Evaluation of the Safety and Efficacy of the OPTIMIZER System With Active Fixation Leads in Subjects With Heart Failure Resulting From Systolic Dysfunction: FIX-HF-5
Phase: NA
Conditions: Heart Failure, Congestive
Sponsor: Impulse Dynamics

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 1 of 51 
 
 
 
 
 
 
Evaluation of the Safety and Efficacy of the 
OPTIMIZER System with Active Fixation Leads in  
Subjects with Heart Failure Resulting from Systolic Dysfunction: 
FIX-HF-5 
 
Clinical Investigation Plan 
 
Protocol #IDPT 2003-07-C 
 
ORIGINAL Version:  April 15, 2003 
Revised April 15, 2004 
Revised May 6, 2004 
Revised November 24, 2004 
Revised January 14, 2005 
Revised April 4, 2005* 
Revised June 17, 2005* 
Revised July 15, 2005 
Revised November 17, 2005* 
Revised September 22, 2006 
Revised January 18, 2011 
Revised August 7, 2014 
 
Sponsor: 
Impulse Dynamics NV 
6 Werfstraat 
Curacao,  
Netherlands Antilles 
 
US Sponsor: 
Impulse Dynamics (USA), Inc. 
30 Ramland Road South 
Suite 101 
Orangeburg, New York 10962 
Tel: 
845-359-2389 
Fax: 
801-601-7832 
 
* Protocol version sent to FDA only and not to the clinical sites. 
 
 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 2 of 52 
 
TABLE OF CONTENTS 
 
Section 
Page 
I. 
Title ----------------------------------------------------------------------------------------------- 4 
II. 
Background Information --------------------------------------------------------------------- 4 
A. Name and description of investigational product  ---------------------------------------- 4 
B. Summary of findings from non-clinical studies that potentially have clinical 
significance and from clinical trials that are relevant to the trial ---------------------- 5 
1. Nonclinical studies ------------------------------------------------------------------------ 5 
a. Basic research ------------------------------------------------------------------------- 5 
b. Chronic animal study ---------------------------------------------------------------- 7 
c. Clinical studies ------------------------------------------------------------------------ 8 
C. Summary of the known and potential risks and benefits, if any, to human 
subjects -------------------------------------------------------------------------------------------- 13 
D. Description of and justification for the route of administration, dosage, dosage 
regimen and treatment period ----------------------------------------------------------------- 19 
E. Statement that the trial will be conducted in compliance with the protocol, 
GCP and the applicable regulatory requirements ----------------------------------------- 20 
F. Description of the population to be studied ------------------------------------------------ 20 
G. References to literature and data that are relevant to the trial and that provide 
background for the trial ------------------------------------------------------------------------ 20 
III. 
Trial Objectives and Purpose --------------------------------------------------------------- 20 
IV. 
Trial Design ------------------------------------------------------------------------------------- 21 
A. Primary and secondary endpoints to be measured during the trial -------------------- 21 
B. Description of the type/design of the trial and a schematic diagram of trial 
design, procedures and stages ---------------------------------------------------------------- 23 
Figure 1.  Study Overview --------------------------------------------------------------- 23 
Table 1.  Schedule of Events ------------------------------------------------------------ 24 
C. Anticipated Rate of Site and Patient Recruitment ---------------------------------------- 25 
D. Data Safety and Monitoring Board (DSMB) ---------------------------------------------- 25 
E. Event Adjudication Committee (EAC) ----------------------------------------------------- 25 
F. A description of the measures taken to minimize/avoid bias --------------------------- 25 
G. A description of study treatments, the dosage and the dosage regimen of the 
investigational product ------------------------------------------------------------------------- 27 
H. Expected duration of subject participation ------------------------------------------------- 28 
I. 
Description of the “stopping rules” or “discontinuation criteria” --------------------- 28 
J. Accountability procedures for investigational products --------------------------------- 28 
K. Maintenance of trial treatment randomization codes and procedures for 
breaking codes ----------------------------------------------------------------------------------- 29 
L. Identification of any data to be recorded directly on CRFs (i.e., no prior 
written or electronic record of data), and to be considered to be source data ------- 29 
V. 
Selection and Withdrawal of Subjects ----------------------------------------------------- 29 
A. Subject inclusion criteria ---------------------------------------------------------------------- 29 
B. Subject exclusion criteria ---------------------------------------------------------------------- 30 
C. Subject withdrawal criteria and procedures specifying --------------------------------- 32 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 3 of 52 
Section 
Page 
VI. 
Treatment of subjects ------------------------------------------------------------------------- 33 
A. Treatments to be administered---------------------------------------------------------------- 33 
1. Screening ------------------------------------------------------------------------------------ 33 
2. Baseline Evaluation and Randomization ---------------------------------------------- 33 
3. Study Procedures --------------------------------------------------------------------------- 34 
B. Treatment of Subjects Enrolled in Phase I of this Study -------------------------------- 40 
C. Medications/treatments permitted (including rescue medication) and not 
permitted before and/or during the trial ----------------------------------------------------
40 
D. Procedures for monitoring subject compliance ------------------------------------------- 40 
VII. 
Assessment of efficacy ------------------------------------------------------------------------ 40 
A. Specifications of efficacy parameters  ------------------------------------------------------ 40 
B. Methods and timing for assessing, recording and analyzing efficacy 
parameters ----------------------------------------------------------------------------------------
41 
VIII. 
Assessment of safety --------------------------------------------------------------------------- 42 
A. Specification of safety parameters ----------------------------------------------------------- 42 
B. Serious, Device Related and Unanticipated Adverse Event Definitions ------------- 43 
C. Procedures for recording and reporting adverse events and intercurrent 
illnesses -------------------------------------------------------------------------------------------
44 
D. Type and duration of follow-up of subjects after adverse events --------------------- 44 
IX. 
Statistical Considerations -------------------------------------------------------------------- 44 
A. Description of the statistical methods to be employed ---------------------------------- 44 
1. Primary efficacy analysis ----------------------------------------------------------------- 44 
2. Primary Safety Analysis ------------------------------------------------------------------ 45 
3. Justification of sample size -------------------------------------------------------------- 46 
4.  Secondary efficacy analyses ------------------------------------------------------------- 47 
5. Other Analyses ----------------------------------------------------------------------------- 49 
B. Number of subjects planned to be enrolled ------------------------------------------------ 49 
C. Study Termination ------------------------------------------------------------------------------ 49 
D. Procedure for accounting for missing, unused and spurious data --------------------- 49 
E. Procedures for reporting deviations from the original statistical plan ---------------- 50 
F. Selection of subjects to be included in the analyses ------------------------------------- 50 
X. 
Direct access to source/data documents --------------------------------------------------- 50 
XI. 
Quality control and quality assurance ----------------------------------------------------- 50 
XII. 
Ethics --------------------------------------------------------------------------------------------- 51 
XIII. 
Data handling and record keeping --------------------------------------------------------- 51 
Appendix A: CCM References 
 
 
Appendix B: Phase II Informed Consent  template / HIPAA template 
 
 
Appendix C: Template Case Report Form 
 
 
Appendix D: Treatment of Phase I Study Subjects 
 
 
Appendix E: Device-device Interaction Testing Procedure 
 
 
Appendix F: OPTIMIZER III Long-term Follow-up 
 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 4 of 52 
 
 
Clinical Investigation Plan 
 
I. 
Title 
Evaluation of the Safety and Efficacy of the OPTIMIZER System with Active 
Fixation Leads in Subjects with Heart Failure Resulting from Systolic Dysfunction 
(FIX-HF-5) 
 
II. 
Background Information 
A. 
Name and description of investigational product  
The investigational product is the OPTIMIZER III System, a system capable of 
delivering non-excitatory cardiac contractility modulation (CCM) signals.  
These electrical signals are intended to influence myocardial properties in 
patients with chronic heart failure.  The System consists of five major 
components: 
1. 
An implantable pulse generator with specialized internal components 
that generate the cardiac contractility modulation (CCM) signal (the 
OPTIMIZERTM III device);  
2. 
Three commercially available percutaneously placed leads:  
a. 
one in the right atrium to sense right atrial activation, and  
b. 
two in the right ventricle to sense ventricular activation and 
deliver CCM signals.   
For purposes of this study, any commercially available atrial lead 
can be used.  For the ventricular sensing and CCM delivery leads 
the St. Jude Tendril DX 1388T or 1688T active fixation lead shall be 
used (or others as qualified by Impulse Dynamics and approved by 
FDA);   

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 5 of 52 
3. 
A programmer which interfaces with the OPTIMIZER implantable 
pulse generator via a standard programming wand, providing the means 
to set System parameters and assess device diagnostics; 
4. 
A battery charging system, consisting of a charger unit, a wand and a 
patient vest;   
5. 
The MONITA Hemodynamic Data Acquisition and Processing 
System is a data acquisition and analysis system that is used to measure 
acute changes in dP/dtmax in response to CCM signals during the 
implantation of the OPTIMIZER III System.  The implanting physician 
shall use this information to decide whether or not to proceed with the 
implantation based upon criteria specified in the protocol below. 
 
B. 
Summary of findings from non-clinical studies that potentially have clinical 
significance and from clinical trials that are relevant to the trial 
1. 
Nonclinical studies 
a. 
Basic research 
Experimental evidence indicates that electrical signals can 
modulate cardiac contractility.  When cardiac contractility 
modulating (CCM) signals were applied to isolated rat myocytes, 
myocyte shortening increased and peak intracellular [Ca2+] 
increased.  This suggested that during CCM signal  application 
there was an increase in intracellular calcium which was the basis 
for the increase in myocyte contractility. 
When CCM signals were applied to isolated rabbit papillary 
muscles, cardiac contractility modulation reached a steady, stable 
state within several seconds and recovered within the same 
amount of time after signal cessation.  Peak tension increased, but 
diastolic tone was not significantly affected.  The CCM signal 
effect was reversed when the polarity of the signal was reversed, 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 6 of 52 
even though the timing and duration of the signal were constant.  
Intracellular microelectrode recordings showed that signals that 
increased cardiac contractiltiy were associated with prolongation 
of the action potential, whereas signals that depressed contractilty 
caused a decrease in action potential duration.  In either case, 
there was no extra action potential elicited by CCM signals, 
indicating that their mechanism does not work by any mechanism 
related to post-extra-systolic potentiation (PESP).  Furthermore, 
when CCM signals were applied in rabbit papillary muscles at 10 
times the threshold current level simultaneously with the pacing 
stimulus, there was no additional force generation.  This 
suggested that the mechanism by which CCM signals enhanced 
myocardial contractility was not related to recruitment of 
additional fibers or to recruitment of fibers with higher 
thresholds. 
Hemodynamic data obtained from experiments on 17 healthy, 
open chest dogs indicated that CCM signals applied to the left 
ventricle in dual chamber paced hearts induced an increase in 
cardiac contractility as indexed by an augmentation of +dP/dtmax.  
Increases in LV systolic pressures and aortic flow were also 
observed, with a trend towards reduction in end diastolic 
pressure. 
CCM 
signals 
were 
applied 
in 
six 
heart-failure 
dogs, 
transvenously in four dogs and epicardially in the other two dogs.  
The results indicated an enhancement in LVP, dP/dtmax and ESP, 
in both AAI and DDI pacing modes and in normal sinus rhythm.  
The CCM signal was applied to 16 DDI paced pigs, resulting in 
an increase in dP/dtmax and an increase in LVP. 
Experiments conducted in healthy dogs suggested that CCM 
signal application to either the left or right ventricle could 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 7 of 52 
improve myocardial contractility with no major adverse effects.  
Inotropic effects were greater from the right side when the signals 
were delivered simultaneously to two electrodes inserted into the 
right ventricular septum. 
 
b. 
Chronic animal study 
A six-month study was conducted in 11 animals to evaluate the 
safety and performance of the OPTIMIZERTM II System under 
simulated clinical conditions.  This study involved seven 
treatment animals and four control animals in which 
OPTIMIZER II Systems were implanted.  In the treatment 
animals, the OPTIMIZER II System delivered CCM signals to 
the myocardium for seven equally-spaced one-hour periods every 
24 hours.  This signal delivery paradigm was similar to the one 
that will be used in the clinical investigation.  In the control 
animals, the device delivered simulated pacing signals under the 
same paradigm. 
The safety of the System was assessed on the basis of the effects 
of the CCM signal on myocardial tissue and on lead integrity, the 
changes in global and regional myocardial function and inotropic 
reserve and the incidence and severity of adverse events. 
At the end of the study, the data showed that the System operated 
as intended and delivered CCM signals on >90% of beats during 
the intended periods.  The pulse generator turned on and off 
automatically for the intended periods.   
The effects of CCM signals on gross and histologic appearance of 
the myocardium were indistinguishable from those observed with 
simulated pacing signals.  At lead insertion sites, mature fibrous 
material devoid of signs of acute inflammation was observed.  

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 8 of 52 
There was no effect on histologic appearance of myocardium 
remote from the lead insertion sites.   
The myocardium retained normal inotropic reserve, as evidenced 
by normal resting function and normal response to dobutamine 
infusion (assessed by dose-dependent changes in heart rate, 
dP/dtmax, dP/dtmin, time constant of relaxation, ventriculography 
and global and regional echocardiographic assessment of 
myocardial function).  There was no untoward effect of CCM 
signal delivery over this period of time on lead integrity, as 
assessed by lead impedances and inspection by scanning electron 
microscopy.   
In aggregate, these data suggested that the device operated as 
intended and the CCM signals had no identified adverse effects 
on normal canine myocardium.  This study is considered to be 
appropriate to provide some insight into long term safety of the 
system because the testing has evaluated a very wide range of 
myocardial properties with no suggestion of deleterious effects.  
The finding of no active inflammation around the lead site is a 
strong indication that there is no ongoing damage created by the 
signals.  Therefore, it is very unlikely that longer term testing in 
animals would yield any additional or contrary information to 
what has been identified in this study. 
 
c. 
Clinical studies 
(1) 
Pilot clinical study 
A pilot clinical study of the application of the CCM signal using 
an external device was conducted with 24 heart failure subjects 
undergoing EP procedures in Milan, Italy.  CCM signals were 
delivered via a Cardima octapolar catheter inserted into the great 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 9 of 52 
cardiac vein (GCV) via the coronary sinus.  The results indicated 
that CCM signals enhanced hemodynamic parameters.  In six 
subjects with left bundle branch block (LBBB), the application of 
the CCM signal was applied in addition to biventricular pacing 
and the effect was additive.   
From the left side experience, the primary findings were:  
 Improved systolic performance 
 No significant change in diastolic function 
 Sensation in a small number of subjects, possibly due to the 
proximity of the CCM electrode to the epicardial nerves 
 Difficulty in optimizing lead position in the coronary sinus  
These observations provided the motivation for testing whether 
CCM signals could be effective hemodynamically if delivered to 
the RV septum.  In a second pilot study, as a basis of comparison, 
eleven subjects had CCM signals applied to the right side of the 
heart.  Primary observations were: 
 Improved systolic performance 
 No sensation in response to CCM signal/application 
 Easily positioned catheters 
A larger inotropic effect from the right side was observed when 
the signal was delivered simultaneously to two right ventricular 
septal leads as compared to when it was delivered from one 
electrode alone. 
(2) 
Chronic feasibility study 
A safety study of the implantable OPTIMIZER System in six 
subjects with functional NYHA Class III heart failure and 
baseline ejection fraction of 35% or less by echocardiography 
was conducted at San Raffaele Hospital in Milan, Italy.  Enrolled 
subjects were evaluated at baseline by echocardiography, a 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 10 of 52 
cardiopulmonary stress test, a 6 minute walk test and 24-hour 
Holter monitoring. 
The CCM leads of the OPTIMIZER System were standard 
pacing electrodes placed percutaneously and guided to the RV 
endocardial septum.  CCM signal amplitude, delay, duration and 
number of pulses (to a maximum of three) were set during the 
implantation procedure to achieve a minimum 5% improvement 
in dP/dtmax.  Subjects underwent an acute and a chronic phase of 
monitored CCM signal application or sham signal application, 
five days per week.  Follow-up testing included echocardiograms, 
24-hour Holter monitor tests, cardiopulmonary stress tests, 6-
minute walk tests and completion of a quality of life 
questionnaire.  All subjects completed participation in the study.  
There were no clinically significant adverse events in any subject. 
(3) 
Chronic safety and performance study (FIX-HF-3 Study) 
A clinical investigation was conducted to evaluate the safety and 
functionality of the OPTIMIZER II System in subjects with 
New York Heart Association (NYHA) Class III heart failure.  
Twenty-two subjects underwent OPTIMIZER™ II System 
implantation.  Subjects underwent application of CCM signals for 
three consecutive hours a day for eight weeks after implantation. 
Device interrogations indicated that CCM signals were delivered 
for the intended 180 minutes per day and on approximately 
84±16% (median 90%) of normal sinus beats.  CCM signals were 
appropriately delivered during the relative refractory period 
(between the QRS complex and the onset of the T-wave) and 
were suppressed on PVCs as designed.   
The data indicated that subject symptoms improved during the 
study.  From Class III at entry, NYHA class decreased in three 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 11 of 52 
subjects to Class I, in 15 subjects to Class II and in two subjects, 
it was unchanged.  Minnessotta Living with Heart Failure 
Questionnaire (MLWHFQ) scores decreased from baseline value 
of 41.9±22.2 to 23.6±17.9 (mean reduction of 16.9±21.9, 
p=0.0027).  Ejection fraction increased from the baseline value of 
21.4±6.3% to 27.4±7.0% at eight weeks (mean increase 
5.9±6.4%, p=0.0006).  There was no significant change in heart 
rate (76±11, median 75), number of PVCs per hour (70.8±176.7, 
median 21.4), number of runs of non-sustained ventricular 
tachycardia per hour (0.04±0.10, median 0.02), or the number of 
premature atrial contractions per hour (17.2±46.8, median 1.7).   
There were four deaths (two during the study period and two after 
study completion), three apparently from cardiac causes in 
subjects with severe heart failure at high risk of mortality.  The 
fourth death was due to a massive pulmonary embolism caused 
by documented deep vein thrombosis.  A subject with a heart 
transplant on chronic immuno-suppressive therapy who suffered 
from chronic rejection and who was treated with the 
OPTIMIZER™ II system on a compassionate basis but who was 
followed according to the protocol, died of sepsis.  All subjects 
continue to be followed closely. 
Overall, the rate and severity of adverse events were generally 
expected for patients with severe heart failure within the context 
of a study of a device-based treatment for heart failure, and were 
observed with a frequency similar to that of a recent study of 
biventricular pacing.  Seventy adverse events were reported, most 
commonly palpitations, shortness of breath, dizziness and water 
retention.  Twenty events in 11 subjects were classified as serious 
and/or severe.  Nine events occurring in five subjects were 
classified as device-related.  The most common device-related 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 12 of 52 
events were pocket hematoma and stimulation sensation.  In 
aggregate, these results indicate that the OPTIMIZER™ II 
System operates as intended, is safe and its use is associated with 
improvements in symptoms of heart failure.   
(4) 
Increased Duration of Exposure to CCM Signals (FIX-HF-3 
Extension Study) 
Fourteen of the patients who participated in the study described 
in (3) above participated in a second clinical study to investigate 
the effects of increased duration of CCM treatment.  In these 
subjects, the OPTIMIZER II device was programmed to deliver 
CCM signal for 7 noncontiguous hours per day (7 cycles of 1 
hour on, 2 hours 24 minutes off) for 6 months.  Upon entry into 
this increased dose safety study, the clinical status was markedly 
improved compared to their original baseline status prior to 
having received CCM treatment.  NYHA averaged 1.6±0.5, 
MLWHFQ averaged 9.6±6.2, 6MW averaged 471±121, peak 
VO2 averaged 1065±215 ml O2/min (~14.0±2.8 ml O2/kg/min) 
and ejection fraction averaged 35±9%.  Over the 24 week follow-
up period, the clinical parameters were maintained at relatively 
constant levels, except for peak VO2 which increased to 
1201±343 ml O2/min (15.8±4.5 ml O2/kg/min; p=0.02).  Medical 
therapy for heart failure did not change in a majority of patients 
during this study, and there was an approximately equal number 
of instances when medication use was increased as when it was 
decreased.   
During the 8 week period of the original FIX-HF-3 study 
described above, there were 43 adverse events reported in these 
14 study subjects.  Ten of these events were classified as serious 
and/or severe.  Twelve of the events were classified by the 
investigators as being definitely, possibly or probably related to 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 13 of 52 
the device.  In contrast, during the 24 week period of the present 
FIX-HF-3 Extension study, there were a total of 43 adverse 
events of which three were classified as serious and 14 were 
classified as being definitely, possibly or probably related to the 
device.  Thus, the rate (number of AEs/time) and severity 
(number of serious AEs) of adverse events was significantly 
lower in the FIX-HF-3 Extension study than in the original FIX-
HF-3 study.  The most common adverse events reported during 
the FIX-HF-3 Extension study were palpitations, dyspnea and 
pulmonary edema, which are similar to what was reported in the 
original FIX-HF-3 study.   
 
In aggregate, these results suggest that the OPTIMIZER™ 
System operates as intended, and appears to be safe when set to 
deliver CCM pulses for 7 hours/day and that further study of the 
OPTIMIZER II system in patients with chronic heart failure 
within the context of randomized, blinded trials to rigorously 
evaluate the safety and efficacy of this form of treatment are 
warranted. 
 
C. 
Summary of the known and potential risks and benefits, if any, to human 
subjects. 
1. 
Known Potential Risks 
The results of bench testing, from preclinical studies using prototype 
devices in animals and from preliminary clinical studies suggest that 
acute applications of CCM signals present no undue risk to subjects.  
However, there are recognized risks associated with the heart failure 
state itself, with interventional cardiovascular procedures in heart failure 
patients and potentially with the use of the OPTIMIZER™ system. 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
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a. 
Death 
Class III and IV heart failure patients are at risk for death from 
their underlying disease, with annual mortality rates ranging from 
~20% for Class III patients to as high as ~75% for Class IV 
patients.  With any invasive cardiovascular procedure in heart 
failure patients there may be added risk of death.  Applying 
appropriate subject selection criteria, using meticulous techniques 
and providing attentive post-procedure care will minimize the 
risks associated with these procedures. 
b. 
Risks associated with placement of a Millar catheter   
During implantation of the OPTIMIZER pulse generator, a 
Millar catheter will be temporarily placed into the left ventricle in 
order to measure the peak rate of LV pressure rise (dP/dtmax).  
The catheter will be inserted via standard percutaneous 
cannulation of a femoral artery.  The risks associated with 
temporary placement of the Millar catheter include infection, 
bleeding, ventricular arrhythmias, and damage to the femoral 
artery, aorta or ventricle.  These risks are minimized by having 
experienced operators insert the catheters and by having the 
procedure performed under fluoroscopic guidance. 
c. 
Risks of implantation of the OPTIMIZER pulse generator 
The risks associated with implantation of the OPTIMIZER 
pulse generator are similar to those of implanting a permanent 
pacemaker, which are well characterized and include (but are not 
limited to) infection, bleeding, pneumothorax, myocardial 
perforation by the leads and pain at the incision site.  Applying 
appropriate subject selection criteria, using meticulous surgical 
technique and providing careful post-operative care will 
minimize the risks associated with these procedures. 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
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d. 
Arrhythmias and/or palpitations associated with CCM signal 
application  
Arrhythmias may occur as a result of CCM signal application.  
Arrhythmias may include bradyarrhythmias or tachyarrhythmias 
as well as ventricular arrhythmias or supraventricular arrhythmias 
and may be associated with palpitations.  These may include 
sinus bradycardia, complete heart block, junctional rhythm, 
asystole, sinus tachycardia, atrial fibrillation, atrial flutter, 
paroxysmal atrial tachycardia, multifocal atrial tachycardia, 
premature atrial contractions, premature ventricular contractions, 
nonsustained or sustained ventricular tachycardia, ventricular 
fibrillation, electromechanical dissociation, or cardiac arrest.  
Palpitations are commonly reported in patients with heart failure 
and may or may not be associated with arrhythmias.  Safety 
algorithms intended to minimize the incidence of arrhythmias 
have been incorporated into the OPTIMIZER System.   
e. 
Myocardial damage 
Tissue damage may occur at the points where the leads are 
inserted into the heart muscle.  The histologic results of 
laboratory animal testing have indicated that application of CCM 
signals through the leads does not induce any clinically 
significant amount of myocardial damage.   
f. 
Infection 
The implantable components of the OPTIMIZER System are 
supplied sterile.  The risk of post-implantation infection is 
minimized by appropriate implantation techniques and care of the 
wound sites.  Infectious complications may include localized 
infections (infections of the device pocket, femoral cannulation 
sites, cellulitis, pneumonia, etc) and sepsis.  

