Wearable Cardioverter Defibrillator in Hemodialysis Patients (WED-HED) Study
Phase: NA
Conditions: Sudden Cardiac Death, Sudden Cardiac Arrest
Sponsor: Zoll Medical Corporation

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Wearable Cardioverter Defibrillator in Hemodialysis Patients (WED-HED) Study 
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90D0126 
Wearable Cardioverter Defibrillator 
in Hemodialysis Patients 
(WED-HED) Study 
Principal Investigators: 
Wojciech Zareba, MD, PhD 
University of Rochester Medical Center, Rochester, NY 
and 
Charles Herzog, MD 
Chronic Disease Research Group 
Minneapolis Medical Research Foundation 
University of Minnesota, Minneapolis, MN 
I have read and understand the infom1ation in the protocol and I understand my requirements for 
executing the protocol based on sound knowledge of GCP and ICH Guideline for Good Clinical 
Practice (E6). 
PRINTED NAME OF fNVESTIGA TOR 
INVESTIGATOR SIGNATURE 
Steven J. s'~iiJ 
Vice President of Medical Affairs 
ZOLL (SPONSOR) 
ZOLL Pittsburgh 
SlTENUMBER 
DATE 
DATE 
Apr 22, 2015

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PROTOCOL SUMMARY 
Objective 
To study the impact of wearable cardioverter defibrillator (WCD) use on sudden cardiac death in 
hemodialysis patients. 
Study Population 
Participants will be patients beginning hemodialysis (<2 months from initiation) who are~ 50 
years old. 
Intervention 
A WCD will be used for protection against sudden cardiac death (SCD). 
Study Design 
The study will be a multi-center, prospective, randomized controlled trial with 1:1 assignment 
of treatment and control. 
Study Size 
The study will enroll up to 2,600 subjects. A maximum of 200 sites will be used for enrollment. 
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1. INTRODUCTION 
End-stage renal disease (ESRD) affects over 400,000 people in the United States. Due to the 
aging population and increasing burden of comorbidities, it is expected that by 2030 the ESRD 
population could significantly increase and reach over 2.2 million. Recent data indicate that the 
treatment of ESRD patients accounts for 6.4% of total Medicare expenditure. 1•2 
I .I 
Incidence and Mortality 
The risk of mortality among ESRD patients, including sudden cardiac death (SCD), 
continues to gain attention among the scientific community as indicated by the recent 
Kidney Disease: Improving Global Outcomes (KDIGO) committee convened in London. The 
high mortality rate of these patients, and the sudden cardiac death rate in particular, was 
one of the main topics among the 80 international experts that attended this meeting to 
discuss the current state of knowledge about chronic kidney disease (CKD) patients. 
KDIGO concluded that every effort should be made to decrease the high mortality rate of 
ESRD patients. 1 
Paralleling the scientific community, the USA government initiative called Healthy People 
2020 has set goals to reducing the mortality among hemodialysis patients. Specifically, one 
goal is a 10% reduction in the number of deaths in dialysis patients within the first 3 
months of initiation of renal replacement therapy. This goal specifically targets incident 
hemodialysis patients as they have a significantly higher mortality. Another goal is a 10% 
reduction in the number of cardiovascular deaths for persons on dialysis. SCD contributes 
significantly to the cardiovascular death tally. 45 
According to United States Renal Data System (USRDS), there were approximately 
388,000 patients on hemodialysis in the USA in 2011 and the death rate for all dialysis 
patients was 198 deaths per 1000 patient-years.2 Mortality rates are substantially higher 
among incident patients, comparable to the mortality of patients with advanced heart 
failure or advanced cancer. The first months are particularly high risk and patients new to 
dialysis experience approximately 14% mortality in the first 6 months.3 
The USRDS database also reveals that 65% of all cardiac deaths are attributable to cardiac 
arrhythmias, making SCD the single largest cause of death in hemodialysis patients and 
responsible for approximately 26% of all mortality in this population.2•9•10 Other studies in 
this population such as the German Diabetes and Dialysis (4D) study, the Hemodialysis 
(HEMO) study and the Evaluation of cinacalcet therapy to lower cardiovascular events 
(EVOLVE) reported similar proportions of mortality attributable to sudden death.6,8,44 
The SCD rate of hemodialysis patients in the US is over 50 times greater than the general 
population, with 53 deaths per 1000 patient-years compared to the approximately 1 death 
per 1000 patient-years in the general population, and SCD accounts for a smaller portion 
(6% to 13%) of deaths in the general population.2•9•1o.u Compared to other modalities such 
as peritoneal dialysis, hemodialysis patients die of sudden cardiac arrest (SCA) and 
arrhythmia at a higher rate (62.2 vs. 42.8 events/1,000 patient-years). 12 Still, the majority 
of SCD occm s outside of dialysis centers where it is very unlikely to be witnessed or have 
resuscitation equipment available. Several studies show the incidence of sudden cardiac 
arrest (SCA) in dialysis patients is only 4.5 per 100,000 hemodialysis sessions or about 7 
per 1000 patient-years based on an average of three hemodialysis sessions per week. 13•14· 15 
The survival rate following SCA in the general population is poor, with a median survival 
rate of 8%, and hemodialysis patients would not be expected to have better results. 16 Even 
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for SCA occurring within the dialysis center where supportive care may be available, the 
survival rate is poor with 60% mortality within 48 hours of the arrest, including 13% in the 
unit and 47% en route or in the hospital-14 In a population-based study of SCA within 
hemodialysis centers, survival of SCA to hospital discharge was reported as 24% with a 
15% one year survival rate.16 In a three year study of 24 patients who had CPR conducted 
during a hemodialysis session, Lai et al. reported that only two patients survived more than 
one month, and none survived to hospital discharge.17 
Even the introduction of the Automated External Defibrillator (AED) into dialysis units 
has not been associated with improved outcomes. Two groups independently reported the 
lack of AED benefit within dialysis centers, finding that available AEDs were used only 
50% of the time prior to EMS arrival. 15•3 1 At the same time, devices such as wearable 
cardioverter defibrillators (WCD) have shown to be very effective in terminating SCA in 
other high-risk populations through rapid response without the need for bystander 
intervention. 
In summary, large registries and clinical studies have shown SCD in hemodialysis patients 
accounts for about one fourth of total mortality and for 60 to 80% of cardiovascular deaths 
(Table 1). Sudden cardiac arrest survival is very poor in this patient population with the 
majority of SCA events occurring outside the dialysis unit. Even within the dialysis unit, 
where supportive care is available, survival is low. The alarming SCD rate in this 
population is a growing concern within the scientific community. In their recent position 
statement, KDIGO emphasized that preventative strategies for SCD should be a public 
health concern, specifically noting research is needed regarding the impact of the WCD on 
survival in the dialysis population. Reducing SCD through the use of modalities such as 
the WCD is thus anticipated to significantly reduce total mortality. 
1.2 
Hemodialysis as an Independent Risk Factor 
The high rate of SCD in hemodialysis patients is not only related to the high prevalence of 
underlying cardiac diseases but also associated with the stress and duration of the dialysis 
sessions. Several studies show that hemodialysis treatment is itself an independent risk 
for SCD. 
1.2.1 
Stress from the Hemodialysis Sessions 
Dialysis treatment-related stresses are important in the genesis of SCA. Bleyer and 
colleagues examined the timing of SCD in hemodialysis patients and identified that 
SCD events increased both before and after starting treatment. They found a 1. 7-
fold increased SCD risk occurring in the 12-hour period after starting dialysis 
procedure and a 3-fold increased risk at the end of the dialysis-free weekend 
interval. In this study, the occurrence of SCD was unrelated to the patient's left 
ventricle function.LS 
Rapid changes in serum electrolytes, specifically serum potassium concentrations, 
and extracellular fluid during dialysis are known to trigger malignant arrhythmias. 
