
9.3.9.1. Procedures for adverse event reporting
The Investigator must have informed Cambridge Heart
within 10 working days, by telefax and/or telephone, of
any unanticipated serious adverse device effects
associated with the use of the CH 2000 or Hi Res(TM) ECG
electrodes.
A serious device effect referred to an event that may
have reasonably suggested that there was a probability
that a device has caused or contributed to a death,
serious injury or serious illness.
A serious device effect also included the failure of a
diagnostic device if information reasonably suggested
that there was a probability that a misdiagnosis or lack
of diagnosis resulting from the failure: (1) had caused
or contributed to a death, serious injury, or serious
illness, or (2) would cause or contribute to a death,
serious illness or serious injury if it were to recur.
Since the TWA results were not used for patient
treatment, this could only apply to use of the CH 2000
for its standard stress test results.
August 20, 1998
<PAGE>
20
A serious illness or injury was one that was life
threatening, resulted in permanent impairment of a body
function or permanent damage to the body structure; or
necessitated immediate medical or surgical intervention
to preclude permanent impairment of a body function or
permanent damage to a body structure.
9.4. EFFICACY AND SAFETY VARIABLES
9.4.1. Efficacy and safety measurements assessed and flow chart
The efficacy variables were TWA, EP, and SAECG results. The
safety variable was adverse events. The following table presents
the sequence of events in the study.
TABLE 1. STUDY FLOW CHART
<TABLE>
<CAPTION>
---------------------------------------------------------
Prior Testing
to
Testing
---------------------------------------------------------
<S> <C> <C>
Informed consent X
---------------------------------------------------------
Demographic information X
---------------------------------------------------------
Cardiovascular medical X
history
---------------------------------------------------------
NYHA functional class X
---------------------------------------------------------
Cardiovascular X
medications/1/
---------------------------------------------------------
TWA/2/ X
---------------------------------------------------------
SAECG X
---------------------------------------------------------
EP/3/ X
---------------------------------------------------------
Adverse events X
---------------------------------------------------------
</TABLE>
/1/ Medications taken at time of first event leading to EP
testing to time of first study procedure
/2/ Recorded during sitting rest for five minutes, exercise on a
bicycle ergometer, and recovery for four minutes.
/3/ Performed after TWA and SAECG testing.
9.4.2. Description of all efficacy variables
The effectiveness of TWA and SAECG outcomes was measured by its
agreement with the EP outcome.
August 20, 1998
<PAGE>
21
9.4.3. Description of all safety variables
Although it was anticipated that a trial of this size would not
allow for the quantitative evaluation of the expected low
incidence of adverse device effects, all adverse events occurring
during the conduct of the TWA or SAECG were reported and
tabulated.
9.5. DATA QUALITY ASSURANCE
9.5.1. Monitoring
All aspects of the study were carefully monitored by qualified
individuals designated by the Sponsor. Monitoring was conducted
according to Good Clinical Practices (GCP) and standard operating
procedures for compliance with applicable government regulations
(21 CFR (S) 812.46). The individuals responsible for monitoring
the trial had access to all records necessary to ensure the
accuracy of the recorded data and periodically reviewed the
progress of the study with the Investigator.
9.5.2. Training of study personnel
Medical & Technical Research Associates personnel were trained by
the Sponsor's Clinical Research Associate at a training session.
9.6. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
9.6.1. Statistical and analytical plans
9.6.1.1. Variables
Demographic data presented include age, sex, height and
weight. Medical history data (e.g., coronary artery
disease, MI, valvular heart disease, etc.) are presented.
Baseline physical findings of the index arrhythmia,
including ECG data, NYHA data, and ejection fraction
data, are presented.
Primary hypothesis data comparing TWA to EP findings are
presented. In addition, secondary hypothesis data
comparing SAECG and TWA results are presented.
August 20, 1998
<PAGE>
22
Safety data included adverse events collected during the TWA
test. Adverse events were coded using the COSTART coding
dictionary. B-blocker and anti-arrhythmic medications, coded
according to the WHO medication coding dictionary, are presented.
9.6.1.2. Analytical plan
Descriptive statistics were tabulated and presented for data
captured on the case report form as follows: for continuous data,
measures for central tendency (mean, median, standard deviation,
minima, and maxima) are presented, while for categorical data,
the number and percent of patients within each category, are
presented. For categorical data, only non-missing values were
used to calculate the percentages.
All data captured on the case report forms are presented in data
listings.
9.6.1.3. Handling of dropouts
The Primary and Secondary Hypotheses for this study were
dependent on patients having determinate outcomes for the three
test methods. As defined in Section 9.6.1.4, Patient populations
analyzed patients with indeterminate outcomes for one or more of
the tests may not have been included in the hypothesis testing.
9.6.1.4. Patient populations analyzed
There were three defined statistical populations in the analysis:
1. The All Patients Sample, defined as patients who have at
least one case report form page completed and entered into
the database.
2. The Primary Hypothesis Patients Sample, defined as patients
who satisfied all the following criteria:
. Determinate EP outcome
August 20, 1998
<PAGE>
23
. Determinate TWA outcome
. Short-acting -blockers withheld for at least 24 hours
prior to T-Wave testing
. No changes in anti-arrhythmic drugs between the TWA and
EP tests
. No protocol violations
3. The Secondary Hypothesis Sample, defined as patients who
were included in the Primary Hypothesis Patients Sample AND
had a determinate SAECG test outcome.
9.6.1.5. Statistical methods
The Primary Hypothesis in this study is:
Ho: TWA is not predictive of EP findings
Ha: TWA is predictive of EP findings
Rejection of the null hypothesis will be considered adequate
evidence that the TWA test outcome is predictive of EP test
outcome. Because determinate TWA and EP findings are required to
test this hypothesis, the Primary Hypothesis Sample was used. A
two-sided Fisher's Exact test was used to test the Primary
Hypothesis. Confidence intervals about the sensitivity,
specificity, predictive value, and other descriptive statistics,
are also presented.
The Secondary Hypothesis in this study is:
Ho: TWA is substantially equivalent to or better than
SAECG testing as a predictor of EP outcome
Ha: TWA is not substantially equivalent to or better
than SAECG testing as a predictor of EP outcome
Failure to reject the secondary hypothesis was considered
adequate evidence that SAECG testing was no better than TWA
testing, compared to EP findings. Since determinate TWA, EP, and
SAECG findings are required to test this
August 20, 1998
<PAGE>
24
hypothesis, the Secondary Hypothesis Sample was used. A two-sided
McNemar's test that the TWA and SAECG findings are in agreement
with respect to EP findings, will be used to test the Secondary
Hypothesis.
9.6.2. Determination of sample size
Of the two hypotheses, the secondary hypothesis requires more
patients and thus the sample size was calculated to address
issues relating to this hypothesis. The secondary hypothesis is
that the clinical accuracy of TWA in predicting susceptibility to
ventricular arrhythmia is substantially equivalent to or better
than the clinical accuracy of SAECG in predicting susceptibility
to ventricular arrhythmia in the patient population being
studied.
To determine the minimum sample size necessary to establish
substantial equivalence, we consider the null hypothesis that TWA
performs better than or equal to SAECG in predicting EP outcome
and determine the minimum sample size that would be required to
reject the null hypothesis if the performance of TWA were in fact
sufficiently poor so as render the tests to be clinically non-
equivalent. That is:
H\0\: P\TWA\ is greater than or equal to P\SA\
H\1\: P\TWA\ is less than P\SA\
where H\0\ is the null hypothesis being tested, H\1\ is the
alternative, P\TWA\ is the probability that for a patient in the
population being studied that TWA will correctly predict the EP
outcome, and P\SA\ is the probability for a patient in the
population being studied that SAECG will correctly predict the EP
outcome.
The minimum sample size for this study was determined as follows:
To determine minimum sample size using McNemar's test one
establishes the minimum difference in the performance of the two
tests which would render them non-equivalent. From our initial
clinical data we estimated that in this population the average
clinical accuracy of the two tests for predicting EP outcome was
approximately 80%. From a clinical perspective, the two tests
would be considered substantially equivalent if their clinical
accuracy's were both in the range of 80 +/- 7%. Thus, the minimum
difference in test performance needed to establish non-
equivalence would occur when P\SA\ = 0.87 and P \TWA\ = 0.73.
August 20, 1998
<PAGE>
25
Assuming that TWA and SAECG were independent in correctly
predicting EP outcome, then the 2 X 2 concordance probability
table of TWA and SAECG was expected to be:
<TABLE>
<CAPTION>
-----------------------------------------------------------------------------------
TWA CORRECT TWA INCORRECT
-----------------------------------------------------------------------------------
<S> <C> <C>
SAECG Correct P\TWA\ .P\SAECG\ (1 - P\TWA\).P\SAECG\
-----------------------------------------------------------------------------------
SAECG Incorrect P\TWA\ .(1 - P\SAECG\) (1 - P\TWA\). (1 - P\SAECG\)
-----------------------------------------------------------------------------------
</TABLE>
Substituting in the values of P\SA\ and P\TWA\ required to
establish non-equivalence (with SAECG being superior to TWA):
<TABLE>
<CAPTION>
-----------------------------------------------------------------------------------
TWA CORRECT TWA INCORRECT
-----------------------------------------------------------------------------------
<S> <C> <C>
SAECG Correct 0.635 0.235
-----------------------------------------------------------------------------------
SAECG Incorrect 0.095 0.035
-----------------------------------------------------------------------------------
</TABLE>
From Rosner/6/, p 387, the sample size required to provide 80%
power to reject the null hypothesis H\0\ at the p less than 0.05
level was calculated as:
[CALCULATION FORMULA APPEARS HERE]
where
p\d\ = 0.33 Was the probability of disagreement between
TWA and SAECG
p\a\ = 0.29 Was the fraction of discordant pairs where
TWA agrees with EP and SAECG does not
q\a\ = 0.71 Was the fraction of discordant pairs where
SAECG agrees with EP and TWA does not
z\1-\ = 1.6449 Number of standard deviations for a
one-tailed less than 0.05
z\1-\ = 0.8416 Number of standard deviations for a 1- more
than 0.80
____________________
/6/ Rosner B, "Fundamentals of Biostatistics"; Duxbury Press, 1995, pp. 377-
387.
August 20, 1998
<PAGE>
26
Solving for n, the required sample size was 100 patients in whom
TWA, SAECG and EP results were determinate.
Therefore, a sample size of 100 patients was considered
sufficient to estimate the overall clinical P\TWA\ with a 95%
confidence interval of approximately +/- 7%.
9.6.3. Data management
All data captured on case report forms was double-key entered
into a Microsoft ACCESS database using a validated data
management system. Verification was performed by comparing the
two passes of data entry and resolving any differences.
Validation checks were run against the verified data, and queries
were sent to investigative sites for resolution. The database was
then updated to reflect the resolved queries. A 10% audit was
performed of the final database against the case report forms.
9.7. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES
This study consisted of two parts, a Pilot Study and a Main
Study. In the Pilot Study data were collected on the first 65
patients, after which enrollment in the Pilot Study was closed
and an analysis was performed of the Pilot Study data. During the
analysis, patients continued to enroll in the study. The Main
Study was initiated by Amendment 5 (July 29, 1997) and included
all those patients not enrolled in the Pilot Study. The results
reported here are only for patients in the Main Study. Refer to
Appendix 14.6 for results of the Pilot Study.
9.7.1. Amendments for the Pilot Study
Although amendments described here are numbered up to six,
because of numbering errors, only four were actually made. The
following is a summary of the changes resulting from each
amendment.
9.7.1.1. Amendment 1: September 23, 1996
The purpose of the this amendment was to:
August 20, 1998
<PAGE>
27
1. Modify the risk assessment statement in the
Informed Consent Form to indicate that
participation in the study did not significantly
increase risk in addition to that already inherent
in the EP study.
2. Modify exclusion criteria to include the standard
contraindications inherent in stress testing, and
to exclude patients with specific known reversible
arrhythmias.
3. Clarify the sequence of testing (TWA and SAECG
must precede EP testing).
4. Add a 510(k) number and input from the FDA about
the device.
5. Modify the statistical analysis plan.
9.7.1.2. Amendment 2: October 9, 1996
The purpose of the this amendment was to:
1. Clarify instructions for use of the SAECG device:
defined the correct modes and settings.
2. Clarify instructions for use of the CH 2000: added
the name of the exercise protocol to be used.
3. Added a statement about Intervening Events: if a
clinical event occurred between the TWA or SAECG
test and the EP study which could change the
correlation of the non-invasive tests with the EP
study, then the non-invasive tests needed to be
repeated or the patient withdrawn from the study.
9.7.1.3. Amendment 3: February 3, 1997
The purpose of the this amendment was to:
1. Clarify "serious ongoing dysrhythmia" in the
exclusion criteria by adding a list of such
dysrhythmias.
9.7.1.4. Amendment 4: April 24, 1997
August 20, 1998
<PAGE>
28
The purpose of the this amendment was to:
1. Clarify the definition of a TWA positive test by
indicating that the alternans needs to start prior
to the end of exercise.
2. Correct an inconsistency for patients over the age
of 70 years. The protocol was changed to specify
that patients should exercise to a heart rate of
70% of maximum predicted by age, or 105 bpm,
-----------
whichever was greater. Otherwise patients over 70
---------------------
would not attain the heart rate of 105 required
for a valid TWA test.
3. Define "artifact-free", a definition that was
omitted in the original protocol.
9.7.2. Amendments to Initiate the Main Study
9.7.2.1. Amendment 5: July 29, 1997
The purpose of the this amendment was to:
1. Modify the primary endpoint to one of substantial
equivalence with or superiority to SAECG.
2. Modify the classification of results of EP study
Original endpoint: Positive defined as prior
documented VT or VF without MI, sustained
monomophic VT induced during EP study, VF induced
during EP study with two or fewer extra-systoles.
Endpoint after Amendment 5: Positive defined as
sustained monomorphic VT induced during EP study.
VF induced during EP study is now indeterminate.
3. Modify the classification of results of TWA
testing.
Original classification: Strongly positive, Weakly
positive, Negative, Indeterminate
Classification after Amendment 5: Positive,
Negative, Indeterminate
4. Change the model number of the SAECG device
August 20, 1998
<PAGE>
29
From: Corazonics, Predictor II or successor system.