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
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g. 
Thromboembolic Events 
Thrombosis or embolism may occur as a result of the placement 
of the leads for the OPTIMIZER II System or as a result of the 
underlying disease.  These events may include deep vein 
thrombosis, renal vein thrombosis, pulmonary embolism and 
mesenteric thrombosis.  Since there is only one additional lead 
compared to a normal dual chamber pacemaker, the added risk is 
considered to be not clinically significant. 
h. 
Right or Left Bundle Branch Block 
Insertion of pacemaker leads on the right ventricular septum can 
occasionally cause transient interruption of the specialized 
conduction system of the heart, which can lead to bundle branch 
block.     
i. 
Worsened heart failure 
CCM signal application is intended to improve the strength of the 
heart beat and lessen symptoms of heart failure.  However, if 
signal application is ineffective, the subject may experience the 
typical symptoms present prior to device implantation or may 
experience the deterioration of symptoms that is characteristic of 
this disease, including shortness of breath at rest or on exertion, 
fluid accumulation and pleural effusion, cardiogenic shock, 
respiratory failure (possibly with the need for mechanical 
ventilation) or may require alteration of medication doses. 
j. 
Risk of Myocardial Perforation 
There is a risk of right ventricular perforation with insertion of 
any pacemaker lead.  If this happened it could result in fluid 
(including blood) accumulation around the heart (as in a 
pericardial effusion) that could compromise ventricular function 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
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August 7, 2014 
Page 17 of 52 
or even cardiac tamponade.  This risk can be minimized by using 
appropriate, standard insertion techniques by experienced 
operators. 
k. 
Vascular laceration and bleeding 
There is a risk of vascular laceration and bleeding as a result of 
the implant procedure.  These may include bleeding at the 
femoral access sites and in the pulse generator pocket.  This risk 
can be minimized by using appropriate surgical technique. 
l. 
Chest wall sensation, phrenic or device pocket stimulation 
CCM signals may cause chest wall sensation or phrenic 
stimulation.  When these have occurred, they have generally been 
short–lived and have been resolved by reducing CCM signal 
voltage.  Occasionally an invasive procedure may be required to 
reposition the leads. 
m. 
Neurologic events 
In addition to the risks discussed above, patients with heart 
failure are at risk for risk of transient ischemic attacks (TIA) and 
stroke.   
n. 
Potential for OPTIMIZER – ICD/Pacemaker interactions 
 
It is possible that the presence of CCM pulses could be sensed by 
an ICD which could be interpreted as ventricular tachycardia by 
the ICD.  In such a case, an inappropriate ICD shock could be 
delivered.  Similarly, if a pacemaker inappropriately sensed a 
CCM pulse for a cardiac depolarization, the pacemaker could be 
inhibited from delivering treatment during a bradycardia (such as 
a sinus bradycardia).  Device interaction testing has indicated that 
these do not occur when true bipolar ICD leads are used and 
when both devices are programmed properly.  To minimize this 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 18 of 52 
risk, all personnel involved with programming the OPTIMIZER 
device are appropriately trained in proper device programming. 
o. 
Surgical revision of the Optimizer System 
There is a potential that any system component could 
malfunction, become damaged, infected, or, in the case of the 
leads, become dislodged.  System component malfunction or 
other clinical circumstances (eg, sepsis) may require noninvasive 
corrective actions or possibly even a surgical revision 
(repositioning, replacement, or removal) of the malfunctioning 
component(s).   
p. 
General Medical  
Patients with heart failure may experience adverse events related 
to their underlying disease and such may be encountered during 
the course of the study.  These may include hypotension, 
dizziness, syncope, worsening renal function, worsening liver 
failure, anemia, etc.  
2. 
Known Potential Benefits 
a. 
CCM signal application 
Based upon available evidence from preclinical laboratory animal 
studies and preliminary clinical safety studies, application of non-
excitatory electrical CCM signals to the heart muscle during the 
absolute refractory period can increase the strength of the heart’s 
contraction.  Subjects receiving CCM signal application may 
experience improvement in myocardial contractility (e.g., 
increased ejection fraction), which could be associated with 
improved exercise tolerance, fewer symptoms of heart failure and 
increased overall quality of life.   
 

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Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
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b. 
Medical Management 
Subjects will receive a significant amount of attention from 
medical professionals during the course of this investigation.  
They will be undergoing cardiac evaluations at frequent intervals.  
Extra attention will be devoted to ensuring that subjects are 
receiving the proper types and doses of medications at the proper 
time.  Many studies have shown that patients benefit significantly 
in how they feel as a result of this type of increased medical 
surveillance, independent of any benefits that might be provided 
by the experimental treatment.  
D. 
Description of and justification for the route of administration, dosage, 
dosage regimen and treatment period. 
CCM signals are delivered through commercially available implanted 
pacemaker leads.  The signals have a specified duration and amplitude (voltage), 
which have been determined in prior pre-clinical and clinical studies.  The 
maximal voltage (7.7V) is delivered unless the subject experiences a side effect 
(e.g., muscular stimulation, sensation), in which case the voltage may be 
decreased.   
The “dose” of CCM signals is determined primarily by the number of hours per 
day that the signal is delivered.  Results of the chronic safety and performance 
study that took place in the European Union (described above) suggest that three 
hours of CCM signal application results in clinical benefit in a majority of 
subjects.  Several subjects initially involved in that study were followed at an 
increased dose (7 hours of CCM signal per day).  The results of that study 
suggested no increase in risk and potentially mild improvements over the 3 hour 
per day regimen.  Phase I of the present study utilized an intermediate dose of 5 
hour/day signal delivery paradigm in order to permit 6 month device longevity 
of the OPTIMIZER™ II system.  Since the safety profile during Phase I of the 
study has been clinically acceptable and for consistency, the present study shall 
continue to use the 5 hour/day dose.   

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 20 of 52 
 
E. 
Statement that the trial will be conducted in compliance with the protocol, 
GCP and the applicable regulatory requirements. 
This clinical trial will be conducted in compliance with the protocol, GCP and 
the applicable regulatory requirements. 
F. 
Description of the population to be studied. 
The patients for whom the OPTIMIZER System is indicated are those with 
reduced ventricular function and symptomatic heart failure.  Subjects entered 
into this investigation will be representative of the patient population with 
stable, moderate to severe heart failure receiving optimal medical therapy that 
are likely to benefit from application of CCM signals. 
G. 
References to literature and data that are relevant to the trial and that 
provide background for the trial. 
Pacemaker implantation has been well characterized and is the standard of care 
for treatment of certain types of cardiac rhythm disorders.  The literature related 
to this therapy is voluminous and readily available.  References specific to CCM 
signal application are listed in Appendix A.  Cardiac resynchronization therapy 
(CRT) is applicable to heart failure patients with conduction abnormalities 
manifested as an increased QRS duration on the body surface electrocardiogram.  
The clinical studies in which CRT has been evaluated have provided important 
information for how to conduct studies of CCM signal application and are 
therefore relevant to the present investigation.   
 
III. 
Trial Objectives and Purpose 
The objective of this investigation is to evaluate the safety and effectiveness of the 
OPTIMIZER System with active fixation leads in subjects with moderate to severe 
heart failure.  Safety and effectiveness endpoints are provided in Section IV below. 
 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
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IV. 
Trial Design 
A. 
Primary and secondary endpoints to be measured during the trial 
1. 
The primary effectiveness endpoint of this study, which will be evaluated 
at the end of six months following the date of scheduled implantation, 
shall consist of the following parameter: 
 
Improvement in exercise tolerance, as quantified by ventilatory 
threshold (VT) measured on cardiopulmonary exercise stress 
testing (CPX), and evaluated by a blinded core lab.  Individual 
patient response will be based on a ≥ 1 mlO2/min/kg 
improvement in VT at 6-months compared to baseline. 
2. 
The secondary efficacy endpoints shall be: 
a. 
Improvement in heart failure class, as assessed by the New York 
Heart Association (NYHA) classification.  NYHA classification 
shall be assigned by:  
i. 
blinded on site clinicians according to their standard clinical 
practice  
ii. by a blinded core lab that evaluates patient responses to a 
standardized questionnaire.1   
b. 
Improvement in quality of life, as assessed by the Minnesota 
Living with Heart Failure (MLWHF) Questionnaire.   
c. 
Improvement in exercise tolerance, as quantified by the six 
minute hall walk test (6MW).   
d. 
Improvement in left ventricular ejection fraction as assessed by 
echocardiography in a blinded core lab. 
e. 
Changes 
in 
left 
ventricular 
size 
as 
indexed 
by 
echocardiographically 
determined 
end-diastolic 
dimension 
determined by a blinded core lab. 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
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August 7, 2014 
Page 22 of 52 
f. 
Improvements in peak VO2 consumption and ventilatory 
efficiency determined on CPX testing.  
g. 
Comparisons of treatment effects separately in subjects whose 
CHF etiology is ischemic or non-ischemic 
h. 
The need for changes in medical treatment for heart failure (either 
up or down titration of doses or changes in the types of 
medications prescribed). 
i. 
Comparison of the primary and secondary safety and efficacy 
outcome measures in subjects with and without a pacemaker or 
ICD. 
j. 
Evaluation of the impact of CCM voltage on primary and 
secondary efficacy and safety outcome measures. 
3. 
The primary safety endpoint of this trial will be: 
 
The proportion of patients experiencing a composite event of all-cause 
mortality and all-cause hospitalizations evaluated at 12 months. 
4. 
The secondary safety endpoints of this trial will be: 
a. 
all-cause mortality 
b. 
cardiac mortality - any sudden death, or death deemed to be related 
to heart failure, arrhythmias, myocardial infarction or any other 
cardiac cause.  The cause of all deaths shall be adjudicated by an 
independent events committee (Section IV.E). 
c. 
the rate of all-cause hospitalizations 
d. 
the rate of cardiac-related hospitalizations - any hospitalization 
during which intravenous diuretics and/or intravenous inotropic 
agents are administered or any other hospitalization otherwise 
deemed to be related to heart failure, arrhythmias, myocardial 
                                                                                                                                                                                        
1 Kubo SH, Schulman S, Starling RC, Jessup M, Wentworth D and Burkhoff D. Development and validation 
of a patient questionnaire to determine New York Heart Association classification. J Card Fail 10: 228-235, 2004. 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 23 of 52 
ischemia or infarction.  The cause of all hospitalizations shall be 
adjudicated by an independent events committee (Section IV.E).  
e. 
overall incidence and seriousness (classified as serious or not) of 
adverse events, all of which are assumed equivalent between the two 
treatment groups. 
f. changes in the frequency of ventricular arrhythmias as assessed on 
Holter monitor recordings. 
 
B. 
Description of the type/design of the trial and a schematic diagram of trial 
design, procedures and stages 
This is a multicenter, prospective, randomized, study in 418 subjects with 
moderate to severe heart failure despite optimal medical therapy.  The study will 
include a baseline eligibility evaluation followed by randomization to either 
receive or not receive an OPTIMIZER device implant.  All patients will be 
followed for twelve-months (Figure 1). Evaluation of subjects will be 
documented on electronic case report forms and will include the tests and 
procedures listed in Table 1. 
FIGURE 1.  Study Overview 
Baseline
Tests
Eligible
Randomi-
zation
Device Implant
Continued Medical
Therapy
12 Months
(primary
safety)
6 Months
(primary
efficacy)
Continued
Follow-up
Scheduled 
Implant Date =
Study Start Date

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Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 24 of 51 
 
TABLE 1.  Schedule of Events 
 
 
  
  
Follow-Up Schedule (relative to Study Start Date§) 
Test 
Screening 
Baseline 
Implant* 
Week 2  
±2 days§ 
+4±1 
Week 
+12±2 
Weeks 
+24±2 
Weeks 
36±2 
Weeks 
50±2 
Weeks 
Every 6 
Months* 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
History 
X 
  
  
X 
X 
X 
X 
X 
X 
X 
NYHA Class (Blinded site clinician assessment) 
X 
  
  
 
 
X 
X 
  
X 
 
NYHA Class (Blinded Core Lab Questionnaire) 
X 
 
 
 
 
X 
X 
 
X 
 
Medications 
X 
  
 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
X 
  
 
X 
X 
X 
X 
X 
X 
 
12-Lead EKG 
 
X 
 
 
 
 
 
 
 
 
Echocardiogram 
  
X 
  
 
 
X 
X 
 
X 
 
MLWHFQ 
  
X 
  
 
 
X 
X 
 
X 
 
6-minute walk 
  
X 
  
 
 
X 
X 
 
X 
 
Cardiopulmonary Stress Test 
  
X 
  
 
 
X 
X 
 
X 
 
24 hour Holter Monitor 
  
X 
  
 
 
X 
X 
 
 
 
Urine pregnancy test 
  
X 
  
 
 
 
X 
 
X 
 
Eligibility determination 
  
X 
  
 
 
 
 
 
 
 
Randomization 
  
X  
 
 
 
 
 
 
 
 
OPTIMIZER™ System Implant* 
  
  
X 
 
 
 
 
 
 
 
Chest X-ray* 
  
  
X 
 
 
 
 
 
 
 
Optimizer Device Interrogation / Programming* 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
ICD Device Interrogation (episodes of VT/VF) 
 
 
 
X 
 
X 
X 
X 
X 
 
Adverse Events, Hospitalizations, and 
Procedures (as needed) /OPTIMZER device-
related SAEs after  50-wks 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 § Study Start Date:  After completion and satisfying all entry criteria, a date shall be scheduled for OPTIMIZER System implant.  This data shall 
serve as the start date for all subjects.  For subjects randomized to CCM Treatment, the OPTIMIZER system shall be implanted on this date.  For 
subjects randomized to the Control group in whom an ICD implant is planned, the Study Start Date shall be the day of the ICD implant.  For 
subjects randomized to the Control group who do not undergo an ICD implant, the scheduled implant shall be cancelled and this date shall serve 
as the Study Start Date from which all future follow-up visits are scheduled.  
 * For subjects randomized to ACTIVE TREATMENT group.  Subjects are followed every 6 months (+/- 4 weeks) after the 50-week interval for 
Optimizer Device Interrogation and safety reporting only (All deaths, and OPTIMIZER Device-related SAEs with the corresponding 
hospitalizations, procedures only). 
 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 25 of 51 
 
The details of the Schedule of Events are provided in the Section VI. A.  
Treatments to be administered. 
C. 
Anticipated Rate of Site and Patient Recruitment 
Four hundred and eighteen (418) study participants will be recruited from an 
estimated 50 study sites.   
D. 
Data Safety and Monitoring Board (DSMB) 
An independent DSMB shall be established to review results and adverse events 
in order to provide unbiased oversight of the study.  The DSMB shall be 
composed of members with clinical trial experience in heart failure, 
electrophysiology and statistics.  The sponsor shall work with the DSMB to 
develop a set of standard operating procedures which shall include the timing 
and format of regularly scheduled meetings, the format in which data shall be 
submitted by the data coordinating center to the DSMB members and the format 
in which the DSMB shall transmit their findings to the Sponsor.     
E. 
Event Adjudication Committee (EAC) 
 
An EAC shall be established.  The EAC will be responsible for the review, 
adjudication and validation of all reported SAEs that occur over the course of 
the study and the subsequent classification of these complications as related to 
the device or procedure.  The committee shall also adjudicate the cardiac 
relatedness of deaths and hospitalizations.  The EAC shall be composed of 
independent physicians not otherwise affiliated with the study.  The committee 
will determine a schedule for meeting times based on the expected rate of patient 
accrual.   
F. 
A description of the measures taken to minimize/avoid bias 
This study has been designed to minimize sources of bias so that clinical device 
performance may be assessed clearly and objectively.  
 
 

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Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
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August 7, 2014 
Page 26 of 52 
1. 
Site selection 
The trial will be a multi-center study, with approximately 50 clinical 
sites located in the United States.  Site selection will be based upon 
investigator and site experience in multi-center studies of heart failure 
treatments, adequate resources and availability of an appropriate patient 
population. 
2. 
Randomization 
Subjects will be randomly assigned to one of two treatment groups.  
Block randomization by site and etiology of heart failure (ischemic 
versus non-ischemic cardiomyopathy) will be used to ensure balanced 
enrollment between the two groups. 
3. 
Objective Primary Efficacy Endpoint 
The primary efficacy endpoints of this study are chosen to provide as 
objective as 
possible assessment of clinical and physiologic 
improvements.  With regard to the physiologic assessment, ventilatory 
threshold shall be used to assess efficacy.  This parameter is determined 
by a blinded core laboratory and is considered to be independent of bias 
and relatively independent of the placebo effect.   
4. 
Core Laboratories 
Core laboratories shall be used to analyze results of cardiopulmonary 
exercise test, echocardiograms, NYHA and Holter recordings.  All 
analyses shall be performed blinded to treatment assignment.  Standard 
operating procedures (SOPs) for each of the core laboratories are 
established in collaboration between the Sponsor and each core lab 
director.  
5. 
Subject accountability 
Every effort will be made to follow all subjects of each cohort to assure 
as complete a data set as possible.  

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Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
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August 7, 2014 
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G. 
A description of study treatments, the dosage and the dosage regimen of the 
investigational product. 
 
1. 
Study treatment 
The trial treatment will consist of the application of non-excitatory 
cardiac contractility modulating (CCM) electrical signals to the heart 
muscle.  
2. 
Description of dosage  
CCM signals resemble pacing signals in that they are characterized by a 
delay, duration and amplitude.  Compared to pacing signals, CCM 
signals are multiphasic, are of wider pulse duration and are higher in 
amplitude.  In this study, the signals will consist of two biphasic pulses 
~10 ms in duration (total duration ~20 ms) with amplitude of ~7.5 V.   
3. 
Dosage Regimen 
In addition to optimal medical therapy, one group of subjects (Treatment 
Group) shall receive five non-contiguous one-hour periods of CCM 
signal application per day for the twelve months of the study, with a 
schedule of one hour ON and three hours 48 minutes OFF.     
A second group of subjects will be assigned to the control group and 
shall continue to receive optimal medical therapy (Control Group).    
4. 
Description of packaging and labeling 
The OPTIMIZER System hardware will be labeled, packaged and 
shipped in a manner that identifies the System as an investigational 
device for clinical investigation only, and that protects the device under 
normal conditions of shipping and handling.  The leads will retain their 
commercial packaging and labeling and will be hand carried or shipped 
in corrugated shipping boxes. 

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Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
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H. 
Expected duration of subject participation 
The duration of each subject’s participation in the main portion of the study is 
expected to be approximately 13 months.  This will include up to one month for 
screening and baseline testing and a one year primary follow-up period.  
Following completion of the main portion of the study, patients with an 
OPTIMIZER™ device shall continue to be followed clinically at approximately 
3 month intervals until the FDA has made a determination about the safety and 
efficacy of the device.  The sequence and duration of trial periods are described 
in Table 1. 
I. 
Description of the “stopping rules” or “discontinuation criteria” 
1. 
Individual subjects 
Individual subjects will be discontinued from the study according to 
Section V.C. Subject Withdrawal Criteria and Procedures Specifying.   
2. 
Entire trial 
The Data and Safety Monitoring Board (DSMB) will review the overall 
safety aspects of the study and make recommendations regarding the 
conduct and continuation of the study as necessary.  DSMB procedures 
will be described in the DSMB charter. No stopping rules will be 
adopted that will allow the trial to stop early to conclude treatment 
effectiveness.  
J. 
Accountability procedures for investigational products. 
Clinical investigators will be trained in the importance of accountability of 
investigational products.  Impulse Dynamics engineers will install any required 
OPTIMIZER System hardware at the site.  Disposable components of the 
System will be hand carried to the site by Impulse Dynamics clinical 
representatives or shipped directly to the Principal Investigator.  Impulse 
Dynamics clinical representatives will account for the investigational products at 
the clinical site. 

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Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
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K. 
Maintenance of trial treatment randomization codes and procedures for 
breaking codes. 
Trial treatment randomization codes will be prepared and maintained by the data 
management center.  
L. 
Identification of any data to be recorded directly on CRFs (i.e., no prior 
written or electronic record of data), and to be considered to be source 
data. 
All data pertaining to this study shall be recorded on electronic case report 
forms.  Draft case report forms are located in Appendix C which begins with a 
summary of which case report forms are required at each study visit.  Source 
documentation shall be made available by the sites to confirm accuracy of data 
recorded in the case report forms.  However, the following data shall be 
recorded directly on case report forms and in these cases the case report forms 
shall be considered the source documentation: 
1. 
New York Heart Association Classification questionnaire 
2. 
Minnesota Living with Heart Failure Questionnaire responses 
 
V. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Four hundred and eighteen (418) subjects will participate in this study. 
A. 
Subject inclusion criteria 
1. 
Subjects who are 18 years of age or older 
2. 
Subjects who are either male or female 
a. 
Females of childbearing potential must be using a medically 
approved method of birth control and must agree to continue to 
use birth control throughout the study, or must be surgically 
sterilized (tubal ligation, hysterectomy) or post menopausal for at 
least 1 year.   