Potassium fluxes during the hemodialysis interval are associated with established 
risk markers for SCD such as increased ventricular ectopy, increased QT interval, 
and an increased QT dispersion. In addition, the increased sympathetic activity 
occurring with hemodialysis is associated with sudden cardiovascular events. 18 
In a small study, Bleyer et al. did not find a significant difference in coronary artery 
disease (CAD) prevalence between patients who experienced sudden and non-
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sudden deaths. Prevention of CAD or its progression through the use of statins did 
not improve survival of chronic kidney disease (CKD) patients in the Study of Heart 
and Renal Protection (SHARP) despite a decrease in cardiovascular events. 
Similarly, 4D and AURORA (A Study to Evaluate the Use of Rosuvastatin in 
Subjects on Regular Hemodialysis) failed to show any benefit of statins in decreasing 
cardiovascular mortality in dialysis patients despite significant decreases in 
cholesterol levels. 6,18. 19 
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T bl 1 S 
f Cli . l St di 
R k fSD. H 
dial 
0 
p • l t' 
Study/Data 
Description 
Sample 
%Female 
Age 
Presence 
HxCD(%) 
~oPts EF 
Sudden 
% SCA 
Sudden death 
Source 
Size/HD 
(mean±SD) 
ofDM(%) 
>40 
Death 
of cv 
definition 
Cohort 
(%). 
deaths 
USRDS2 
United States 
n= 395,656 
44.0 
<!:50yrs 
45.1 
85 
NR 
24 
65 
SCA/cardiac arrhythmia 
Renal Data 
(Total study 
(n=174,111) 
=80.0% 
(n=178,269) 
(Incidence 
System 2013. 
N=430,273) 
of HTN) 
(2011 
data) 
406 
Atorvastatin 
n=1255 
46.1 
65.7 ± 8.3 
100 
>43 
NR 
25.9 
59.2 
Unexpected death 
RCT in HD+ 
(control 
w~hout K + > 7.5 mmol 
OM (type II) 
group=636, 
per l~er before the start 
pts, composite 
treatment 
of the three most recent 
endpoint of 
group=619) 
sessions of HD (sudden 
cardiac death, 
European 
cardiac death) 
nonfatal Ml, 
HD patients 
stroke. 
(1998-2002) 
HEMOI.I 
RCT of high-
n-1846 
56.2 
57.6 ± 14.0 
44.6 
80.1 (pre-
NR 
24.9 
23.9 
Witnessed or 
flux dialyzer 
HD patients 
existing 
unwitnessed unexpected 
membrane on 
CD) 
death; symptoms onset < 
survival or 
24 hours if witnessed or 
morbidity with 
< time since last 
cardiac event 
dialysis session if 
sub-analysis. 
unwitnessed. 
( 1995-2000) 
DOPPS (US)20 
Prospective, 
n=3856 
46.6 
60.5 ± 15.5 
45.7 
83.2(HTN) 
NR 
NA 
NR 
NA 
observational 
US HD pts 
study ofHD 
(Total study 
patients in EU, 
N=16,720) 
Japan, and 
us (1996-
2002) 
Bleyer11 
Retrospective 
n=80 sudden 
58.8 
60.3 ± 14.1 
57.5 
92.5 
75.3 (EF 
35 
80 
Cardiovascular related 
examining 
deaths 
(HTN) 
>35%) 
(73% of SO due to SCA) 
sudden death 
(total N=228) 
56.3 
in HD patients. 
(CAD) 
EVOLVE" 
Prospective 
3883 
40 
55.4 
33.4% 
NR 
NR 
24.5 
45 
NR 
study of 
hemodialysis 
cinacalcet 
patients 
Mangrum21.22 
Single-<:enter, 
N= 241 
NR 
NR 
NR 
63.0 (89 
35 
74 
Arrhythmias/SeA 
retrospective 
HD patients 
pts echo 
mortality 
available) 
analysis of 
prevalent 
hemodialysis 
pts evaluating 
SCDand LV 
function 
(1999-2003) 
Pun 
Retrospective 
n=424 
48.6 
61 (median) 
63.0 
89.4 
52 (lOR 
24.2 per 
NR 
Death resulting from the 
(2009)23 
study of GFR 
(HTN) 
40, 60) 
1000 
sudden, unexpected 
and risk of 
HD (58.7%) 
patient 
cessation of cardiac 
SCD in a CKD 
and non-HD 
years 
activity with 
cohort. Duke 
pts 
(HD pts) 
hemodynamic collapse 
Databank for 
(eGFR<15 
Cardiovascula 
mllmin) with 
r Disease 
documented 
(DDCD)was 
CAD 
used. 
(1995-2006) 
*Out of total mortality 
1.2.2 
Duration of Hemodialysis 
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The 2011 annual overall mortality for prevalent dialysis patients in US was 198 
deaths per 1000 patient years, which rose to 224.5 deaths per 1000 patient years for 
patients between the ages of65 and 74 years. The 2011 death rate in patients within 
the first three months of dialysis initiation was markedly higher with 335.4 deaths 
per 1000 patient years for all patients and 368.2 per 1000 patient year s for patients 
between the ages of 65 and 7 4 years. Like overall mortality, the hazard of 
cardiovascular mortality and SCD is not uniform over the duration of dialysis 
therapy and patients who are initiated on hemodialysis have a 1. 7 to 2 fold increased 
risk of SCD during first few months on dialysis.2 According to the USRDS, total 
mortality for the fu·st six months following dialysis initiation is approximately 14% 
and sudden cardiac death is approximately 4% (Figure 1). 2 
Figure 1 
Probability of death in incident dialysis patients, by 
cause of death, 2009 
figure u (Volume 2) 
0.25 
0.20 
~0.15 
:0 
"' 
.D 
£0.10 
0.05 
0.00 """"--------
0 1 2 3 4 5 6 7 8 9 10 11 12 
Months after initiation 
Herzog et al. found that the rate of SCD was approximately 50% higher for 
hemodialysis patients within three months of dialysis initiation, compared with 
patients on dialysis longer. 24 The USRDS 2009 report revealed that sudden death 
rates averaged > 100 deaths per 1000 patient-years in the first 3 months, and nearly 
90 deaths per 1000 patient-years over the first 6 months (Figure 2). As the SCD rate 
reported by Herzog trends similar to the USRDS cardiovascular mortality, it is clear 
that the risk of SCD is highest in the first six months as opposed to the last six 
months of the first year of dialysis, paralleling total mortality.24•25 
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Figure 2. 
Adjusted monthly rate of SCD after 
hemodialysis initiation, by incidence year 
150 
120 
~ 
~ 90 
.. 
0. 
8 
60 
0 ... ... .. 
0. 
30 
cs 
-
2000 
-
2005 
v 
VI 
0 
-
2009 
2 
3 
.. 
5 
6 
7 
8 
9 
10 
11 
12 
Month aft~r dialysis Initiation 
'USIQS 
Ll S, Herzog CA. ASN 2012 
The DOPPS study confirms the USDRS data, and shows the higher mortality in 
the fin t six months after dialysis initiation is not unique to the US population. 43 
The trend is more pronounced in the older population but still exists for those 
under 65 years of age. Closer examination of data from a commercial hemodialysis 
provider indicates that mortality is highly time dependent and declines weekly 
following hemodialysis initiation (Figure 3). 46 
Figure 3. Relative risk of death at one week intervals after starting chronic 
dialysis, compared to a reference group who survived one year of dialysis. 
A 3.0 
2.5 
~ 
, ·c 
41 2.0 
> 
: 
ell 
~ 
1.. 
1.5 
1.0 
10 
20 
30 
40 
50 
time on dialysis (weeks) 
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1.3 
Hemodialysis and Preserved Left Ventricular Function 
Left ventricular dysfunction, as measured by the left ventricle ejection fraction (LVEF), is 
well-known as an independent risk stratifier for SCD in the general population. However, 
L VEF does not provide the same utility in assessing risk of SCD in end stage renal disease 
(ESRD) patients, despite the high risk of arrhythmic events in this group. The rationale 
for LVEF and other risk factors for determining the proposed patient population are 
supported by three US based studies. 