To: ART (Arrhythmia Research Technology, Inc.) LP-Pac
Q(TM) ver. 1.10q Late Potential Analysis Software (the
successor to the Predictor II)
5. Terminate the Pilot Study and start the Main Study.
9.7.3. Amendments During the Main Study
9.7.3.1. Amendment 6: March 25, 1998
The purpose of the this amendment was to:
1. Transpose the primary and secondary hypotheses.
2. Divide the definition of an indeterminate test into two
definitions: an incomplete test (in which the patient was
not able to exercise adequately), and an indeterminate
test (in which the test results are obscured too severely
for an adequate reading).
9.7.4. Changes in the Conduct of the Study
In the original protocol, the outcome of the EP study was to be
determined by an independent electrophysiologist in accordance with a
set of rules defined in the protocol. A decision was later made to
determine this outcome in accordance with a set of programming
specifications reviewed by the Principal Investigator to conform to
the intent of the rules in the protocol. These programming
specifications are detailed below:
Outcome Determination Algorithm for EP Studies:
-----------------------------------------------
If the following criterion was true for a patient, then we had a
POSITIVE EP finding:
. At least one ventricular site had a finding of Sustained VT
(FINDING = 2) and the Number of Stimuli Delivered for that
ventricular site (same record) was less than or equal to three
(STIMULI less than or equal to 3).
If the following three criteria were ALL true for a patient, then we
had a NEGATIVE EP finding:
August 20, 1998
<PAGE>
30
. The patient did not satisfy the criteria for a POSITIVE
finding.
. The Index Arrhythmia was Documented VT, Documented VF,
Suspected VT or Suspected VF or Other, and the number of
unique ventricular sites with the Number of Stimuli Delivered
having a Number of Stimuli Delivered field response of at
least three (STIMULI less than or equal to 3) was greater than
or equal to two.
OR
. The Index Arrhythmia was Documented SVT or Suspected SVT and
the number of unique ventricular sites with the Number of
Stimuli Delivered field having a response of at least two
(STIMULI greater than or equal to 2) was greater than or equal
to one.
(Note that if multiple Ventricular Sites were listed with the
same Anatomical Site (i.e., all RV) they were considered to be
unique and different sites).
. There was no entry of "Sustained VT", "V Fib", "V Flutter" or
a comment of "Sustained Polymorphic VT" under Findings for any
ventricular site in which the Number of Stimuli Delivered was
less than or equal to three (STIMULI less than or equal to 3).
If the following three criteria were ALL true for a patient, then
we had an INDETERMINATE finding:
. The patient did not have a Positive finding.
. The patient did not have a Negative finding.
. The patient had a result for the EP study denoted as a non-
missing Findings field.
10. STUDY PATIENTS
10.1. DISPOSITION OF PATIENTS
A total of 272 patients were enrolled in the study by nine investigators at
10 sites (one investigator was affiliated with two sites). Two-hundred-
seventeen completed the study and all observations.
Of the 63 that did not complete the study and all observations: 34 were not
able to complete all study procedures, 19 were removed because of
August 20, 1998
<PAGE>
31
protocol violations, one patient died, and nine were removed for a variety
of reasons: incomplete EP testing (5 patients), equipment failure (2
patients), excessive ectopy (1 patient), and failure to withhold -blockers
(1 patient). Note that 8 patients are had more than one reason for early
termination. Table 2 presents patient dispositions as reported by the
investigator.
TABLE 2. PATIENT DISPOSITION
<TABLE>
<CAPTION>
--------------------------------------------------------------------------
Number of Percent of
Patients Patients
--------------------------------------------------------------------------
<S> <C> <C>
All Patients 272 100.0
--------------------------------------------------------------------------
Completed Study 217 79.8
--------------------------------------------------------------------------
Did Not Complete Study 63 20.2
--------------------------------------------------------------------------
Unable to Complete all Study 34 12.5
Procedures
--------------------------------------------------------------------------
Protocol Violation 19 7.0
--------------------------------------------------------------------------
Death 1 0.4
--------------------------------------------------------------------------
Other/a/ 9 3.3
--------------------------------------------------------------------------
</TABLE>
/a/ The categories other and lost to follow-up were pooled for this
category. Source: Appendix VI, Tables 1.1 and 1.3.
10.2. PROTOCOL VIOLATIONS
Eleven patients were reported by the investigator to be protocol violators
on the Termination case report form page. In addition, it was determined
from review of case report form data that an additional eight patients
violated the protocol due to the following: -Blockers not withheld for
testing (seven patients: 12-042, 21-027, 22-062, 22-105, 27-026, 40-001,
and 40-005), and Anti-arrhythmic medications changed between EP and TWA
tests (one patient, 21-022). Note that for patient 27-026, since there was
no given stop date for -Blockers on the case report form, it was assumed
that -Blockers were not withheld for testing.
All protocol violators were excluded from both the Primary and Secondary
Hypothesis Samples. The proportion of patients reported to have
experienced these protocol violations was not clinically significantly
different across sites.
August 20, 1998
<PAGE>
32
TABLE 3. PROTOCOL VIOLATIONS
<TABLE>
<CAPTION>
-------------------------------------------------------------------------
Site Patient Number Description of Protocol Violation
-------------------------------------------------------------------------
<S> <C> <C>
12 002 Patient Not In Sinus Rhythm
-------------------------------------------------------------------------
042 (B)-Blocker Not Held For Testing
-------------------------------------------------------------------------
21 022 Anti Arrhythmic Medication Between
Procedures
-------------------------------------------------------------------------
026 TWA Test Done After The EP Study
-------------------------------------------------------------------------
027 (B)-Blocker Not Held For Testing
-------------------------------------------------------------------------
029 TWA Test Done After The EP Study
-------------------------------------------------------------------------
22 023 Programmed Ventricular Stimulation Not
Completed Because Of Difficulties
Encountered With Mapping The Accessory
Pathway
-------------------------------------------------------------------------
029 TWA Test Done After The EP Study
-------------------------------------------------------------------------
045 Patient Not In Sinus Rhythm
-------------------------------------------------------------------------
054 No Recovery Time Recorded
-------------------------------------------------------------------------
062 (B)-Blocker Not Held For Testing
-------------------------------------------------------------------------
105 (B)-Blocker Not Held For Testing
-------------------------------------------------------------------------
109 SAECG Done After The EP Study
-------------------------------------------------------------------------
26 034 (B)-Blocker Not Held For Testing
-------------------------------------------------------------------------
056 Incomplete EP Study
-------------------------------------------------------------------------
27 026 Unknown (B)-Blocker Stop Date
-------------------------------------------------------------------------
031 TWA Test Done After The EP Study
-------------------------------------------------------------------------
40 001 (B)-Blocker Not Held For Testing
-------------------------------------------------------------------------
005 (B)-Blocker Not Held For Testing
-------------------------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 1.4.
11. EFFICACY EVALUATION
11.1. DATA SETS ANALYZED
Table 7 of the appendices lists all patients and which population samples
they are included in this analysis.
There were three defined statistical populations used in the study:
1. All Patients Sample: all 272 enrolled patients.
August 20, 1998
<PAGE>
33
2. Primary Hypothesis Sample: 140 patients who had determinate TWA and EP
outcomes, and who were not in violation of the protocol.
3. Secondary Hypothesis Sample: 103 patients who were included in the
Primary Hypothesis Sample AND had a determinate SAECG test outcome.
Table 1.2 in Appendix VI lists the number of patients in each dataset by
investigational site. The proportion of patients enrolled at each site who
were eligible for inclusion in the Primary Hypothesis Sample ranged from
30.8% to 66.7%, and for inclusion in the Secondary Hypothesis Sample ranged
from 17.8% to 58.3%.
TABLE 4. STATISTICAL POPULATIONS
<TABLE>
<CAPTION>
N %
------------------------------------------------------------------------
<S> <C> <C>
All Patients Sample 272 100.0
------------------------------------------------------------------------
Patients with No Protocol Violations 253 93.0
------------------------------------------------------------------------
No Protocol Violation, Determinate EP Outcome 189 69.5
------------------------------------------------------------------------
No Protocol Violation, Determinate EP and TWA 140 51.5
------------------------------------------------------------------------
No Protocol Violation, Determinate EP, TWA and SAECG 103 37.9
------------------------------------------------------------------------
Primary Hypothesis Patients Sample 140 51.5
------------------------------------------------------------------------
Secondary Hypothesis Patients Sample 103 37.9
------------------------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 1.1.
11.2. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Table 5 presents demographic and baseline characteristics for the All
Patients Sample (N = 272). Mean age for patients in the study was 56.9
years (ranging from 18 to 86 years), 66.2% of the patients were male, mean
height was 68.2 inches, and mean weight was 176.0 pounds (ranging from 97
to 302 pounds).
August 20, 1998
<PAGE>
34
TABLE 5. DEMOGRAPHICS: ALL PATIENTS
<TABLE>
<CAPTION>
------------------------------------
N %
------------------------------------
<S> <C> <C>
Age (years)
------------------------------------
N 271
------------------------------------
Mean 56.87
------------------------------------
Median 57
------------------------------------
Std. Dev. 15.31
------------------------------------
Minimum 18
------------------------------------
Maximum 86
------------------------------------
Sex
------------------------------------
Male 180 66.2
------------------------------------
Female 92 33.8
------------------------------------
Height (inches)
------------------------------------
N 270
------------------------------------
Mean 68.18
------------------------------------
Median 68
------------------------------------
Std. Dev. 3.81
------------------------------------
Minimum 59
------------------------------------
Maximum 82
------------------------------------
Weight (pounds)
------------------------------------
N 270
------------------------------------
Mean 176.03
------------------------------------
Median 175
------------------------------------
Std. Dev. 39.60
------------------------------------
Minimum 97
------------------------------------
Maximum 302
------------------------------------
</TABLE>
Source: Appendix VI, Table 2.0.
August 20, 1998
<PAGE>
35
Table 6 presents medical history reported by the patients at screening.
More than one medical history condition may have been reported for each
patient. The most frequently reported cardiac abnormalities were coronary
artery disease (48.2%) (which included Coronary artery disease, myocardial
infarctions, and Ischemic DCM), and other cardiac conditions (55.1%). Non-
cardiac conditions were reported by 62.5% of patients.
TABLE 6 MEDICAL HISTORY: ALL PATIENTS
<TABLE>
<CAPTION>
-------------------------------------------------------
Event N %
-------------------------------------------------------
<S> <C> <C>
Total Coronary Artery Disease 131 48.2
-------------------------------------------------------
Coronary Artery Disease 118 43.4
-------------------------------------------------------
Myocardial Infarction 93 34.2
-------------------------------------------------------
DCM, Ischemic 42 15.4
-------------------------------------------------------
DCM, Non Ischemic 29 10.7
-------------------------------------------------------
Valvular Heart Disease 29 10.7
-------------------------------------------------------
Other Structural Cardiac Abnormality 7 2.6
-------------------------------------------------------
HCM 2 0.7
-------------------------------------------------------
Cardiac Arrest 10 3.7
-------------------------------------------------------
Revascularization, PTCA 25 9.2
-------------------------------------------------------
Revascularization, CABG 39 14.3
-------------------------------------------------------
Other Cardiac 150 55.1
-------------------------------------------------------
Diabetes 47 17.3
-------------------------------------------------------
Other Non Cardiac 170 62.5
-------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 3.0.
August 20, 1998
<PAGE>
36
Table 7 presents the counts of cardiovascular Index Event for all patients
in the study. (The Index Event was the cardiovascular arrhythmia or
symptom that led to referral for EP study.) The most frequently reported
arrhythmia was suspected VT (42.8%), and the most frequently reported
symptoms were syncope (33.9%) and pre-syncope (34.7%).
TABLE 7. INDEX EVENT: ALL PATIENTS
<TABLE>
<CAPTION>
----------------------------------------------------
N %
----------------------------------------------------
<S> <C> <C>
Arrhythmia
----------------------------------------------------
Documented VF 8 3.0
----------------------------------------------------
Suspected VF 12 4.4
----------------------------------------------------
Documented VT 37 13.7
----------------------------------------------------
Suspected VT 116 42.8
----------------------------------------------------
Documented SVT 28 10.3
----------------------------------------------------
Suspected SVT 40 14.8
----------------------------------------------------
Other 30 11.1
----------------------------------------------------
Missing 1 1
----------------------------------------------------
Symptoms
----------------------------------------------------
Asymptomatic 25 9.2
----------------------------------------------------
Cardiac Arrest 14 5.2
----------------------------------------------------
Syncope (LOC) 92 33.9
----------------------------------------------------
Pre-Syncope (light-headedness) 94 34.7
----------------------------------------------------
Other 46 17.0
----------------------------------------------------
Missing 1 1
----------------------------------------------------
</TABLE>
Source: Appendix VI, Table 4.1.
August 20, 1998
<PAGE>
37
Table 8 presents ECG information for all patients in the study. Most
patients in the study (97.0%) were in sinus rhythm at baseline, and 71.2%
did not have any intraventricular conduction defects reported. The most
frequently reported conduction defects were complete left bundle branch
block (7.7%) and other defects (7.4%). Mean ventricular rate was 77.8
beats per minute (standard deviation of 16 bpm, with a range from 44 to 153
bpm).
TABLE 8. BASELINE ELECTROCARDIOGRAM: ALL PATIENTS
<TABLE>
<CAPTION>
--------------------------------------------------
N %
--------------------------------------------------------
<S> <C> <C>
Baseline ECG Rhythm
--------------------------------------------------------
Sinus 263 97.0
--------------------------------------------------------
Other 8 3.0
--------------------------------------------------------
Missing 1
--------------------------------------------------------
Intraventricular Conduction Defect
--------------------------------------------------------
None 193 71.2
--------------------------------------------------------
RBBB Complete 14 5.2
--------------------------------------------------------
RBBB Incomplete 12 4.4
--------------------------------------------------------
LBBB Complete 21 7.7
--------------------------------------------------------
LBBB Incomplete 8 3.0
--------------------------------------------------------
Left Anterior Hemiblock 3 1.1
--------------------------------------------------------
Left Posterior Hemiblock 0 0.0
--------------------------------------------------------
Other 20 7.4
--------------------------------------------------------
Missing 1
--------------------------------------------------------
Ventricular Rate (bpm)
--------------------------------------------------------
N 269
--------------------------------------------------------
Mean 77.82
--------------------------------------------------------
Median 75
--------------------------------------------------------
Std. Dev. 15.98
--------------------------------------------------------
Minimum 44
--------------------------------------------------------
Maximum 153
--------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 4.2.