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Study #IDPT 2003-07-C  
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3. 
Condition 
a. 
Subjects who have a baseline ejection fraction of 35% or less by 
echocardiography. 
b. 
Subjects who have been treated for heart failure for at least 90 
days (including treatment with a β-blocker for at least 90 days 
unless the patient is intolerant) and are in New York Heart 
Association functional Class III or IV at the time of enrollment. 
c. 
Subjects receiving appropriate, stable medical therapy during the 
30 days prior to enrollment for treatment of heart failure, 
consisting of the appropriate doses of diuretics, ACE-inhibitor or 
angiotensin II receptor blocker and -blocker.  Stable is defined 
as no more than a 100% increase or 50% decrease in dose. 
d. 
Subjects who, in the opinion of the Principal Investigator (based 
on the current guidelines for clinical practice2), have a clinical 
indication for an implanted cardiac defibrillator (ICD) and/or 
pacemaker, must have an existing device or agree to undergo 
implantation of such a device unless the patient refuses to 
undergo the implantation of such device for personal reasons. 
e. 
Subjects who are willing and able to return for all follow-up 
visits. 
B. 
Subject exclusion criteria 
1. 
Subjects whose baseline VO2,max is < 9 ml O2/min/kg 
2. 
Subjects who have a potentially correctible cause of heart failure, such as 
valvular heart disease or congenital heart disease.  
3. 
Subjects who have clinically significant angina pectoris, consisting of 
angina during daily life (i.e., Canadian Cardiovascular Society Angina 
                                                          
2 ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices. 
Text which can be found at:  
http://www.acc.org/clinical/guidelines/pacemaker/incorporated/index.htm 
 
 

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Study #IDPT 2003-07-C  
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Page 31 of 52 
score of II or more), an episode of unstable angina within 30 days of 
enrollment, or angina and/or ECG changes during exercise testing 
performed during baseline evaluation. 
4. 
Subjects who have been hospitalized for heart failure which required the 
use of inotropic support within 30 days of enrollment. 
5. 
Subjects who have a clinically significant amount of ambient ectopy, 
defined as more than 8,900 PVCs per 24 hours on baseline Holter 
monitoring.3 
6. 
Subjects having a PR interval greater than 275 ms. 
7. 
Subjects who have chronic (permanent or persistent) atrial fibrillation or 
atrial flutter or those cardioverted within 30 days of enrollment. 
8. 
Subjects whose exercise tolerance is limited by a condition other than 
heart failure (e.g., angina, COPD, peripheral vascular disease, orthopedic 
or rheumatologic conditions) or who are unable to participate in a 6-
minute walk or a cardiopulmonary stress test. 
9. 
Subjects who are scheduled for a CABG or a PTCA procedure, or who 
have undergone a CABG procedure within 90 days or a PTCA procedure 
within 30 days of enrollment. 
10. 
Subjects who have a biventricular pacing system or who have an 
accepted indication for such a device.    
11. 
Subjects who have had a myocardial infarction within 90 days of 
enrollment. 
12. 
Subjects who have mechanical tricuspid or aortic valves. 
13. 
Subjects who have a prior heart transplant. 
                                                          
3 Note:  This number is based on the following assumptions:   
1. It is desired to deliver CCM signals for ≥70% of the time;  
2. CCM signals are suppressed for 3 beats following a PVC.  Therefore, if there is one PVC every 13 beats there will be 9 CCM 
signals delivered (no CCM on the PVC and no CCM for 3 additional NSR beats);  
3. If the average HR is 85, there are 115,200 beats/day.   
4. If 1/13 of these are PVCs, that equals an estimated 8861 beats/24 hours.  The actual percent of CCM signal delivery will depend 
on whether PVCs occur as singlets, doublets, runs, etc.     

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Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
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14. 
Subjects who are participating in another experimental protocol. 
15. 
Subjects who are unable to provide informed consent. 
 
C. 
Subject withdrawal criteria and procedures specifying: 
A patient is enrolled in the study after signing the IRB-approved Informed 
Consent Form.  All subjects who sign Informed Consent will be accounted for in 
the final report of this study.  Subjects randomized to the Treatment who 
withdraw or are withdrawn from the study prior to OPTIMIZER™ device 
implantation or Control subject who withdraw at any time will be returned to the 
care of their primary care physician without further study follow-up required 
(unless specified below).  Patients may be withdrawn for the following reasons: 
a. 
Voluntary decision to withdraw made by the subject 
b. 
Subject does not meet one or more of the protocol selection 
criteria or are unable to complete one or more of the baseline 
assessments.  
c. 
Non-cardiac intercurrent illness that prohibits the subject from 
complying with follow-up evaluations. 
Good faith efforts will be made to contact all subjects who have received a 
randomization assignment (including all Phase I patients with an OPTIMIZER 
device) to ascertain their vital status, important intercurrent medical events and 
changes in medical condition as reported by the subjects. Every effort will be 
made to follow all subjects in both cohorts to assure as complete a data set as 
possible. 
 

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Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
 
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Page 33 of 52 
 
VI. 
Treatment of subjects 
A. 
Treatments to be administered 
1. 
Screening  
Potentially eligible subjects will be informed of the relative risks and 
potential benefits of participating in the study and then asked to sign an 
informed consent document.  A copy of the Informed Consent document 
is located in Appendix B; this document includes a proposed form to 
authorize making information available for the purpose of clinical 
research in compliance with recently enacted patient privacy laws 
(HIPAA Clinical Research Authorization).  It is recognized that each 
participating institution shall have their own requirements related to the 
wording of both the informed consent document and the HIPAA form.  
For each subject, medical history, physical examination, NYHA 
classification (including a questionnaire for NYHA that will be evaluated 
by a blinded core lab) and a history (past 90-days) and current usage of 
medications will be obtained. 
2. 
Baseline Evaluation and Randomization 
All enrolled subjects will complete a Minnesota Living with Heart 
Failure Questionnaire and undergo an ECG, echocardiogram (for site 
assessment of LV ejection fraction and end-diastolic dimension), a 
cardiopulmonary stress test (CPX, which shall include assessment of 
VO2,max, RER, ventilatory threshold (VT) and ventilatory efficiency 
(equal to VE/VCO2), a 6-minute walk test and a 24-hour Holter monitor 
test (for assessment of the number PVCs).  The 6-minute walk test and 
CPX tests may be performed on the same day a minimum of 3 hours 
apart.  Females of childbearing potential will undergo a urine pregnancy 
test within 7 days of the schedule implantation procedure. 
If the results of the baseline tests indicate that the subject is eligible for 
participation, a device implantation date shall be scheduled.  The 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
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scheduled implant date shall serve as the Study Start Date for all 
subjects.  The subject shall then be randomized to one of two groups:   
a. 
Treatment Group, in which case the patient shall undergo device 
implantation on the scheduled implant date.  These subjects shall 
go on to receive CCM treatment for one year as detailed below.   
b. 
Control Group, in which case the subject will be followed with 
continued medical therapy for one year.  For subjects randomized 
to the Control group who do require an ICD implant based on 
standard clinical criteria, the ICD implant shall occur on this 
scheduled date.  For patients not requiring an ICD implant, the 
scheduled implant date shall be cancelled. 
3. 
Study Procedures 
a. 
Treatment  
i. 
Control Subjects 
 
Subjects randomized to the control group shall continue 
to receive optimal medical therapy and shall be seen 
according to the same follow-up schedule as those in the 
Treatment group. 
ii. 
Treatment Subjects 
 
Subjects randomized to active treatment with CCM will 
undergo implantation of an OPTIMIZER pulse 
generator and associated leads.  These subjects will be 
prepared for device implantation according to the 
procedure of the institution.  The precordial region of the 
chest (left or right subclavian region) will be prepped and 
draped using sterile technique.  Similarly, an appropriate 
region for arterial access (such as the femoral region) 
shall be prepared and draped for cannulated and 

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introduction of a Millar catheter that will be placed into 
the left ventricle in a retrograde fashion and connected to 
a data acquisition and real-time analysis system.   
After access to the subclavian or cephalic vein, an atrial 
lead will be placed transvenously into the right atrium for 
sensing atrial activity.  Two additional leads will be 
placed transvenously into the right ventricle for sensing 
ventricular activity and delivering CCM signals.  The 
preferred lead arrangement is for one RV lead to be 
placed in the anterior septal groove and the other in the 
posterior groove approximately half way between the base 
and apex.  The second most preferred lead arrangement 
would be for both leads to be positioned in the anterior or 
posterior septal groove with a separation of at least ~2 cm.   
The minimum acceptable CCM signal effect required to 
proceed with OPTIMIZER pulse generator implantation 
will be a 5% improvement in dP/dtmax.  If, after the first 
CCM signal application, the effect is not 5% or greater, 
the ventricular leads used to deliver the signal will be 
repositioned.   
If the minimum acceptable signal effect cannot be 
achieved after several attempts at optimization, the 
procedure will be terminated.  The device will not be 
implanted and all OPTIMIZER System leads will be taken 
out.  Where clinically indicated and planned, these 
subjects shall undergo implantation of an ICD and/or dual 
chamber pacemaker.  These subjects will be discharged 
from the hospital when deemed appropriate by the 
Principal Investigator and followed according to the 

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protocol with the exception of Optimizer System device 
interrogations.  
If the minimum acceptable CCM signal effect can be 
achieved, the OPTIMIZER pulse generator will be 
implanted.  Where indicated, subjects may also undergo 
implantation of an ICD and/or dual chamber pacemaker 
during the same procedure.  Leads which are in place in 
subjects with a prior ICD and/or pacemaker implant will 
continue to be used for those devices, but may not be 
connected to the OPTIMIZER system.  To ensure that the 
OPTIMIZER System does not interfere with proper 
functioning of the ICD and/or pacemaker, these devices 
shall be interrogated during application of CCM signals.  
The main mechanisms whereby device interaction could 
occur is the potential that the CCM signal is sensed and 
counted in addition to the QRS as an extra electrical 
depolarization; this is called double counting.  To ensure 
that this is not the case, the ICD/pacemaker should be 
programmed to its non-therapy delivering mode and the 
OPTIMIZER™ System should be activated to deliver 
CCM signals.  The physician then accesses the marker 
channels of the ICD/pacemaker to check if double 
counting is present.  If so, the physician should modify the 
ICD/pacemaker parameters (e.g., increase the blanking 
period) until double counting is no longer evident. 
b. 
Predischarge (for subjects randomized to Treatment Group) 
When each of the implanted subjects is stable and suitable for 
hospital discharge (a minimum 12 hour stay is recommended), he 

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or she will undergo a chest X-ray according to hospital policy to 
rule out pneumothorax and to evaluate lead placement.   
If the patient has an implanted pacemaker and/or a defibrillator 
these devices will be activated immediately and remain active.  
The OPTIMIZER™ pulse generator will be activated prior to 
hospital discharge with the subject on telemetry.  The subject will 
be observed during this time and device parameters will be 
adjusted as needed.  If the patient has a pacemaker and/or 
defibrillator implanted, the pacemaker and/or defibrillator will be 
interrogated to assure proper functioning.  The OPTIMIZER™ 
will be interrogated at the end of the activation period to ensure 
proper functioning.  The OPTIMIZER™ will be programmed in a 
“monitor only” mode, which means it will not deliver CCM 
signals, but it will track and record the number of cardiac cycles.  
If patient has an implanted pacemaker and/or defibrillator the 
pacemaker/defibrillator will remain active.  At the discretion of 
the Principal Investigator, the subject may be observed for 
additional days of device activation in the hospital prior to 
discharge. 
Prior to discharge, patients may be introduced to the battery 
charging system and provided a comprehensive overview on the 
use of this equipment.  If not at discharge, this training will at 
least be provided when CCM therapy is turned on (Week 2 
Follow-up visit).  
c. 
Week 2 Follow up 
Two weeks after the OPTIMIZER System implant or 2 weeks 
following study start date for control subjects, each subject will 
return for follow up. This visit shall include an interim medical 
history, a medication review, and a physical examination.  For 

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patients randomized to the treatment arm the pulse generator will 
be interrogated to confirm proper functioning and parameters 
shall be adjusted as needed.  At this time, the OPTIMIZER 
System shall be activated (turned ON).  These subjects will also 
be educated on the use of the OPTIMIZER System charger. 
d. 
Weeks 4, 12, 24, 36 and 50 following Study Start Date 
Subjects randomized to active treatment will receive CCM 
signals for five one-hour periods equally spaced over the course 
of each day.  Subjects in the control group will receive continued 
optimal medical treatment.     
All subjects will return to the hospital for follow-up at weeks 4, 
12, 24, 36 and 50 following Study Start Date.  Each visit shall 
include an interim medical history, a medication review, and a 
physical examination.  On study Weeks 12, 24 and 50 following 
Study Start Date, a blinded clinician will perform a site-based 
NYHA classification and administer a questionnaire for core lab 
determination of NYHA classification, a 6-minute walk, 
cardiopulmonary stress test, an echocardiogram and a MLWHFQ 
will be obtained in addition to device interrogations.  6-minute 
walk and CPX may be done on the same day a minimum of 3 
hours apart.  On Weeks 12 and 24, subjects will undergo a Holter 
monitor examination.     
The ICD will be interrogated at 12, 24, 36, and 50-weeks to 
ascertain proper functioning of the device, in subjects with an 
ICD.   For all subjects, medical regimen for heart failure 
treatment shall remain fixed unless clinical circumstances dictate 
otherwise; changes in medical regimen shall be elicited and 
recorded during the scheduled follow-up visits. 

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All female subjects shall be asked to notify the Investigators in 
the event of pregnancy.  In addition, women of child bearing 
potential using medical birth control who receive an OPTIMIZER 
System implant shall be asked to undergo a pregnancy test at the 
week 24 and 50 visits.   If a patient randomized to device 
treatment becomes pregnant the device will be turned off.  Any 
study patient who becomes pregnant will continue to be followed 
for evaluation of safety endpoints.  
e. 
Post Study Follow-Up 
Following the 50 week follow up, subjects in the Control group 
shall resume routine follow-up from their primary care providers.  
Subjects in the Treatment group can continue to receive treatment 
with CCM signals.  These patients shall be seen at ~6 month 
intervals at the investigational site.  These follow-up visits shall 
include an Optimizer device interrogation and reporting of any 
Optimizer 
device-related 
serious 
adverse 
events 
(and 
corresponding hospitalizations and  procedures, if any) and all 
deaths.  These visits shall continue until FDA has made a 
determination of device safety and efficacy.  In the event that the 
study is terminated prior to approval, the device is found to be 
ineffective or at the request of the patient, the device can be 
removed.  Alternatively, the device can be left in place and 
deactivated; in this case, the device charger would be retrieved 
from the patient in order to eliminate the possibility of further use 
of the device. 
f. 
Device retrieval in case of subject death 
 
In the event that a study participant dies, every attempt will be 
made to secure permission from the family to retrieve the device.  

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Study #IDPT 2003-07-C  
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In such cases, the device shall be shipped to the sponsor where it 
shall be inspected and interrogated. 
B. 
Treatment of Subjects Enrolled in Phase I of this Study 
Phase I of this study was designed as a double blind study in which all subjects 
underwent OPTIMIZER II System implant and were randomized for 6 months to 
either receive or not receive CCM treatment.  This is then followed by a 6 month 
period of open label CCM treatment.  Fifty patients were enrolled in this phase 
at 10 investigational sites.  Treatment of patients enrolled in Phase I is further 
detailed in Appendix D.  In brief, these patients shall be offered an OPTIMIZER 
III device when the battery of the OPTIMIZER II system becomes depleted. 
C. 
Medications/treatments permitted (including rescue medication) and not 
permitted before and/or during the trial 
Subjects will remain on their initial medication regimens throughout the study, 
unless clinical circumstances dictate a change.  There are no restrictions on the 
types of medications that may be used during the trial. 
D. 
Procedures for monitoring subject compliance 
Clinical monitoring will be performed by/or under the management direction of 
the Impulse Dynamics Clinical Affairs Department. 
 
VII. 
Assessment of efficacy 
A. 
Specifications of efficacy parameters  
The primary efficacy parameter shall be: 
 Change in ventilatory threshold as assessed by cardiopulmonary stress 
test as evaluated by a blinded core lab. 
The secondary efficacy parameters shall include: 
 Change in heart failure class, as assessed by the New York Heart 
Association (NYHA) classification. NYHA classification shall be 
assigned by: 

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o  the blinded site clinician according to their standard clinical 
practice 
o by a blinded core lab  
 Change in Quality of Life, as assessed by the Minnesota Living with 
Heart Failure Questionnaire 
 Change in exercise tolerance, as assessed by the six-minute walk test 
 Change in left ventricular ejection fraction, as assessed by 
echocardiography and determined by a blinded core lab 
 Changes in left ventricular end-diastolic dimension as assessed by 
echo and determined by a blinded core lab 
 Changes in peak oxygen consumption and ventilatory efficiency as 
assessed by cardiopulmonary stress test 
 Comparisons of treatment effects separately in subjects whose CHF 
etiology is ischemic or non-ischemic 
 Changes in medical treatment for heart failure (either up or down 
titration of doses or changes in the types of medications prescribed). 
 Comparison of the primary and secondary efficacy and safety 
outcome measures in subjects with and without a pacemaker or ICD. 
 Evaluation of the impact of CCM voltage on primary and secondary 
efficacy and safety outcome measures. 
B. 
Methods and timing for assessing, recording and analyzing efficacy 
parameters 
The timing of efficacy parameter assessments, as summarized in Table 1, will 
be at approximately three-month intervals. 
 

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VIII. Assessment of safety 
 
Although results of prior pre-clinical and clinical studies have suggested means by 
which CCM signals may improve symptoms for patients with heart failure, it is 
acknowledged that the actual mechanism of action is not known.  This is not atypical 
for investigation of new treatments in medicine, including devices and pharmacologic 
agents.  As for any new treatment, whether the mechanism is known or unknown, 
assessment of safety rests on careful ascertainment and documentation of adverse 
effects within the context of a randomized, controlled clinical trial.   
A. 
Specification of safety parameters 
The safety of the OPTIMIZER™ System will be assessed by evaluating the 
incidence and seriousness of adverse events (see section IX.A.2 for statistical 
analysis plan).   The primary safety endpoint shall be the proportion of patients 
experiencing a composite event of all-cause mortality and all-cause 
hospitalization by the 12 month visit.   
An adverse event is defined as any undesirable clinical occurrence in a subject, 
including death.  Examples of adverse events that could occur as a result of the 
surgical procedure and implantation of the device components are listed below 
in hierarchical order of clinical severity: 
1. 
Death   
2. 
Arrhythmias (tachy- or bradycardias) 
3. 
Stroke or transient ischemic attack (TIA) 
4. 
Respiratory failure 
5. 
RV perforation 

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6. 
Bleeding 
7. 
Infection 
8. 
Pleural and pericardial effusion 
9. 
Pneumothorax 
Examples of additional adverse events that could occur as a result of the 
subjects’ underlying disease (i.e., heart failure) or CCM signal application are 
listed below in hierarchical order of clinical severity: 
1. 
Abnormalities of cardiac function 
2. 
Worsening of heart failure 
3. 
Myocardial tissue damage 
4. 
Chest pain 
 
B. 
Serious, Device Related and Unanticipated Adverse Event Definitions. 
Adverse events that occur during this study may be associated with the implant 
procedure, or specifically associated with the use of the device.  An adverse 
event will be considered to be device-related when, in the judgment of the 
Principal Investigator, there is a logical connection between the use of the device 
and the occurrence of the event, above and beyond the study procedure itself. 
A serious adverse event is any untoward medical occurrence that results in 
death, is life-threatening, requires inpatient hospitalization, prolongation of 
existing hospitalization or invasive treatment, results in persistent or significant 
disability/incapacity or is a congenital anomaly/birth defect.  An unanticipated 
adverse device event is defined as any serious adverse effect on the health or 
safety of a subject or any life-threatening problem or death caused by or 
associated with the device, which was not listed in the Investigational Plan or 
the labeling for the device. 
A serious device-related adverse event is any serious adverse event (as defined 
above) that is considered definitely related to the Optimizer System. An adverse 
event will be considered device-related when, in the judgment of the Principal 

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Investigator, there is a logical connection between the use of the device and the 
occurrence of the event, above and beyond the study procedure itself. Examples 
include: 
 Optimizer lead failure (dislodgement, fracture) requiring surgical 
revision  
 Optimizer IPG failure requiring surgical revision  
 Optimizer pocket erosion requiring surgical revision 
 Pocket stimulation secondary to CCM, requiring surgical revision 
 
C. 
Procedures for recording and reporting adverse events and intercurrent 
illnesses. 
The Investigator shall report all adverse events to Impulse Dynamics and to the 
reviewing IRB (according to Hospital policy).  All device malfunctions and 
serious adverse events, including, but not limited to events associated with 
prolongation of hospitalization, and/or a new hospitalization or death shall be 
reported to Impulse Dynamics within 24 hours of the Investigator learning of the 
event.  Impulse Dynamics will report serious adverse events to the Data Safety 
and Monitoring Board (during the 1 year study only) and to the FDA as required. 
D. 
Type and duration of follow-up of subjects after adverse events. 
All subjects experiencing serious adverse events will be followed as required by 
their condition.  Impulse Dynamics will investigate any anticipated or 
unanticipated serious adverse effect or subject death.  If it is determined that the 
adverse event could present an unreasonable risk to other subjects, all 
investigations or parts of investigations presenting that risk will be terminated.  
Investigation of the event and notification of study termination will occur within 
five working days after notice of the effect is received at Impulse Dynamics.  
The terminated investigation will not be resumed without IRB approval. 
 
IX. 
Statistical Considerations 
A. 
Description of the statistical methods to be employed 
1. 
Primary efficacy analysis 

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The primary efficacy analysis will compare responder rates between the 
Treatment and Control groups at the 6-month follow-up visit.  The 
primary outcome measure will be: 
 change from baseline in the ventilatory threshold (VT) 
determined on cardiopulmonary stress testing 
Individual patient response will be defined as an increase of ≥ 1 ml 
O2/kg/min in VT at 6 months as compared with baseline. Responder 
rates will be calculated and compared between the treatment and control 
groups based on both the intent-to-treat population and the per-protocol 
population using a one-sided binomial comparison with an alpha of 
0.025.  
The statistical hypothesis to be tested is: 
 
H0: πc > πt  
vs. HA: πc < πt 
 
Where πc is the proportion of patients in the control group that have > 1 
ml O2/kg/min improvement in VT at 6 months from baseline and πt is the 
proportion of patients in the treatment group that have > 1 ml O2/kg/min 
improvement in VT at 6 months from baseline. 
 
2. Primary Safety Analysis 
 
The primary safety analysis shall evaluate the composite event rate of all 
cause mortality and all cause hospitalization at 12 months.  The 
statistical hypothesis shall be that the proportion of patients in the 
treatment group where an event occurs by 12 months will be non-inferior 
to the proportion of patients where an event occurs by the 12 month visit 
in the control group. 
The statistical hypothesis to be tested shall be: 
t > c +  
vs. 

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t < c + 
where =0.125 (clinically insignificant difference) and c is the event rate 
in the control group and the t is the event rate in the treatment group. 
 
The statistical test to be used shall be the Blackwelder non-inferiority test 
and will be evaluated based on the intent-to-treat patient population and 
the per protocol patient population.  Censoring is expected to be 
minimal, but in order to determine if there are different patterns of 
mortality between groups, Kaplan-Meier curves will also be constructed, 
with Log-rank tests used to determine statistical significance between 
groups.  
 
The nature, frequency, and seriousness of adverse events between the 
two groups shall be compared using descriptive summary statistics.   
 
3. 
Justification of sample size 
Results of prior studies of CCM and biventricular pacing in which VT 
has been employed as an endpoint provide estimates for standard 
deviations of changes and standard deviations of absolute values that 
may be observed in the present study.   
For the safety endpoint, the composite event rate of all cause mortality 
and all cause hospitalization at 12 months shall be used. Based on prior 
studies with cardiac resynchronization therapy and preliminary 
experience with CCM, if we assume a total event rate (mortality or 
hospitalization for any cause) of 50% (a conservative estimate for sample 
size purposes), an alpha of .05, 80% power and a delta of 12.5%, 198 
patients per group would be needed to show non-inferiority between 
groups at 12 months.  With regard to this analysis, we do not expect any 
dropouts (i.e., we expect to be able to account for mortality and 
hospitalizations in all patients enrolled); however, adjusting for a 

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potential 5% loss to follow-up results in a total sample size of 418 
patients (209 per treatment group). 
 