In a retrospective study by Bleyer and colleagues it was shown that LVEF was not 
predictive of the occurrence of SCD in 80 hemodialysis patients. In fact, 75% of the patients 
who suffered sudden death had preserved LVEF (>35%). Arrhythmias accounted for 35% 
of the total sudden deaths. 18 
Similarly, in a study which evaluated overall cardiac function and SCD in the hemodialysis 
population, low L VEF alone did not account for the high risk of SCD associated with 
advanced CKD. On the contrary, the majority of the SCD (71 %) occurred in patients with 
an EF > 30%. 21•22 Additionally, Duke University examined the risk ofSCD in a large cohort 
of their CKD patients and found that the subgroup of 424 patients with glomerular 
filtration rates (GFR) < 15 ml/min, of whom 66% of patients were on hemodialysis, had a 
median LVEF of 52% (IQR 40, 60). The rate of SCD for the patients on hemodialysis was 
24.2 per 1000 patient-years, nearly double the SCD rate for those patients with similar 
GFRs of <15 ml/min but not yet on dialysis. 23 
Although the USRDS database does not capture LVEF data, it is the opinion of our 
investigators that the risk of SCD in hemodialysis patients with preserved EF shown in 
these studies, totaling 448 cases of hemodialysis patients suffering SCD, are representative 
of the risk inherent in the US hemodialysis population. 
1.4 
Hemodialysis Patients 2:50 Years 
Published data indicates both hemodialysis and mortality rates rise as age progresses. 
According to the USRDS database, approximately 87.9% of the dialysis population is over 
45 years of age, while approximately 50.3% of the dialysis population is over 65 years of 
age.2 
Ample data shows that age is also independently associated with increased risk for SCD in 
this population. SCD risk increases at least 1.5 times with every incremental age range. 
Results from r andomized controlled trials, prospective observational, and retrospective 
studies report similar findings. 8·18•20 In the DOPPS study, patients who were older than 65 
years had more than double the risk of dying compared to younger patients.20 The HEMO 
study showed that the risk of SCD increased by 41% with every 10-year increment. Age 
was one of the strongest predictors of death in this randomized trial. 7·8 Bleyer et al. also 
reported that the incidence of SCA was 93.7/1000 patient-years at risk for dialysis patients 
>65 years of age. 18 Among non-diabetic hemodialysis patients in the United States, those 
45 years old or older have double the SCD rates of those below 45 years of age.25 Details are 
shown in Tables 1 and 2. 
In the DOPPS study, patients >65 years old (who constitute the majority of dialyzed 
patients) had exceptionally high mortality rates ranging from 211-412 deaths per 1000 
patient-years in the first 8 months after initiation of hemodialysis. 43 This translates to 
cumulative 6-month mortality of up to 15.4% for subjects beginning follow-up within a 
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month of initiating dialysis, and 14.1% for subjects beginning 6-month follow-up 1 to 2 
months post-initiation. 
Table 2. US Renal Database System: SCD Rates by Primary Cause of ESRD and Age 
Unadjusted cardiac arrest/arrhythmia mortality rates combined 2005-2007 period prevalent hemodialysis 
patients (deaths per 1,000 patient years), by primary cause of ESRD and age 
-
· • 
,. I 
I 
. • · 
· 
. . . . 
. . 
. -
Cardiac Arrest 
Cardiac Arrest 
AGE 
N= 
Death Count 
Yrs at Risk 
Rate 
Death Count 
Yrs at Risk 
Rate 
20-44 
39,052 
1,380 
31,334 
44.0 
1,920 
106,525 
18.0 
45-64 
227,994 
10,054 
184,152 
54.6 
7,151 
192,998 
37.0 
65-74 
143,528 
8,395 
112,626 
74.6 
5,644 
92,434 
61.1 
75+ 
94,462 
7,333 
68,880 
106.5 
11,231 
116,694 
96.4 
popu!atjOO' period prevalent hemodialysis patients combined 2005·2007 who we re age 20 and above, resided in the US 50 states, Washington D.C. 
U.S. Rena l Data System, USRDS 2009 Annual Data Report: Atla s of End·Stage Renal Disease i n the United States, Nati onal Institutes of Health, National 
Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2009. 
1.5 
Management of SCD Risk in Hemodialysis Patients 
The in-center SCA rate is reported to be as low as 3.5 per 100,000 hemodialysis 
sessions. 14•15·29·30,3 t Therefore, the majority of arrhythmic events occur at home where 
patients are not supervised. The accumulation of electrolytes and fluids between dialysis 
sessions contributes to the arrhythmogenic predisposition. Even SCA occurring during 
hemodialysis has a poor survival rate, despite attendance by trained personnel. About 60% 
of patients die within 48 hours of the SCA, including 13% while still in the dialysis unit.14 
In another population-based study of hemodialysis facilities, survival to discharge from the 
hospital was reported as 24% with 15% survival at 1 year. 15 Moss et al and Lai et al reported 
even worse in-hospital death rates of 92% and 100%. 17•32 There is a tremendous need to 
improve survival of these very high-risk patients. Rapid treatment with defibrillation 
remains the best option when SCA occurs. 
1.5. 1 
Automatic External Defibrillator (AED) 
Automated external defibrillators have been broadly introduced into dialysis units. 
However, published data indicate that even when available these devices were 
attached in only half of cases prior to EMS arrival. Furthermore, the introduction of 
AED in dialysis unit has not shown improved outcomes for patients experiencing 
SCA. Two groups independently reported lack of benefit in SCA victims among 
outpatient dialysis centers with versus without AED availability. 15·3 1 One-year 
survival after in-center SCA was reported as low as 8.4% despite AED availability. 
1.5.2 
Implantable Cardioverter Defibrillator (ICD) 
Implantable cardioverter defibrillators provide protection from SCD, but these 
devices are underused or not practical in patients undergoing hemodialysis. 
Physicians are less likely to refer patients in with ESRD for ICD implantation not 
only due to potential complications (infections, difficulties with venous access) but 
also due to lack of data from randomized trials as patients with ESRD have been 
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traditionally excluded from major ICD clinical trials. Therefore, there are very 
limited data on ICD use in dialysis patients. A study by Herzog et al reported that 
of 6,000 dialysis patients eligible for ICDs, only 8% received them.4 Despite the low 
proportion of implantation, ICD use was associated with a significant 42% reduction 
in death risk as compared to non-ICD group. Charytan and colleagues conducted a 
similar analysis but found a lower yet statistically significant reduction in all-cause 
mortality with ICDs.33 
1.5.3 
Wearable Cardioverter Defibrillator (WCD) 
The life-saving effects of the WCD were documented in the WEARIT/BIROAD 
studies designed and conducted by Drs. Klein, Hall, and Moss. 5 Following these 
studies, CMS approved WCD use in patients who meet coverage criteria for ICD 
implantation, but without the waiting periods established after a significant cardiac 
event. A small proportion of dialysis patients meet these criteria. Since ICDs are 
underutilized in dialysis patients, the WCD provides an opportunity to save the lives 
of numerous hemodialysis patients.40 
2. WEARABLE CARDIOVERTER DEFIBRILLATOR DESCRIPTION 
The LifeVestTM wearable cardioverter defibrillator is composed of four dry, non-adhesive 
capacitive electrodes and three dry-to-wet non-adhesive defibrillation electrodes incorporated 
into a chest strap assembly, along with a 0.8 kg defibrillator unit carried on a waist belt or 
shoulder strap. The monitoring electrodes are positioned circumferentially around the chest and 
held in place by approximately 0.5 kg of tension. The defibrillation electrodes are positioned for 
apex-posterior defibrillation. If an arrhythmia is detected, an escalating alarm sequence starts, 
including a vibration against the skin, audible tones, and a voice cautioning bystanders of an 
impending shock. Patients are trained to hold a pair of response buttons during these alarms. 