August 20, 1998
<PAGE>
38
Table 9 presents NYHA functional classifications and ejection fraction at
baseline for all patients in the study. The majority of patients had a
Class I NYHA functional level (66.7%), while 22.6% were classified as NYHA
Class II, 10.0% were Class III, and 0.7% were Class IV. The most
frequently used method of determining ejection fraction was echocardiogram
(75.4%). While the mean ejection fraction reported was 39.1%, many
patients did not have a numeric value reported for ejection fraction, but
rather had a descriptive assessment. Of the 98 patients with a descriptive
assessment, 59 of those patients were reported as having a 'Normal'
ejection fraction.
TABLE 9. NYHA FUNCTIONAL CLASS AND EJECTION FRACTION AT BASELINE: ALL
PATIENTS
<TABLE>
<CAPTION>
---------------------------------------------------
N %
---------------------------------------------------
<S> <C> <C>
NYHA Functional Class
---------------------------------------------------
I 180 66.7
---------------------------------------------------
II 61 22.6
---------------------------------------------------
III 27 10.0
---------------------------------------------------
IV 2 0.7
---------------------------------------------------
Missing 2
---------------------------------------------------
Ejection Fraction (%)
---------------------------------------------------
N 170
---------------------------------------------------
Mean 39.11
---------------------------------------------------
Median 35
---------------------------------------------------
Std. Dev. 18.84
---------------------------------------------------
Minimum 10
---------------------------------------------------
Maximum 99
---------------------------------------------------
Method of Ejection Fraction
Determination
---------------------------------------------------
Radionuclide Ventriculogram 14 5.6
---------------------------------------------------
Contrast Ventriculography 33 13.1
---------------------------------------------------
Echocardiogram 190 75.4
---------------------------------------------------
Other 7 2.8
---------------------------------------------------
Unknown 8 3.2
---------------------------------------------------
Missing 20
---------------------------------------------------
</TABLE>
Source: Appendix VI, Table 4.3.
August 20, 1998
<PAGE>
39
Table 10 presents the number and percent of patients taking -blockers and
anti-arrhythmic medications upon entry into the study. Patients may have
been taking more than one medication upon entry into the study. The
majority of patients in the study (69.9%) were not taking any medications
at the time of enrollment. Of the 65 patients (23.9%) taking -blockers, 23
were taking metaprolol, 14 were taking atenolol, and 10 were taking
lopressor. Twenty patients (7.4%) were taking the anti-arrhythmic agent
amiodarone.
There was one patient each where the medications Clonidine and Prinivil,
which are not beta blockers nor antiarrhythmic agents, were erroneously
reported in this CRF form; they are not reported in Table 10 below.
TABLE 10. NUMBER (%) OF PATIENTS TAKING B-BLOCKER AND ANTI-ARRHYTHMIC
MEDICATIONS BY WHO DRUG CLASS AND DRUG NAME: ALL PATIENTS
<TABLE>
<CAPTION>
----------------------------------------------
WHO Drug Class and Drug Name N %
----------------------------------------------
<S> <C> <C>
At Least One Medication 82 30.1
----------------------------------------------
No Medications 190 69.9
----------------------------------------------
----------------------------------------------
Beta Blocking Agents 65 23.9
----------------------------------------------
Atenolol 14 5.1
----------------------------------------------
Carvedilol 3 1.1
----------------------------------------------
Coreg 1 0.4
----------------------------------------------
Lopressor 10 3.7
----------------------------------------------
Metoprolol 23 8.5
----------------------------------------------
Metoprolol Sr 1 0.4
----------------------------------------------
Metoprolol Succinate 1 0.4
----------------------------------------------
Metoprolol Tartrate 2 0.7
----------------------------------------------
Nadolol 2 0.7
----------------------------------------------
Sotalol 1 0.4
----------------------------------------------
Tenormin 4 1.5
----------------------------------------------
Toprol Xl 7 2.6
----------------------------------------------
Calcium Channel Blockers 2 0.7
----------------------------------------------
Cardizem 1 0.4
----------------------------------------------
Cardizem Cd 1 0.4
----------------------------------------------
</TABLE>
August 20, 1998
<PAGE>
40
TABLE 10. NUMBER (%) OF PATIENTS TAKING B-BLOCKER AND ANTI-ARRHYTHMIC
MEDICATIONS BY WHO DRUG CLASS AND DRUG NAME: ALL PATIENTS
(CONTINUED)
<TABLE>
<CAPTION>
---------------------------------------------
WHO DRUG CLASS AND DRUG NAME N %
---------------------------------------------
<S> <C> <C>
Cardiac Therapy 20 7.4
---------------------------------------------
Amiodarone 11 4.0
---------------------------------------------
Digoxin 1 0.4
---------------------------------------------
Flecainide 1 0.4
---------------------------------------------
Lanoxin 1 0.4
---------------------------------------------
Lidocaine 2 0.7
---------------------------------------------
Procainamide 1 0.4
---------------------------------------------
Procan Sr 1 0.4
---------------------------------------------
Propafenone 2 0.7
---------------------------------------------
Tambocor 1 0.4
---------------------------------------------
</TABLE>
Source: Appendix VI, Table 10.
11.3. EFFICACY RESULTS
11.3.1. All patients analysis
All data used in the efficacy results are presented by-patient in
Table 7 of the Appendix 15.2.
Table 11 presents a comparison of the results of TWA and EP testing
using the All Patients Sample (N = 272), and include all patients
whose results were either incomplete or indeterminate, as well as
those patients with either a missing TWA or a missing EP test. TWA
and EP testing concurred on positive results for 26 patients
(10.9%) and on negative results for 73 patients (30.7%).
August 20, 1998
<PAGE>
41
TABLE 11. COMPARISON OF T-WAVE ALTERNANS TO ELECTROPHYSIOLOGY
FINDINGS: ALL PATIENTS
<TABLE>
<CAPTION>
--------------------------------------------------------------------
ELECTROPHYSIOLOGY
--------------------------------------------------------------------
T-WAVE ALTERNANS POSITIVE NEGATIVE INDETERMINATE MISSING
<S> <C> <C> <C> <C>
--------------------------------------------------------------------
Positive 26 (10.9) 39 (16.4) 15 (6.3) 2
--------------------------------------------------------------------
Negative 10 (4.2) 73 (30.7) 22 (9.2) 7
--------------------------------------------------------------------
Incomplete 13 (5.5) 27 (11.3) 13 (5.5) 4
--------------------------------------------------------------------
Missing 6 8 2 5
--------------------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 5.1.
11.3.2. Primary hypothesis analysis
Table 12 presents a comparison of the results of TWA and EP findings
using the Primary Hypothesis Sample (N = 140), defined as those
patients who were not in violation of the protocol and had a
determinate test for both TWA and EP.
The primary null hypothesis in this study is that TWA findings are not
predictive of EP findings, with the alternative hypothesis being that
TWA findings are predictive of EP findings. The alternative
hypothesis is considered the desired outcome in this study.
The two-sided Fisher's Exact test, testing the null hypothesis, was
statistically significant (p-value less than 0.0001), resulting in the
rejection of the null hypothesis in favor of the alternative
hypothesis. Thus, the data in this study support the conclusion that
the TWA test is a statistically significant predictor of EP test
outcome.
TABLE 12 COMPARISON OF T-WAVE ALTERNANS TO ELECTROPHYSIOLOGY FINDINGS:
PRIMARY HYPOTHESIS SAMPLE
<TABLE>
<CAPTION>
-------------------------------------------------
ELECTROPHYSIOLOGY
-------------------------------------------------
T-WAVE POSITIVE NEGATIVE P-VALUE
ALTERNANS
-------------------------------------------------
<S> <C> <C> <C>
Positive 25 37 less than
0.0001
-------------------------------------------------
Negative 8 70
-------------------------------------------------
</TABLE>
Table 13 presents the point estimates and 95% confidence intervals
(using a Z-statistic of 1.96 to calculate the interval) for a
August 20, 1998
<PAGE>
42
number of descriptive statistics related to the comparison of TWA to
EP. The sensitivity of TWA to predict positive EP findings was 75.8%,
while the specificity of TWA to predict negative EP findings was
65.4%. TWA and EP outcomes were in agreement in 67.9% of the patients.
The relative risk was 3.93. Thus, in the Primary Hypothesis Sample,
the relative risk of having a positive EP finding for those patients
with positive TWA finding was 3.93 times that of those patients with a
negative TWA finding.
TABLE 13 POINT ESTIMATES AND 95% CONFIDENCE INTERVALS OF COMPARATIVE
STATISTICS BETWEEN TWA AND EP FINDINGS: PRIMARY HYPOTHESIS SAMPLE
<TABLE>
<CAPTION>
------------------------------------------------------------------
POINT 95% CONFIDENCE
ESTIMATE INTERVAL
------------------------------------------------------------------
<S> <C> <C>
Sensitivity 75.8 (67.7,82.9)
------------------------------------------------------------------
Specificity 65.4 (57.5,73.3)
------------------------------------------------------------------
Predictive Value of Negative 89.7 (84.7,94.8)
------------------------------------------------------------------
Predictive Value of Positive 40.3 (32.2,48.4)
------------------------------------------------------------------
True Negative 50.0 (41.7,58.3)
------------------------------------------------------------------
True Positive 17.9 (11.5,24.2)
------------------------------------------------------------------
False Negative 5.7 (1.9,9.6)
------------------------------------------------------------------
False Positive 26.4 (19.1,33.7)
------------------------------------------------------------------
Correct Classification 67.9 (60.1,75.6)
------------------------------------------------------------------
Relative Risk 3.93
------------------------------------------------------------------
Fisher's Exact P-Value 0.0001
less than
------------------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 5.2.
11.3.3. Secondary hypothesis analysis
Table 14 presents the results of the comparison between TWA and SAECG
to EP findings in the Secondary Hypothesis Sample.
Of the patients in the Secondary Hypothesis Sample, 57.3% had correct
classifications for both TWA and SAECG, 6.8% had incorrect
classifications for both TWA and SAECG, while the remaining patients
had an incorrect classification for either TWA or SAECG, when compared
to EP findings. The secondary null hypothesis in this study was that
the TWA and SAECG tests are in agreement with each other with respect
to EP testing, with the alternative hypothesis being that TWA and
SAECG tests are not in
August 20, 1998
<PAGE>
43
agreement with each other with respect to EP testing. No rejection of
the null hypothesis would indicate that TWA and SAECG testing are in
agreement with each other when compared to EP findings, which is
considered the desired outcome.
The two-sided McNemar's test, testing the null hypothesis, was not
statistically significant, p-value = 0.2498 (one-sided p-value =
0.1249), resulting in no rejection of the null hypothesis in favor of
the alternative hypothesis. Thus, the ability of TWA test findings to
predict EP test findings is not statistically different from the
ability of SAECG test findings to predict EP test findings.
TABLE 14 COMPARISON OF T-WAVE ALTERNANS AND SIGNAL-AVERAGED ECG TO
ELECTROPHYSIOLOGY FINDINGS: SECONDARY HYPOTHESIS SAMPLE
<TABLE>
<CAPTION>
T-WAVE ALTERNANS
--------------------------------------------
SAECG CORRECT INCORRECT P-VALUE
--------------------------------------------
<S> <C> <C> <C>
Correct 59(57.3) 22(21.6) 0.2498
--------------------------------------------
Incorrect 15(14.6) 7(6.8)
--------------------------------------------
</TABLE>
Source: Appendix VI, Table 6.
Table 15 presents a comparison of the results of testing of the
primary null hypothesis using the Secondary Hypothesis Sample patients
(N=103) for both TWA and SAECG.
While both the TWA findings and the SAECG findings were statistically
significant in predicting the EP findings (Fisher's Exact p-value =
0.0001 for TWA, and 0.0014 for SAECG), with respect to the ability to
detect true positives compared to the EP findings, a much greater
sensitivity in detecting true positives was displayed by TWA testing
(80.0%) than SAECG testing (50.0%). In other words, the TWA testing
detected true positives more often than did the SAECG testing.
Specificity in detecting true negatives was greater using SAECG
(85.5%) as compared to TWA (69.9%).
In the Secondary Hypothesis Sample, the relative risk of having a
positive EP finding for those patients with positive TWA finding was
6.05 compared with those patients with a negative TWA finding. Thus,
patients in the Secondary Hypothesis Sample with a positive TWA
finding were 6.05 times more likely to have had a positive EP finding
than those patients with a negative TWA finding. Patients in the
Secondary Hypothesis Sample with a positive SAECG finding were only
3.68 times more likely to have had a positive EP finding than those
patients with a negative SAECG finding.
August 20,1998
<PAGE>
44
Thus, while there was no statistically significant difference, in the
Secondary Hypothesis Sample, between the ability of TWA to predict EP
outcome and the ability of SAECG to predict EP outcome, based upon the
relative risk, there appeared to be a stronger association between TWA
test findings and EP test findings than between SAECG and EP test
findings.
TABLE 15 COMPARISON OF T-WAVE ALTERNANS AND SIGNAL-AVERAGED ECG TO
ELECTROPHYSIOLOGY FINDINGS: SECONDARY HYPOTHESIS SAMPLE
<TABLE>
<CAPTION>
-------------------------------------------------------------
TWA POINT SAECG POINT
ESTIMATE ESTIMATE
-------------------------------------------------------------
<S> <C> <C>
Sensitivity 80.0 50.0
-------------------------------------------------------------
Specificity 69.9 85.5
-------------------------------------------------------------
Relative Risk 6.05 3.68
-------------------------------------------------------------
Fisher's Exact P-Value less than less than
0.0001 0.0014
---------------------------------------------------------------
</TABLE>
Source: Appendix VI, Tables 5.3 and 5.4.
The statistical analysis supports the hypothesis that TWA was
substantially equivalent to or better than SAECG in its ability to
predict EP outcome.
11.3.4. Efficacy conclusions
The desired primary and secondary hypothesis conclusions in this study
were both met.
With respect to the primary hypothesis, TWA was a statistically
significant predictor of EP test outcome (Fisher's Exact test, p-value
less than 0.0001), with sensitivity equal to 75.8% and specificity
equal to 65.4%. The relative risk of having a positive EP finding for
those patients with a positive TWA finding was 3.93 times that of
those patients with a negative TWA finding.
With respect to the Secondary Hypothesis, TWA was found to be
substantially equivalent to or better than SAECG in its ability to
predict EP outcome. The desired outcome was obtained that there was
no statistically significant difference between TWA and SAECG findings
in their prediction of EP findings: McNemar's test, p-value = 0.2498
(one-sided p-value = 0.1249). However, there appeared to be stronger
association between TWA findings and
August 20,1998
<PAGE>
45
EP findings than between SAECG findings and EP findings, as
reflected in the measure of relative risk.