For the efficacy endpoint, the response rate based on a ≥ 1 ml 
O2/kg/min increase in VT at 6 months compared with baseline, will 
be compared between the two treatment groups.4  Due to the natural 
progression of heart failure, we anticipate VT may actually worsen in a 
considerable portion of control patients.  Furthermore, because of the 
anticipated variability in test results and based on prior studies of heart 
failure, including those on CRT (e.g., the MIRACLE study, Abraham et 
al, N Engl J Med 2002;346:1845-53 and the Medtronic InSync 
Biventricular Pacing System’s Summary of Safety and Effectiveness 
P010015) it is also expected that a certain number of control patients will 
meet the success criterion.  It is estimated that that a reasonable estimate 
of the responder rate would be ~20% in the control group based on a 
preliminary analysis of limited clinical data collected in Europe and prior 
studies of heart failure.  We expect to observe a relatively large 
difference (e.g., 30% or larger) between groups.  In this case, the sample 
size shall be determined based on the safety analysis.  Even after 
allowing for a 5% lost to follow-up for efficacy purposes (i.e., which 
would result in 198 evaluable patients) this sample size would provide 
sufficient power to detect a 13% or greater difference in responder rates 
between groups if a 20% responder rate was observed.   
 
Thus, in order to have adequate power for all study endpoints, the study 
will enroll 209 patients per treatment group. 
 
4.  
Secondary efficacy analyses 
                                                          
4 A difference in VT of 1 ml O2/kg/min is justified as being clinically significant based on prior studies of cardiac 
resynchronization therapy showing that there is an approximately 1 ml O2/kg/min change in response to that 
approved therapy (Auricchio et al.  J Am Coll Cardiol 2003;42:2109-16) 

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The secondary analyses will include: 
a. 
Comparison between groups of the change from baseline in New 
York Heart Association (NYHA) classification.  NYHA 
classification shall be assigned by:  
i. 
blinded on site clinicians according to their standard clinical 
practice  
ii. by a blinded core lab that evaluates patient responses to a 
standardized questionnaire.5   
b. 
Comparison between groups of the changes from baseline in 
quality of life, as assessed by the Minnesota Living with Heart 
Failure (MLWHF) Questionnaire.   
c. 
Comparison between groups of the change from baseline in 
exercise tolerance, as quantified by the six minute hall walk test 
(6MW).   
d. 
Comparison between groups of the change from baseline in left 
ventricular ejection fraction as assessed by echocardiography in a 
blinded core lab. 
e. 
Comparison between groups of the change from baseline in left 
ventricular size as indexed by echocardiographically determined 
end-diastolic dimension determined by a blinded core lab. 
f. 
Comparison between groups of the change from baseline in peak 
VO2 and ventilatory efficiency determined on CPX testing.  
g 
Comparisons of treatment effects separately in subjects whose 
CHF etiology is ischemic or non-ischemic 
h. 
Comparison between groups of the change from baseline in 
medical treatment for heart failure (either up or down titration of 
doses or changes in the types of medications prescribed). 
                                                          
5 Kubo SH, Schulman S, Starling RC, Jessup M, Wentworth D and Burkhoff D. Development and validation 
of a patient questionnaire to determine New York Heart Association classification. J Card Fail 10: 228-235, 2004. 

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i. 
Comparison within the treatment group of the primary and 
secondary safety and efficacy outcome measures in subjects with 
and without a pacemaker or ICD. 
j. 
Evaluation of the impact of CCM voltage on primary and 
secondary efficacy and safety outcome measures. 
 
5. 
Other Analyses 
Baseline comparisons between the treatment and control groups will be 
made with respect to baseline evaluations (including NYHA Class, peak 
VO2, MLWHFQ, initial medications and additional implanted devices).  
If any significant differences are observed in the aforementioned baseline 
factors or other covariates, all primary and secondary analyses will be 
repeated with an adjustment for the significant factors. 
 
 
Additionally, an exploratory comparison for treatment effects across sites 
will be performed along with a statistical comparison using a chi-squared 
test for homogeneity. 
 
B. 
Number of subjects planned to be enrolled 
Based upon the power calculations in Section IX.A.3 above, 418 subjects will be 
randomized in a 1:1 ratio between the two groups.   
C. 
Study Termination 
The study shall be considered complete approximately 50 weeks after the last 
study subject is randomized, when all non-withdrawn subjects have completed 
the Week 50 follow-up.  Patients with an implant who choose to continue CCM 
therapy shall continue to be followed every six months until FDA has completed 
their review of this study. 
D. 
Procedure for accounting for missing, unused and spurious data. 

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Subjects must have baseline measurements of VT to be eligible for the study.  
Every attempt will be made to record the endpoints on all subjects at all follow-
up points, but especially at Week 24 (the primary efficacy endpoint assessment) 
and 50 weeks (the primary safety endpoint assessment).  An intent-to-treat 
analysis will be performed on the primary efficacy and safety endpoints and will 
include all patients randomized, regardless of whether patients withdrew prior to 
study completion.  The main reasons for withdrawal are anticipated to be failure 
to reach ≥ 5% improvement in dP/dtmax during the system implant procedure 
(for patients randomized to treatment) and voluntary decision by the patient (for 
patients randomized to control).  Imputation of missing data will include a 
conservative scenario and missingness patterns will be compared across 
treatment groups.  Where missing data are present, a worst case analysis (control 
subjects assumed to satisfy success criteria and treatment subjects assumed to 
fail success criteria) shall also be performed for the primary safety and efficacy 
analyses. 
E. 
Procedures for reporting deviations from the original statistical plan. 
Deviations from the original statistical plan will be reported at the time that the 
statistical report is issued. 
F. 
Selection of subjects to be included in the analyses. 
All subjects will be accounted for in the analyses (See Section 9.E.). 
 
X. 
Direct access to source/data documents 
The investigators and institutions will permit trial-related monitoring, audits, IRB 
review, and regulatory inspections, providing direct access to source/data documents. 
 
XI. 
Quality control and quality assurance 
Quality control and quality assurance will be the responsibility of the Impulse Dynamics 
clinical representatives. 

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XII. 
Ethics 
Heart failure is a prevalent health problem throughout the world.  Development of 
therapies to improve heart function to relieve symptoms, reduce hospitalizations and 
improve survival is a high priority in cardiovascular medicine.  
Studies in animals have demonstrated the safety of the OPTIMIZER System with 
commercially available active fixation leads and the performance of the CCM signal in 
improving ventricular function.  Results of preliminary clinical studies suggest that brief 
applications of CCM signals do not pose an unreasonable risk to heart failure subjects.  
The present study represents the next step in the evaluation of this device.  The study is 
justifiable because the potential benefits of using the device outweigh the risks to 
participating subjects. 
Prior to the initiation of the study, the Principal Investigator will provide Impulse 
Dynamics with a copy of the Patient Informed Consent document that has been 
approved by the IRB at the investigational site.  Before enrollment, each subject will be 
informed of the overall requirements and potential risks and benefits of the study and 
his/her written consent will be obtained. 
 
XIII. Data handling and record keeping 
All study data will be entered directly into an electronic data capture system (EDC) by 
clinical site personnel throughout the course of the study. Access to clinical study 
information will be based on individuals’ roles and responsibilities and will be 
controlled by login and password provided by the database administrator. The 
application provides hierarchical user permission data entry, viewing, and reporting 
options. For optimum security, the system operates Secure Socket Layer (SSL) 128-bit 
encryption protocol over Virtual Private Networks. This application is designed to be in 
full compliance with the FDA’s Code of Federal Regulations (CFR) Number 21 Part 11, 
Electronic Records and Electronic Signatures, the FDA’s Guidance: Computerized 

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Systems used in Clinical Trials, and the Privacy Rule of the Health Insurance Privacy 
and Portability Act of 1996 (HIPAA) 
Original source documents will remain at the sites for data verification during 
monitoring visits. De-identified source documents may be retrieved for presentation to 
oversight committees when requested. The documents will be maintained in the Impulse 
Dynamics Regulatory Affairs office in Orangeburg, New York.  Database development 
and management shall be performed by: 
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Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
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CONFIDENTIAL  
IDE - Investigational Plan Section 
August 7, 2014 
Page 1 of 9 
 
APPENDIX A 
CCM References 
 
Impulse Dynamics - Articles   
1. A New Algorithm for Detection and Verification of Ventricular Arrhythmia from the Left 
Ventricular Pressure Waveform . Authors : T Harel, I Shemer, S Policker, Y Mika, S Ben Haim, N 
Darvish . Impulse Dynamics, Tirat Carmel , Israel . Computers in Cardiology 2000; 27: p.351-354  
2. Electric Currents Applied During the Refractory Period can Modulate Cardiac Contractility In 
Vitro and In Vivo . Authors : Daniel Burkhoff, Itzik Shemer, Bella Felsen, Juichiro Shimizu, Yuval 
Mika , Marc Dickstein, David Prutchi, Nissim Darvish, Shlomo A. Ben Haim. Heart Failure 
Reviews; Vol. 6, No' 1; (January 2001) p.27-34.  
3. Global Improvement in Left Ventricular Performance Observed with Cardiac Contractility 
Modulation is the Result of Changes in Regional Contractility . Authors : David J. Callans, 
Shmuel Fuchs, Yuval Mika , Itzhak Shemer, Ricardo Aviv , Walid Haddad, Nissim Darvish, 
Shlomo Ben Haim, Ran Kornowski. Heart Failure Reviews; Vol. 6, No' 1; (January 2001) p.35-44  
4. Cardiac Contractility Modulation with the Impulse Dynamics Signal: Studies in Dogs with Chronic 
Heart Failure . Authors : Hani N. Sabbah, Walid Haddad, Yuval Mika , Itzhak Shemer, Ricardo 
Aviv , Victor G. Sharov, Victor Maltseu, Bella Felzen, Albertas I. Undrovinas, Sidney Goldstein, 
Nissim Darvish, Shlomo A. Ben Haim. Heart Failure Reviews; Vol. 6, No' 1; (January 2001) p. 45-
53.  
5. Electrical Modulation of Cardiac Contractility: Clinical Aspects in Congestive Heart Failure . 
Authors : Carlo Pappone, Gabriele Vicedomini, Adriano Salvati, Carlo Meloni, Walid Haddad, 
Ricardo Aviv , Yuval Mika , Nissim Darvish, Yoav Kimchy, Itzhak Shemer, Yehuda Snir, David 
Prutchi, Shlomo A. Ben Haim, Itzhak Kronzon. Heart Failure Reviews; Vol. 6, No' 1; (January 
2001) p. 55-60  
6. Cardiac Contractility modulation by electric currents applied during the refractory period . 
Authors : Satoshi Mohri, Kun-Lun He, Marc Dickstein, Yuval Mika , Juichiro Shimizu, Itzhak 
Shemer, Geng-Hua Yi, Jie Wang, Shlomo Ben-Haim , and Daniel Burkhoff. AJP Heart Circ 
Physiol Vol. 282, May 2002 p.H1642-1647. First published January 17, 2002 
7. Nonexcitatory Stimulation: 2002: A Pace Odyssey Author : Kirstin Ellison, M.D. Editorial 
Comment, Journal of Cardiovascular Electrophysiology, Volume 13, No. 7, July 2002, p. 696-697.  
8. Nonexitatory Stimulus Delivery Improves Left Ventricular Function in Hearts with Left Bundle 
Branch Block . Authors : Nassir F. Marrouche, M.D., Stephen V. Pavia, M.D., Shaowei Zhuang, 
M.D., Yung-Jin Kim, M.D., Tomotsugu Tabata, M.D.,Don Wallick, Ph.D., Eduardo Saad, M.D., 
Ahmad Abdul-Karim, M.D., Robert Schweikert, M.D., Walid Saliba, M.D., Patrick Tchu, M.D., 
and Andrea Natale, M.D. The Section of Pacing and Electrophysiology, Department of 
Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland , Ohio . Journal of 
Cardiovascular Electrophysiology Vol 13 Issue 7 July 2002, p. 691-695.  

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9. Cardiac Contractility Modulation by Electric Currents Applied During the Refractory Period in 
Patients with Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy . 
Authors : Carlo Pappone, MD, PhD, Salvatore Rosanio, MD, PhD, Daniel Burkhoff, MD, PhD, 
Yuval Mika , DSc, Gabriele Vicedomini, MD, Giuseppe Augello, MS, Itzhak Shemer, MD, David 
Prutchi, DSc, Walid Haddad, PhD, Ricardo Aviv , DSc, Yehuda Snir, DSc, Itzhak Kronzon, MD, 
Ottavio Alfieri, MD, and Shlomo A. Ben-Haim, MD, PhD. From the Department of Cardiology, 
San Raffaele University Hospital, Milan, Italy, Division of Circulatory Physiology, Columbia 
University, New York, NY. Department of Physiology and Biophysics, Technion-Israel Institute of 
Technology, Haifa, Israel, and Division of Cardiology, New York University Medical Center, New 
York, NY. The American Journal of Cardiology, 15 December 2002, Vol. 90, Issue 12, Pages 
1307-1313 .  
10. Cardiac Contractility Modulation With Nonexcitatory Electric Signals Improves Left Ventricular 
Function in Dogs With Chronic Heart Failure . Authors : Morita H, Suzuki G, Haddad W, Mika 
Y, Tanhehco EJ, Sharov VG, Goldstein S, Ben-Haim S, Sabbah HN. Departments of Medicine, 
Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Henry Ford Health 
System, Detroit , Michigan 48202 , USA J Card Fail. 2003 Feb;9(1): 69-75 
11. Electric Currents Applied during Refractory Period Enhance Contractility and Systolic Calcium in 
the Ferret Heart Authors : Mohri S, Shimizu J, Mika Y, Shemer I, Wang J, Ben-Haim S, Burkhoff 
D. Am J Physiol Heart Circ Physiol. 2003 Apr;284(4): H1119-23. Epub 2002 Nov 21. 
12. Nonexcitatory Electrical Currents for Congestive Heart Failure: Exciting or Not? Editorial 
Comment Authors : Mevan Wijetunga and Adam Strickberger Journal of Cardiovascular 
Electrophysiology, Vol 15, April 2004, p.428-429.   
13. Cardiac Contractility Modulation by Nonexcitatory Electrical Currents for Treating Systolic Heart 
failure Early Multicenter Experience. Authors : Giuseppe Augello, Carlo Pappone, Salvatore 
Rosanio, Gabriele Vicedomini, Eustachio Agricola, Simoe Sala, Yuval Mika , Michael Wolzt, 
Gunter Stix, Herwig Schmidinger. JACC March 3, 2004 Abs. # 1035-217  
14. First Human Chronic Experience with Cardiac Contractility Modulation by Non - Excitatory 
Electrical Currents for Treating Systolic Heart Failure (Mid-term safety and efficacy Results from 
a Multicenter Study) Authors : Carlo Pappone, MD, PhD, FACC; Giuseppe Augello, MD; 
Salvatore Rosanio, MD, PhD, FACC; Gabriele Vicedomini, MD; Vincenzo Santinelli, MD; 
Massimo Romano, MD; Eustachio Agricola, MD; Francesco Maggi, DSc; Gerhard Buchmayr , 
DSc; Giovanni Moretti; Yuval Mika , DSc; Shlomo A. Ben-Haim MD, PhD; Michael Wolzt, MD; 
Guenter Stix, MD; and Herwig Schmidinger, MD. J Cardiovasc Electrophysiol, Vol. 15, pp. 418-
427, April 2004 .  
15. Long-Term Effects of Non-Excitatory Cardiac Contractility Modulation Electric Signals on the 
Progression of Heart Failure in Dogs Authors : Hideaki Morita, George Suzuki, Walid Haddad, 
Yuval Mika , Elaine J. Tanhehco, Sidney Goldstein, Shlomo Ben-Haim , Hani N. Sabbah. The 
European Journal of Heart Failure 2004 Mar 1;6(2): 145-50  
16. Chronic electrical stimulation during the absolute refractory period of the myocardium improves 
severe heart failure . Authors : Guenter Stix, Martin Borggrefe, Christian Wolpert, Gerhard 
Hindricks , Hans Kottkamp, Dirk Böcker, Thomas Wichter, Yuval Mika , Shlomo Ben-Haim , 
Daniel Burkhoff, Michael Wolzt, Herwig Schmidinger. European Heart Journal 2004 Apr; 
25(8):650-5  

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
IDE - Investigational Plan Section 
August 7, 2014 
Page 3 of 9 
17. Nonexcitatory stimulation as novel treatment for heart failure: cause for excitement? Editorial 
Authors : Rik Willems, Karin R. Sipido European Heart Journal (2004) 25, pp. 626-628  
18. Die nicht exzitatorische myokardiale Stimulation führt zu einer Verbesserung der Kontraktilität 
ohne Änderung des Sauerstoffverbrauchs . Authors : Chr. Butter, E. Wellnhofer, M. Schlegl, G. 
Winbeck, E. Fleck. Deutsches Herzzentrum Berlin , Berlin . NASPE – Abstract #3880 - Heart 
Rhythm 2004 - San Francisco , California , May 19 – 22  
19. Cardiac contractility modulation by non-excitatory electrical currents. The new frontier for 
electrical therapy of heart failure. Authors : Augello G, Santinelli V, Vicedomini G, Mazzone P, 
Gulletta S, Maggi F, Mika Y, Chierchia G, Pappone C. Ital Heart J. 2004 Jun;5 Suppl 6:68S-75S.  
20. Nonexcitatory electrical signals for enhancing ventricular contractility: rationale and initial 
investigations of an experimental treatment for heart failure.   Authors : Burkhoff D, Ben-Haim 
SA. Am J Physiol Heart Circ Physiol . 2005 Jun;288(6):H2550-6  
21. Cardiac Contractility Modulation by Non-Excitatory Currents: Studies In Isolated Cardiac Muscle. 
Authors : Corinna B Brunckhorst, MD; Itzak Shemer , MD ; Yuval Mika , DSc; Shlomo A Ben-
Haim, MD, PhD; Daniel Burkhoff, MD, PhD. In press: European Journal of Heart Failure  
22. Electric Signals Applied during the Absolute Refractory Period: An Investigational Treatment of 
Advanced Heart Failure in Patients with Normal QRS Duration. Authors : Thomas Lawo MD, 
Martin Borggrefe MD, Christian Butter MD, Gerhard Hindricks MD, Herwig Schmidinger MD, 
Yuval Mika PhD, Daniel Burkhoff MD PhD, Carlo Pappone MD PhD, Hani N Sabbah PhD. In 
press: J. Am. Coll. Cardiol.  
 
Impulse Dynamics - Abstracts  
1. An Implantable Device to enhance Cardiac Contractility through Non-Excitatory Signals . 
Authors : David Prutchi, Yuval Mika , Yehuda Snir, Jacob Ben Arie, Nissim Darvish, Yoav 
Kimchy, Impulse Dynamics, Tirat HaCarmel Israel , Shlomo Ben Haim, Tech, Haifa , Israel . 
Supplement I, Circulation; Vol. 100, No' 18;1566 (November 2, 1999) (AHA Abs.) p. I-300  
2. Delivery of Non-Excitatory Contractility-Modulation electric Signals Improve Left Ventricular 
Performance in Dogs with Heart Failure ; Authors : Hani N. Sabbah, Henry Ford Heart and 
Vascular Inst. Detroit: Yuval Mika , Ricardo Aviv , Walid Haddad, Nissim Darvish, Impulse 
Dynamics, Tirat HaCarmel Israel: Shlomo Ben Haim, Tech, Haifa Israel. Pervais Chaudrhy 
,Takayuki Mishima, Sidney Goldstein, Henry Ford Heart and Vascular Inst. Detroit , MI . Abs. 631, 
Supplement I, Circulation; Vol. 100, No' 18; 631 (November 2, 1999) (AHA Abs.) p. I 122  
3. First Clinical Experience Demonstrating Improvement of Hemodynamic Parameters in Heart 
Failure Patients Through the Application of Non-Excitatory Electrical Signals . Authors: Carlo 
Pappone, Gabriele Vicedomini, Maria L. Loricchio, Carlo Meloni, Andriano Salvati, Yoav 
Kimchy, Walid Haddad, Ricardo Aviv , Yuval Mika , Nissim Darvish, Itzhak Kronzon, Shlomo 
Ben Haim. San Raphael hospital, Milano, Italy; Impulse Dynamics, Tirat HaCarmel; Technion, 
Haifa, Israel; New York University. New York , USA . Supplement I, JACC; Vol. 35, No' 2; 901-1 
(February 2000) (ACC Abs.) p.229A  
4. Myocardial Contractility Modulation Using a Non Excitatory Electrical Signal . Authors : Itzhak 
Shemer, Bella Felsen, Yuval Mika , Yaakov Haham, Shlomo Ben Haim, Nissim Darvish.Impulse 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
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IDE - Investigational Plan Section 
August 7, 2014 
Page 4 of 9 
Dynamics, Tirat Hacarmel;The Bruce Rappaport Faculty of Medicine, Technion, Haifa , Israel . 
Supplement A, American College of Cardiology; Vol. 35, No' 2;1186-71 (February 2000) (ACC 
Abs.) p.148A  
5. Application of Non-Excitatory Electrical Signals Combined with Biventricular Pacing Improves 
Hemodynamic Parameters in Heart Failure Patients beyond the improvement achieved by 
biventricular pacing alone ; Authors: Carlo Pappone, MD, Gabriele Vicedomini, MD, Maria L 
Ioriccio, MD, Carlo Meloni , MD, Andriano Salvati, MD, San Raphael Hospital, Milano, Italy; 
Yoav Kinchy, DSc., Walid Haddad, PhD, Ricardo Aviv , DSc., Itzhak Shemer, MD, Yehuda Snir, 
BSc, Yuval Mika , DSc., David Prutchi, PhD, Nissim Darvish, MD, DSc, Impulse Dynamics; Tirat 
Hacarmel, Israel; Shlomo Ben Haim, MD, DSc. Technion, Haifa, Israel. Pacing and Clinical 
Electrophysiology; Vol. 23, Part II;150 (April 2000) (NASPE Abs.) p. 590.  
6. Non-Excitatory Electrical Currents Enhance Cardiac Contractility by Increasing Peak Calcium 
Transients in Ferret Hearts . Authors: Juichiro Shimizu, David Prutchi, Yoav Kinchy, Yuval Mika 
, Nissim Darvish, Daniel Burkhoff. Columbia University , New York , New York . Pacing and 
Clinical Electrophysiology; Vol. 23, No' 4;618 (April 2000) (NASPE Abs.) p. 707  
7. Non Excitatory Signal does not Impair Left Ventricular Diastolic Function . Authors : Nassir F. 
Marrouche, Don Wallick, Shaowei Zhuang, Tommy Tabata, Stephen V Pavia, Patrick Tchou, 
Andrea Natale.The Cleveland Clin. Fdn, Cleveland , OH . Pacing and Clinical Electrophysiology; 
Part II; Vol. 23 No' 4;668, (April, 2000) (NASPE Abs.)  
8. Non-Excitatory Signal Subthreshold Pacing versus Bi-Ventricular Pacing in an Animal Model with 
Left Bundle Branch Block . Authors : Nassir F Marrouche, Don W Wallick, Shaowei Zhuang, 
Stephen V Pavia, Tommy Tabata, Patrick Tchou and Andrea Natale. The Cleveland Clin. Fdn, 
Cleveland , OH . Pacing and Clinical Electrophysiology; Part II; Vol. 23 No' 4;576, (April, 2000) 
(NASPE Abs.)  
9. Inotropic effects of non-excitatory electrical current in heart failure patients. Results from an acute 
haemodynamic and echocardiographic study . Authors: C. Pappone, S. Rosanio, G. Vicedomini, 
M. Tocchi, A. Salvati, Y. Kinchy, I. Shemer, R. Aviv; S. Ben Haim. Supplement, European Heart 
Journal; Vol. 21, P1131 (August/September 2000) (ESC Abs.) p.196  
10. Cardiac Contractility Modulation Signal Improve Left Ventricular Performance in Dogs: Initial 
Results from Chronic Application Authors: Hani N. Sabbah, Omar Nass, Pervaiz A Chaudhry, 
Petros V Anagnostopoulos, Walid Hadad, George Suzuki, Bella Felsen, Yuval Mika , Nissim 
Darvish, Sidney Goldstein, Ricardo Aviv , Yoav Kimchy, Offer Glasberg, Andre Routh Shlomo 
Ben Haim. Impulse Dynamics, Tirat Hacarmel, Israel;Technion, Haifa, Israel; Henry Ford Heart 
and Vascular Insitute, Detroit, MI. Supplement 2, Journal of Cardiac Failure; Vol. 6, No' 3;064 
(September 2000) (HFSA Abs)p. 16  
11. Application of Cardiac Contractility Modulating Signals Enhance Myocardial Contraction in Pigs 
Authors: Yoav Kimchy, Walid Hadad, Itzhak Shemer, Ricardo Aviv , Bella Felsen, Offer 
Glasberg, Yehuda Snir, Yakov Haham, Yuval Mika , Nissim Darvish and Shlomo Ben Haim. 
Impulse Dynamics, Tirat Hacarmel , Israel ;Technion, Haifa , Israel . Supplement 2, Journal of 
Cardiac Failure; Vol. 6, No' 3;063 (September 2000) (HFSA Abs.) p. 17  
12. Cardiac Contractility Modulation Signals Applied to the Heart Tend to Reduce the Occurrence of 
Ectopic Beats in Heart Failure Patients . Authors: Itzhak Shemer,Tamar Harel, Shai Poliker, 