Responding acts as a test of consciousness: if no response occurs, the device extrudes gel from 
the defibrillation electrodes and delivers up to five 150-Joule biphasic shocks. 
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3. OBJECTIVES 
3. 1 Primary Objective 
The study will test the hypothesis that ESRD patients, who are at least 50 years of age 
and beginning hemodialysis (either scheduled for their fu·st session or within two months 
of the initial treatment), will experience a 60% relative risk reduction in SCD mortality 
through WCD use as measured at six calendar months after randomization. The primary 
objective will be evaluated using intention-to-treat analysis. 
WCD therapies are anticipated to reduce the risk of SCD by 60% over the course of use, 
similar to other personal defibrillation therapies such as ICDs. The hypothesized relative 
reduction in SCD translates to a 2.1% absolute reduction in the risk of SCD mortality over 
6 months of follow-up, given that the SCD rate during that period is expected to be 3.5%. 
The hypothesized 60% reduction in SCD is also expected to result in a 15% reduction in 
total mortality over 6 months for this patient group, a consequence that would be of major 
clinical importance. 
3.2 
Secondary Objectives 
The specific secondary objectives are: 
3.2.1 
Evaluate the effect of WCD use on total mortality at 6 calendar months 
The relative risk reduction in SCD at 6 months is anticipated to be 60%. Given that 
total mortality during the same time period is 14% and that SCD comprises 25% of 
the total mortality, the relative risk reduction in total mortality is anticipated to be 
15%. The absolute reduction in total mortality is expected to be the same as the 
reduction in SCD, 2.1%. 
3.2.2 
Evaluate the effect of WCD use on sudden cardiac death at 6 calendar months (as-
treated analysis) 
Intention-to-treat analyses have several advantages but are generally conservative 
in estimating the treatment effect, due to noncompliance in the treatment arm, 
crossover of subjects to opposing study arms, etc. Therefore secondary as-treated 
analyses will be used to estimate the relative risk of wearing versus not wearing 
WCD. Detailed data will be obtained regarding actual daily use of WCD in each 
subject enrolled in the trial. The as-treated analysis will be based on a Cox model 
with a time-dependent indicator for wearing versus not wearing WCD, allowing 
subjects to dynamically move back and forth between the "wearing WCD" and "not 
wearing WCD" groups every time the WCD is put on and taken off. Thus, events 
occurring while wearing WCD will be attributed to "wearing WCD," while events 
occurring while not wearing WCD will be attributed to "not wearing WCD." A 
likelihood ratio test will be used to obtain a p-value for the resulting hazard ratio 
for wearing WCD, and the estimated hazard ratio along with a 95% confidence 
interval will also be reported. 
3.2.3 
Evaluate the clinical status of SCA survivors 48 hours after the event 
Resuscitation from SCA due to VTNF is high in commercial use of WCD. Similar 
results are anticipated in hemodialysis patients. Survival will be evaluated at 48 
hours after the SCA event. 
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3.2.4 
Evaluate the incidence of potentially life-threatening arrhythmias as documented 
by the WCD, regardless of treatment by the WCD, at 6 calendar months 
Some patients who experience VT may not lose consciousness and will use the WCD 
response buttons to prevent a treatment from occurring. Such patients, after the 
documentation of a sustained VT event, are indicated to receive an ICD. This may 
reduce the incidence of SCD without actual WCD therapy being delivered. Likewise, 
asystole may be the initial rhythm during an SCA event and impact SCA 
resuscitation success. Alternatively, smviving an asystole event and receiving a 
pacemaker may reduce SCD without defibrillation. 
3.2.5 
Evaluate the risk of inappropriate WCD therapy at 6 months 
The rate of inappropriate therapies (i.e., a treatment shock in the absence of a VTNF 
arrhythmia) during commercial WCD use is low, occurring less than 0.9% per 
patient-month of use. This rate will be confirmed for hemodialysis patients. 
3.2.6 
Evaluate compliance with WCD therapy 
Compliance is high in commercial use of WCD, exceeding 90%. Similar results are 
anticipated in hemodialysis patients. 
3.2.7 
Evaluate quality of life 
Psychosocial issues are one of the major concerns in the overall health of 
hemodialysis patients. Patients with ESRD, especially those undergoing dialysis, 
are under continuous stress related not only with a disease itself but also with the 
mode of treatment. Depression and anxiety disorders are among the most frequently 
encountered in ERDS patients. Social and family issues related with end-stage 
illness and dialysis-dependency should also be emphasized. 
Quality of life will be assessed by means of a specific Kidney Disease and Quality of 
Life (KDQOL) survey. This questionnaire is composed of 36 questions evaluating 
overall health perception, kidney disease-related issues and its influence on 
patient's daily life as well as satisfaction with care. Kidney Disease Quality of Life 
Working Group website: http://gim.med. ucla.edu/kdgol/ 
3.2.8 
Evaluate clinical variables that may be predictive for mortality and arrhythmic 
events 
4. SUBJECT SELECTION CRITERIA 
The population for this study will be ESRD patients who are beginning hemodialysis. 
4.1 
Inclusion Criteria 
The specific inclusion criteria are (all must be true): 
4.1.1 
The patient has end stage renal disease requiring hemodialysis. 
4.1.2 
The patient is on hemodialysis for S 2 calendar months or scheduled to begin 
hemodialysis within 1 calendar month. 
4.1.3 
The patient is 2:50 years of age. 
4.1.4 
The patient has a documented EF > 35% within the previous calendar year. 
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4. 1.4. 1 If the patient has been hospitalized for a myocardial infarction or heart 
failure decompensation, the EF measurement must have occulTed during 
the last hospitalization or after discharge. 
4.2 
Exclusion Criteria 
The specific exclusion criteria are (none may be true): 
4.2. 1 
The patient is receiving or will receive hemodialysis due to acute kidney injury and 
is not expected to receive subsequent chronic hemodialysis therapy. 
4.2.2 
The patient has an active ICD. 
4.2.3 
The patient has a unipolar pacemaker. 
4.2.4 
The patient has physical or mental conditions preventing him/her from interacting 
with or wearing a WCD. For example, patients unable to understand device use, 
unable to hear alarms, or unable to use response buttons. 
4.2.5 
The patient has a chest circumference at the level of the xiphoid of < 24 inches. 
4.2.6 
The patient has a chest circumference at the level of the xiphoid of > 56 inches. 
4.2.7 
The patient has an advance directive prohibiting resuscitation. 
4.2.8 
The patient has cancer or other terminal disease (excluding ESRD) with expected 
survival less than 6 months. 
4.2.9 
The patient is medically unstable for reasons not specifically related to kidney 
disease. 
4.2. 1 0 The patient is scheduled for live-donor kidney transplantation within 6 calendar 
months. 
4.2.1 I The patient is unable to consent. 
5. STUDY SIZE 
A minimum of 1,300 and a maximum of 2,600 subjects will be enrolled into this study. A 
maximum of 200 sites will enroll patients into the trial. 
6. STUDY PROCEDURE 
6. I 
Screening 
Patients undergoing hemodialysis or those with a scheduled start date for the initiation of 
dialysis will be screened regarding their eligibility for the study based on age, EF and 
length of time on hemodialysis. 
6.1.1 
Left ventricular ejection fraction (EF) assessment 
EF must be assessed within one calendru: year prior to enrollment. The most recent 
test must be used. In patients with a history of myocardial infarction or heart failure 
hospitalization within the past year, it is expected that an echocardiogram or other 
method for measuring EF should have been obtained during or after the time of the 
event. If there is more than one hospitalization for myocardial infar ction or heart 
failure, the EF measurement used must be associated with the most recent 
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hospitalization. If there is no EF measurement available from the last 
hospitalization for myocardial infarction or heart failure, potential subjects should 
be treated as if no EF measurement is available. 