12. SAFETY EVALUATION
12.1. ADVERSE EVENTS
Only adverse events considered to be possibly, probably, or definitely
related to the TWA procedure were included in the adverse event tables
for this study. Details of adverse events reported but not considered
by the Sponsor or Investigator to be related to TWA testing may be
found in Appendix VI, Listing 8.1 to 8.3.
Table 16 presents a summary of the number and percent of patients
reporting adverse events during the study. Three patients reported an
adverse event that was possibly, probably, or definitely related to
the test procedure. Patient 30-001 experienced VT, and two patients
(Patients 26-006 and 38-006) reported a rash.
One death occurred during this study (Patient 26-053). This death was
not considered by either the Sponsor or the Investigator (Dr.
Bloomfield) to be related to the TWA procedure, and consequently was
not recorded as an adverse event and will not be found in either the
adverse event tables or listings. Refer to Section 12.2.4 for a
narrative of this patient's experience.
August 20, 1998
<PAGE>
46
TABLE 16 NUMBER (%) OF PATIENTS EXPERIENCING ADVERSE EVENTS BY COSTART
BODY SYSTEM AND PREFERRED TERM: ALL PATIENTS
<TABLE>
<CAPTION>
------------------------------------------------
COSTART BODY SYSTEM/PREFERRED N %
TERM
------------------------------------------------
<S> <C> <C>
At Least One Adverse Event 3 1.1
------------------------------------------------
No Adverse Events 269 98.9
------------------------------------------------
------------------------------------------------
Cardiovascular 1 0.4
------------------------------------------------
Tachycardia Vent 1 0.4
------------------------------------------------
Dermatological 2 0.7
------------------------------------------------
Rash 1 0.4
------------------------------------------------
Rash Vesic Bull 1 0.4
------------------------------------------------
</TABLE>
Source: Appendix VI, Table 8.
Table 17 presents a summary of adverse events by relationship to TWA
testing. Of the three adverse events reported, two were considered by
the investigator to be possibly related to TWA testing (VT and rash)
and one was considered definitely related (rash and vesicular bullae).
TABLE 17. NUMBER (%) OF PATIENTS EXPERIENCING ADVERSE EVENTS BY
RELATIONSHIP TO T-WAVE ALTERNANS PROCEDURE, COSTART BODY
SYSTEM AND PREFERRED TERM
<TABLE>
<CAPTION>
-----------------------------------------------------------------------
BODY SYSTEM/PREFERRED POSSIBLE % PROBABLE % DEFINITE %
TERM
-----------------------------------------------------------------------
<S> <C> <C> <C> <C> <C> <C>
At Least One Adverse 2 0.7 0 0.0 1 0.4
Event
-----------------------------------------------------------------------
Cardiovascular 1 0.4 0 0.0 0 0.0
-----------------------------------------------------------------------
Tachycardia Vent 1 0.4 0 0.0 0 0.0
-----------------------------------------------------------------------
Dermatological 1 0.4 0 0.0 1 0.4
-----------------------------------------------------------------------
Rash 1 0.4 0 0.0 0 0.0
-----------------------------------------------------------------------
Rash Vesic Bull 0 0.0 0 0.0 1 0.4
-----------------------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 9.
12.2. DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT
ADVERSE EVENTS
12.2.1. Deaths
August 20, 1998
<PAGE>
47
One death occurred during this study (Patient 26-053). This death was
not considered by the Investigator (Dr. Bloomfield) to be related to
the TWA procedure, and consequently was not recorded as an adverse
event. Refer to Section 12.2.4 for a narrative of this patient's
experience.
12.2.2. Other serious adverse events
No other serious adverse events occurred during this study.
12.2.3. Other significant adverse events
Not applicable.
12.2.4. Narratives of serious adverse events, and certain other
significant adverse events
One patient died during the study.
PATIENT 053
Patient 053 at Site 26 was a 53 year-old male with a history of
coronary artery disease, MI, diabetes, ischemic DCM, and PTCA. He was
enrolled in the study on March 16, 1998 and TWA testing was performed
the next day. The decision was subsequently made to send him for
coronary artery bypass grafting (CABG) on March 31, 1998, and EP
testing was postponed until after surgery. He underwent CABG on the
scheduled date and did well for the first 24 hours. His hemodynamic
indices were improving and he was being weaned from the ventilator and
from pressors. He subsequently developed rapid and incessant
monomorphic VT in the Open Heart Recovery Room. Despite
cardioversion, and treatment with lidocaine and amiodarone he was
subsequently placed on extra-corporeal membrane oxygenation and died
April 1, 1998.
This death was not considered by either the Sponsor or the
Investigator (Dr. Bloomfield) to be related to the TWA procedure, and
consequently was not recorded as an adverse event.
August 20, 1998
<PAGE>
48
13. DISCUSSION AND OVERALL CONCLUSIONS
This study examined the ability of TWA testing to predict, using the spectral
method of the CH 2000 Cardiac Diagnostic System and Hi Res ECG electrodes,
increased susceptibility to ventricular arrhythmias, defined as sustained
monomorphic VT induced during EP testing. In addition, the substantial
equivalence of TWA to SAECG for the purpose of measuring increased
susceptibility to ventricular arrhythmias was assessed.
A total of 272 male and female patients, being evaluated for known or suspected
cardiac arrhythmias, were enrolled in the study. The following criteria defined
subsets of the population for statistical analysis:
1. All Patients Sample: all 272 enrolled patients.
2. Primary Hypothesis Sample: 140 patients who had determinate TWA and EP
outcomes and who were not in violation of the protocol.
3. Secondary Hypothesis Sample: 103 patients who were included in the Primary
Hypothesis Sample AND had a determinate SAECG test outcome.
Both the primary and secondary hypotheses were met. The first, that TWA findings
were predictive of EP findings, was statistically significant (p-value less than
0.0001). Sensitivity of the TWA test to predict a positive EP finding was 75.8%,
while specificity to detect a negative EP finding was 65.4%. The relative risk
of having a positive EP finding for those patients with a positive TWA finding
was 3.93 compared with those patients with a negative TWA finding.
The strength of the association between TWA findings and EP findings was more
evident than the association between SAECG findings and EP findings when the
primary null hypothesis was tested using the Secondary Hypothesis Sample. TWA
showed a much greater sensitivity for predicting true positives (80.0%) than did
SAECG (50.0%). The relative risk using the Secondary Hypothesis Sample was even
greater than that noted for the Primary Hypothesis Sample. In the Secondary
Hypothesis Sample, the relative risk of having a positive EP finding for those
patients with positive TWA finding was 6.05 compared with those patients with a
negative TWA finding. This relative risk was much higher than that of the
corresponding SAECG relative risk of 3.68 in the same population of patients.
The greater relative risk noted with the TWA test compared to the SAECG test is
probably due to the increased sensitivity of the TWA test over the SAECG test,
when compared to the EP test.
It may also be noted that, in the population studied, there was a low incidence
of positive EP findings. Based on the results indicated in this study, TWA
testing
August 20, 1998
<PAGE>
49
would probably show a much stronger predictive value of EP in a population with
a higher incidence of positive EP findings, than that of SAECG testing.
With respect to the Secondary Hypothesis, TWA was found to be substantially
equivalent to or better than SAECG in its ability to predict EP outcome. The
desired outcome was obtained that there was no statistically significant
difference between TWA and SAECG findings in their prediction of EP findings:
McNemar's test, p-value = 0.2498 (one-sided p-value = 0.1249). However, as
discussed above, there was a trend toward a greater association between TWA
findings and EP findings than between SAECG findings and EP findings, as
reflected in the measure of relative risk.
The TWA procedure was safe and well tolerated. Only three adverse events were
reported to have been possibly associated with the procedure: VT (from
exercising) and two reports of rash. One death occurred during the study
unrelated to the TWA testing. Subsequent to TWA testing, the patient underwent
CABG. During the post operative period he suffered incessant VT that was not
relieved by cardioversion and treatment with antiarrhythmics, with death as the
final outcome.
August 20, 1998
<PAGE>
EXHIBIT 99.3
1. TITLE PAGE
INTEGRATED CLINICAL STATISTICAL REPORT
(INTERIM REPORT)
A 12 MONTH FOLLOW-UP STUDY OF PATIENTS ENROLLED IN A
PROSPECTIVE MULTI-CENTER STUDY
TO DETERMINE THE EFFECTIVENESS OF T-WAVE ALTERNANS
IN PREDICTING SUSCEPTIBILITY
TO VENTRICULAR ARRHYTHMIAS
<TABLE>
- -----------------------------------------------------------------------------------------
<S> <C>
INDICATION: Patients referred for evaluation of known or suspected
cardiac arrhythmias and enrolled in Protocol
95-CH2000-3.0
- -----------------------------------------------------------------------------------------
METHODS: Follow-up of a prospective, multi-center, open-label,
single-test comparison study (95-CH2000-3.0)
- -----------------------------------------------------------------------------------------
SPONSOR NAME AND ADDRESS: Cambridge Heart, Inc.
1 Oak Park Drive
Bedford, MA 01730
- -----------------------------------------------------------------------------------------
PROTOCOL IDENTIFICATION: Protocol 95-CH2000-3.1
- -----------------------------------------------------------------------------------------
REGULATORY STATUS: Non-significant-risk device CH 2000 510(k) Numbers
K950018 and K981697(pending); Hi-Res electrodes
K962115.,
- -----------------------------------------------------------------------------------------
STUDY INITIATION DATE: October 25, 1996 (First patient enrolled in Protocol
3.0)
- -----------------------------------------------------------------------------------------
STUDY COMPLETION DATE: Interim Report: Patients enrolled on or before
February 28, 1998; Follow-up data received as of June
30, 1998
- -----------------------------------------------------------------------------------------
INVESTIGATORS: Refer to Section 6 for a list of Investigators.
- -----------------------------------------------------------------------------------------
</TABLE>
<PAGE>
ii
<TABLE>
- -----------------------------------------------------------------------------------------
<S> <C>
SIGNATURES:
- -----------------------------------------------------------------------------------------
COMPLIANCE STATEMENT: This study was performed in compliance with Good
Clinical Practices (GCP).
- -----------------------------------------------------------------------------------------
DATE OF REPORT: August 20, 1998
- -----------------------------------------------------------------------------------------
</TABLE>
August 20, 1998
<PAGE>
iii
2. STUDY SYNOPSIS
<TABLE>
==========================================================================================================
<S> <C>
Title of Study: A 12 Month Follow-Up Study of Patients Enrolled in a Prospective Multi-Center Study To
Determine The Effectiveness Of T-Wave Alternans In Predicting Susceptibility To Ventricular Arrhythmias
==========================================================================================================
Investigators: Refer to Section 6 for a list of Investigators.
==========================================================================================================
Study Center(s): Refer to Section 6 for a list of study centers.
==========================================================================================================
Publication (reference): None.
==========================================================================================================
Studied period (years): 1 year, 8 months Regulatory status: Non-significant-risk
(date of first enrollment): 10/25/96 device: CH 2000 510(k) Numbers K950018 and
(date of last completed): Study is Ongoing K981697(pending); Hi-Res electrodes
K962115.
==========================================================================================================
Objectives: The objective of this study was to demonstrate that, in patients being evaluated for known,
suspected or risk of cardiac arrhythmias, the presence of T-wave alternans (TWA) measured during
exercise using the CH 2000 spectral method, was predictive of a spontaneous ventricular tachyarrhythmic
event (VTE). In addition, an analysis was performed of the ability of T-wave alternans to predict a
combined endpoint of VTE or death. Finally, an analysis was made of signal-averaged electrocardiogram
(SAECG) and EP study results with regard to their prediction of both endpoints: (1) VTE and (2) VTE or
death.
==========================================================================================================
Methodology: Follow-up of a prospective, multi-center, open-label, single-test comparison study
(95-CH2000-3.0).
==========================================================================================================
Number of patients (planned and analyzed): All patients enrolled in the Pilot and Main study of Study
95-CH2000-3.0 who were not in violation of that protocol, planned. 246 patients were included in the All
Patients Sample for this interim report; of these follow-up data was available for 201 patients.
==========================================================================================================
Diagnosis and main criteria for inclusion: Patients referred for electrophysiology (EP) testing for
evaluation of known, suspected or risk of cardiac arrhythmias, enrolled in Study 95-CH2000-3.0, (both
the Pilot and Main Study), who were not in violation of the protocol of that study are to be followed
for one year. This interim report includes only patients who were enrolled on or before February 28,
1998 and includes follow up data received as of June 30, 1998.
==========================================================================================================
</TABLE>
August 20, 1998
<PAGE>
iv
<TABLE>
==========================================================================================================
<S> <C>
Device serial number(s): 95016, 96024, 96035, 96036, 96052, 96058, 96059, 28030100, 28100146, 29010167
==========================================================================================================
Criteria for evaluation:
Efficacy: Efficacy was determined by the ability of each test to predict risk of ventricular
- --------
tachyarrhythmias as determined by the occurrence of a (1) VTE or of a (2) VTE or death.
Safety: Not applicable to this protocol. No procedures were performed for this study.
- ------
==========================================================================================================
Statistical methods: Demographic and baseline characteristics were analyzed using descriptive statistics
for all patients and all patients with follow-up data. Kaplan-Meier plots of event-free survival versus
of the number of days from the date of the TWA, SAECG or EP test were generated. Analysis of positive
versus negative TWA, SAECG, and EP findings for each endpoint type are presented. Endpoint types are:
(1) VTE and (2) VTE or Death.
==========================================================================================================
SUMMARY - CONCLUSIONS:
EFFICACY RESULTS: The primary null-hypothesis test was that the event-free survival (e.g., the absence
of an occurrence of a VTE) of patients with a negative TWA test result, and patients with a positive
TWA test result, were the same. This null hypothesis was formally tested using a two-sided log rank
statistic. The desired outcome (rejection of the null hypothesis in favor of the alternative
hypothesis) was that the event-free survival of patients with a negative TWA test result differed
from patients with a positive TWA test result. This outcome was achieved. The log rank test
statistic p-value for the test of the null hypothesis was 0.007, resulting in a rejection of the null
hypothesis.