Impulse Dynamics (USA), Inc. 
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IDE - Investigational Plan Section 
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Walid Hadad, Ricardo Aviv , Itzhak Kronson, Yuval Mika , Nissim Darvish and Shlomo Ben Haim 
. Journal of Cardiac Failure; Vol 6, No' 3;158 supplement 2, September 2000. (HFSA) abs. p.42  
13. Potential Gain in Left Ventricular Contractility with Non-Stimulatory Signals On Top of 
Biventricular Pacing . Authors: Ricardo Aviv , Yoav Kimchy, Walid Hadad, Itzhak Shemer, 
Yehuda Snir, Yuval Mika , David Prutchi, Nissim Darvish and Shlomo Ben Haim. Supplement 2, 
Journal of Cardiac Failure; Vol. 6, No' 3; 048 (September 2000) (HFSA Abs.) p.13  
14. Myocardial Contractility Modulation Using an electrical Signal . Authors: Itzhak Shemer, Bella 
Felsen, Yuval Mika , Yaakov Haham, Shlomo Ben Haim and Nissim Darvish; Impulse Dynamics, 
Tirat Hacarmel , Israel ; The Bruce Rappaport Faculty of Medicine, Technion, Haifa , Israel . 
Supplement 2, Journal of Cardiac Failure; Vol. 6, No' 3; 157 (September 2000) (HFSA Abs.) p.142  
15. Application of Non-Excitatory Electrical Signals in Multi Site Locations Improves Left Ventricular 
Contractility in Pigs Beyond the Improvement Achieved with Single site Application . Authors : 
Yoav Kimchy, Walid Haddad, Ricardo Aviv , Itzhak Shemer, Yehuda Snir, Yuval Mika , David 
Prutchi, Bella Felsen, Offer Glasberg, Nissim Darvish, Shlomo Ben Haim. Impulse Dynamics, Tirat 
Hacarmel , Israel . Supplement II, Circulation; Vol. 102, No' 18;2600 (October 31, 2000) (AHA 
Abs.) p.II-534.  
16. Non-Excitatory Electrical Signals Enhance Contractility of Failing Human Myocardium Obtained 
from Heart Transplant Recipients . Authors : Juichiro Shimizu, Alessandro Barbone, Mehmet C 
Oz., Jie Wang, Daniel Burkhoff. Supplement II Circulation Vol. 102 No.18 October 31, 2000 p. II-
720  
17. Acute Hemodynamic Effects of Non Excitatory Cardiac Contractility Modulating Currents in 
Patients with Dilated Cardiomyopathy . Authors : Gabriele Vicedomini, Carlo Pappone, Yuval 
Mika , Stefano Nardi, , Patrizio Mazzone, Vincenzo Santinelli, C. DiCandia, Filippo Gugliotta, 
Itzhak Shemer, Walid Haddad, Yuval Mika , Nissim Darvish, Shlomo Ben Haim. Columbia Univ. , 
New York , NJ, HSR, Milan , Italy and Tech., Haifa , Israel . Pacing and Clinical 
Electrophysiology; Part II; Vol. 24, No' 4;40 (April, 2001) (NASPE Abs.) p.548  
18. Continuous (6 hours) Application of the Impulse Dynamics Cardiac Contractility Modulation 
(CCM) Electrical Signal Improves Left Ventricular Function in Dogs with Chronic Heart Failure . 
Authors: Hani N. Sabbah, Walid Hadad, George Suzuki, Hideaki Morita, Yuval Mika , Andre 
Routh, Nissim Darvish, Sidney Goldstein, Shlomo Ben Haim. Henry Ford health System, Detroit, 
MI, Impulse Dynamics, Tirat Hacarmel, Israel and Tech Israel Inst. Of Technology, Haifa , Israel . 
Pacing and Clinical Electrophysiology; Vol. 24, No' 4, Part II; 41 (April, 2001) (NASPE Abs.) 
p.549  
19. Non-Excitatory Signal Improves Diastolic Function in Patients with Heart Failure . Authors: 
Carlo Pappone, Gabriele Vicedomni, Stefano Nardi, Patrizio Mazzone, Filippo Gugliotta, Vincenzo 
Santinelli, Itzhak Shemer, Haddad Walid, Yuval Mika , Nissim Darvish, Daniel Burkhoff and 
Shlomo Ben Haim. Columbia Univ., New York, NJ, HSR, Milan, Italy, Impulse Dynamics Ltd. 
Tirat HaCarmel , Israel , S. Raffaele Hosp. (HSR), Milan , Italy and Tech., Haifa , Israel . Pacing 
and Clinical Electrophysiology; Vol. 24, No' 4, Part II; 42 (April, 2001) (NASPE Abs.) p.549  
20. Enhancement of Cardiac Contractility by Application on Non-Excitatory Electrical Stimulation 
into The Septal Wall of the Right Ventricle . Authors : Itzhak Shemer, Walid Haddad, Yuval Mika , 
Nissim Darvish, Andre Rout, George Wnton, Shlomo Ben Haim, and Daniel Burkhoff. Columbia 
Univ. , New York , NJ., Impulse Dynamics, Tirat HaCarmel , Israel . Tech., Haifa , Israel and Tirat 

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HaCarmel , Israel . Pacing and Clinical Electrophysiology; Vol. 24, No' 4, Part II; 319 (April, 
2001) (NASPE Abs.) p.618  
21. Non-Excitatoy Electrical Currents Enhance Cardiac Contractility by Increasing Peak Calcium 
Transients and in Ferret Hearts . Authors : Juichiro Shimizo, David Prutchi, Yoav Kimchy, Yuval 
Mika , Nissim Darvish, Daniel Burkhoff. Columbia Univ. , New York , New York . Pacing and 
Clinical Electrophysiology; Vol. 23, No' 4, Part II; 319 (April, 2001) (NASPE Abs.) p.707  
22. Frequency Modulation Potentiates Enhancement of Cardiac Contractility of Non-Excitatory 
Electrical Stimulation Delivered into the septal wall of the right ventricle . Authors : Itzhak 
Shemer, Walid Haddad, Yuval Mika , Nissim Darvish, Shlomo Ben Haim. Impulse Dynamics & 
The Bruce Rappaport Faculty of Medicine, Technion, Haifa , Israel . The Journal of Heart Disease; 
Vol. 2, No' 1;144 (July 2001) (Abs.) p.36  
23. Dual Site Application of Non-Excitatory stimulation to the Right Ventricular Septal Wall Yields an 
Additive Effect on Contractility . Authors : Walid Haddad, Itzhak Shemer, Yuval Mika , Shlomo 
Ben Haim, Impulse Dynamics, Tirat Hacarmel and the Bruce Rappaport Faculty of Medicine, 
Technion, Haifa , Israel . The Journal of Heart Disease; Vol. 2, No' 1;330 (July 2001) (Abs.) p.83  
24. Contractility Enhancement By Non-Excitatory Stimuli Does Not Involve Adrenergic Receptor . 
Authors : I. Shemer, Y Mika, B Felsen, Y Haham, S Ben Haim. Physiology, The Bruce Rappaport 
Faculty of Medicine, Technion, Haifa , Israel ; Impulse Dynamics, Tirat Hacarmel , Israel . 
Supplement I, Cardiac Failure; Vol. 7, No' 3; 075 (September 2001) (HFSA Abs.).  
25. Selective Locations at right ventricular septum show improved CCM Efficacy on Left Ventricle 
Hemodynamics . Authors : Walid Haddad, Itzhak Shemer, Ricardo Aviv , Yuval Mika , Shlomo 
Ben Haim. Rappaport Faculty of Medicine , Israel ; Impulse Dynamics , Israel . Supplement I, 
Cardiac Failure; Vol. 7, No' 3; 074 (September 2001) (HFSA Abs.).p.22  
26. Frequency Modulation of NonExcitatory Electrical Signals at the Right Ventricular Septum 
Potentiates the Enhancement of Left Ventricular Contractility . Authors : Itzhak Shemer, Walid 
Haddad, Yehuda Snir, Yuval Mika , Ricardo Aviv , Shlomo Ben Haim. Physiology, School of 
Medicine , Technion, Haifa , Israel ; Impulse Dynamics, Tirat Hacarmel , Israel . Supplement I, 
Cardiac Failure; Vol. 7, No' 3; 071 (September 2001) (HFSA Abs.) p.21  
27. Improved LV mechanics by non-excitatory current delivered to right ventricular septum as tested 
by a simultaneous echo color kinesis and haemodynamics study . Authors : C. Pappone, C. Lu, y. 
Mika, W. Haddad, S. Nardi, S. Rosanio, A. Salvati, S. Itzhak, G. Winton, S. Ben Haim. Hospital of 
San Raffaele , Cardiology Dept., Milan , Italy , Impulse Dynamics, Tirat Hacarmel , Israel . 
European Heart Journal Volume 22, Abstr. Suppl. September 2001, page 533.  
28. Bi-Regional Delivery of Non Excitatory Stimuli to the right ventricular septum exhibit higher 
increase in left ventricular contractility compared to stimuli delivery via single site . Authors : 
Itzhak Shemer Walid Haddad, Shlomo Ben Haim, Yuval Mika . Submitted to American College 
Cardiology abs. 2002.  
29. Non-excitatory Cardiac Contractility Modulation in Heart Failure – Influence of Stimulated 
Chamber on Hemodynamic and Mechanical Response . Authors : Carlo Pappone, Salvatore 
Rosanio, Daniel Burkhoff, Yuval Mika , Gabriele Vicedomini, Monica Tocchi, Vincenzo 
Santinelli, Itzhak Shemer, David Prutchi, Walid Haddad, Yehuda Snir, Shlomo A. Ben Haim, San 

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Raffaele University Hospital, Milano, Italy, Technion - Israel Institute of Technology, Haifa, Israel. 
JACC, March 2002, poster session on 17 March, 2002.  
30. Lack of Adrenergic Involvement in Non-Excitatory Cardiac Contractility Enhancement . Authors : 
I Shemer MD, Y Mika PhD, S. Ben Haim MD PhD. Technion- Israel Institute of Technology, Haifa 
, Israel . (NASPE Abs. 2002 ).  
31. Nonexcitatory Cardiac Contractility Modulation in Heart Failure: Influence of Stimulated 
Chamber on Hemodynamic and Mechanical Response . Authors : Carlo Pappone, Salvatore 
Rosanio, Daaniel Burkhoff, Yuval Mika , Gabriele Vicedomini, Monica Tocchi, Vincenzo 
Santinelli, Itzhak Shemer, David Prutchi, Walid Haddad, Yehuda Snir, Shlomo A. Ben Haim, San 
Raffaele University Hospital, Milano, Italy, Technion-Israel Institute of Technology, Haifa, Israel. 
JACC, March 2002 Abs. # 1014,156.  
32. Electrical modulation of cardiac contractility in congestive heart failure – a promising new 
therapy . Authors : D. Burkhoff, H. Sabbah, C. Pappone, M. Borggrefe, Y. Mika, S. Ben-Haim. 
The Journal of Heart Failure, Volume 7, number 1 July 2002, #245.  
33. Improvement of Heart Failure by electrical Modulation of cardiac Contractility Authors : G.J. 
Stix, M. Wolzt, C. Mayer, T. Pezawas, J. Kastner, H. Schmidinger Dept. of cardiology, University 
of Vienna , Vienna , Austria . Journal of Heart Failure, Volume 7, No. 1, July 2002, Abst. # 252  
34. Non-excitatory cardiac contractility modulation electric signals attenuate left ventricular 
remodeling and improve ejection fraction in dogs with heart failure . Authors : H. Morita, G. 
Suzuki, W. Haddad, Y. Mika, S. Goldstein, S. Ben Haim, H.N. Sabbah. Henry Ford Health System, 
Detroit MI , United States of America . European Heart Journal Vol 4, Abstr. Suppl. August 2002, 
page 200  
35. Optimization of Non-Excitatory Electrical Signals Applied to the Right Ventricular Septum . 
Authors : Walid Haddad, Itzhak Shemer, Yuval Mika , Shlomo Ben Haim, Impulse Dynamics, 
Haifa , Israel ; The Bruce Rappaport Faculry of Medicine, Technion, Haifa , Israel . Abstract #091 
Journal of Cardiac Failure, Volume 8, Number 4 August 2002, p.59.  
36. Six Hours Application of Non-Excitatory Cardiac Contractility Modulation Electrical Signal 
Improves Global Left Ventricular Function in Dogs with Heart Failure . Authors : Walid Haddad, 
George Suzuki, Hideaki Morita, Yuval Mika , Sidney Goldstein, Shlomo Ben Haim, Hani N. 
Sabbah. Impulse Dynamics, Haifa, Israel; Cardiovascular Research, Henry Ford Health System, 
Detroit, MI. Abstract #051 Journal of Cardiac Failure, Volume 8, Number 4, Suppl. 1, August 
2002.  
37. First Chronic Clinical Study Suggests That 2 Months treatment with Non - Excitatory Electrical 
Signals Increases Ejection Fraction and Improves Heart failure. Authors : Martin Borggrefe, Univ 
Clin Mannheim, Mannheim , Germany ; Dan Burkhoff for the European Investigators, div of 
Circulatory Physiology and Cardiology, Columbia Univ, New York , NY . AHA poster session 
115348, 18 November, 2002  
38. Nonexcitatory Electric Signals Improve Systemic Hemodynamics and Cardiac Contractility in 
Conscious Dogs with Chronic Heart failure (CHF) Authors : K.L. He, H. Zhou, S. Mohri, G.H. Yi, 
D. Burkhoff, J. Wang; Columbia University, New York City, NY, USA. 8 th . World Congress on 
Heart Failure: Mechanisms and Management, July 14, 2002 poster session (Abs. # 095).  

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
IDE - Investigational Plan Section 
August 7, 2014 
Page 8 of 9 
39. Preliminary Mid-Term Safety and Efficacy Results of Cardiac Contractility Modulation by Non-
Exitatory Electrical Currents for Heart Failure . Authors : Carlo Pappone, Salvatore Rosanio, 
MD, phD, Giuseppe Augello, Gabriele Vicedomini, Francesco Maggi, Yuval Mika , Micheal 
Wolzt, Gerhard Buchmayr , Gunter Stix and Herwig Schmidinger. San Raffaele Univ. Hosp., 
Milan, Italy, Technion- Isreal Inst. of Technology, Haifa , Isreal and Univ.-Klinik fur Innere 
Medizin II, Vienna , Austria . NASPE Abst. # 13. PACE Vol.26 Part II, April 2003, p. 932.  
40. Preliminary Mid-term Safety and Efficacy Results of Cardiac Contractility Modulation by Non-
excitatory Electrical Currents for Heart Failure . Authors : C. Pappone, G. Augello, G. 
Vicedomini 1 , F. Maggi 2 , Y. Mika 3 , P. Mazzone 1 , S.Gulletta 1 , S. Rosanio 1 ; 1 San Raffaele 
University Hospital – Milan – Italy, 2 Impulse Dynamics – Zug – Switzerland, 3 Impulse Dynamics 
– Tirat Hacarmel – Israel . ESC Congress 2003, Abst. # P1522, August 2003.  
41. Therapy With Non-Excitatory Cardiac Contractility Modulation Electric Signals Reserve the 
Maladaptive Fetal Gene Program in LV Myocardium of Dogs With Heart Failure . Authors : 
Sharad Rastogi, Sudish Mishra, Omar Habib, Makoto Imai, Ramesh C Gupta, Henry Ford Health 
System, Detroit, MI; Walid Haddad, Yuval Mika , Impulse Dynamics USA, Orangeburg, NY; 
William C Stanley, Case Western Reserve University, Cleveland, OH; Hani N Sabbah; Henry Ford 
Health System, Detroit, MI (November 2003, AHA). Supplement IV Circulation Vol 108, No 17 
October 28, 2003 abstract # 2041  
42. Improvement of Heart Failure by Electrical Modulation of Cardiac Contractility . Authors : 
Guenter Stix, Michael Wolzt, University of Vienna, Vienna, Austria; Gabriele Vicedomini, 
Salvatore Rosanio, San Raffaele University Hospital, Milan, Italy; Marton Borggrefe, Christian 
Wolpert, I. Medizinische Klinik, University Hospital, Mannheim, Germany; Gerhard Hindricks , 
Hans Kottkamp, Department of Cardiology, University of Leizig, Leipzig, Germany; Dieter 
Horstkotte, Barbara Lamp, Department of Cardiology, University of Bochum, Bochum, Germany; 
Dirk B Ö cker, Thomas Wichter, Department of Cardiology and Angiology, Westf ä lische 
Wilhelms-Universit ä t, M Ü nster, Germany; Yuval Mika , Shlomo Ben-Haim , Technion – Israel 
Institute of Technology, Haifa, Israel; Daniel Burkhoff, Department of Medicine, Columbia 
University, New York, NY; Herwig Schmidinger, University of Vienna, Vienna, Austria 
(November 2003, AHA). Supplement IV Circulation Vol 108, No 17 October 28, 2003 abstract # 
2551  
43. Non-excitatory cardiac contractility modulation electric signals improve left ventricular function 
in dogs with heart failure without increasing myocardial oxygen consumption. Authors : Hani N. 
Sabbah, Makoto Imai, Walid Haddad, Omar Habib, William C. Stanley, Margaret P. Chandler and 
Yuval Mika . Supplement to Heart Rhythm, Vol. 1, No. 1 (Issue 1S), May 2004, Poster session # 
576, p. S181  
44. Enhanced inotropic state by cardiac contractility modulation signals is not associated with 
changes in myocardial oxygen consumption. Authors : Christian Butter, Ernst Wellnhofer, Michael 
Schlegl, Georgia Winbeck, Daniel Burkhoff, Eckart Fleck. Supplement to Heart Rhythm, Vol. 1, 
No. 1 (Issue 1S), May 2004, abstract # 889, p. S278  
45. Improvement of Heart Failure by chronic electrical stimulation during myocardial refractoriness. 
Authors : Stix G, Borggrefe M, Wolzt M, Wolpert C, Hindricks G, Kottkamp H, Hansky B, Lamp 
B, Böcker D, Wichter T., Mika Y, Ben-Haim S, Burkhoff D, Schmidinger H. Europace 
supplements, Volume 6 Supplement 1 June 2004 Abstract # 249/5, p.195  

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
IDE - Investigational Plan Section 
August 7, 2014 
Page 9 of 9 
46. Therapy with Non-excitatory Cardiac Contractility Modulation Electrical signals Partially 
Restores mRNA expression of Connexin 43 in Left Ventricular Myocardium of Dogs with Heart 
Failure Authors : Sudhish Mishra 1 , Ramesh C. Gupta 1 , Walid Haddad 2 , Sharad Rastogi 1 , 
Makoto Imai 1 , Yuval Mika 2 , Hani N. Sabbah 1 ; 1 Medicine, Henry Ford Health System, Detroit 
, MI ; 2 Impulse Dynamics USA, Orangeburg , NY . Supplement to Journal of Cardiac Failure , 
Vol. 10 No. 4, August 2004 , Abstract #153, Page S59  
47. Short-Term Therapy with Nonexcitatory Cardiac Contractility Modulation Electric Signals 
increases Phosphorylation of Phospholamban in Left Ventricular Myocardium of Dogs With 
Chronic Heart Failure. Authors : Sudhish Mishra, Ramesh C Gupta, Sharad Rastogi, Henry Ford 
Health System, Detroit MI; Walid Haddad, Yuval Mika , Impulse Dynamics USA, Mount Laurel, 
NJ; Hani N Sabbah; Henry Ford Health System, Detriot, MI. Supplement III Circulation , Vol 110, 
No 17, Abstract #2808, October 26, 2004.  
48. Non-Excitatory Cardiac Contractility Modulation Electric Signals Normalize Phosphorylation and 
expression of the Sodium Calcium Exchange in Left Ventricular Myocardium of Dogs with Heart 
Failure. Authors : Ramesh C. Gupta, Sudish Mishra, Sharad Rastogi, Makato Imai, Walid Haddad, 
Yuval Mika , Hani N. Sabbah. JACC 2005;45:151A.  
49. Cardiac Contractility Modulation with Non-Excitatory Electrical Signals Normalizes Expression of 
the Transcriptional Factor GATA-4 in Dogs with Chronic Heart Failure Authors : Ramesh C. 
Gupta, PhD, Sudhish Mishra, PhD, Makoto Imai , MD , Yuval Mika , PhD and Hani N. Sabbah, 
PhD. Heart Rhythm 2005 Scientific Sessions, May 5, 2005, New Orleans , LA , Poster # P2-12  
50. Chronic Therapy With Non-Excitatory Cardiac Contractility Modulation Electric Signals Improves 
Left Ventricular Function, Reduces Myocardial Oxygen Consumption and Increases Myocardial 
Mechanical Efficiency Authors : Hani N. Sabbah, PhD, Makoto Imai, MD, Sharad Rastogi, MD, 
Naveen Sharma, PhD, Margaret P. Chandler, PhD, Walid Haddad, PhD, Yuval Mika , PhD and 
William C. Stanley, PhD. Heart Rhythm 2005 Scientific Sessions, May 5, 2005, New Orleans , LA 
, Abstract # AB22-5  
51. Effects of CCM (Cardiac Contractility Modulation) Signal Delivery on Left Ventricular 
Contractility Authors : Thomas Lawo, MD, Thomas Deneke, Andreas Mügge, MD and Matthias 
Vogt . Heart Rhythm 2005 Scientific Sessions, May 6, 2005, New Orleans , LA , Poster # P5-103  

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
IDE - Investigational Plan Section 
August 7, 2014 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix B 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Phase II, Version: August 7, 2014 
 
Page 1 of 10 
 
Subject ID Number:___-________ 
 
Evaluation of the Safety and Efficacy of the 
OPTIMIZER System with Active Fixation Leads in 
Subjects with Heart Failure Resulting from Systolic Dysfunction: 
FIX-HF-5 
 
INFORMED CONSENT 
 
Introduction 
Your doctor has explained to you that your heart strength is decreased and this may be causing 
you to experience tiredness and shortness of breath.  This condition, called heart failure, is 
usually treated with medications to improve the strength of the heart muscle and reduce the 
amount of work the heart has to do.  However, medications are not always successful in making 
heart failure patients feel better.  A new experimental medical device has been developed to 
improve heart strength using electrical signals applied to the heart.  The experimental medical 
device is called the OPTIMIZER System.  The experimental treatment delivered by the 
OPTIMIZER™ System for stimulating the heart muscle with an electrical signal is called cardiac 
contractility modulation (CCM) treatment. 
 