Potential subjects who have never had an EF evaluation or whose EF was obtained 
greater than one calendar year prior to randomization will be required to have an 
echocardiogram to assess cardiac function prior to enrollment, ideally within 14 
days prior to enrollment but in no circumstances later than one calendar month 
prior to enrollment. 
Echocardiographic assessment of LVEF is most frequently performed in clinical 
practice. Nevertheless, similar to ICD trials, other imaging modalities (MUGA, 
MRI) may be used to document LVEF. Also similar to ICD trials, local assessment 
of L VEF will be accepted. Although there are likely to be differences in EF 
assessment among enrolling sites and practices, these differences are not expected 
to affect the outcome of the trial. 
6. 1.2 
Patients on home hemodialysis will be eligible for enrollment in the study. 
6.2 
Pre-study Visit (only required if EF needs to be collected) 
6.2. 1 
Inclusion/exclusion will be verified 
6.2.2 
Informed consent will be obtained. 
6.2.3 
Patients requiring collection of LVEF must have an echocardiogram (or other 
appropriate EF assessment) prior to enrollment at Visit 1. The EF assessment must 
be completed within 1 calendar month of the pre-study visit but ideally should be 
completed within 14 days. 
6.2.4 
Enrollment will occur once all screening criteria have been met, including EF. 
6.3 
Visit 1 (Day 1) 
Prior to Visit 1, call ZOLL to schedule a Patient Service Representative (PSR) to be 
present the day of enrollment. A PSR should be available to fit the patient with a WCD in 
the event that the patient is randomized to the WCD arm. 
For all subjects: 
6.3. 1 
Inclusion/exclusion will be verified. 
6.3 .2 
Informed Consent will be obtained. 
6.3.3 
Subjects will be randomized to WCD or conventional therapy. 
6.3.4 
Clinical history data will be collected, including laboratory and ECG if available. 
6.3.5 
Subjects will be asked to complete quality of life questionnaire. 
6.3.6 
If the patient has started hemodialysis, general hemodialysis data will be collected. 
6.3.7 
Medication usage will be collected. 
For subjects randomized to WCD only: 
6.3.8 
Subjects will be instructed and trained regarding usage of WCD by a ZOLL 
representative. 
6.3.9 
Subjects will be instructed to wear the WCD for six months. 
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6.4 
Visit 2 (2 calendar months from enrollment± 14 days) 
6.4.1 
For all subjects: 
6.4.1. 1 
Subjects will be asked to complete quality of life questionnaire reflecting 
their experience over the previous 4 weeks. 
6.4.1.2 
Collect general hemodialysis data. 
6.4.1.3 
Collect any changes to medications. 
6.4.1.4 
Collect device, adverse, and cardiac event information including laboratory 
data from the medical record as available. 
6.4.2 
For subjects randomized to WCD therapy: 
6.4.2.1 
Compliance will be evaluated and encouraged. 
6.5 
Visit 3 (4 calendar months from enrollment ± 14 days) 
6.5 .1 
For all subjects: 
6.5. 1.1 
Collect general hemodialysis data. 
6.5.1.2 
Collect any changes to medications. 
6.5. 1.3 
Collect device, adverse and cardiac event information including laboratory 
data from the medical record as available. 
6.5.2 
For patients randomized to WCD therapy: 
6.5.2.1 
Compliance will be evaluated and encouraged. 
6.6 
Visit 4 (at least 6 calendar months from enrollment, with up to 14 additional days) 
6.6. I 
For all subjects: 
6.6. 1.1 
Collect general hemodialysis data. 
6.6. 1.2 
Collect any changes to medications. 
6.6. 1.3 
Collect device, adverse and cardiac event information as needed. 
6.6. 1.4 
Subjects will be asked to complete quality of life questionnaire reflecting 
their experience over the past calendar month. 
6.6.2 
Collect survival data. 
6.7 
Unscheduled Visit (e.g., if resuscitation from SCA) 
6.7.1 
For all subjects: 
6.7.1. 1 
Collect general hemodialysis data. 
6. 7 .1.2 
Collect any changes to medications. 
6.7.1.3 
Collect device, adverse and cardiac event information as needed, including 
laboratory data as available from medical record. 
6.7.2 
For patients randomized to WCD therapy: 
6.7.2. 1 
Compliance will be evaluated and encouraged. 
6.8 
Final survival assessment (1 calendar year from enrollment, with up to 14 additional 
days) 
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Sites will be asked to determine survival for all subjects enrolled in the study through either 
routine dialysis records and appointments, or a phone call to the subject. 
6.9 
Post-study follow-up 
Long-term outcome assessment may be performed using databases maintained by the 
United States Renal Data System and the Centers for Medicare and Medicaid. 
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Table 3: Visit and Data Collection Schedule 
Pre-
Visit 4 (Month 6) 
Unscheduled 
study 
Visit 1 
Visit 2 
Visit3 
or Terminal Event 
Visit or SCA 
Visit a 
(Enrollment) 
(Month 2) 
(Month 4) 
or Withdrawal 
Event 
Consent 
X 
X 
Confirm lnc/Exc 
(confirm presence of EF or 
x b 
schedule echocardiogram) 
X 
Medical History/ESRD 
History 
x c 
Laboratory 
Assessment e 
X 
x t 
xt 
X t 
X 
WCD 
Introduction/Training 
X 
Randomization 
X 
WCD Fitting (WCD subjects 
x d 
only) 
WCD Compliance (for 
x d 
x d 
xd 
x d 
x d 
WCD subjects only) 
Collection of Dialysis 
Information and 
Medication Use 
X 
X 
X 
X 
X 
Collect device, adverse 
and cardiac events 
(includes defibrillation events) 
X 
X 
X 
X 
KDQOL (Quality of Life) 
X 
X 
x s 
a for patients without EF data 
b LVEF must have been collected within 1 calendar year prior to enrollment, or during or after Ml or CHF 
hospitalization, whichever is more recent. LVEF may be collected from Echocardiogram, MUGA, MRI. 
c included ECG if available 
d for WCD subjects only 
e collected at local lab 
1 only if cardiac event/shock occurs 
8 if not terminal event 
6. I 0 Managing WCD Therapy 
6. I 0. I The WCD System continuously monitors and records critical patient data to help 
diagnose and treat arrhythmic conditions. Device data will be uploaded at least 
weekly to a central server located in Pittsburgh, PA. In the event that uploads are 
not occurring on a routine basis, subjects should call ZOLL Technical Support for 
instructions. 
6. I 0.2 Subjects having questions or difficulty managing their WCD should be instructed to 
call ZOLL Technical Support. 
6. I 0.3 Clinicians will be blinded to the arrhythmia recordings in the group assigned to wear 
the WCD. This is necessary to prevent co-interventions with inappropriate anti-
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arrhythmic drugs or early implantation of an ICD. If unblinding is required, the 
investigator may be able to view the device recorded data through a secure website 
and/or receive ECG strips recorded by the WCD. The following provisions for 
unblinding are available when clinically indicated. 
6. 1 0.3.1 Automatic unblinding will be initiated by ZOLL, and results in electronic 
notification to the site as well as the transmission of ECG data. Automatic 
unblinding will be initiated when any of the following events occurs: 
6.1 0.3. 1.1 
The subject receives a treatment by the WCD. 
6.1 0.3. 1.2 VTIVF lasting 2: 30 seconds is detected and recorded by the 
WCD, regardless of treatment by the device. 
6.1 0.3. 1.3 Asystole or bradycardia less than 20 BPM is detected and 
recorded by the WCD. 
6.1 0.3.2 Clinical sites can request unblinding and receive ECG strips recorded by 
the WCD under the following circumstances: 
7. STUDY DESIGN 
6.1 0.3.2.1 Subject suffers a cardiac arrest or reports receiving a shock. 