TWA was substantially more predictive of a ventricular tachyarrhythmic event than was SAECG, as
evidenced by the relative risks of the tests (6.68 for TWA versus 2.57 for SAECG) and the log-rank
test statistic p-values comparing the positive and negative event-free survival findings, which were
statistically significant for TWA (p = 0.007) but not for SAECG (p = 0.092). TWA was also more
predictive of a ventricular tachyarrhythmic event or death than was SAECG, as evidenced by the
relative risks of the tests (10.99 for TWA versus 1.79 for SAECG) and the log-rank test statistic
p-values comparing the positive and negative event-free survival findings, which were
statistically significant for TWA (p less than 0.001) but not for SAECG (p = 0.220).
TWA was somewhat more predictive of a ventricular tachyarrhythmic event than was EP, as evidenced by
the relative risks of the tests (6.68 for TWA versus 4.90 for EP) and the log-rank test statistic
p-values comparing the positive and negative event-free survival findings, which were statistically
significant for both TWA (p = 0.007) and EP (p = 0.001). But, TWA was somewhat also more
predictive of a ventricular tachyarrhythmic event or death than was EP, as evidenced by the
relative risks of the tests (10.99 for TWA versus 3.12 for EP). The log-rank test statistic
p-values comparing the positive and negative event-free survival findings were statistically
significant for both TWA (p less than 0.001) and for EP (p = 0.006).
==========================================================================================================
</TABLE>
August 20, 1998
<PAGE>
v
<TABLE>
=========================================================================================================
<S> <C>
SAFETY RESULTS: Not applicable to this study.
- --------------
CONCLUSION: The results of this study indicated that, in this population, TWA was predictive of
risk of ventricular arrhythmias and/or death. TWA was substantially more predictive than SAECG
and was somewhat more predictive than EP.
Date of the report: August 20, 1998
==========================================================================================================
</TABLE>
August 20, 1998
<PAGE>
vi
3. TABLE OF CONTENTS
<TABLE>
<S> <C>
1. TITLE PAGE............................................................................ I
2. STUDY SYNOPSIS........................................................................ III
3. TABLE OF CONTENTS..................................................................... VI
4. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS........................................ IX
5. ETHICS................................................................................ 1
5.1. Institutional Review Board (IRB)...................................................... 1
5.2. Ethical review........................................................................ 1
5.3. Ethical conduct of the study.......................................................... 1
6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE...................................... 2
6.1. Investigators......................................................................... 2
6.2. Sponsor's study personnel............................................................. 3
7. INTRODUCTION.......................................................................... 3
7.1. Device information.................................................................... 3
7.1.1. The CH 2000........................................................................... 3
7.1.2. The HI RES(TM) ECG Electrode.......................................................... 3
7.2. Background............................................................................ 3
7.3. Prior Studies......................................................................... 4
7.4. Clinical Implications................................................................. 5
</TABLE>
August 20, 1998
<PAGE>
vii
<TABLE>
<S> <C>
8. STUDY OBJECTIVES...................................................................... 6
9. STUDY POPULATION...................................................................... 6
9.1. Inclusion Criteria.................................................................... 6
9.2. Exclusion Criteria.................................................................... 6
10. STUDY PROCEDURES...................................................................... 7
10.1. Follow-Up............................................................................. 7
10.2. Termination........................................................................... 7
10.3. Withdrawal Criteria................................................................... 7
11. EFFICACY AND SAFETY VARIABLES......................................................... 8
11.1. Efficacy and safety measurements assessed............................................. 8
11.2. Description of all efficacy variables................................................. 8
11.3. Description of all safety variables................................................... 8
11.4. Data Quality Assurance................................................................ 8
11.5. Statistical Methods And Determination Of Sample Size.................................. 8
11.5.1. Statistical and analytical plans...................................................... 8
11.5.2. Determination of sample size.......................................................... 10
11.5.3. Data management....................................................................... 11
11.6. Changes In The Conduct Of The Study Or Planned Analyses............................... 12
11.6.1. Changes in the Conduct of the Study................................................... 12
12. STUDY PATIENTS........................................................................ 12
12.1. Disposition Of Patients............................................................... 12
12.2. Protocol Deviations................................................................... 13
</TABLE>
August 20, 1998
<PAGE>
viii
<TABLE>
<S> <C>
13. EFFICACY EVALUATION................................................................... 13
13.1. Data Sets Analyzed.................................................................... 13
13.2. Demographic And Other Baseline Characteristics........................................ 13
13.3. Endpoint Events....................................................................... 20
13.3.1. TWA Testing: Ventricular Tachyarrhythmic Event....................................... 23
13.3.2. TWA Testing: Ventricular Tachyarrhythmic Event or Death.............................. 24
13.3.3. SAECG Testing: Ventricular Tachyarrhythmic Event..................................... 25
13.3.4. SAECG Testing: Ventricular Tachyarrhythmic Event or Death............................ 26
13.3.5. EP Testing: Ventricular Tachyarrhythmic Event........................................ 27
13.3.6. EP Testing: Ventricular Tachyarrhythmic Event or Death............................... 28
13.4. Efficacy conclusions.................................................................. 30
14. DISCUSSION AND OVERALL CONCLUSIONS.................................................... 31
</TABLE>
August 20, 1998
<PAGE>
ix
4. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
<TABLE>
<CAPTION>
TERM ABBREVIATION
<S> <C>
BPM Beats per minute
Congestive heart failure CHF
Coronary artery bypass graft CABG
Electrocardiogram ECG
Electrophysiology EP
Implantable cardioverter defibrillator ICD
Institutional review board IRB
New York Heart Association NYHA
Signal-averaged ECG SAECG
T-wave alternans TWA
Ventricular fibrillation VF
Ventricular tachycardia VT
Ventricular Tachyarrhythmic Event VTE
</TABLE>
August 20, 1998
<PAGE>
1
5. ETHICS
This was a non-significant-risk study involving no risk to the patients. There
were no procedures required for this study.
5.1. INSTITUTIONAL REVIEW BOARD (IRB)
This study was performed in accordance with the principals of the
Declaration of Helsinki and in accordance with 21 CFR 50 Protection of
Human Patients and 21 CFR 56 Institutional Review Boards.
Prior to initiating this study, the protocol and Informed Consent Form were
reviewed and approved by a properly constituted Institutional Review Board
(IRB). The Principal Investigator at each site submitted an application to
that site's IRB. The Principal Investigator at each site bore complete
responsibility for the conduct of the study at that site.
The opinions of the IRB were dated and given in writing. A list of those
present at the committee meeting (names and positions) was attached
whenever possible. It was the responsibility of the Investigator to forward
to Cambridge Heart before the initiation of the study a copy of the
approval from the IRB clearly identifying the protocol submitted for
review.
5.2. ETHICAL REVIEW
The Investigator was responsible for informing the IRB of any serious
adverse events, amendments to the protocol as well as notification of the
termination/completion of the study as per local requirements. All
correspondence with the committee was maintained by the Investigator.
5.3. ETHICAL CONDUCT OF THE STUDY
The conduct of the study was audited by the Sponsor for conformance with
the GCP guidance E6 released by FDA in April 1996.
August 20, 1998
<PAGE>
2
6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
6.1. INVESTIGATORS
The study was conducted by six Investigators at seven investigational
sites. All investigators contributed patients to this interim analysis.
<TABLE>
<CAPTION>
---------------------------------------------------------------------------
INVESTIGATOR SITE (NUMBER)
---------------------------------------------------------------------------
<S> <C>
Kelley P. Anderson, MD University of Pittsburgh Medical Center
200 Lothrup Street
Pittsburgh, PA 15213-2582 (21)
---------------------------------------------------------------------------
Daniel M. Bloomfield, MD Columbia Presbyterian Medical Center
Director, Syncope Center
Harkness Pavilion, Room 362
180 Ft. Washington Ave.
New York, NY 10032 (26)
---------------------------------------------------------------------------
Nabil El-Sherif, MD SUNY Health Sciences Center
Professor of Medicine and Physiology
Room B-2 325
Box 1199
450 Clarkston Ave.
Brooklyn, NY 11203 (12)
And
VA Medical Center
800 Poly Place
Brooklyn, NY 11209 (12)
---------------------------------------------------------------------------
Mark Estes, MD New England Medical Center
Director Cardiac Arrhythmia Service
NEMC 197
750 Washington St.
Boston, MA 02111 (11)
---------------------------------------------------------------------------
Michael R. Gold, MD, PhD University of Maryland Medical Center
(Principal Investigator) Director Cardiac Electrophysiology
Service
Room N3W79
22 South Greene Street
Baltimore, MD 21201-1595 (22)
---------------------------------------------------------------------------
David J. Wilber, MD University of Chicago Hospitals
Director, Electrophysiology
Department of Cardiology, MC09024
DCAM room 5734
Chicago, IL 60367 (27)
---------------------------------------------------------------------------
</TABLE>
August 20, 1998
<PAGE>
3
6.2. SPONSOR'S STUDY PERSONNEL
Jeffery Arnold, CEO, was the Sponsor's representative for the study.
7. INTRODUCTION
7.1. DEVICE INFORMATION
7.1.1. The CH 2000
The CH 2000 Cardiac Diagnostic System received FDA 510(k) clearance
on February 29, 1996 (510(k) Number K950018).
The CH 2000 is a computerized platform which supports a wide range
of standard stress test protocols as well as performing TWA
computation at rest, during exercise, pacing or pharmacologic
stress. TWA is computed by the spectral method as published by J.M.
Smith et al., Circulation 1988; 77:110-21. The CH 2000 meets the
standards for diagnostic electrocardiographic devices and where
applicable, for cardiac monitors, heart rate meters and alarms.
7.1.2. The HI RES(TM) ECG Electrode
The Hi Res(TM) ECG Electrode is manufactured by Cambridge Heart,
Inc. It received FDA 510(k) clearance on August, 29, 1996 (510(k)
Number K962115).
The Hi-Res(TM) ECG Electrode is a pregelled, single use, multi
segment, Silver/Silver Chloride electrode for short-term use to
measure ECG signals with the Cambridge Heart CH 2000 Stress Test
System.
7.2. BACKGROUND
Approximately 300,000 patients die each year of sudden cardiac death in the
United States alone. The proximate cause of death in the vast majority of
these cases is a ventricular rhythm disturbance. Patients known to be at
high risk for ventricular arrhythmias may be treated with various
modalities, including anti-arrhythmic drugs, placement of internal
defibrillators and/or ablation procedures, conducted in the catheterization
August 20, 1998
<PAGE>
4
laboratory or operating room, which attempt to selectively destroy cardiac
tissue to prevent arrhythmias.
The standard clinical technique for identifying individuals at risk for
ventricular arrhythmias is electrophysiology (EP) testing, an invasive
procedure in which catheter electrodes are placed into the patient's heart
and electrical impulses are delivered in a deliberate attempt to induce the
arrhythmias. Because EP testing is an expensive, invasive procedure which
involves significant risk to the patient, a variety of clinical data are
used to determine which patients should undergo EP testing.
One of the techniques used for this purpose is the signal-averaged
electrocardiogram (SAECG). The SAECG is a technique for measuring low
amplitude potentials in the ECG which are predictive of an individual's
risk of ventricular arrhythmias/1/. Recently, measurement of low levels of
repolarization or T-wave alternans (TWA) in the electrocardiogram (ECG),
during increased heart rate, has also been shown to be predictive of an
individual's risk of ventricular arrhythmias/2/.
In Rosenbaum et al., 1994, the heart rate of patients undergoing
electrophysiology study was raised by pacing the heart electrically in the
catheterization laboratory. Studies currently underway in Europe and the US
have indicated that the use of an exercise stress test as a noninvasive
means of raising the patients' heart rate is adequate to measure TWA levels
in patients scheduled to undergo EP testing. The current investigation uses
exercise as a non-invasive method of raising heart rate.
7.3. PRIOR STUDIES
A prior study was completed in the US to determine the value of TWA as a
predictor of risk of ventricular arrhythmias as determined by the results
of EP testing and to compare this predictive value to that of SAECG. TWA
was recorded during sinus rhythm and with the heart rate elevated
_________________________
/1/ M.E. Cain, J.L. Anderson, M F. Arnsdorf, J.W. Mason, M.M. Scheinman, A.L.
Waldo. ACC Expert Consensus Document, Signal-Averaged Electrocardiography,
JACC Vol. 27, No. l, 238-49, 1996
/2/ D.S. Rosenbaum, L.E. Jackson, J.M. Smith, H.G. Garan, J.N. Ruskin and R.J.
Cohen. Electrical Alternans and Vulnerability to Ventricular Arrhythmias,
New England Journal of Medicine, 330:235-24 l, 1994.
August 20, 1998
<PAGE>
5
by exercise./3/ TWA recordings were made at rest and during a bicycle
exercise protocol to maintain the heart rate at 100 beats per minute (BPM).
A total of 27 patients undergoing EP testing were included, based on their
ability to complete the exercise protocol. Results in this patient
population indicated that TWA had a sensitivity of 89% and specificity of
75%, and an overall clinical accuracy of 80% (P lesser than 0.003). TWA was
superior to SAECG which was not a statistically significant predictor in
this study.
A second study compared microvolt TWA to EP testing and to other currently
used noninvasive methods with respect to prediction of future ventricular
tachyarrhythmic events in 95 patients with a history of ventricular
tachyarrhythmias scheduled to undergo implantation of a
cardioverter/defibrillator./4/ In addition to TWA and EP testing, the
patients underwent determination of left ventricular ejection fraction,
baroreflex sensitivity, SAECG, analysis of 24-hour Holter monitoring for
heart rate variability and the presence of nonsustained ventricular
tachycardia (VT), and the measurement of QT dispersion from the 12-lead
ECG. The endpoint of the study was the first appropriate firing of a
cardioverter/defibrillator for ECG-documented ventricular fibrillation (VF)
or ventricular tachycardia during follow-up. Kaplan-Meier event-free
survival analysis revealed that only TWA (P lesser than 0.006) and left
ventricular ejection fraction (P lesser than 0.04) were statistically
significant risk stratifiers. Multivariate Cox regression analysis
suggested that TWA was the only statistically significant independent risk
factor.
7.4. CLINICAL IMPLICATIONS
Patients being evaluated for anti-arrhythmic therapy, either with drugs
such as sotalol, amiodarone or quinidine, or with the placement of
implantable cardioverter/defibrillators (ICDs) will most likely undergo an
EP study. Electrophysiology studies are expensive and present a significant
risk to patients. The process of determining which patients should undergo
these studies involves the evaluation of information from many sources,
including family history, the patient's medical history, results from ECGs,
tilt-table tests, exercise-tolerance tests and other tests
______________________
/3/ N.A.M. Estes, G. Michaud, D.P. Zipes, N. El-Sherif, F.J. Venditti, D.S.