Research 
You are being asked to consider voluntary participation in a research study of the CCM treatment 
with the OPTIMIZER™ System sponsored by IMPULSE DYNAMICS (USA), Inc.  The purpose 
of the study is to determine whether the CCM treatment improves the way you feel.  We would 
like to give you all the information necessary to help you make an informed decision about 
participating in this research study.  Before you give your consent please read the following 
information carefully.   
 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Phase II, Version: August 7, 2014 
 
Page 2 of 10 
The information given here is not intended to be a substitute for the opinion of your doctor, who 
will answer all your questions about this study. 
 
Expected Duration of Study Participation 
Your participation in this study is expected to be approximately 13 months.  This will include up 
to one month for screening and baseline testing with a one year follow-up period.  If you receive 
an OPTIMIZER System implant, you will be asked to return for follow-up every 3 months for as 
long as you have the device in place and choose to keep it active until the FDA completes their 
review of this study. This follow up may take up to 5 years.  
 
Study Procedures  
Certain medical tests will be performed to determine if you are eligible to participate in this 
study. These tests include a physical examination with a medical history; an electrocardiogram 
(to check the electrical activity in your heart); two different types of stress tests (one test 
performed on a treadmill while the oxygen in your breath is analyzed and a second test to see 
how far you can walk on flat ground), an echocardiogram (to check the strength of your heart), 
two questionnaires that ask you about your heart failure symptoms and a 24-hour Holter monitor 
test (a tape recording of your heart rhythm over the course of an entire day).  If you are a woman 
of childbearing potential, a pregnancy test will be done within 7 days of scheduled implant to 
make sure that you are not pregnant; in addition, you must agree not to become pregnant as long 
as you are in this study.  Women of childbearing potential must be using a medically approved 
method of birth control such as an IUD, surgical sterilization (hysterectomy, tubal ligation), or 
must be post-menopausal for at least one year.  
If the results of these tests indicate that you are eligible to participate, you will be randomly 
assigned (like flipping a coin) to one of two groups: either a group that receives an OPTIMIZER 
System or a group that does not receive the OPTIMIZER System.  Regardless of which group 
you are in, you will continue to be followed closely to ensure that you are receiving optimal 
medical therapy for your heart failure.   

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Phase II, Version: August 7, 2014 
 
Page 3 of 10 
If you are randomized to receive the OPTIMIZER System,  you may require additional 
testing in accordance with the procedures followed by your institution. These tests may include 
blood testing, urinalysis, and a chest x-ray.  These procedures vary at each institution, so your 
doctor will discuss them with you.  At the beginning of the implant procedure, your doctor will 
temporarily place a catheter inside the main pumping chamber of your heart (left ventricle) 
through a small incision in an artery in your groin.  This catheter will be used to measure the 
effects of CCM treatment on your heart.  If the effects of the CCM treatment do not reach a 
certain level the OPTIMIZER System will not be implanted. If the effect does reach a certain 
level, the OPTIMIZER System will be implanted.  The implant includes three electrical wires 
(leads) that connect the device to your heart through the veins inside your chest, very similar to 
procedures used when implanting a pacemaker device.  The leads are used to record the normal 
electrical signals generated by your heart and to deliver the CCM treatment to your heart.  The 
implantation is performed under sterile conditions with local anesthesia while you are awake, but 
possibly sedated.  The implantation will be done either in an operating room or in a cardiac 
catheterization laboratory, depending upon the normal practices for implanting heart devices at 
your hospital.  
Many patients with heart failure develop a need for a device called an implantable cardiac 
defibrillator (ICD) and/or a pacemaker.  If you do not already have one of these devices, your 
doctor may recommend that one be implanted.  If you are randomized to receive the 
OPTIMIZER System, the devices can be implanted at the same time.  If you do have both 
devices, your doctor will perform tests to make sure that the devices do not interfere with each 
other.  This could include a standard test used to confirm proper ICD function during which your 
heart is stimulated to beat abnormally (ventricular tachycardia or fibrillation).   
Following a device implant you will have a chest X-ray before you are sent home.  The 
OPTIMIZER System will be turned on for a brief period to make sure it is operating properly.  
During this time, you may also be instructed in how to use the battery charger.  Before you leave 
the hospital, however, the OPTIMIZER System will be turned to sensing mode until your next 
visit to the doctor. 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Phase II, Version: August 7, 2014 
 
Page 4 of 10 
If you are randomized to the control group that does not receive the OPTIMIZER System 
you will continue to receive optimal medical therapy and you shall receive the same study related 
assessments as detailed below.  If your doctor indicates that you have an indication for an ICD 
and/or pacemaker, this may be offered to you. 
All patients will be asked to return to the hospital in two weeks after the beginning of the study.  
A physical examination and check of your medications will be performed.  In subjects that have a 
pacemaker and/or ICD, that device will also be tested to make sure it is working properly.  If you 
have received an OPTIMIZER implant, the device will be checked to make sure it is working 
properly and will be adjusted if necessary.  The OPTIMIZER System will be turned ON to 
deliver the CCM treatment, which you will receive for the next 12 months. You will also receive 
instruction on when and how to use the battery charger, which you will take home with you.  The 
OPTIMIZER System has a rechargeable battery, meaning that it can remain active for many years 
without having to be replaced.  During normal use, the battery needs to be recharged every week 
for approximately 90 minutes.  The energy for recharging is delivered through your skin by a 
device that you position over your collar bone.  No wires or needles are required for this process.    
All patients, including those in which the OPTIMIZER device was unable to be implanted, will 
be asked to return for follow-up visits at Weeks 4, 12, 24, 36 and 50 following your study start 
date.  At every visit you will undergo medication review, medical history, physical examination 
and device interrogation.  At weeks 12, 24 and 50 you will also be asked to complete the 
questionnaires about symptoms you have during your daily life, to undergo stress tests to see how 
much you can exercise (the 6 minute walk and the cardiopulmonary stress test) and to undergo an 
echocardiogram to check the strength of your heart.  At weeks 12 and 24, the Holter monitor tests 
will be repeated to check the rate of your heart beat.  As noted above, female patients of child 
bearing potential who received an OPTIMIZER System shall be asked to have a pregnancy test at 
weeks 24 and 50. 
At the end of one year (50 weeks), if you have the OPTIMIZER System, you will have the option 
of continuing to receive CCM treatment if you and your doctor believe that it’s the best choice 
for you.  In such case,  a medical history, medication review, physical examination and device 
interrogation will be performed at 3-month intervals until the FDA has completed its review of 
this study.   

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Phase II, Version: August 7, 2014 
 
Page 5 of 10 
 
Foreseeable Risks Associated with Study Participation for Patients with the OPTIMIZER 
System 
1. Risks associated with temporary placement of a catheter  in your heart 
Your doctor will temporarily place a catheter inside the main pumping chamber of your heart 
(left ventricle) through a small incision in an artery in your groin.  This catheter will be used 
to measure the effects of the CCM treatment on your heart. The risks associated with 
temporary placement of this catheter include: 
 infection 
 bleeding 
 irregular heartbeats (ventricular arrhythmias) 
 damage to the heart or blood vessels 
 death 
 
2. Risks Associated with the OPTIMIZER System Implant and CCM Treatment 
The risks associated with implantation of the OPTIMIZER System (which includes 
implantation of the pulse generator and the leads that connect the generator to your heart) and 
application of CCM treatment include: 
 injury to the heart or blood vessels 
 bleeding 
 irregular heartbeats (arrhythmias, including abnormally slow or fast heart beats) 
 damage to the heart muscle 
 damage to specialized tissue in the heart responsible for initiating each heart beat (i.e., 
the heart’s conduction system) 
 formation of blood clots 
 stroke 
 chest wall sensations 
 pain at the incision site 
 infection 
 collapsed lung 
 perforation of the leads through the heart wall 
 lead dislodgement 
 fluid or blood accumulation around the heart 
 death 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Phase II, Version: August 7, 2014 
 
Page 6 of 10 
 
3. Risks Associated with the Use of Local Anesthesia 
Risks associated with the use of local anesthesia used during the OPTIMIZER System 
implantation procedure are as follows: 
 puncture of a vein 
 localized pain at or around injection site 
 numbness at or around injection site 
 bruising 
4. Risks associated with possible ICD and/or pacemaker device interactions 
If you have an ICD, it is possible that the CCM pulses delivered by the OPTIMIZER System 
could be sensed and falsely interpreted by the ICD as a fast heart beat (ventricular 
tachycardia).  If this should happen, the ICD may send an unnecessary shock to your heart.  
Studies in animals have not found this to be a problem when the ICD and the OPTIMIZER 
System are programmed correctly.  Also, it cannot be excluded that the Optimizer III will 
cause the ICD to fail to deliver treatment for a life threatening arrhythmia. However, the 
Optimizer device is designed to minimize this possibility and prior testing and experience in 
patients confirm the unlikeliness of this occurring. Additionally, all personnel involved with 
programming the OPTIMIZER System have been trained on device programming and device 
interaction testing. 
If you have a cardiac pacemaker it is possible that the CCM pulses delivered by the 
OPTIMIZER System could be sensed and falsely interpreted by the pacemaker as a regular 
heart beat.  If this should happen, the pacemaker might not send pacing signals to your heart 
at a rate needed by your body, and could result in an abnormally slow or unsteady heart 
rhythm (bradycardia).  Symptoms of bradycardia result from a lack of oxygen enriched blood 
being delivered to your body and include dizziness, fainting, extreme fatigue and shortness of 
breath.   
Many of the risks associated with the implantation of the OPTIMIZER System are minimized 
by having trained and experienced physicians perform the implantation procedure, through 
the use of meticulous care during the implantation procedure and by having experienced 
physicians involved in your care throughout the study period.   

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Phase II, Version: August 7, 2014 
 
Page 7 of 10 
 
5. Risk of an Optimizer System Surgical Revision  
There is a potential that any system component could malfunction, become damaged, 
infected, or, in the case of the leads, become dislodged.  System component malfunction or 
other clinical circumstances (e.g., sepsis) may require noninvasive corrective actions or 
possibly even a surgical revision (repositioning, replacement, or removal) of the 
malfunctioning component(s).   
6. Unknown Risks 
Because the OPTIMZER System is an experimental device, the application of CCM 
treatment to your heart may involve risks that are currently unknown.  If you receive the 
OPTIMIZER System, you will be notified of any additional risks that become known during 
the study that may affect your decision of whether to continue in the study. 
 
Foreseeable Risks Associated with Study Participation for All Study Patients 
There is a risk for all patients enrolled in this study, whether you receive an OPTIMIZER System 
or not, that your heart failure signs and symptoms may become worse.  Heart failure signs and 
symptoms include:  
 Stroke or transient ischemic attacks (TIA) 
 heart attack 
 dizziness or lightheadedness 
 palpitations 
 increased fatigue/weakness 
 shortness of breath or difficulty breathing 
 fluid retention in the lungs 
 severe swelling of the legs, feet and ankles 
 abnormal heart rhythms (too fast or too slow) 
There is also a risk of death associated with many of the signs and symptoms listed above.  

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Phase II, Version: August 7, 2014 
 
Page 8 of 10 
Reasonably Expected Benefits to You and to Others 
Your heart failure symptoms may improve as a result of receiving CCM treatment and this may 
help you exercise more or feel better.  The study will determine the degree to which these 
benefits occur.  However, because the therapy is not yet proven to be effective, you may not 
benefit from this study. 
 
Appropriate Alternative Procedures or Treatments  
Before offering you participation in this study, your doctor has made sure that you are already 
receiving the best possible medications for treating heart failure.  Your doctor may discuss other 
treatment options, such as giving you a drug continuously into a vein to increase the strength of 
your heart (known as positive inotropic agents) or cardiac resynchronization therapy (another 
pacemaker like device for treating heart failure patients with certain types of cardiac conduction 
abnormalities).  Therefore, the alternative to participating in this study is to choose not to 
participate and continue with your current medications or consider one of these other treatments.   
 
Confidentiality 
For the purpose of this study, your health data will be recorded and reviewed by the sponsor of 
the study (Impulse Dynamics) and by the US Food and Drug Administration (FDA) for 
evaluation.  Representatives of the sponsor and the US FDA will inspect your health data.  Any 
data that may be published in scientific journals will not reveal the identity of the study 
participants. Any information that is obtained in connection with this study that can be identified 
with you will remain confidential. 
   
Compensation and Cost  
The study sponsor will compensate you for your participation in this study according to the 
schedule listed below: 
2-week follow-up visit: 
$40 
4-week follow-up visit: 
$50 
12-week follow-up visit: 
$100 
24-week follow-up visit: 
$100 
36-week follow-up visit: 
$50 
50-week follow-up visit: 
$250 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Phase II, Version: August 7, 2014 
 
Page 9 of 10 
You will receive a single payment in one check that includes compensation for each visit that you 
completed.  You will be given that payment after the 50-week follow-up visit.  If you terminate 
your participation in the study prior to the 50-week visit, you will still receive a single payment 
for each visit that you completed.  In addition, you may also be compensated for your 
transportation costs to and from the facility and your home (for travel over 75 miles), parking, 
meals and reasonable lodging (for travel over 75 miles).  Mileage will be reimbursed at the 
standard rate of $0.36 per mile, which includes the cost of gasoline.  You will be asked to 
maintain and submit receipts for reimbursement. 
The study sponsor will be responsible for covering the research specific costs associated with 
your care.  In some cases, insurance companies may continue to pay for routine procedures and 
services that you would typically incur whether or not you would be participating in the trial.  A 
routine procedure or service is one that your doctor would have prescribed for you even if you 
were not in the clinical trial.  In these cases, your insurer will be billed for these services.  You 
will be responsible for paying any copayments and deductibles that you would normally be 
expected to pay. 
Some insurers will cover some of the research related procedures and services.  An example of a 
research related cost is the device, if you are in the group that receives the OPTIMIZER System.  
In these cases, you may be responsible for copayments and deductibles that you would ordinarily 
be expected to pay.  Importantly, however, if you are required to have a procedure or service that 
is related to the clinical trial and is not reimbursed by your insurer, the study sponsor will cover 
the cost and you will not incur the cost for that procedure or service. 
 
Injury  
If you believe that you have suffered injury or damage to your health due to your participation in 
this study, it is necessary to immediately inform the Principal Investigator, Dr.___________.   
Reasonable and necessary medical expenses incurred by you as a direct result of the treatment of 
an injury resulting from the OPTIMIZER System, the implant procedure or other procedures 
required by this study (other than standard of care procedures) and administered in accordance 
with the study protocol will be paid by the Study Sponsor to the extent such expenses are not 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Phase II, Version: August 7, 2014 
 
Page 10 of 10 
subject to your medical coverage and are not caused by the negligence or willful wrongdoing of 
the Hospital. 
 
Contacts 
Your doctor, will answer any of your questions about this study or about your rights as a research 
participants. If at any time you have any problems or questions regarding this study, please 
contact the following doctor: __________________________, MD at telephone:____________. 
 
Voluntary Participation 
Your participation in this study is voluntary. You may refuse to participate in this study or 
discontinue your participation at any time without any penalty or loss of benefits. Your decision 
will not influence the standard medical treatment you receive for your heart failure.  If you 
received the OPTIMIZER System, and you choose to withdraw from the study, your doctor will 
ask you to return the battery recharger and the CCM therapy will be stopped. 
 
Consent 
I have carefully read the above information. I have asked any questions that I may have 
concerning the study and the experimental CCM treatment and I have been given a copy of this 
consent form for my records.  By signing this form, I agree to participate in the study and to 
allow a representative of the sponsor and of the US FDA to inspect my health data. 
 
 
 
 
Printed Name of Participant 
 
 
 
 
 
Signature of Participant 
 
Date 
 
 
 
Investigator Signature 
 
Date 
 
 
 
Legally Authorized Representative (if applicable) 
 
Date 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
IDE - Investigational Plan Section 
August 7, 2014 
Page 1 of 2 
HIPAA Clinical Research Authorization 
AUTHORIZATION TO USE AND DISCLOSE HEALTH INFORMATION 
[name of study] 
 
I agree to permit [hospital], my doctors, and my other health care providers (together 
“Providers”), and [name of investigator(s)] and [his/her/their/its] staff (together “Researchers”), 
to use and disclose health information about me as described below.  
 
1. The health information that may be used and disclosed includes: 
 all information collected during the research described in the Informed Consent Form 
for the [name of study] (“the Research”); and 
 health information in my medical records that is relevant to the Research. 
 
2. The Providers may disclose health information in my medical records to: 
 the Researchers; 
 the sponsor of the Research, IMPULSE DYNAMICS, and its agents and contractors 
(together “Sponsor”); and 
 representatives of government agencies, review boards, and other persons who watch 
over the safety, effectiveness, and conduct of research.   
 
3. The Researchers may use and share my health information: 
 among themselves and with other participating researchers to conduct the Research; and 
 as permitted by the Informed Consent Form.   
 
4. The Sponsor may use and share my health information as permitted by the Informed 
Consent Form.   
 
5. Once my health information has been disclosed to a third party, federal privacy laws 
may no longer protect it from further disclosure.   
 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
IDE - Investigational Plan Section 
August 7, 2014 
Page 2 of 2 
6. Please note that: 
 You do not have to sign this Authorization, but if you do not, you may not 
participate in the Research. 
 You may change your mind and revoke (take back) this Authorization at any time 
and for any reason.  To revoke this Authorization, you must write to 
____________________________________.  However, if you revoke this 
Authorization, you will not be allowed to continue taking part in the Research.  
Also, even if you revoke this Authorization, the Researchers and the Sponsor may 
continue to use and disclose the information they have already collected as 
permitted by the Informed Consent Form. 
 [Note—Include this bullet point only if the IRB determines that suspension of 
participants’ access to information is appropriate.]  While the Research is in 
progress, you will not be allowed to see your health information that is created or 
collected by the [Hospital entity] in the course of the Research.  After the Research 
is finished, however, you may see this information as described in [Hospital 
entity]’s Notice of Privacy Practices.   
7. This Authorization does not have an expiration (ending) date. 
 
8. You will be given a copy of this Authorization after you have signed it. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of participant or participant’s legal 
representative 
 
  
 
 
 
 
 
 
 
 
 
Date 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed name of participant or participant’s 
legal representative 
 
 
  
 
 
 
 
 
 
 
 
 
Representative’s relationship to participant 
 
 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Version: August 7, 2014 
 
Page 1 of 2 
 
APPENDIX C 
 
TEMPLATE CASE REPORT FORMS 
 
Data for this study will actually be recorded into data entry screens using the Medidata electronic 
data capture system.  Template case report forms are available on disk for reference use only.  Due to 
the extensive use of drop-down options available on each form, the printed version is over 500 pages.  
The following is a list of the electronic Case Report Forms available on Medidata: 
 
Screening Visit Forms: 
Demographics 
Medical History  
Baseline Medications  
Baseline Physical Examination 
 
Baseline Visit Forms: 
Pregnancy Test  
NYHA Classification  
NYHA Questionnaire 
Minnesota Living with Heart Failure Questionnaire 
Echocardiogram 
6 Minute Walk Test 
Cardiopulmonary Stress Test 
12-Lead ECG 
24 Hour Holter Monitor 
Eligibility Determination  
Randomization 
Health Insurance Coverage 
 
Implant Folder (for Subjects Randomized to the Optimizer System): 
Follow Up Medications 
Follow-up Physical Examination 
Implant Success 
Implant- PSA Measurements 
Implant- dP/dt Evaluation 
Implant- Optimizer and Lead Information 
Implant- Equipment Notes, & Personnel 
Discharge 
Optimizer Interrogation 
 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Version: August 7, 2014 
 
Page 2 of 2 
Follow-up Folders: 
Interim Medical History 
Follow Up Medications 
Follow-Up Physical Examination 
NYHA Classification 
NYHA Questionnaire 
Minnesota Living with Heart Failure Questionnaire 
Echocardiogram 
6 Minute Walk Test 
Cardiopulmonary Stress Test 
24 Hour Holter Monitor 
Health Insurance Coverage 
Optimizer Interrogation (for subjects randomized to the Optimizer System) 
VT-VF Episodes 
Pregnancy Test 
 
 
Miscellaneous Forms 
ICD System/ Pacemaker 
Concomitant Device Interaction Testing 
End of Study/Withdrawal 
Patient Correspondence Log 
Protocol Deviation  
Adverse Event Log 
Adverse Event Forms 
Optimizer System Device Malfunction Log 
Hospitalization Log 
Procedure Log 
Mortality Form

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Version: August 7, 2014 
 
Page 1 of 4 
APPENDIX D 
 
TREATMENT OF SUBJECTS ENROLLED IN PHASE I OF THE FIX-HF-5 STUDY 
 
Background 
On May 6, 2004, FDA conditionally approved the Evaluation of the Safety and Efficacy of 
the OPTIMIZER™ II System with Active Fixation Leads in Subjects with Heart Failure 
Resulting from Systolic Dysfunction: FIX-HF-5.  The evaluation was designed as a 
prospective, double-blind, multi-center study of subjects with moderate to severe heart 
failure.  An interim safety evaluation was planned after completion of the first 50 implants 
(Phase I), with a DSMB decision required before proceeding with additional patient 
enrollment (Phase II).  All Phase I patients received an OPTIMIZER™ II System and were 
randomized to either have the device either turned “ON” or “OFF” for the first six months of 
follow-up.  Patients were informed that if their device was turned “ON” for the first six 
months, the battery would deplete and the device would need to be replaced.  If their device 
was turned “OFF” for the first six months, it would be turned “ON” after they completed the 
first six months of follow-up.   
 
Changes are now proposed to the study design and to the device.  The new generation of the 
device, the OPTIMIZER™ III System is now being introduced; this device has a rechargeable 
battery meaning that it does not have to be replaced after every 6 month period.  Because of 
this, however, the study design is now extending to two groups (treatment versus control) that 
are followed for twelve (12) instead of six (6) months.  The study will transition into an un-
blinded safety and effectiveness evaluation of patients who will either receive or not receive 
the OPTIMIZER™ III System.  This appendix is intended for those centers that enrolled 
patients into Phase I of the IDE study, and describes the methods used for the ongoing 
evaluation of those subjects. 
 