6.1 0.3.2.2 Subject complains of excessive alarms or alarms suspicious of an 
arrhythmic event that is not associated with syncope, pre-
syncope or palpitations. In this circumstance, a protocol 
deviation will be reported. 
6.1 0.3.2.3 Subject complains of syncope or pre-syncope associated with 
WCD alarms. 
6.1 0.3.2.4 Subject complains of palpitations associated with WCD alarms. 
6.10.3.2.5 A treating physician deems it to be medically necessary. In this 
circumstance, a protocol deviation will be reported. 
This study will employ a group sequential two-arm randomized clinical trial to test the 
hypothesis that the wearable cardioverter defibrillator (WCD) reduces overall mortality within 
a 6 calendar month period beginning at the time of randomization, which is to occur no later 
than 2 calendar months after the initiation of hemodialysis. 
Enrolled subjects will be 1:1 randomized to WCD or non-WCD, stratified by enrolling site and, 
implicitly, by calendar time of enrollment. All subjects will be followed for at least 6 calendar 
months regardless of compliance. The primary endpoint is the binary event of whether or not 
sudden cardiac death occurs within the 6 month follow-up period. The primary analysis will be 
an intention-to-treat analysis based on the randomization, ignoring the fact that some subjects 
randomized to WCD may discontinue use of the device early while some subjects randomized to 
the non-WCD arm may obtain and wear a WCD. 
Overall mortality at 6 calendar months in the non-WCD arm is expected to be 14%, with one 
quarter of all deaths due to sudden cardiac death (SCD rate of 3.5%).2 Taking some anticipated 
noncompliance into consideration, as some subjects are expected to discontinue WCD prior to 6 
months, we hypothesize that the WCD will provide a relative reduction in SCD of 60%. Thus, we 
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expect an absolute reduction of 2. 1% in SCD mortality, corresponding to a relative risk (RR) of 
0.40 and an odds ratio (OR) of 0.39. 
The exact number of subjects to be randomized is uncertain since the group sequential trial was 
designed to have 46% power to stop at the first interim look at 650 (50%) subjects per arm, and 
69% power to stop at the second interim look at 975 (75%) subjects per arm, while controlling 
the overall significance level at a= 0.05. But if the study continues to the third and final look, a 
maximum of 1,300 subjects will be enrolled in each arm, for a total of 2,600 subjects providing 
91% power to detect the hypothesized 60% relative reduction in overall6-month SCD mortality 
from 3.5% down to 1.4%. 
7. 1 Endpoint Assessment 
A Mortality Committee will provide an assessment regarding mortality events with a 
categorization of the death based on underlying cause and mechanism of death. All deaths 
will be adjudicated by the Mortality Committee and classified as 'sudden (SCD)', 'not 
sudden' or 'indeterminate'. In addition, the death will be classified as 'cardiac', and 'non-
cardiac'. All deaths will be used as endpoints in the primary analysis and the adjudicated 
results used as endpoints in the secondary analyses. 
This committee will be blinded to information regarding the use of a WCD. The death 
reports from enrolling sites will be transcribed by an unblinded individual and provided in 
a uniform format to the adjudication committee. Transcribed notes will be redacted of 
information regarding WCD or WCD therapy to maintain the blinding of the committee. 
The Mortality Committee will not utilize WCD or AED interrogation information when 
classifying death as cardiac or non-cardiac, and as sudden or non-sudden. 
7. 1. 1 
SCD definitions 
For witnessed deaths, sudden cardiac death (SCD) will be defined as an unexpected, 
non-traumatic, non-self-inflicted fatality in otherwise stable subjects who die within 
one hour of the onset of the terminal symptoms (and for whom dialysis-
noncompliance or withdrawal have been excluded). Subjects dying more than one 
hour after a sudden cardiac arrest (SCA) from a ventricular arrhythmia will be 
designed as non-sudden death due to ventricular arrhythmia. 
For unwitnessed deaths, participants will meet the definition of sudden cardiac 
death if they are found dead within 24 hours of being well, assuming there is no 
evidence of another cause of death during that time period including dialysis-
noncompliance (or withdrawal). Autopsy results may be used when available. 
7.1 .2 
Arrhythmia Adjudication 
A separate Wearable Defibrillator Interrogation Adjudication Committee will focus 
on assessing cardiac arrhythmias triggering WCD therapy regarding its 
appropriateness and effectiveness. All events will be reviewed by an independent 
committee and will be categorized as appropriate, inappropriate, or indeterminate. 
Details of arrhythmic events and related therapy will be recorded. 
7.2 
Statistical Methods 
The primary analysis will be based on a 1-df likelihood ratio test (LRT) of the null 
hypothesis that the 6 calendar month SCD mortality rate is identical for subjects 
randomized to WCD versus non-WCD (i.e. odds ratio of 1), conditional on enrolling site and 
date of enrollment (stratification variables that define randomized blocks), and further 
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parametrically adjusted for five additional pre-specified risk factors via conditional logistic 
regression (CLR): 
• age (continuous, and flexibly modeled via a 4-df continuous piecewise linear spline with 
knots at 60, 70, and 80 years of age, allowing for a separate odds ratio per year 
within each decade of age), 
• ejection fr action (continuous, and modeled via a 2-df continuous piecewise linear spline 
with a knot at 50%, allowing for a separate odds ratio per year above and below 50%, 
given that it is expected that mortality risk likely decreases smoothly up to about 
50% but then perhaps levels off thereafter), 
• race/ethnicity (binary: white non-Hispanics versus all others), 
• diabetes (binary: yes versus no), 
• myocardial infarction (binary: yes versus none), 
• dialysis access (binary: catheter versus no catheter). 
The adjusted odds ratio (OR) for WCD along with its corresponding 95% confidence interval 
(CI) will be estimated via CLR. Note that, in stark contrast to case-control studies, there is 
essentially no loss of efficiency due to heavy stratification resulting in a large number of 
strata, provided almost every stratum contains at least 1 patient from each group (WCD, 
non-WCD). This condition is guaranteed, given the plan to stratify on only those variables 
defining blocks for randomization. This was verified by simulation and supported by results 
in DeStavola and Cox, which states that there is no loss of efficiency if the strata are 
perfectly balanced (e.g. via stratified randomization).39 Thus, there is no concern of "over-
stratifying," even if SCD were independent of enrolling site and date of enrollment. In fact, 
in order for CLR to be computationally feasible it is necessary that no stratum be too large. 
Furthermore, even if SCD were independent of some or all of the 5 variables (8 elf) 
parametrically adjusted for, the loss of efficiency and precision would be negligible since 
randomized treatment is completely independent of all risk factors. On the other hand, to 
the extent that SCD is associated with any of the adjustment or stratification variables, 
failing to control for them at the analysis stage could result in a substantial loss of 
efficiency. Standard power calculations assume that subjects are independent and 
identically distributed, at least given the adjustments, but this assumption would be 
violated if important predictors of SCD were not controlled for, thus resulting in lower 
power than that suggested by standard sample size and power calculations. 
Exploratory analysis of the secondary endpoint of all-cause mortality will be based on a 
single 2-sided nominal 0.05 level LRT, using the same CLR method as used to analyze SCD, 
with whatever sample size (650, 975, or 1300 patients per arm) happens to be available 
when the trial ends. A simple nominal 0.05 level test will be performed for the analysis of 
all-cause mortality, treating the resulting data as a fixed sample size. 
Secondary analyses will test interactions between WCD and SCD risk factors in order to 
investigate whether there are subgroups for whom WCD might be especially effective. 
Interactions between pairs of SCD risk factors will also be explored in secondary analyses. 
7.3 
Group Sequential Design 
Standard group sequential methods38 can be applied, given the large-sample approximate 
normality of the estimated log(OR), and PASS 11 software was used to compute the alpha 
and power values for our custom group sequential stopping rule. We plan to conduct 2 
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7.4 
interim analyses once the 6 calendar month SCD outcome has been observed for 112 and 
3/4 of the subjects. Our custom stopping boundaries retain 4% nominal alpha for the third 
and final look, provided the study doesn't stop early, while testing each of the 2 interim 
analyses at the nominal alpha level of 0.01375 (see Table 4). The overall alpha level for the 
study is .05. 