Rosenbaum, P. Albrecht, P.J. Wang, R.J. Cohen. "Electrical Alternans During
Rest and Exercise as Predictors of Vulnerability to Ventricular
Arrhythmias". Am J Cardiol 1997;80:1314-1318.
/4/ S.A. Hohnoloser, T. Klingenheben, M. Zebel, J. Peetermans, R. Cohen. "T
Wave Alternans as a Toll for Risk Stratification in Patients with Malignant
Arrhythmias: Prospective Comparison with conventional Risk Markers".
Submitted for publication.
August 20, 1998
<PAGE>
6
that might be indicated. Even with all the information currently available,
many of those patients referred for EP studies (approximately 50% according
to Rosenbaum et al., 1994) will not be inducible in the laboratory.
TWA is predictive of increased risk of ventricular arrhythmias. As such it
is a valuable addition to the physicians' armamentarium to aid in
identifying those patients who will benefit from further diagnostic tests
or therapeutic interventions as well as those patients who may not benefit
from additional testing or interventions.
8. STUDY OBJECTIVES
The objective of this study was to demonstrate that, in patients being evaluated
for known, suspected or risk of cardiac arrhythmias, the presence of T-wave
alternans (TWA) measured during exercise using the CH 2000 spectral method, was
predictive of a spontaneous ventricular tachyarrhythmic event (VTE). In
addition, an analysis was performed of the ability of T-wave alternans to
predict a combined endpoint of VTE or death. Finally, an analysis was made of
signal-averaged electrocardiogram (SAECG) and EP study results with regard to
their prediction of both endpoint types: (1) VTE and (2) VTE or death.
All patients enrolled in protocol 95-CH2000-3.0 and all its amendments since
October 1996 and who were not in violation of the protocol of that study were
followed for 12 months under this protocol. This interim report includes
patients enrolled on or before February 28, 1998 and follow-up received on or
before June 30, 1998.
9. STUDY POPULATION
9.1. INCLUSION CRITERIA
The patient is enrolled in Protocol 95-CH2000-3.0 or one of its amendments.
9.2. EXCLUSION CRITERIA
The patient was enrolled in Protocol 95-CH2000-3.0 in violation of the
terms of that protocol.
August 20, 1998
<PAGE>
7
10. STUDY PROCEDURES
10.1. FOLLOW-UP
Follow-up was obtained from medical records, letters or telephone calls to
referring physicians or by direct contact with patients. Follow-up
information included a record of cardiac arrhythmias, syncopal episodes,
cardiac arrest, implantation of cardiac defibrillators or pacemakers,
modification of blocker or anti-arrhythmic medications, cardiac surgery,
revascularization procedures, myocardial infarction and death. No
additional testing was required. Classification of follow-up events was
made by the individual investigators and then reviewed by an Events
Committee consisting of two independent physicians who conferred and made
the final determination.
10.2. TERMINATION
The patient's participation in this study was completed when the 12-month
follow-up had been obtained or until the patient was withdrawn from the
study for any reason, was lost to follow-up, or experienced an event.
10.3. WITHDRAWAL CRITERIA
If a patient was withdrawn from the Protocol 95-CH2000-3.0 for any reason,
then that patient was not enrolled in this study. The reason for early
termination was recorded on the Protocol 95-CH2000-3.0 case report form. A
patient was withdrawn from the Protocol 95-CH2000-3.0 study for any of the
following reasons:
1. Death (prior to completion of all Protocol 95-CH2000-3.0 study
procedures)
2. Noncompliance or uncooperativeness
3. Patient request
4. Lost to Follow-up
5. Investigator's judgment that withdrawal was in the best interest of the
patient
6. Termination of the research by the sponsor
August 20, 1998
<PAGE>
8
11. EFFICACY AND SAFETY VARIABLES
11.1. EFFICACY AND SAFETY MEASUREMENTS ASSESSED
Follow-up was obtained from medical records, letters or telephone calls to
referring physicians or by direct contact with patients. Follow-up
information included a record of cardiac arrhythmias, syncopal episodes,
cardiac arrest, implantation of cardiac defibrillators or pacemakers,
modification of blocker or anti-arrhythmic medications, revascularization
procedures, cardiac surgery, myocardial infarction and death. No additional
testing was required.
11.2. DESCRIPTION OF ALL EFFICACY VARIABLES
The predictive value of TWA was determined by collecting information on
subsequent spontaneous ventricular tachyarrhythmic events and deaths.
11.3. DESCRIPTION OF ALL SAFETY VARIABLES
No procedures were performed in this study so no safety information was
collected.
11.4. DATA QUALITY ASSURANCE
Monitoring of patient enrollment data was performed as part of Protocol 95-
CH2000-3.0. Source documentation of events was reviewed by the Events
Committee.
11.5. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
11.5.1. Statistical and analytical plans
11.5.1.1. Variables
Baseline and demographic data for this study were collected
during the study conducted under Protocol 095-CH2000-3.0.
Demographic data presented included age, sex, height and
weight. Medical history data (e.g., coronary artery
disease, myocardial infarction, valvular heart disease,
etc.) are
August 20, 1998
<PAGE>
9
presented. Baseline physical findings of the index
arrhythmia, including ECG data, New York Heart Association
(NYHA) data, and ejection fraction data, are presented.
Endpoint event summary data findings included type of
endpoint event and censoring event category.
11.5.1.2. Analytical plan
Descriptive statistics were tabulated and presented for
data as follows: for continuous data, measures for central
tendency (mean, median, standard error of the mean, minima,
and maxima) are presented, while for categorical data, the
number and percent of patients within each category are
presented. For categorical data, only non-missing values
were used to calculate the percentages.
11.5.1.3. Handling of dropouts
Using Kaplan-Meier methodology, dropouts were included in
the analysis as appropriate.
11.5.1.4. Patient populations analyzed
There were two defined statistical populations in the
analysis:
1. The All Patients Sample, defined as patients who were
enrolled in Study 95-CH2000-3.0 (both the Pilot and
Main Study) on or before February 28, 1998, and who
were not in violation of the protocol of that study.
2. The Patients With Follow-up Sample, defined as patients
in the All Patients Sample for whom follow-up data are
not missing. Determination of follow-up was performed
as follows: Patients with less than 15 days of follow-
up for whom no endpoint events have occurred are
considered to have follow-up data missing.
11.5.1.5. Statistical methods
August 20, 1998
<PAGE>
10
Demographic and baseline characteristics were analyzed
using descriptive statistics for All Patients and All
Patients with Follow-up data. Kaplan-Meier plots of event-
free survival (to first endpoint event) versus of the
number of days from the date of the TWA, SAECG or EP test
were generated. Analysis of positive versus negative TWA,
SAECG, and EP findings for each type of endpoint are
presented. Endpoint types include (1) VTE and (2) VTE or
Death.
For the endpoint of VTE, follow-up data were censored upon
the occurrence of cardiac surgery other than CABG,
myocardial infarction, or initiation or discontinuation of
antiarrhythmic drugs (Vaughn Williams Class I or III). For
the endpoint of VTE or Death, no censoring was applied.
The total number of events of each type are presented, as
well as the relative risk and a two-sided log-rank p-value
testing the equivalence of the positive and negative
findings for each of the tests. Statistical significance
was declared at the alpha = 0.05 level.
All data used in the Kaplan-Meier plots are presented in
data listings.
11.5.2. Determination of sample size
The primary hypotheses was that, in the population being studied,
the presence of TWA measured during exercise is predictive of
subsequent ventricular arrhythmic events. The sample size required
was calculated to address issues related to this hypothesis stated
as:
H\0\: Event-free survival rate of TWA+ = event-free survival rate
of TWA-
H\1\: Event-free survival rate of TWA+ not equal to event-free
survival rate of TWA-
Where H\0\ is the null hypothesis being tested and H\1\ is the
alternative. The Fisher's Exact Test/5/ the Kaplan-Meier life table
analysis, and a log-rank statistic were used to test this
hypothesis.
The minimum sample size for this study was determined as follows:
August 20, 1998
<PAGE>
11
From Rosenbaum et al/6/ we estimated that at one year in this
population the event-free survival rate of TWA+ patients and TWA-
patients would be 60% and 95% respectively.
From Fleiss, pg. 41, the sample size required to provide 80% power
to reject the null hypothesis H\0\ at the p less than 0.05 level
was calculated as:
[CALULATION FORMULA APPEARS HERE]
where:
[CALULATION FORMULA APPEARS HERE]
P\1\ = 0.95 is the one year event-free survival rate for TWA-
Q\1\ = 0.05 is the one year event rate for TWA-
P\2\ = 0.60 is the one year event-free survival for TWA+
Q\2\ = 0.40 is the one year event rate for TWA+
P = 0.775 is the overall mean one year event-free survival rate
Q = 0.225 is the overall mean one year event rate
C\a/2\\ = 1.645 is the Z score for alpha less than 0.05 (single
sided)
C\/1-\b\ = 0.842 is the Z score for power = 80%
Solving for n, the required sample size was 39 evaluated patients
per group (total 78 patients). The expected determinate rate for TWA
studies was 80%. Therefore it was expected that approximately 100
patients would have to be enrolled.
11.5.3. Data management
All data captured on the Events Summary Form was double-key entered
into a Microsoft ACCESS database using a validated data management
system. Verification was performed by comparing the two passes of
data entry and resolving any differences.
11.6. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES
Two amendments were made to the clinical protocol. The following is a
summary of the changes resulting from each amendment. Both amendments were
implemented prior to collection of follow-up data for the first patient in
the study.
August 20, 1998
<PAGE>
12
11.6.1. Changes in the Conduct of the Study
11.6.1.1. Amendment 1: March 6, 1998
The purpose of this amendment was to add a more precise
definition of endpoint events, and the statement that
classification of follow-up events were made by the
individual investigators and reviewed by an independent
physician. (In actuality, at the request of the independent
physician, a second independent physician was added. These
two are referred to as the Events Committee.)
11.6.1.2. Amendment 2: March 25, 1998
The purpose of this amendment was to add an exclusion
criterion: patients who were enrolled in Protocol
95-CH2000-3.0 in violation of the terms of that protocol
were excluded from this study.
12. STUDY PATIENTS
12.1. DISPOSITION OF PATIENTS
A total of 246 patients from Study 95-CH200-3.0 (both the Pilot Study and
the Main Study) were enrolled in the study by six investigators at seven
sites (one investigator was affiliated with two sites). Of these, 201
(81.7%) had follow-up data. The mean number of days of follow-up was 257.6
(ranging from 18 to 521 days). Table 1 presents the number of patients in
the study.
August 20, 1998
<PAGE>
13
TABLE 1. PATIENT DISPOSITION
<TABLE>
<CAPTION>
---------------------------------------------------------------------------
Number of Percent of
Patients Patients
---------------------------------------------------------------------------
<S> <C> <C>
All Patients/a/ 246 100.0
---------------------------------------------------------------------------
All Patients with Follow-up Sample/b/ 201 81.7
---------------------------------------------------------------------------
Duration of Follow-up (days)
---------------------------------------------------------------------------
N 201
---------------------------------------------------------------------------
Mean 257.6
---------------------------------------------------------------------------
Median 264
---------------------------------------------------------------------------
Std. Dev. 116.4
---------------------------------------------------------------------------
Minimum 18
---------------------------------------------------------------------------
Maximum 521
---------------------------------------------------------------------------
</TABLE>
/a/ Includes all patients from the 95-CH2000-3.0 study, who were not in
violation of the protocol, and for whom the first procedure in the 95-
CH2000-3.0 study was prior to February 28, 1998.
/b/ Includes those in the All Patients Sample who had follow-up data.
Source: Appendix VI, Table 1.1.
12.2. PROTOCOL DEVIATIONS
No significant protocol deviations occurred during this study.
13. EFFICACY EVALUATION
13.1. DATA SETS ANALYZED
13.2. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Data used for this analysis were collected during Study 95-CH2000-3.0.
Table 2 presents demographic and baseline characteristics for both samples
at screening during Study 95-CH2000-3.0. Patients who had
August 20, 1998
<PAGE>
14
follow-up data (those patients included in the All Patients With Follow-up
Sample) were representative of those included in the All Patients Sample.
There were no clinically significant differences between the two sample
populations with respect to any of these variables. Mean age was
approximately 56 years, mean height was approximately 68 inches, and mean
weight was approximately 175 pounds. Similar proportions of males and
females were included in both the All Patients and the All Patients With
Follow-up samples.
August 20, 1998
<PAGE>
15
TABLE 2. DEMOGRAPHICS
<TABLE>
<CAPTION>
---------------------------------------------------------------------------
ALL PATIENTS ALL PATIENTS WITH FOLLOW-UP
(N = 246) (N = 201)
---------------------------------------------------------------------------
N % N %
---------------------------------------------------------------------------
<S> <C> <C> <C> <C>
Age (years)
---------------------------------------------------------------------------
N 245 201
---------------------------------------------------------------------------
Mean 56.1 56.1
---------------------------------------------------------------------------
Median 57 57
---------------------------------------------------------------------------
Std. Dev. 15.5 15.4
---------------------------------------------------------------------------
Minimum 18 18
---------------------------------------------------------------------------
Maximum 86 86
---------------------------------------------------------------------------
Sex
---------------------------------------------------------------------------
Male 158 64.2 126 62.7
---------------------------------------------------------------------------
Female 88 35.8 75 37.3
---------------------------------------------------------------------------
Height (inches)
---------------------------------------------------------------------------
N 244 199
---------------------------------------------------------------------------
Mean 67.9 67.9
---------------------------------------------------------------------------
Median 68 68
---------------------------------------------------------------------------
Std. Dev. 3.9 3.8
---------------------------------------------------------------------------
Minimum 59 59
---------------------------------------------------------------------------
Maximum 82 82
---------------------------------------------------------------------------
Weight (pounds)
---------------------------------------------------------------------------
N 244 201
---------------------------------------------------------------------------
Mean 177.7 173.9
---------------------------------------------------------------------------
Median 174 171
---------------------------------------------------------------------------
Std. Dev. 40.9 39.9
---------------------------------------------------------------------------
Minimum 97 97
---------------------------------------------------------------------------
Maximum 298 298
---------------------------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 2.0.
August 20, 1998
<PAGE>
16
Table 3 presents medical history reported by the patients at screening
during Study 95-CH2000-3.0. Again, there were no clinically significant
differences between the two sample populations, and thus the patients with
follow-up data were representative of all the patients included in the
study.