The sequence and duration of these follow-up intervals are described in Table 1.   
 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Version: August 7, 2014 
 
Page 2 of 4 
Study Procedures 
The main changes to the original protocol (May 6, 2004) in which 50 Phase I study subjects 
are participating shall be: 
1. At the point of OPTIMIZER II battery depletion, all subjects shall be offered the 
opportunity to have a device replacement with an OPTIMIZER™ III pulse generator 
as a replacement device.  For subjects randomized to “ON” during the first 6 months, 
this replacement is expected to occur following completion of the first 6 months of 
the study.  For subjects randomized to “OFF” during the first 6 months, this 
replacement is expected to occur following completion of the second 6 month period.  
The decision of whether or not to perform the replacement shall be made by the 
patient in consultation with the Principal Investigator and shall be based upon their 
clinical decision as to whether or not the patient appeared to have benefited from the 
treatment.   
2. In addition to the tests specified in the original protocol, Phase I subjects shall be 
asked to undergo a cardiopulmonary stress test (CPX), an echocardiogram and a 6 
minute hall walk test (6MW) at the 50 week follow-up visit.   
3. The expected duration of subject participation shall not change from the originally 
indicated 13 months (including the screening, baseline, and 12 months of follow-up).  
However, subjects who choose to have an OPTIMIZER™ III pulse generator implant 
shall be asked to return for routine follow-up and generator checks at 3 month 
intervals for as long as long as they choose to have the device in place and choose to 
keep it active until the FDA completes their review of this study. 
The subjects enrolled in Phase I of the study shall be informed of the changes to the protocol 
since they originally agreed to participate and shall be asked to sign an informed consent 
document that describes the risks and potential benefits of the changes.  The risks include 
those associated with performing the additional tests described above (CPX, 6MW and an 
echocardiogram).  The risks associated with these test are considered to be minimal and 
clinically acceptable, as detailed in the original study.  Participation shall be voluntary.  Any 
subject not wishing to participate is free to withdraw from the study.   
 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form 
Version: August 7, 2014 
 
Page 3 of 4 
OPTIMIZER II => III Device Replacement  
The OPTIMIZER II pulse generator will be replaced with the OPTIMIZER™ III rechargeable 
pulse generator, which is connected to the three leads placed during the initial implant 
procedure.  The device replacement procedure is performed under sterile technique.  Device 
interaction (if the patient has an ICD) and function is checked and a chest X-ray taken 
according to hospital policy to evaluate lead placement.  Patients may be instructed on when 
and how to use the battery charger and will be discharged with the device turned on.    
Patients will be asked to return to the hospital two weeks after the device replacement for a 
physical examination, a medication check, and device interrogation.  Additional instruction 
on use of the battery charger will be provided as necessary.      
 
Post Study Follow-Up 
Following the 50 week follow up, subjects can continue to receive treatment with CCM 
signals.  These patients shall be seen at ~6 month intervals at the investigational site.  These 
follow-up visits shall include an Optimizer device interrogation and reporting of any 
Optimizer device-related serious adverse events (and the corresponding hospitalizations and 
procedures, if any) and all deaths.  These visits shall continue until FDA has made a 
determination of device safety and efficacy.  In the event that the study is terminated prior to 
approval, the device is found to be ineffective or at the request of the patient, the device can 
be removed.  Alternatively, the device can be left in place and deactivated; in this case, the 
device charger would be retrieved from the patient in order to eliminate the possibility of 
further use of the device. 
 
Consent Materials 
A template consent for the Phase I Patients requesting a device exchange is attached. 
A consent addendum is included in Appendix F to inform subjects with the OPTIMIZER III 
System of the modified follow-up requirements and the availability of the OPTIMIZER IVs 
System. 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
August 7, 2014 
CONFIDENTIAL  
 
 
 
 
 
 
 
 
 
Page 4 of 4 
TABLE 1.  Schedule of Events 
Post-Randomization 
TEST 
Screening 
Baseline 
Implant 
Week 2§ 
+2days 
Week 4‡ 
+2days 
+4 
±1  
wks 
+12±1 
wks 
+22±1 
wks 
+24+1 
wks 
Device 
Exchange† 
+2 wks 
+2days† 
36±2  
wks 
50±2 
wks 
Device 
Exchange†† 
Every 6 
Months 
** 
Informed consent 
X 
  
  
  
  
  
  
  
 
X* 
 
  
  
X* 
  
Medical History  
X 
  
  
X 
X 
X 
X 
  
X 
 
X 
X 
X 
 
X 
Physical Examination 
X 
  
X 
X 
X 
X 
X 
  
X 
 
X 
X 
X 
 
 
Medications 
X 
  
X 
X 
X 
X 
X 
  
X 
 
X 
X 
X 
 
 
NYHA Classification 
X 
  
  
  
  
X 
X 
  
X 
 
 
X 
X 
 
 
Echocardiogram 
  
X 
  
  
  
  
X 
  
X 
 
 
  
 X 
 
  
MLWHFQ 
  
X 
  
  
  
X 
X 
  
X 
 
 
 X 
X 
 
 
6-minute walk 
  
X 
  
  
  
X 
X 
  
X 
 
 
  
 X 
 
 
Cardiopulmonary Stress Test 
  
X 
  
  
  
  
X 
  
X 
 
 
  
 X 
 
  
24 hour Holter Monitor 
  
X 
  
  
  
X 
X 
  
X 
 
 
  
  
 
  
Urine pregnancy test 
  
X 
  
  
  
  
 
  
X 
 
 
  
 X 
 
 
Eligibility determination 
  
X 
  
  
  
  
  
  
 
 
 
  
  
 
  
OPTIMIZER™ II System 
Implant 
  
  
X 
  
  
  
  
  
 
 
 
  
  
 
  
Chest X-ray 
  
  
X 
  
  
  
  
  
 
 
 
  
  
 
  
In-Hospital System Activation 
  
  
X 
  
  
  
  
  
 
X 
 
  
  
X 
  
Device Interrogation / 
Programming 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
Randomization  
  
  
  
X§ 
X‡ 
  
  
  
 
 
 
  
  
 
  
OPTIMIZER™ 
Device 
Exchange 
  
  
  
  
  
  
  
  
 
X† 
 
  
  
X†† 
  
Adverse Events, 
Hospitalizations, Procedures (as 
needed) /OPTIMZER device-
related SAEs after  50-wks 
  
X 
X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
NOTE: Subjects withdrawn due to an unsuccessful implant procedure (includes cases that failed to achieve ≥5% increase in dP/dtmax during acute CCM signal application) should be 
evaluated again between 2 and 4 weeks after the procedure and report any post-procedural adverse events as needed. 
* 
Phase 2 informed consent required one time prior to device exchange at 24 weeks to receive the Optimizer III System or the 50-week interval. 
§ 
All subjects will undergo a visit 2 weeks after device implantation.  “Single” implant subjects will be randomized and device activated according to group assignment. 
‡ 
Dual implant subjects (i.e., those who underwent ICD/pacemaker implant at the same time as OPTIMIZER™ II implant) will undergo a second post-implantation visit 4 weeks after 
device implantation at which point the device will be activated according to group assignment. 
† 
For subjects randomized to have the OPTIMIZER II device “ON” for the first 6 months, the device will reach end-of-battery life on average at 26-weeks and shall be offered the 
OPTIMIZER III pulse generator at that point.  Patients will be seen 2 weeks after their device exchange procedure. 
†† 
For subjects randomized to have the OPTIMIZER II device “OFF” for the first 6 months and then “ON” for the second 6 month period, the device will reach end-of-battery life on 
average at 52-weeks and shall be offered the OPTIMIZER III pulse generator at that point.  Patients will be seen 2 weeks after their device exchange procedure. 
** 
Patients receiving the OPTIMIZER III device will be followed every six months following the 50-week interval for as long as they have the device in place and choose to keep it 
active, until either the study is terminated or the FDA completes their review of this study.  Patients with a depleted OPTIMIZER II System battery who choose not to receive the 
OPTIMIZER III pulse generator have met the protocol follow-up requirements after the 50-week visit and may be discontinued from the study.  Follow-up window is +/- 4 weeks.

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form Addendum 
Phase I, August 7, 2014 
 
Page 1 of 8 
 
 
 
Subject ID Number:___-________ 
 
Evaluation of the Safety and Efficacy of the 
OPTIMIZER System with Active Fixation Leads in 
Subjects with Heart Failure Resulting from Systolic Dysfunction: 
FIX-HF-5 
 
INFORMED CONSENT 
 
Introduction 
Several months ago you signed an informed consent document and were enrolled in a research 
study for the OPTIMIZER™ II System (an experimental medical device).  The OPTIMIZER™ II 
System battery has now depleted and in order to continue CCM treatment, the portion of the 
device that contains the battery needs to be replaced.    
You are now being asked to consider continuing your voluntary participation in this research 
study, which is being sponsored by a company called IMPULSE DYNAMICS (USA), Inc.  
Please read the following information carefully and discuss any questions you have with your 
doctor.   
 
Expected Duration of Study Participation 
Your participation in this study is expected to be an additional 6 months (for those subject 
randomized to have CCM treatment ON for the first six months of the study), with additional 
follow-up every 3 months for as long as you have the device in place and choose to keep it active 
until the FDA completes their review of this study.  This follow up may take up to 5 years. 
 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form Addendum 
Phase I, August 7, 2014 
 
Page 2 of 8 
 
 
Study Procedures  
The battery in the OPTIMIZER™ II System that you had implanted several months ago has now 
depleted.  The study sponsor has modified that version of the device to one that is now 
rechargeable, called the OPTIMIZER™ III System.  The replacement device (OPTIMIZER™ III) 
will be connected to the three electrical wires (leads) that were already implanted in your heart 
when you received the OPTIMIZER™ II System.  The device replacement procedure is 
performed under sterile conditions with local anesthesia while you are awake.  The implantation 
will be done either in an operating room or in a cardiac catheterization laboratory, depending 
upon the normal practices for implanting heart devices at your hospital.  
After the OPTIMIZER™ III device is implanted, your doctor will perform tests to make sure that 
it is functioning properly.  If you have an ICD (defibrillator) and/or pacemaker in your heart, your 
doctor will also do a test to verify that the devices are not interfere with each other’s function.  
You will have a chest X-ray taken to verify that the leads in your heart are still optimally placed.  
Before you leave the hospital, the OPTIMIZER III System will be turned on to deliver the CCM 
treatment, which you will receive for as long as you choose to keep the device charged. You will 
be instructed on how to use the battery charger, which you will take home with you.  The 
OPTIMIZER III System has a rechargable battery, meaning that it can remain active for many 
years without having to be replaced.  During normal use, the battery needs to be recharged every 
week for approximately 90 minutes.  The energy for recharging is delivered through your skin by 
a device that you position over your collar bone.  No wires or needles are required for this 
process.   Your doctor will continue to follow you closely to ensure that you charging the device 
appropriately and are receiving optimal medical therapy for your heart failure condition.   
You will be asked to return to the hospital in two weeks after the device replacement for a 
physical examination and a check of your medications.  If you have a pacemaker and/or ICD, that 
device as well as the OPTIMIZER III System will be tested to make sure they are working 
properly and adjusted if necessary.     
If you have not done so already, you will be asked to return for follow-up visits at Weeks 36 and 
50 following the date of your initial OPTIMIZER II System implant.  During these two visits you 
will undergo medication review, medical history, physical examination and device  

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form Addendum 
Phase I, August 7, 2014 
 
Page 3 of 8 
 
 
interrogation.  At week 50 you will also be asked to complete the two questionnaires about 
symptoms you have during your daily life, to undergo stress tests to see how much you can 
exercise (the 6 minute walk and the cardiopulmonary stress test) and to undergo an 
echocardiogram to check the strength of your heart.    
At the end of one year (~50 weeks) or after receiving the OPTIMIZER III System (whichever 
comes last), you will have the option of continuing to receive CCM treatment if you and your 
doctor believe that it’s the best choice for you.  In such case, you will continue to be followed at 
approximately 3 month intervals until the FDA has completed its review of this study.   
 
Foreseeable Risks Associated with the OPTIMIZER System 
1. Risks Associated with replacement of the OPTIMIZER System and CCM Treatment 
The risks associated with replacement of the OPTIMIZER System and application of CCM 
treatment include: 
 bleeding 
 pain at the incision site 
 infection 
2.   Risks Associated with the OPTIMIZER System Implant and CCM Treatment 
The risks associated with implantation of the OPTIMIZER System (which includes 
implantation of the pulse generator and the leads that connect the generator to your heart) and 
application of CCM treatment include: 
 injury to the heart or blood vessels 
 bleeding 
 irregular heartbeats (arrhythmias, including abnormally slow or fast heart beats) 
 damage to the heart muscle 
 damage to specialized tissue in the heart responsible for initiating each heart beat (i.e., 
the heart’s conduction system) 
 formation of blood clots 
 stroke 
 chest wall sensations 
 pain at the incision site 
 infection 
 collapsed lung 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form Addendum 
Phase I, August 7, 2014 
 
Page 4 of 8 
 
 
 perforation of the leads through the heart wall 
 lead dislodgement 
 fluid or blood accumulation around the heart 
 death 
 
3.   Risks Associated with the Use of Local Anesthesia 
Risks associated with the use of local anesthesia used during the OPTIMIZER System 
replacement procedure are as follows: 
 puncture of a vein 
 localized pain at or around injection site 
 numbness at or around injection site 
 bruising 
4.   Risks associated with ICD/pacemaker device interaction 
If you have an ICD, it is possible that the CCM pulses delivered by the OPTIMIZER System 
could be sensed and falsely interpreted by the ICD as a fast heart beat (ventricular 
tachycardia).  If this should happen, the ICD may send an unnecessary shock to your heart.  
Studies conducted in animals indicate that this should not occur when the appropriate type of 
ICD lead is used and when the ICD and the OPTIMIZER System are programmed correctly.   
If you have a pacemaker that is set for pacing your heart beat, it is possible that the CCM 
pulses delivered by the OPTIMIZER System could be sensed and falsely interpreted by the 
pacemaker as a regular heart beat.  If this should happen, the pacemaker might not send 
pacing signals to your heart at a rate needed by your body, and could result in an abnormally 
slow or unsteady heart rhythm (bradycardia).  Symptoms of bradycardia result from a lack of 
oxygen enriched blood being delivered to your body and include dizziness, fainting, extreme 
fatigue and shortness of breath.   
Many of the risks associated with the replacement of the OPTIMIZER System are minimized 
by having trained and experienced physicians perform the implantation procedure, through 
the use of meticulous care during the replacement procedure and by having experienced 
physicians involved in your care throughout the study period.  Also, it cannot be excluded 
that the Optimizer III will cause the ICD to fail to deliver treatment for a life threatening 
arrhythmia. However, the Optimizer device is designed to eliminate this possibility and prior 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form Addendum 
Phase I, August 7, 2014 
 
Page 5 of 8 
 
 
testing and experience in patients confirm the unlikeliness of this occurring. Additionally, all 
personnel involved with programming the OPTIMIZER System have been trained on device 
programming and device interaction testing. 
5.   Risks Associated with Heart Failure 
There is a risk for all patients enrolled in this study that your heart failure signs and 
symptoms may become worse.  Heart failure signs and symptoms include:  
 stroke 
 heart attack 
 dizziness or lightheadedness 
 palpitations 
 increased fatigue/weakness 
 shortness of breath or difficulty breathing 
 fluid retention in the lungs 
 severe swelling of the legs, feet and ankles 
 abnormal heart rhythms (too fast or too slow) 
There is also a risk of death associated with many of the signs and symptoms listed above.  
 
6. Risk of an Optimizer System Surgical Revision  
There is a potential that any system component could malfunction, become damaged, 
infected, or, in the case of the leads, become dislodged.  System component malfunction or 
other clinical circumstances (e.g., sepsis) may require noninvasive corrective actions or 
possibly even a surgical revision (repositioning, replacement, or removal) of the 
malfunctioning component(s).   
7.   Unknown Risks 
Because the OPTIMZER System is an experimental device, the application of CCM 
treatment to your heart may involve risks that are currently unknown.  You will be notified of 
any additional risks that become known during the study that may affect your decision of 
whether to continue in the study. 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form Addendum 
Phase I, August 7, 2014 
 
Page 6 of 8 
 
 
 
Reasonably Expected Benefits to You and to Others 
Your heart failure symptoms may improve as a result of receiving CCM treatment and this may 
help you exercise more or feel better.  The study will determine the degree to which these 
benefits occur.  However, because the therapy is not yet proven to be effective, you may not 
benefit from this study. 
 
Alternative Procedures or Treatments  
As a participant in this study, your doctor is making sure that you are receiving the best possible 
medications for treating heart failure.  Your doctor may discuss other treatment options, such as 
giving you a drug continuously into a vein to increase the strength of your heart (known as 
positive inotropic agents) or cardiac resynchronization therapy (another pacemaker like device 
for treating heart failure patients with certain types of cardiac conduction abnormalities).  
Therefore, the alternative to continuing your participation in this study is to choose not 
participate (and not to receive a replacement OPTIMIZER System) and continue with your 
current medications or consider one of the other treatments mentioned above.   
 
Confidentiality 
For the purpose of this study, your health data will be recorded and reviewed by the sponsor of 
the study (Impulse Dynamics) and by the US Food and Drug Administration (FDA) for 
evaluation.  Representatives of the sponsor and the US FDA will inspect your health data.  Any 
data that may be published in scientific journals will not reveal the identity of the study 
participants. Any information that is obtained in connection with this study that can be identified 
with you will remain confidential. 
 
Compensation and Cost  
You will not be compensated for your participation in this study but you may be reimbursed for 
the following costs you may incur as a study participant:  

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form Addendum 
Phase I, August 7, 2014 
 
Page 7 of 8 
 
 
 Transportation costs to and from the facility and your home (for travel over 75 miles). 
Mileage will be reimbursed at the standard rate of $0.36 per mile (or current standard 
rate), which includes the cost of gasoline.   
 Parking  
 Meals and reasonable lodging (for travel over 75 miles)   
NOTE:  You will be asked to maintain and submit receipts for reimbursement. 
The study sponsor will be responsible for covering the research specific costs associated with 
your care.  In some cases, insurance companies may continue to pay for routine procedures and 
services that you would typically incur whether or not you would be participating in the trial.  A 
routine procedure or service is one that your doctor would have prescribed for you even if you 
were not in the clinical trial.  In these cases, your insurer will be billed for these services.  You 
will be responsible for paying any copayments and deductibles that you would normally be 
expected to pay. 
Some insurers will cover some of the research related costs (such as the cost of the OPTIMIZER 
System), procedures and services.  In these cases, you may be responsible for copayments and 
deductibles that you would ordinarily be expected to pay.  Importantly, however, if you are 
required to have a procedure or service that is related to the clinical trial and is not reimbursed by 
your insurer, the study sponsor will cover the cost and you will not incur the cost for that 
procedure or service. 
Injury  
If you believe that you have suffered injury or damage to your health due to your participation in 
this study, it is necessary to immediately inform the Principal Investigator, Dr.___________.   
Reasonable and necessary medical expenses incurred by you as a direct result of the treatment of 
an injury resulting from the OPTIMIZER System, the implant procedure or other procedures 
required by this study (other than standard of care procedures) and administered in accordance 
with the study protocol will be paid by the Study Sponsor to the extent such expenses are not 
subject to your medical coverage and are not caused by the negligence or willful wrongdoing of 
the Hospital. 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form Addendum 
Phase I, August 7, 2014 
 
Page 8 of 8 
 
 
Contacts 
Your doctor, will answer any of your questions about this study or about your rights as a research 
participants. If at any time you have any problems or questions regarding this study, please 
contact the following doctor: _________________________, MD at telephone:_____________. 
Voluntary Participation 
Your participation in this study is voluntary. You may refuse to participate in this study or 
discontinue your participation at any time without any penalty or loss of benefits. Your decision 
will not influence the standard medical treatment you receive for your heart failure.  If you 
choose to withdraw from the study, your doctor will ask you to return the battery recharger and 
the CCM therapy will be stopped. 
Consent 
I have carefully read the above information. I have asked any questions that I may have 
concerning the study and the experimental CCM treatment and I have been given a copy of this 
consent form for my records.  By signing this form, I agree to continue my participation in the 
study and to allow a representative of the sponsor and of the US FDA to inspect my health data. 
 
 
 
 
Printed Name of Participant 
 
 
 
 
 
Signature of Participant 
 
Date 
 
 
 
Investigator Signature 
 
Date 
 
 
 
Legally Authorized Representative (if applicable) 
 
Date 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
IDE - Investigational Plan Section 
August 7, 2014 
Page 1 of 2 
HIPAA Clinical Research Authorization 
 
AUTHORIZATION TO USE AND DISCLOSE HEALTH INFORMATION 
[name of study] 
 
I agree to permit [hospital], my doctors, and my other health care providers (together 
“Providers”), and [name of investigator(s)] and [his/her/their/its] staff (together “Researchers”), 
to use and disclose health information about me as described below.  
 
1. The health information that may be used and disclosed includes: 
 all information collected during the research described in the Informed Consent Form 
for the [name of study] (“the Research”); and 
 health information in my medical records that is relevant to the Research. 
 
2. The Providers may disclose health information in my medical records to: 
 the Researchers; 
 the sponsor of the Research, IMPULSE DYNAMICS, and its agents and contractors 
(together “Sponsor”); and 
 representatives of government agencies, review boards, and other persons who 
watch over the safety, effectiveness, and conduct of research.   
 
3. The Researchers may use and share my health information: 
 among themselves and with other participating researchers to conduct the Research; 
and 
 as permitted by the Informed Consent Form.   
 
4. The Sponsor may use and share my health information as permitted by the Informed 
Consent Form.   
 

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form Addendum 
Optimizer III Long-term Follow-up 
August 7, 2014 
Page 2 of 2 
5. Once my health information has been disclosed to a third party, federal privacy laws 
may no longer protect it from further disclosure.   
 
6. Please note that: 
 You do not have to sign this Authorization, but if you do not, you may not participate in 
the Research. 
 You may change your mind and revoke (take back) this Authorization at any time and 
for 
any 
reason. 
 
To 
revoke 
this 
Authorization, 
you 
must 
write 
to 
____________________________________. 
 
However, 
if 
you 
revoke 
this 
Authorization, you will not be allowed to continue taking part in the Research.  Also, 
even if you revoke this Authorization, the Researchers and the Sponsor may continue to 
use and disclose the information they have already collected as permitted by the 
Informed Consent Form. 
 [Note—Include this bullet point only if the IRB determines that suspension of 
participants’ access to information is appropriate.]  While the Research is in progress, 
you will not be allowed to see your health information that is created or collected by the 
[Hospital entity] in the course of the Research.  After the Research is finished, however, 
you may see this information as described in [Hospital entity]’s Notice of Privacy 
Practices.   
7. This Authorization does not have an expiration (ending) date. 
 