Table 4: Group sequential design for the two-arm randomized clinical trial. 
Look 
Relative 
#WCD 
# non-WCD 
#Total 
Nominal 
Corrected 
Information sub"ects 
sub"ects 
sub·ects 
Al ha 
Al ha 
1 
50% 
650 
650 
1,300 
0.01375 
0.01375 
2 
75% 
975 
975 
1,950 
0.01375 
0.02231 
3 
100% 
1,300 
1,300 
2,600 
0.04000 
0.05000 
Sample Size and Power 
Although the odds ratio (OR) is the canonical parameter for our CLR analysis, we have 
specified power here in terms of the relative risk (RR), which is generally easier to interpret. 
As is well known, the OR will always be more extreme than the RR, though not by much if 
the outcome is rare in both groups (as it is here) or if the effect size is small. 
This study is designed to provide 91% power to detect RR = 0.40 (OR= 0.39), assuming the 
SCD rate in the non-WCD arm is 3.5%. Our group sequential design increases the 
maximum sample size by just 4%, relative to a non-sequential study (1,250 per arm), while 
yielding - if the true RR = 0.4Q- a 36% reduction in expected sample size (804 per arm), as 
there is 69% chance of stopping early, and 46% chance of stopping at the very first look with 
just 650 subjects per arm. 
Power is tabulated in Table 5 for 9 scenarios, varying the RR (.30, .40, .50) as well as the 
SCD mortality rate among controls (3.0%, 3.5%, 4.0%). 
Table 5: Power as a function of RR and the SCD rate in the control arm. 
Power 
Power 
Power 
% SCD 
% SCD 
Absolute 
Relative 
(%)at 
(%)at 
(%)at 
(WCD) 
(non-WCD) 
Reduction Risk 
Look 3 Look 2 Look 1 
in % SCD 
(RR) 
96 
80 
57 
0.90 
3.00 
2.10 
0.30 
85 
60 
38 
1.20 
3.00 
1.80 
0.40 
67 
40 
23 
1.50 
3.00 
1.50 
0.50 
98 
87 
66 
1.05 
3.50 
2.45 
0.30 
91 
69 
46 
1.40 
3.50 
2.10 
0.40 
74 
47 
28 
1.75 
3.50 
1.75 
0.50 
99 
92 
73 
1.20 
4.00 
2.80 
0.30 
94 
76 
53 
1.60 
4.00 
2.40 
0.40 
80 
54 
33 
2.00 
4.00 
2.00 
0.50 
A relative risk of 0.50 (OR= 0.49), i.e. a relative reduction of 50% and an absolute reduction 
of 1.75% in SCD, corresponds with a 12.5% reduction in all-cause mortality due to WCD, 
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assuming the all-cause mortality rate is 14% with about 25% of deaths attributable to SCD 
(3.5% SCD rate). Even under these conservative assumptions, our study maintains 74% 
power, as shown in Table 5. We believe that the risk reduction will be higher (at least 60% 
reduction in SCD, corresponding with at least a 15% reduction in all-cause mortality), thus 
providing 91% power. F UI·thermore, this study maintains 85% power to detect RR = 0.40 
(OR = 0.39) even if the SCD rate were only 3% (rather than 3.5%) among controls. 
7.5 
Randomization Scheme 
Enrolled subjects will be 1:1 randomized to WCD or non-WCD, stratified by enrolling site 
and, implicitly, by calendar time of enrollment given the prospective nature of the study. 
That is, each enrolling site will have its own randomization sequence, ensuring treatment 
balance within each enrolling site. Each such randomization sequence will consist of a 
string of random 4- and 6-blocks. That is, there will be a 50% chance that the first block 
will consist of 4 subjects (2 WCD + 2 non-WCD, in random order), and a 50% chance that it 
will contain 6 subjects (3 WCD + 3 non-WCD, in random order). Each subsequent block size 
will similarly be randomly selected. This procedure makes it very difficult for anyone to 
predict whether the next treatment assignment will be WCD or non-WCD, helping to 
ensure integrity of the study. In contrast, if each block were of size 4, then it would be trivial 
to perfectly predict every 4th treatment assignment (as well as the 3rct, if the first two were 
both WCD, or both non-WCD) which would be undesirable. Using such small blocks will 
also guarantee near perfect balance no matter where the sequence is truncated, i.e. 
regardless of how many subjects are enrolled in each site, and it will further guarantee 
temporal balance not only overall but also within each enrolling site (i.e. balanced 
treatment x time interaction strata) since each randomization block will contain an equal 
number of WCD and non-WCD subjects, with the possible exception of the last (incomplete) 
block in each enrolling site. 
7.6 
Statistical Analysis 
Upon completion of the trial, a two-tailed p-value will be computed as the probability of the 
realized stopping point (under null conditions) plus the probability of all more extreme 
stopping points, defined via the stage wise ordering of the sample space. 38 If the study stops 
at the first look, p :S 0.01375 and inference proceeds as if there were no future potential 
stopping rules. If the study stops at the second look, we know 0.01375 < p :S 0.02231; and 
if the study continues to the third and final look, then either 0.02231 < p :S 0.05 (if nominal 
p :S 0.04) or else p > 0.05 (if nominal p > 0.04). SAS PROC SEQTEST will be used to compute 
the actual p-value, as well as a median unbiased estimated OR, along with 95% confidence 
intervals (CI). 
A point estimate of the true OR, a median unbiased estimate, is that value for OR for which 
the probability of stopping points more extreme than the reached stopping point equals the 
probability of stopping points less extreme than the reached point - and hence the estimate 
is just as likely to underestimate as to overestimate the true risk ratio. Confidence bounds 
for the OR are found similarly: the value of OR for which the probability of more extreme 
values is at most 2.5% and the value of OR for which the probability ofless extreme values 
is at most 2.5% together yield a 95% confidence interval for OR. 
8. RISKS AND BENEFITS 
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Resuscitation success rates decline approximately 10% per minute of delayed defibrillation. The 
LifeVest is designed to deliver defibrillation within one minute of syncopal VTNF. Although 
emergency medical service response times vary by location, the device is expected in general to 
defibrillate faster than the local emergency medical services response and possibly result in a 
better resuscitation success rate. 
Without LifeVest use, the patient is dependent on outpatient emergency medical services for 
treatment in the event of a sudden cardiac arrest. If the device is not worn, if the device fails to 
detect an episode of VTNF, or if having detected the arrhythmia it fails to convert the VTNF, 
then the patient would again be dependent on emergency medical services. 
Prior investigations and current use indicate that the probability of an unnecessary shock 
episode is less than one per 100 months of patient use.5•41•42 The experience of an unnecessary 
shock may be painful and startling, but is not likely induce heart damage or arrhythmia. 
However, there is a small risk that an unnecessary shock will induce a fatal arrhythmia. Non-
sustained VT following an inappropriate shock from a wearable cardioverter defibrillator has 
been observed in about 0.25% of inappropriate shocks (about one in 350 to 400 inappropriate 
shocks). 4 1•42 
If standard defibrillation is required on a patient wearing the device, the electrode belt should 
be unbuckled and the monitor disconnected. If the monitor is not disconnected prior to standard 
defibrillation, there is a possibility that some of the defibrillation current could be shunted 
through the electrodes. Although not directly harmful to the patient, such shunting might reduce 
the effectiveness of the rescue defibrillation. A warning label on the garment instructs emergency 
medical personnel to disconnect the system before using a standard defibrillator. 