TABLE 3 MEDICAL HISTORY
<TABLE>
<CAPTION>
----------------------------------------------------------------------
All Patients All Patients with Follow-up
(N = 246) (N = 201)
----------------------------------------------------------------------
Event N % N %
----------------------------------------------------------------------
<S> <C> <C> <C> <C>
Total Coronary Artery 116 47.2 96 47.8
Disease
----------------------------------------------------------------------
Coronary Artery 102 41.5 84 41.8
Disease
----------------------------------------------------------------------
Myocardial 85 34.6 71 35.3
Infarction
----------------------------------------------------------------------
DCM, Ischemic 43 17.5 33 16.4
----------------------------------------------------------------------
DCM, Non Ischemic 18 7.3 12 6.0
----------------------------------------------------------------------
Valvular Heart Disease 30 12.2 26 12.9
----------------------------------------------------------------------
Other Structural Cardiac 9 3.7 6 3.0
Abnormality
----------------------------------------------------------------------
Cardiac Arrest 7 2.8 7 3.5
----------------------------------------------------------------------
Revascularization, 17 6.9 14 7.0
PTCA
----------------------------------------------------------------------
Revascularization, 34 13.8 29 14.4
CABG
----------------------------------------------------------------------
Other Cardiac 144 58.5 114 56.7
----------------------------------------------------------------------
Diabetes 43 17.5 34 16.9
----------------------------------------------------------------------
Other Non Cardiac 150 61.0 119 59.2
----------------------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 3.0.
August 20, 1998
<PAGE>
17
Table 4 presents the counts of cardiovascular Index Events for patients in
both samples. (The Index Event was the cardiovascular arrhythmia or symptom
that led to referral for EP study.) Again, there were no clinically
significant differences between the sample populations, and the patients
with follow-up data were representative of all the patients included in the
study. For both samples, the most frequently reported arrhythmia was
suspected VT (38%), and the most frequently reported symptom was syncope
(36%).
TABLE 4. INDEX EVENT
<TABLE>
<CAPTION>
-------------------------------------------------------------------
All Patients All Patients with Follow-up
(N = 246) (N = 201)
-------------------------------------------------------------------
N % N %
-------------------------------------------------------------------
<S> <C> <C> <C> <C>
Arrhythmia
-------------------------------------------------------------------
Documented VF 6 2.4 4 2.0
-------------------------------------------------------------------
Suspected VF 9 3.7 9 4.5
-------------------------------------------------------------------
Documented VT 35 14.3 28 14.0
-------------------------------------------------------------------
Suspected VT 96 39.2 76 38.0
-------------------------------------------------------------------
Documented SVT 37 15.1 33 16.5
-------------------------------------------------------------------
Suspected SVT 36 14.7 27 13.5
-------------------------------------------------------------------
Other 26 10.6 23 11.5
-------------------------------------------------------------------
Missing 1 1
-------------------------------------------------------------------
Symptoms
-------------------------------------------------------------------
Asymptomatic 24 9.8 19 9.5
-------------------------------------------------------------------
Cardiac Arrest 11 4.5 10 5.0
-------------------------------------------------------------------
Syncope (LOC) 87 35.5 71 35.5
-------------------------------------------------------------------
Pre-Syncope 79 32.2 59 29.5
(light-headedness)
-------------------------------------------------------------------
Other 44 18.0 41 20.5
-------------------------------------------------------------------
Missing 1 1
-------------------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 4.1.
August 20, 1998
<PAGE>
18
Table 5 presents ECG information reported by the patients at screening
during Study 95-CH2000-3.0. There were no clinically significant
differences between populations, and the patients with follow-up data were
representative of all the patients included in the study. Ninety-seven
percent of patients had sinus rhythm at baseline, and 70% of the patients
had no intraventricular conduction defect at baseline. The ventricular rate
averaged approximately 79 beats per minute.
TABLE 5. BASELINE ELECTROCARDIOGRAM: ALL PATIENTS
<TABLE>
<CAPTION>
--------------------------------------------------------------------
All Patients All Patients with Follow-up
(N = 246) (N = 201)
--------------------------------------------------------------------
N % N %
--------------------------------------------------------------------
<S> <C> <C> <C> <C>
Baseline ECG Rhythm
--------------------------------------------------------------------
Sinus 239 97.6 195 97.5
--------------------------------------------------------------------
Other 6 2.4 5 2.5
--------------------------------------------------------------------
Missing 1 1
--------------------------------------------------------------------
Intraventricular
Conduction Defect
--------------------------------------------------------------------
None 174 70.6 140 70.0
--------------------------------------------------------------------
RBBB Complete 11 4.7 10 5.0
--------------------------------------------------------------------
RBBB 13 5.5 11 5.5
Incomplete
--------------------------------------------------------------------
LBBB Complete 19 7.5 13 6.5
--------------------------------------------------------------------
LBBB 7 3.1 7 3.5
Incomplete
--------------------------------------------------------------------
Left Anterior 4 1.6 4 2.0
Hemiblock
--------------------------------------------------------------------
Left Posterior 0 0 0 0
Hemiblock
--------------------------------------------------------------------
Other 17 7.1 15 7.5
--------------------------------------------------------------------
Missing 1 1
--------------------------------------------------------------------
Ventricular Rate (bpm)
--------------------------------------------------------------------
N 243 199
--------------------------------------------------------------------
Mean 78.3 78.9
--------------------------------------------------------------------
Median 76 76
--------------------------------------------------------------------
Std. Dev. 18.4 18.9
--------------------------------------------------------------------
Minimum 44 44
--------------------------------------------------------------------
Maximum 188 188
--------------------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 4.2.
August 20, 1998
<PAGE>
19
Table 6 presents NYHA functional classifications and ejection fraction at
baseline for patients in both samples. There were no clinically significant
differences between the two sample populations.
TABLE 6. NYHA FUNCTIONAL CLASS AND EJECTION FRACTION AT BASELINE: ALL
PATIENTS
<TABLE>
<CAPTION>
-----------------------------------------------------------
All Patients All Patients with
(N = 246) Follow-up
(N = 201)
-----------------------------------------------------------
N % N %
-----------------------------------------------------------
<S> <C> <C> <C> <C>
NYHA Functional Class
-----------------------------------------------------------
I 164 67.2 135 67.5
-----------------------------------------------------------
II 50 20.5 38 19.0
-----------------------------------------------------------
III 28 11.5 25 12.5
-----------------------------------------------------------
IV 2 0.8 2 1
-----------------------------------------------------------
Missing 2 1
-----------------------------------------------------------
Ejection Fraction (%)
-----------------------------------------------------------
N 158 131
-----------------------------------------------------------
Mean 39.9 40.3
-----------------------------------------------------------
Median 36 38
-----------------------------------------------------------
Std. Dev. 19.2 19.2
-----------------------------------------------------------
Minimum 4 4
-----------------------------------------------------------
Maximum 99 99
-----------------------------------------------------------
Method of Ejection
Fraction Determination
-----------------------------------------------------------
Radionuclide 12 5.3 11 5.8
Ventriculogram
-----------------------------------------------------------
Contrast 32 14.1 26 13.8
Ventriculography
-----------------------------------------------------------
Echocardiogram 162 71.4 133 70.4
-----------------------------------------------------------
Other 11 4.8 10 5.4
-----------------------------------------------------------
Unknown 10 4.4 9 4.8
-----------------------------------------------------------
Missing 19 12
-----------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 4.3.
August 20, 1998
<PAGE>
20
13.3. ENDPOINT EVENTS
Table 7 presents all patients with follow-up data who had an endpoint event
(N = 201). A total of ten patients died -- four from a fatal VTE (sudden
death), two resulting from a non-VTE cardiac event, and four from a non-
cardiac or unknown cause. A total of 17 cases of VTE occurred (13 of these
were non-fatal).
TABLE 7. ENDPOINT EVENTS
<TABLE>
<CAPTION>
--------------------------------------------------------
ALL PATIENTS WITH FOLLOW-UP
--------------------------------------------------------
N %
--------------------------------------------------------
<S> <C> <C>
End-Point Event 21 10.5
--------------------------------------------------------
Non-Fatal VTE 13
--------------------------------------------------------
Fatal VTE 4
--------------------------------------------------------
Total VTE 17
--------------------------------------------------------
Non-VTE Cardiac Death 2
Other Death 4
--------------------------------------------------------
</TABLE>
Source: Appendix VI, Table 5.0.
August 20, 1998
<PAGE>
21
For the endpoint of VTE, follow-up was terminated upon the occurrence of a
censoring event. Table 8 presents censoring event categories for those
patients with censoring events. Twenty-four (12%) of the patients in the
All Patients Sample experienced a censoring event; 22 (11%) patients in the
follow-up sample experienced a censoring event (two patients in the All
Patients Sample had a change in anti-arrhythmic medications within 15 days
of their EP test, and did not have additional follow-up. Thus, these two
patients are not included in the All Patients with Follow-up Sample.) Both
samples had 166 (83%) patients with no censoring event. The most frequent
censoring event was a change in anti-arrhythmic medications (10% of the All
Patients with Follow-up Sample), while one patient had cardiac surgery and
two had cardiac transplants.
TABLE 8. CENSORING EVENT CATEGORIES
<TABLE>
<CAPTION>
---------------------------------------------------------------------------
ALL PATIENTS ALL PATIENTS WITH FOLLOW-UP
(N = 246) (N = 201)
---------------------------------------------------------------------------
<S> <C> <C> <C> <C>
Censoring Event 24 12.0 22 11.0
---------------------------------------------------------------------------
Change in Anti-Arrhythmic 22 12.0 20 10.0
---------------------------------------------------------------------------
Drugs
---------------------------------------------------------------------------
Cardiac Surgery (other than 1 0.5 1 0.5
CABG or transplant)
---------------------------------------------------------------------------
New Myocardial Infarction 0 0 0 0
---------------------------------------------------------------------------
Cardiac Transplant 2 1.0 2 1.0
---------------------------------------------------------------------------
No Event 166 83.0 166 83.0
Missing 45 0
---------------------------------------------------------------------------
</TABLE>
A patient may have had more than one censoring event. Refer to Tables 6.1-
8.2 for listings including patient censoring event information.
Source: Appendix VI, Table 5.0.
Figures 1.1 through 3.2 present Kaplan Meier curves of positive versus
negative findings for TWA, SAECG, and EP testing, while Appendix Tables
6.1-8.2 present the patient data used to construct the curves. As follow-up
data were necessary to perform these analyses, the All Patients With
Follow-up sample was used for all Kaplan Meier curves and subsequent event-
free survival analyses. In addition, each patient with determinate test
findings (e.g., a positive or negative finding) in a test (TWA, SAECG, or
EP) was included in the analysis of that test, regardless of whether the
patient had determinate findings in the other
August 20, 1998
<PAGE>
22
two tests. Patients were censored by the following events: cardiac surgery
other than CABG, myocardial infarction, and initiation or discontinuation
of antiarrhythmic drugs. While there were 19 patients with more than 400
days of follow-up, none of these patients had an event after the 400/th/
day of follow-up. Thus, the Kaplan Meier curves were determined using up to
the first 400 days of follow-up for each patient. Event-free survival and
relative risk were computed at the 400 day time point. Results are
presented for VTE, and VTE or death for each of TWA, SAECG and EP testing.
Note that the y-axis of the Kaplan Meier curves, labeled as the "survival
distribution function", indicates the probability of event-free survival at
a given timepoint.
Table 9 below summarizes the number of events, the relative risk, the
probability of event-free survival for those with positive and negative
findings, and the log rank test statistic p-values, testing that the
probability of event-free survival for patients with positive and negative
test findings are the same, for the TWA, SAECG, and EP tests.
TABLE 9. SUMMARY OF EVENT-FREE SURVIVAL ANALYSIS FINDINGS FOR TWA, SAECG,
AND EP TESTS
<TABLE>
<CAPTION>
------------------------------------------------------------------------------------------------------------
NUMBER RELATIVE LOG-RANK PROBABILITY PROBABILITY
OF RISK P-VALUE OF SURVIVAL OF SURVIVAL
EVENTS (POSITIVE) (NEGATIVE)
------------------------------------------------------------------------------------------------------------
FIRST
VENTRICULAR TACHYARRHYTHMIC EVENT
------------------------------------------------------------------------------------------------------------
<S> <C> <C> <C> <C> <C>
TWA 9 6.68 0.007 0.8380 0.9758
------------------------------------------------------------------------------------------------------------
SAECG 11 2.57 0.092 0.8414 0.9384
------------------------------------------------------------------------------------------------------------
EP 13 4.9 0.001 0.7911 0.9574
------------------------------------------------------------------------------------------------------------
FIRST
VENTRICULAR TACHYARRHYTHMIC EVENT OR DEATH
------------------------------------------------------------------------------------------------------------
TWA 12 10.99 0.001 0.7460 0.9769
------------------------------------------------------------------------------------------------------------
SAECG 13 1.79 0.220 0.8498 0.9162
------------------------------------------------------------------------------------------------------------
EP 17 3.12 0.006 0.7676 0.9255
------------------------------------------------------------------------------------------------------------
</TABLE>
Source: Appendix VI, Figures 1.1 to 3.2.
August 20, 1998
<PAGE>
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13.3.1. TWA Testing: Ventricular Tachyarrhythmic Event
There were 9 patients with follow-up data who had a determinate TWA
test finding and experienced a ventricular tachyarrhythmic event. The
relative risk of experiencing an event for those with a positive TWA
test result compared to those with a negative TWA test result was
6.68, indicating that those with a positive TWA test result were more
than six times more likely to experience a ventricular tachyarrhythmic
event than those with a negative TWA test result. The probability of
not experiencing a ventricular tachyarrhythmic event for those with a
positive TWA test result was 0.8380, while the probability of not
experiencing a ventricular tachyarrhythmic event for those with a
negative TWA test result was 0.9758, indicating that those with a
positive TWA test result were more likely to experience an event than
those with a negative test result.
The null hypothesis that the event-free survival (e.g., the absence of
an occurrence of a ventricular tachyarrhythmic event) of those
patients with a negative TWA test result and those patients with a
positive TWA test results were the same, was formally tested using a
two-sided log rank statistic. The desired outcome was a rejection of
the null hypothesis in favor of the alternative hypothesis that the
event-free survival of those patients with a negative TWA test result
differed from those patients with a positive TWA test result.
The log rank test statistic p-value for the test of the null
hypothesis was 0.007, resulting in a rejection of the null hypothesis.
Thus, the event-free survival (e.g., the absence of an occurrence of a
ventricular tachyarrhythmic event) of those patients with a negative
TWA test result differed from those patients with a positive TWA test
result.
Figure 1 below presents the Kaplan Meier curves of positive and
negative TWA for first ventricular tachyarrhythmic event in the All
Patients With Follow-up Sample.
August 20, 1998
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24
[CHART APPEARS HERE]
FIGURE 1. KAPLAN MEIER CURVES OF EVENT-FREE SURVIVAL FOR TWA TEST
RESULTS: FIRST VENTRICULAR TACHYARRHYTHMIC EVENT
13.3.2. TWA Testing: Ventricular Tachyarrhythmic Event or Death
There were 12 patients with follow-up data who had a determinate TWA
test finding and experienced either a ventricular tachyarrhythmic
event or death. The relative risk of experiencing an event for those
with a positive TWA test result compared to those with a negative TWA
test result was 10.99, indicating that those with a positive TWA test
result were almost eleven times more likely to experience a
ventricular tachyarrhythmic event or death than those with a negative
TWA test result. The probability of not experiencing a ventricular
tachyarrhythmic event or death for those with a positive TWA test
result was 0.7460, while the probability of not experiencing a
ventricular tachyarrhythmic event or death for those with a negative
TWA test result was 0.9769, indicating that those with a positive TWA
test result were more likely to experience an event than those with a
negative test result.
The null hypothesis that the event-free survival (e.g., the absence of
an occurrence of a ventricular tachyarrhythmic event or death) of
those patients with a negative TWA test result and those patients with
a positive TWA test results are the same, was formally tested using a
two-sided log rank statistic. The desired outcome was a rejection of
the null hypothesis in favor of the alternative hypothesis that the
event-free survival of those patients with a negative TWA test result
differed from those patients with a positive TWA test result.
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25
The log rank test statistic p-value for the test of the null
hypothesis was less than 0.001, resulting in a rejection of the null
hypothesis. Thus, the event-free survival (e.g., the absence of an
occurrence of a ventricular tachyarrhythmic event or death) of those
patients with a negative TWA test result differed from those patients
with a positive TWA test result.
Figure 2 below presents the Kaplan Meier curves of positive and
negative TWA for the first ventricular tachyarrhythmic event or death
in the All Patients With Follow-up Sample.
[CHART APPEARS HERE]
FIGURE 2. KAPLAN MEIER CURVES OF EVENT-FREE SURVIVAL FOR TWA TEST
RESULTS: FIRST VENTRICULAR TACHYARRHYTHMIC EVENT OR DEATH
13.3.3. SAECG Testing: Ventricular Tachyarrhythmic Event
There were 11 patients with follow-up that had a determinate SAECG
test finding and experienced a ventricular tachyarrhythmic event. The
relative risk of experiencing an event for those with a positive SAECG
test result compared to those with a negative SAECG test result was
2.57, indicating that those with a positive SAECG test result were
more than two and a half times more likely to experience a ventricular
tachyarrhythmic event than those with a negative SAECG test result.
The probability of not experiencing a ventricular tachyarrhythmic
event for those with a positive SAECG test result was 0.8414, while
the probability of not experiencing a ventricular tachyarrhythmic
event for those with a negative SAECG test result was 0.9384,
indicating that those with a positive SAECG test result were more
likely to experience an event than those with a negative test result.
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26
The null hypothesis that the event-free survival (e.g., the absence of
an occurrence of a ventricular tachyarrhythmic event) of those
patients with a negative SAECG test result and those patients with a
positive SAECG test results were the same, was formally tested using a
two-sided log rank statistic.
The log rank test statistic p-value for the test of the null
hypothesis was 0.092, resulting in failure to reject the null
hypothesis. Thus, there was no statistical evidence that the event-
free survival (e.g., the absence of an occurrence of a ventricular
tachyarrhythmic event) of those patients with a negative SAECG test
result differed from those patients with a positive SAECG test result.
Figure 3 below presents the Kaplan Meier curves of positive and
negative SAECG findings for first ventricular tachyarrhythmic event
endpoint in the All Patients With Follow-up Sample.
[CHART APPEARS HERE]
FIGURE 3. KAPLAN MEIER CURVES OF EVENT-FREE SURVIVAL FOR SAECG
TEST RESULTS: FIRST VENTRICULAR TACHYARRHYTHMIC EVENT
13.3.4. SAECG Testing: Ventricular Tachyarrhythmic Event or Death
There were 13 patients with follow-up data who had a determinate SAECG
test finding and experienced either a ventricular tachyarrhythmic
event or death. The relative risk of experiencing an event for those
with a positive SAECG test result compared to those with a negative
SAECG test result was 1.79, indicating that those with a positive
SAECG test result were less than two times more likely to experience a
ventricular tachyarrhythmic event than those with a negative SAECG
test result. The probability of not
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27
experiencing a ventricular tachyarrhythmic event or death for those
with a positive SAECG test result was 0.8498, while the probability of
not experiencing a ventricular tachyarrhythmic event or death for
those with a negative SAECG test result was 0.9162, indicating that
those with a positive SAECG test result were more likely to experience
an event than those with a negative test result.
The null hypothesis that the event-free survival (e.g., the absence of
an occurrence of a ventricular tachyarrhythmic event or death) of
those patients with a negative SAECG test result and those patients
with a positive SAECG test results were the same, was formally tested
using a two-sided log rank statistic.
The log rank test statistic p-value for the test of the null
hypothesis was 0.220, resulting in a failure to reject the null
hypothesis. Thus, there was no statistical evidence that the event-
free survival (e.g., the absence of an occurrence of a ventricular
tachyarrhythmic event or death) of those patients with a negative
SAECG test result differed from those patients with a positive SAECG
test result.
Figure 4 below presents the Kaplan Meier curves of positive and
negative SAECG for first ventricular tachyarrhythmic event or death
endpoint in the All Patients With Follow-up Sample.
[CHART APPEARS HERE]
FIGURE 4. KAPLAN MEIER CURVES OF EVENT-FREE SURVIVAL FOR SAECG
TEST RESULTS: FIRST VENTRICULAR TACHYARRHYTHMIC EVENT OR DEATH
13.3.5. EP Testing: Ventricular Tachyarrhythmic Event
There were 13 patients with follow-up who had a determinate EP test
finding and experienced a ventricular tachyarrhythmic event. The
relative risk of experiencing an event for those with a positive
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28
EP test result compared to those with a negative EP test result was
4.90, indicating that those with a positive EP test result were almost
five times more likely to experience a ventricular tachyarrhythmic
event than those with a negative EP test result. The probability of
not experiencing a ventricular tachyarrhythmic event for those with a
positive EP test result was 0.7911, while the probability of not
experiencing a ventricular tachyarrhythmic event for those with a
negative EP test result was 0.9574, indicating that those with a
positive EP test result were more likely to experience an event than
those with a negative test result.
The null hypothesis that the event-free survival (e.g., the absence of
an occurrence of a ventricular tachyarrhythmic event) of those
patients with a negative EP test result and those patients with a
positive EP test results are the same, was formally tested using a
two-sided log rank statistic.
The log rank test statistic p-value for the test of the null
hypothesis was 0.001, resulting in a rejection of the null hypothesis.
Thus, the event-free survival (e.g., the absence of an occurrence of a
ventricular tachyarrhythmic event) of those patients with a negative
EP test result is not the same as those patients with a positive EP
test result.
Figure 5 below presents the Kaplan Meier curves of positive and
negative EP findings for first ventricular tachyarrhythmic event
endpoint in the All Patients With Follow-up Sample.
[CHART APPEARS HERE]
FIGURE 5. KAPLAN MEIER CURVES OF EVENT-FREE SURVIVAL FOR EP TEST
RESULTS: FIRST VENTRICULAR TACHYARRHYTHMIC EVENT
13.3.6. EP Testing: Ventricular Tachyarrhythmic Event or Death
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29
There were 17 patients with follow-up data who had a determinate EP
test finding and experienced either a ventricular tachyarrhythmic
event or death. The relative risk of experiencing an event for those
with a positive EP test result compared to those with a negative EP
test result was 3.12, indicating that those with a positive EP test
result were more than three times more likely to experience a
ventricular tachyarrhythmic event than those with a negative EP test
result. The probability of not experiencing a ventricular
tachyarrhythmic event or death for those with a positive EP test
result was 0.7676, while the probability of not experiencing a
ventricular tachyarrhythmic event or death for those with a negative
EP test result was 0.9255, indicating that those with a positive EP
test result were more likely to experience an event than those with a
negative test result.
The null hypothesis that the event-free survival (e.g., the absence of
an occurrence of a ventricular tachyarrhythmic event or death) of
those patients with a negative EP test result and those patients with
a positive EP test results were the same, was formally tested using a
two-sided log rank statistic.
The log rank test statistic p-value for the test of the null
hypothesis was 0.006, resulting in a rejection of the null hypothesis.
Thus, the event-free survival (e.g., the absence of an occurrence of a
ventricular tachyarrhythmic event or death) of those patients with a
negative EP test result differed from those patients with a positive
EP test result.
Figure 6 below presents the Kaplan Meier curves of positive and
negative EP findings for the first ventricular tachyarrhythmic event
or death endpoint in the All Patients With Follow-up Sample.
[CHART APPEARS HERE]
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30
FIGURE 6. KAPLAN MEIER CURVES OF EVENT-FREE SURVIVAL FOR EP TEST
RESULTS: FIRST VENTRICULAR TACHYARRHYTHMIC EVENT OR DEATH
13.4. EFFICACY CONCLUSIONS
The primary objective of this study was to demonstrate that the presence of
T wave Alternans was predictive of spontaneous ventricular tachyarrhythmic
events. The null hypothesis tested was that the event-free survival (e.g.,
the absence of an occurrence of a ventricular tachyarrhythmic event) of
those patients with a negative TWA test result and those patients with a
positive TWA test results were the same. This null hypothesis was formally
tested using a two-sided log rank statistic. The desired outcome, rejection
of the null hypothesis in favor of the alternative hypothesis, was that
event-free survival of patients with a negative TWA test result differed
from patients with a positive TWA test result. This outcome was achieved.
The log rank test statistic p-value for the test of the null hypothesis was
0.007, resulting in a rejection of the null hypothesis. Thus, the presence
of a negative TWA test result was predictive of spontaneous ventricular
tachyarrhythmic events.
In addition to testing the primary objective as noted above, testing was
performed to demonstrate that the presence of T wave Alternans was
predictive of a spontaneous ventricular tachyarrhythmic event or death. The
null hypothesis test was that the event-free survival (e.g., the absence of
an occurrence of a ventricular tachyarrhythmic event or death) of those
patients with a negative TWA test result and those patients with a positive
TWA test results are the same. This null hypothesis was formally tested
using a two-sided log rank statistic. The desired outcome, rejection of the
null hypothesis in favor of the alternative hypothesis that the event-free
survival of those patients with a negative TWA test result differed from
those patients with a positive TWA test result, was achieved. The log rank
test statistic p-value for the test of the null hypothesis was less than
0.001, resulting in a rejection of the null hypothesis. Thus, the presence
of a positive TWA test result was predictive of spontaneous ventricular
tachyarrhythmic events alone, and the presence of a positive TWA test
result was also predictive of spontaneous ventricular tachyarrhythmic event
or death.
Another objective of this study was to analyze SAECG and EP results with
respect to their ability to predict spontaneous ventricular
tachyarrhythmic events, and spontaneous ventricular tachyarrhythmic event
or death.
TWA was substantially more predictive of a ventricular tachyarrhythmic
event than was SAECG, as evidenced by the relative risks of the tests
(6.68 for TWA versus 2.57 for SAECG) and the log-rank test statistic p-
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31
values comparing the positive and negative event-free survival findings,
which were statistically significant for TWA (p = 0.007) but not for SAECG
(p = 0.092). TWA was also more predictive of a ventricular tachyarrhythmic
event or death than was SAECG, as evidenced by the relative risks of the
tests (10.99 for TWA versus 1.79 for SAECG) and the log-rank test statistic
p-values comparing the positive and negative event-free survival findings,
which were statistically significant for TWA (p less than 0.001) but not
for SAECG (p = 0.220).
TWA was somewhat more predictive of a ventricular tachyarrhythmic event
than was EP, as evidenced by the relative risks of the tests (6.68 for TWA
versus 4.90 for EP) and the log-rank test statistic p-values comparing the
positive and negative event-free survival findings, which were
statistically significant for both TWA (p = 0.007) and EP (p = 0.001).
But, TWA was somewhat more predictive of a ventricular tachyarrhythmic
event or death than was EP, as evidenced by the relative risks of the tests
(10.99 for TWA versus 3.12 for EP). The log-rank test statistic p-values
comparing the positive and negative event-free survival findings were
statistically significant for both TWA (p less than 0.001) and for EP (p =
0.006).
14. DISCUSSION AND OVERALL CONCLUSIONS
This study followed patients enrolled in Protocol 95-CH2000-3.0 for 12 months to
assess the ability of TWA testing to predict, using the spectral method of the
CH 2000 Cardiac Diagnostic System and Hi Res ECG electrodes, increased risk of
ventricular arrhythmias, evidence by the occurrence of spontaneous ventricular
tachyarrhythmic events or ventricular tachyarrhythmic events or death.
A total of 246 male and female patients, enrolled in study 95-CH2000-3.0 prior
to February 28, 1998, and were not in violation of the Protocol of that study,
were included in these analyses. At the time the database closed for this
report, June 30, 1998, a subset of these patients (N = 201) who had follow-up
data, were used to analyze efficacy. No safety data were collected during the
study.
The primary objective of this study, to show that positive TWA findings are
predictive of increased risk of ventricular arrhythmias, was achieved. In
addition, it was shown that positive TWA findings are predictive of increased
risk of ventricular arrhythmias or death. The secondary objective of this study
was to analyze SAECG and EP predictability of increased risk to ventricular
arrhythmias.
Comparison of the results of the three tests indicated that, in the study
population, positive TWA findings were substantially more predictive of
August 20, 1998
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32
increased risk of ventricular arrhythmias than were positive SAECG findings, and
positive TWA findings were somewhat more predictive of increased risk of
ventricular arrhythmias as were positive EP findings. Comparison of the results
of TWA, SAECG, and EP predictability of increased risk of ventricular
arrhythmias or death, was also performed.
The results of this study indicated that TWA findings were a substantially
better predictor of both endpoint event types than SAECG findings. TWA findings
were also somewhat more predictive of both endpoint events than EP findings.
August 20, 1998