9. SUBJECT CONSENT AND CONFIDENTIALITY 
Each patient will be informed of the purpose of the investigation, as well as the potential risks 
and benefits of the study prior to their enrollment in the study. The patient must freely sign the 
current IRB reviewed Informed Consent Form prior to enrollment. In the event that the 
information regarding potential risks and benefits contained in the Informed Consent Form 
changes, the subject must sign the new Informed Consent Form at the next return visit or be 
informed as directed by the reviewing IRB. 
Each subject will receive a unique subject identification number. The subject's name and identity 
will be known to the local principal investigator and the Sponsor, as necessary for device use and 
study conduct, but will be kept confidential. Authorized personnel from the IRB and regulatory 
authorities may have access to original subject records. 
At the end of the data collection period, a fully de-identified, HIPAA-compliant dataset will be 
created using all variables available from the Case Report Forms and device data contained 
within Life Vest network. This dataset will be used for analysis and publication purposes. 
10. ETHICAL CONSIDERATIONS 
The protocol, informed consent form, and relevant supporting information must be submitted to 
the IRB for review and must be approved before the study is initiated. In addition, any patient 
recruitment materials must be approved by the IRB prior to being used. This study will be 
conducted in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with Good Clinical Practice and applicable regulatory 
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requirements. The study must be conducted in accordance with the regulations of the United 
Stated Food and Drug Administration (FDA) as described in 21 CFR 50, 56 and 812, applicable 
laws and the IRB requirements. 
11. ADVERSE EVENTS 
The Investigators are responsible for recording and reporting adverse events deemed to be 
related to the use of the WCD in the Adverse Event Case Report Form. The Investigator must 
first assess whether the adverse event may be or is clearly not causally related to the WCD 
device. Adverse events must be reported to reviewing IRBs per local reporting requirements. 
The Investigator must next assess the seriousness of the adverse event. Serious adverse events 
include any event which is fatal or life-threatening, requires or prolongs hospitalization, is 
permanently disabling, or requires medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body structure or a body function. 
The Investigator should also assess whether the adverse event is anticipated or unanticipated. 
An unanticipated adverse event is any adverse event not identified by nature, severity or 
frequency prior to the investigation. The following events are commonly reported in patients 
having hemodialysis and therefore should not be reported unless deemed related to WCD wear: 
infection, hypotension, access site cellulitis, anemia, electrolyte imbalance, dyspnea, muscle 
cramps, pruritus, restlessness, and seizures. Anticipated events that may be caused by WCD 
use are as follows: skin rash or irritation, sleeplessness due to WCD alarms occurring at night 
and inappropriate shocks. 
If the adverse event may be causally related, and is serious and unexpected, the Investigator 
must immediately record the event in the Case Report Form. These events will be reported to 
the Sponsor from the Data Coordination Center (DCC) upon entry to into the CRF. 
The 
reviewing IRB must also be notified within 10 working days. 
11.1 Unanticipated Adverse Device Effect (DADE) 
The investigational device exemption (IDE) regulations define an unanticipated adverse 
device effect (DADE) as "any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, 
or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects". UADEs must be reported by the clinical investigator to the 
sponsor and the reviewing IRB, as described below: 
• 
For device studies, investigators are required to submit a report of a UADE no event 
than 10 working days after the investigator first learns of the event. UADE information 
must be entered into the CRF as soon as possible so notification of the event to the 
sponsor can occur through the DCC. 
• 
Sponsors must immediately conduct an evaluation of a UADE and must report the 
results of the evaluation to FDA, all reviewing IRBs, and participating investigators 
within 10 working days after the sponsor first receives notice of the effect. 
12. DATA MANAGEMENT 
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The Data Coordinating Center (DCC) for the study will be Heart Research Follow-up Program 
at the University of Rochester. The Heart Research Follow-up Program has provided program 
coordination and data management for several large NIH clinical studies during the past 25 
years and for major clinical intervention trials related to the series of Multicenter Automatic 
Defibrillator Implantation Trials (MADIT) involving thousands of subjects. The DCC will 
develop and coordinate data management through dedicated personnel. In this study, electronic 
web-based data entry using the clinical data-management system developed by Omnicomm. 
This system permits data expansion, easy updating, and rapid retrieval; it has simplified report-
generating routines and an audit trail component. 
As with any study, accurate and timely completion of documentation is essential for the 
successful completion of the trial. The Investigators will be responsible for obtaining and 
maintaining Informed Consent Forms (90D0126_ICD) and completing Case Report Forms 
(90D0126_CRF) through the electronic web-based data entry system maintained by the DCC. A 
copy of the Informed Consent Form will be given to every subject. 
The Sponsor stores ECG and compliance information from the WCD, obtained through periodic 
downloading during device use. A subset of this information containing at a minimum daily 
device use (compliance) and ECG recordings, including baseline and those recorded during 
alarms lasting at least 30 seconds, will be periodically sent to the DCC. This information will be 
de-identified and assigned a study identification number prior to transmission to the DCC. 
13. ADMINISTRATIVE RESPONSIBILITIES 
ZOLL, the Sponsor, is responsible for study administration as well as providing devices and 
related materials for the study. The Sponsor will select appropriate investigators, assure 
collection of investigator agreements, assure IRB approval of the protocol, and monitor informed 
consent records. 
The Sponsor will designate appropriately trained and qualified individuals to monitor the 
investigation. These individuals will verify the adherence to procedures specified in the protocol, 
and verify maintenance of required subject and data records. Monitoring activities will be 
conducted according to ZOLL's Monitoring of Clinical Studies Standard Operating Procedure 
(ZOLL 90D0013) and will be documented. 
The Sponsor will provide trained and qualified individuals to fit subjects randomized to wear the 
WCD and to provide training on the use of the WCD. 
The Steering Committee will be responsible for general scientific oversight and progress of the 
study. Steering Committee Members will be appointed by the Sponsor. The committee will be 
chaired by Dr. Wojciech Zareba and co-chaired by Dr. Charles Herzog, and include a 
representative from the Sponsor. The Steering Committee will be responsible for overseeing 
study progress including ancillary studies, scientific policies, integrity and direction. It will 
appoint the analysis and publications committee and writing groups, ensuring that information 
from the study is disseminated in the scientific literature and at scientific meetings. The Steering 
Committee will meet at least twice in the first year, and then at least once yearly in person or 
by conference call. An executive subgroup of the Steering Committee will be responsible for 
decisions that require attention between Steering Committee meetings, and for major financial, 
administrative, and operational decisions. The Executive Committee will consist of Dr. Zareba 
(chair), Dr. Herzog (co-chai1'), and a representative from the Sponsor. 
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The Data Coordination Center (DCC) will be the Heart Research Follow-up Program at the 
University of Rochester, and have responsibility for clinical data coordination. The DCC will 
provide management of data for the overall project independent of the Sponsor. All case report 
forms will be collected directly by the DCC. 
The study will be monitored by an independent Data Safety Monitoring Board (DSMB). The 
DSMB will be appointed by the Sponsor. The DSMB will review and validate all events used for 
the stopping rule. 
They will also periodically review all aspects of the trial, including 
inappropriate therapies, to ensure the safety of the participants. The DSMB is responsible for 
appointing adjudication committees for significant endpoints including deaths (through the 
Mortality Committee) and ECG analysis (through the Wearable Defibrillator Interrogation 
Adjudication Committee). The DSMB will communicate directly with the DCC and the 
adjudication committees. 
The Investigators are responsible for obtaining and maintaining ethics approval of the study 
protocol. The Investigators are responsible for obtaining patient consent, and maintaining 
Informed Consent Forms and Case Report Forms for each subject. All forms must be signed by 
the Investigator or by the Investigator's designee. If the Investigators designate an individual to 
sign these forms, written notification must be provided to the Sponsor. The Investigators are 
responsible for maintaining records of study protocol deviations and amendments and all 
correspondence relating to the study. The Sponsor will provide an Investigator Notebook to serve 
as a study reference and regulatory binder. At the conclusion of the study, the Investigators will 
provide a summary report to the Sponsor and the reviewing IRB. 
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