8. You will be given a copy of this Authorization after you have signed it. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of participant or participant’s legal 
representative 
 
  
 
 
 
 
 
 
 
 
 
Date 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed name of participant or participant’s 
legal representative 
 
 
  
 
 
 
 
 
 
 
 
 
Representative’s relationship to participant 
 
 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
Optimizer III Long-term Follow-up 
August 7, 2014 
Page 1 of 2 
APPENDIX E 
Device-device Interaction Testing Procedure 
 
Subjects that have a concomitant device (e.g., ICD, pacemaker) will undergo additional testing 
at the end of the implant procedure to ensure appropriate function of both the Optimizer III and 
the concomitant device. The following steps summarize the required testing: 
1. Program the sensing windows of the Optimizer and ensure that the Optimizer III can be 
programmed to consistently delivery CCM therapy in the presence of the concomitant 
device. 
2. Activate CCM therapy and evaluate the real-time intracardiac electrograms and marker 
channels to ensure that CCM therapy does not cause inappropriate oversensing during 
normal sinus rhythm that cannot be resolved through reprogramming or lead 
repositioning.  
3. Activate CCM therapy and evaluate the real-time intracardiac electrograms and marker 
channels to ensure that CCM therapy does not cause inappropriate undersensing during 
normal sinus rhythm that cannot be resolved through reprogramming or lead 
repositioning. 
4. While CCM therapy is being delivered, ensure that CCM therapy does not cause 
inappropriate inhibition of bradycardia pacing. In patients that require bradycardia pacing, 
activate CCM therapy during pacing and evaluate the real-time intracardiac electrograms 
and marker channels to ensure that CCM therapy does not cause inappropriate inhibition 
of bradycardia pacing therapy that cannot be resolved through reprogramming or lead 
repositioning. 
5. Program the ICD to detect and convert an induced ventricular tachyarrhythmia. Program 
the Optimizer III to deliver continuous CCM therapy. While CCM therapy is being 
delivered, induce VT/VF and ensure that the implanted ICD can appropriately detect the 
ventricular tachyarrhythmia.  Ensure that CCM therapy does not cause inappropriate 
undersensing during VT/VF that cannot be resolved through reprogramming or lead 
repositioning. 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
Optimizer III Long-term Follow-up 
August 7, 2014 
Page 1 of 2 
Appendix F  
OPTIMIZER III Long-term Follow-up  
 
Background 
The FIX-HF-5 study included a Phase I and Phase II, with all active study subjects currently 
implanted with the OPTIMIZER™ III System.  This appendix is intended for those centers that 
enrolled patients into the FIX-HF-5 study with subjects who currently have the Optimizer III 
System implanted and are being seen for follow-up every 3 months.  The OPTIMIZER III IPG 
is no longer being manufactured the Sponsor.  The Sponsor believes subjects should have the 
option to receive the current generation IPG, the OPTIMIZER IVs. 
Study Follow-Up 
The requirement to bring subjects back for a follow-up visit every 3 months is no longer 
consistent with current practice regarding other electrophysiology devices, including those that 
are life-saving devices. Additionally, in markets where the Optimizer System is market 
approved, follow-up visits after the initial acute follow-up phase are only required on an as 
needed basis when the patient receives a message on their device during a charging session or 
are unable to charge the device. To reduce the burden on the patient, the research institution and 
the Sponsor, the follow-up frequency is being extended to every 6 months. 
Device Replacement  
Another protocol called the FIX-HF-5C Confirmatory Study protocol is being conducted under 
the same IDE as the FIX-HF-5 Study.  Subjects in the FIX-HF-5C Study will receive the new 
generation device, the OPTIMIZER™ IVs System. The OPTIMIZER IVs is very similar in its 
design to the OPTIMIZER III System with regard to its intended use, safety, performance, and 
design characteristics. The Optimizer IVs System employs the same atrial and ventricular leads 
as Optimizer III System.  The purpose of the OPTIMIZER IVs is to offer patients a smaller and 
thinner IPG with a smaller and more portable charger. The OPTIMIZER III IPG is no longer 
being manufactured by Impulse Dynamics, so if IPG replacement becomes necessary, subjects 
will be provided the OPTIMIZER IVs System at that time.   Subjects who do not wish to have 
the newer OPTIMIZER IVs implanted will have the OPTIMIZER III IPG de-activated and if 
they wish, the device may be explanted.     

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form Addendum 
Optimizer III Long-term Follow-up 
August 7, 2014 
Page 2 of 2 
IRB Approval 
OPTIMIZER III IPG replacement with the OPTIMIZER™ IVs pulse generator will only be 
performed at centers with IRB approval of the FIX-HF-5C Confirmatory Study, which includes 
the OPTIMIZER IVs Patient Manual and OPTIMIZER IVs Physician Manual. 
Any FIX-HF-5 Study Investigator not participating in the FIX-HF-5C Study that wishes to use 
an OPTIMIZER IVs IPG for a revision/replacement procedure must request an “Approved 
Deviation From Protocol” from their IRB, the Sponsor and the FDA. 
Consent Materials 
A template informed consent addendum is attached for all subjects currently active in the FIX-
HF-5 protocol. 
 

Impulse Dynamics (USA), Inc. 
Study #IDPT 2003-07-C  
US Pivotal Study Clinical Plan FIX-HF-5 
Optimizer III Long-term Follow-up 
August 7, 2014 
Page 1 of 2 
Informed Consent Addendum for Participation in Research Activities 
Impulse Dynamics FIX-HF-5 Optimizer Study 
 
 
Dear Optimizer Study Research Participant: 
You are currently taking part in the above-named research study. Before beginning this research 
study, you signed an Informed Consent that fully described the study and your rights as a 
research participant. The purpose of this Informed Consent Addendum is to provide you with 
new information about the study. Though the initial phase of the research study is completed, 
minimal data continues to be collected at approximately 3-month intervals primarily to 
determine if your Optimizer device is functioning appropriately.   
We are writing to inform you that routinely scheduled visits will now take place approximately 
every 6-months, unless your doctor decides more frequent visits are necessary. You should still 
contact and see your doctor whenever you have a problem with your device or you do not feel 
well.  You are reminded to continue charging your OPTIMIZER device on a weekly basis.  
Failure to keep your device battery charged may cause permanent damage to the battery. 
We also want to let you know that if you ever need the Optimizer device replaced, you will be 
offered the most current version of the device called the Optimizer IVs System, which is the 
next generation of the device you currently have.  The Optimizer IVs device is very similar to 
your current device but is smaller and thinner and uses a smaller more portable charger.  If you 
do not wish to have the newer OPTIMIZER IVs implanted, the OPTIMIZER III IPG will be 
turned off, if it hasn’t been already, and if you wish, the device may be removed.  

Impulse Dynamics (USA), Inc.  
US IDE Study 
Informed Consent Form Addendum 
Optimizer III Long-term Follow-up 
August 7, 2014 
Page 2 of 2 
STATEMENT OF CONSENT: 
I have read all of the new information in this addendum concerning the study I am currently 
participating in.  I have been given the opportunity to discuss the information contained in this 
addendum. All of my questions have been answered to my satisfaction.  I understand that all 
previous statements of informed consent that were contained in the original consent document 
that I signed are still applicable, including potential benefits and risks.   
I give my informed and voluntary consent to continue as a participant in this study. A copy of 
this form will be given to me. 
_____________________________ 
 
 
 
              ________ 
 
 
 
 
Signature of Research Participant                                         
Date         
_____________________________ 
 
 
 
               
Print Name of Research Participant     

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The Statistical Analysis Report for the FIX-HF-5 Clinical Study of the OPT I MI ZE R  
System in Patients with Medically R efractory Heart Failure 
 
By 
 
R ichard P. Chiacchierini, Ph.D. 
 
 
I . 
I ntroduction 
 
Moderate to severe heart failure is associated with disability that significantly limits 
exercise tolerance and is associated with poor quality of life.  The OPTIMIZER 
System delivers cardiac contractility modulation, non-excitatory signals during the 
myocardial absolute refractory period synchronized with locally sensed electrical 
activity, intended to improve symptoms in treated subjects. 
 
The statistical analysis below provides a detailed description of the analyses 
conducted, hypotheses tested, the precise statistical methods used and the populations 
analyzed.  The analysis methods provide a thorough evaluation of the OPTIMIZER 
System in the population of moderate to severe heart failure subjects. 
 
I I . 
Study Design 
 
This is a multicenter, randomized, prospective, parallel group clinical trial to evaluate 
the safety and efficacy of the OPTIMIZERTM System with active fixation leads in 
subjects with moderate to severe heart failure.  Four hundred and twenty eight (428) 
subjects from 50 centers in the US were randomized with equal probability to 
implantation of the OPTIMIZERTM System in combination with optimal medical 
treatment (OMT) for heart failure or to OMT alone. Randomization used permuted 
blocks of four and was stratified by center and etiology of heart failure (ischemic 
versus non-ischemic cardiomyopathy). The nature of the treatment and requirement 
for one-year follow up precluded blinding of subjects and their treating clinicians, 
however, safety data were adjudicated by an independent committee of physician 
experts according to pre-specified criteria. 
 
I I I . 
Objective 
 
The objective of this investigation was to evaluate the safety and effectiveness of the 
OPTIMIZER System with active fixation leads in subjects with moderate to severe 
heart failure. 
 
I V . 
Study Sites and Patient Distribution 
 
The distribution of patients by study site and treatment group is given in the table 
below. 
 

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Table IV. 1  Distribution of Patients by Treatment Group and Study Site 
Site Number and Name 
Consented 
Control 
n (%) 
Optimizer 
n (%) 
Total 
Randomized 
01 Lancaster General Hospital 
17 
2 (33.3) 
4 (66.7) 
6 
02 Mayo Clinic 
5 
2 (66.7) 
1 (33.3) 
3 
03 CVMG of S. California 
19 
5 (50.0) 
5 (50.0) 
10 
04 Medical College of Virginia 
3 
1 (50.0) 
1 (50.0) 
2 
05 St. Luke's - Roosevelt Hospital 
4 
1 (50.0) 
1 (50.0) 
2 
06 Ohio State University 
10 
4 (57.1) 
3 (42.9) 
7 
08 Stern Cardiovascular Center 
14 
3 (42.9) 
4 (57.1) 
7 
09 Tyler CVC 
53 
13 (50.0) 
13 (50.0) 
26 
10 Aurora Denver Cardiology 
5 
1 (33.3) 
2 (66.7) 
3 
11 Hershey Medical Center 
2 
0 (0.0) 
0 (0.0) 
0 
12 Beth Israel (Newark) 
16 
5 (50.0) 
5 (50.0) 
10 
13 St. Joseph's Hospital 
37 
10 (52.6) 
9 (47.4) 
19 
14 UAB 
5 
1 (50.0) 
1 (50.0) 
2 
15 St. Luke's (Milwaukee) 
18 
6 (50.0) 
6 (50.0) 
12 
16 UCSD Medical Center 
2 
0 (0.0) 
0 (0.0) 
0 
17 Pacific Rim EP 
28 
8 (47.1) 
9 (52.9) 
17 
18 Forsyth Medical Center 
7 
3 (60.0) 
2 (40.0) 
5 
19 Deborah Heart & Lung Center 
9 
2 (40.0) 
3 (60.0) 
5 
20 Heart Care Associates 
32 
9 (56.3) 
7 (43.7) 
16 
21 Harper University Hospital 
24 
6 (66.7) 
3 (33.3) 
9 
22 Texas Cardiac Arrhythmia 
17 
6 (54.5) 
5 (45.5) 
11 
23 Baylor (Houston) 
9 
3 (42.9) 
4 (57.1) 
7 
24 Overlake Hospital - Hope Heart Institute 
3 
2 (100.0) 
0 (0.0) 
2 
25 St. Francis Hospital 
10 
2 (40.0) 
3 (60.0) 
5 
26 UT Southwestern 
35 
11 (47.8) 
12 (52.2) 
23 
27 Lone Star Arrhythmia 
85 
25 (50.0) 
25 (50.0) 
50 
28 University of Florida (Tampa) 
8 
1 (33.3) 
2 (66.7) 
3 
29 Henry Ford Hospital 
9 
1 (50.0) 
1 (50.0) 
2 
30 Riverside Regional Medical Center 
23 
4 (50.0) 
4 (50.0) 
8 
31 Midwest Heart Foundation 
13 
2 (40.0) 
3 (60.0) 
5 
32 Ochsner 
30 
6 (42.9) 
8 (57.1) 
14 
33 St. Paul Heart Clinic 
16 
4 (44.4) 
5 (55.6) 
9 
34 LBCVRF at Moses Cone 
3 
0 (0.0) 
1 (100.0) 
1 
35 Northwestern University 
13 
5 (55.6) 
4 (44.4) 
9 
36 Inova Arrhythmia Associates 
18 
8 (57.1) 
6 (42.9) 
14 
37 Mt. Sinai Hospital (Miami Beach) 
22 
7 (58.3) 
5 (41.7) 
12 
38 Texsan Heart Hospital 
6 
1 (50.0) 
1 (50.0) 
2 
39 Arizona Arrhythmia Consultants 
10 
2 (40.0) 
3 (60.0) 
5 
40 Deaconess Medical Center 
5 
0 (0.0) 
3 (100.0) 
3 
41 Bryan LGH Heart Institute 
46 
17 (50.0) 
17 (50.0) 
34 

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Page 3 of 53 
 
Table IV.1  Distribution of Patients by Treatment Group and Study Site (Continued) 
Site Number and Name 
Consented 
Control 
n (%) 
Optimizer 
n (%) 
Total 
Randomized 
42 Vanderbilt Univ. Medical Center 
7 
1 (25.0) 
3 (75.0) 
4 
43 California Pacific Medical Center 
8 
3 (60.0) 
2 (40.0) 
5 
44 Emory 
15 
4 (50.0) 
4 (50.0) 
8 
45 NYU 
5 
1 (33.3) 
2 (66.7) 
3 
46 Lahey Clinic 
10 
2 (33.3) 
4 (66.7) 
6 
47 Cardiovascular Associates 
5 
1 (33.3) 
2 (66.7) 
3 
48 University of Wisconsin Hospital 
6 
3 (100.0) 
0 (0.0) 
3 
49 Presbyterian Medical Center 
23 
9 (56.3) 
7 (43.7) 
16 
50 Scripps Clinic 
4 
0 (0.0) 
0 (0.0) 
0 
Grand Totals 
774 
213 (49.8) 
215 (50.2) 
428 
 

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V . 
Patient Accountability 
 
The accountability of patients with study visits is presented in the table below.  
 
Table V.1  Patient Accountability and Follow-up 
Interval 
Week 
2 
Week 
4 
Week 
12 
Week 
24 
Week 
36 
Week 
50 
Control 
Enrolled 
213 
213 
213 
213 
213 
213 
Died1 
0 
0 
1 
1 
3 
7 
Withdrawn1 
 24 
44 
64 
84 
94 
224  
Intervention not 
Withdrawn1 
0 
0 
0 
1 
1 
4 
Eligible2 
211 
209 
206 
203 
199 
181 
Visit in Window 
 155 
 179 
173  
 166 
165  
 143 
Visit Outside 
Window 
31 
18 
18 
23 
19 
34 
No Visit 
 25 
 12 
15 
14 
 15 
3 
Optimizer 
Enrolled 
215 
215 
215 
215 
215 
215 
Died1 
1 
1 
73 
103 
123 
133 
Withdrawn1 
34 
44 
44 
54 
84 
114 
Intervention not 
Withdrawn1 
0 
0 
0 
0 
0 
2 
Eligible2 
211 
210 
204 
200 
195 
189 
Visit in Window 
186 
192 
185 
177 
171 
164 
Visit Outside 
Window 
17 
11 
11 
18 
19 
24 
No Visit 
8 
7 
8 
5 
5 
1 
1Deaths, intervention, and withdrawn patients are cumulative over time. 
2The number eligible is the number enrolled minus the number that died and the number that withdrew 
or were intervened. 
3Three patients (08-212, 09-239, and 27-217) assigned to the Optimizer were too ill to receive the 
implant and died between 4 and 12 weeks from the study start date. 
4Two patients assigned to the Control (13-204 and 13-215) and two patients assigned to the Optimizer 
(13-206 and 29-204) withdrew after randomization but prior to the study start date. 
 

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The reasons for study withdrawal by treatment group are presented in the table below. 
 
Table V.2 Withdrawn Patients with Reason for Withdrawal by Study Group 
Control Group 
Patient 
Study 
Days1 
Reason for Discontinuation or Withdrawal  
13-215 
-3 
Subject and family members decided to see a cardiologist closer to their home. 
13-204 
0 
Subject received heart transplant. 
17-221 
13 
Patient did not wish to travel for control group 
27-214 
15 
Subject called and requested withdrawal from the study. 
36-215 
35 
Subject no longer wishes to take part in Optimizer Study 
13-212 
52 
Patient not aware that he was on the Impulse Dynamics study 
25-206 
135 
Patient has verbalized via telephone her refusal to continue participation. 
27-209 
150 
Pt is noted to be non-compliant, refuses to return for follow up visits. 
17-206 
154 
The patient underwent implant an ICD for cardiac resynchronization therapy. 
13-228 
301 
Patient deemed completed prior to 50 week window. 
20-231 
318 
Patient deemed completed prior to 50 week window. 
06-204 
324 
Patient deemed completed prior to 50 week window. 
17-217 
327 
Patient noncompliant with scheduled appointments. 
43-208 
329 
Patient deemed completed prior to 50 week window. 
13-218 
331 
Patient deemed completed prior to 50 week window. 
18-202 
331 
Patient deemed completed prior to 50 week window. 
20-222 
332 
Patient deemed completed prior to 50 week window. 
21-218 
332 
Patient deemed completed prior to 50 week window. 
23-205 
334 
Patient deemed completed prior to 50 week window. 
37-219 
334 
Patient deemed completed prior to 50 week window. 
14-202 
335 
Patient deemed completed prior to 50 week window. 
48-205 
335 
Patient deemed completed prior to 50 week window. 
Optimizer 
Patient 
Study 
Days 
Reason for Discontinuation or Withdrawal  
29-204 
-5 
Patient himself chose to withdraw due to  follow up compliance issues 
13-206 
-3 
Patient withdrawn because patient wanted a second opinion. 
22-202 
8 
Patient not implanted due to developed prolonged PR interval. 
36-206 
20 
Patient was "too scared to proceed" 
35-211 
150 
Patient's cardiologist chose to enroll in a different device trial. 
37-211 
194 
Patient noncompliant with scheduled appointments. 
12-205 
210 
Patient had implantation of an investigational LVAD 
12-207 
224 
Patient underwent heart transplantation 
12-208 
306 
Patient had heart transplant and removal of Optimizer device. 
37-216 
331 
Patient deemed completed prior to 50 week window. 
01-216 
332 
Patient deemed completed prior to 50 week window. 
1Study days relative to study start date (SSD), which is the scheduled day of device implantation. 

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V I . 
Baseline Comparability 
 
A comparison of baseline characteristics is given in the four tables below.  The first 
comparison is for baseline quantitative variables such as age. 
 
Table V I.1  Baseline Demographics – Quantitative Variables 
 Variable  
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
Age (yrs) 
58.55 (12.23) 213  
59 (26, 86) 
58.09 (12.79) 215  
57 (19, 85) 
0.51091 
QRS Duration (ms)3    
101.51 (12.81) 212  
102 (60, 130) 
101.63 (15.30) 214  
100 (70, 160) 
0.59682 
PR Interval4 
180.00 (31.59) 211 
177.0 (24, 263) 
181.04 (32.58) 214 
179.0 (65, 272) 
0.71551 
Holter (PVCs/24hr) 
1365.1 (2000.9) 213 
456.6 (0, 9960.5) 
1323.3 (1930.6) 215 
338.6 (0, 9298.0) 
0.51131 
LVEF (%) (site) 
26.09 (6.54) 213  
27 (10, 35) 
25.74 (6.60) 215  
25 (10, 40) 
0.56411 
LVEDD (mm) (site)5 
63.01 (8.56) 211 
62 (46, 88) 
62.41 (9.22) 215 
63 (30,  89) 
0.77151 
MLWHFQ 
57.38 (22.62) 213  
59 (1, 102) 
60.49 (23.00) 215  
64 (0, 100) 
0.11091 
6MW (meters)6 
323.99 (92.44) 212  
321 (80, 600) 
326.38 (82.10) 215  
330 (95, 525) 
0.59711 
CPX (site)7 
  Peak VO2 (ml/kg/min) 
14.72 (2.86) 212  
15.0 (9.0, 21.4) 
14.81 (3.20) 215  
14.7 (6.0, 25.9) 
0.97841 
  RER 
1.13 (0.09) 212 
1.11 (0.91, 1.43) 
1.14 (0.10) 215 
1.13 (0.96, 1.64) 
0.35001 
  Exercise Time (minutes) 
11.59 (3.55) 212 
11.67 (2.73, 22.00) 
11.40 (3.25) 215 
11.33 (4.00, 21.55) 
0.47701 
Physical Exam 
  Weight (kg) 
93.30 (22.16) 213 
90.9 (45.4, 169.0) 
91.17 (23.27) 215 
88.90 (44.7, 184.5) 
0.16321 
  Height (cm) 
173.30 (9.71) 213 
175.0 (142.0, 201.0) 
172.77 (9.68) 215 
173.0 (142.0 193.0) 
0.55911 
  BMI (kg/m2) 
30.95 (6.53) 213 
30.45 (18.63, 61.09) 
30.44 (7.04) 215 
29.65 (18.38, 60.99) 
0.21791 
  Resting HR (bpm)8 
73.74 (12.19) 213 
72.0 (49.0, 118.0) 
73.98 (13.13) 214 
72.0 (46.0, 115.0) 
0.96811 
  SBP (mmHg)8 
115.61 (17.61) 213  
114 (78, 174) 
116.65 (19.48) 214  
115 (78, 195) 
0.86951 
  DBP (mmHg)8 
70.35 (10.66) 213 
70.0 (44.0, 106.0) 
71.32 (11.89) 214 
70.0 (42.0, 119.0) 
0.46901 
  MBP8 
85.43 (11.72) 213 
84.67 (59.33, 119.33) 
86.43 (13.31) 214 
85.17 (54.67, 144.33) 
0.67441 
1Two-sided Wilcoxon rank sum test. 
2Two-sided unequal variance two-sample t-test. 

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3One patient from each group did not report a QRS duration. 
4Two Control patients and one Optimizer patient did not report a PR interval. 
5Two Control patients did not report LVEDD. 
6One Control patient did not have a 6 minute walk time at baseline. 
7One Control patient did not have any variable reported for the Site CPX. 
8One Optimizer patient did not report heart rate or blood pressure at baseline. 
 
The table above demonstrates that there are no statistically significant differences for 
baseline quantitative variables indicating good balance between the two study groups.  
The table below presents the comparison of baseline categorical variables such as 
gender. 
 
Table VI.2  Baseline Demographics and Medical History Categorical Variables 
 Variable 
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value 
Male     
151/213 (70.89) 
158/215 (73.49) 
0.59011 
Ethnicity   
                White 
                Black 
                Hispanic 
                Asian 
                Native American 
                Other 
 
142/213 (66.67) 
45/213 (21.13) 
19/213 (8.92) 
4/213 (1.88) 
1/213 (0.47) 
2/213 (0.94) 
 
154/215 (71.63) 
36/215 (16.74) 
13/215 (6.05) 
5/215 (2.33) 
2/215 (0.93) 
5/215 (2.33) 
 
0.50262 
CHF Etiology   
               Ischemic 
               Idiopathic 
               Valvular 
               Congenital 
               Hypertrophic 
               Peri/Postpardum 
               Adriamycin 
               Other 
 
142/213 (66.67) 
48/213 (22.54) 
4/213 (1.88) 
1/213 (0.47) 
3/213 (1.41) 
3/213 (1.41) 
4/213 (1.88) 
8/213 (3.76) 
 
139/215 (64.65) 
58/215 (26.98) 
1/215 (0.47) 
0/215 (0.00) 
4/215 (1.86) 
1/215 (0.47) 
3/215 (1.40) 
9/215 (4.19) 
 
0.64652 
Prior MI  
126/213 (59.15) 
125/215 (58.14) 
0.84491 
Prior CABG  
86/213 (40.38) 
82/215 (38.14) 
0.69231 
Prior PCI  
83/213 (38.97) 
86/215 (40.00) 
0.84371 
Diabetes  
102/213 (47.89) 
91/215 (42.33) 
0.28531 
NYHA (site)  
               Class I 
               Class II 
               Class III 
               Class IV 
0 (0.0) 
1/213 (0.47) 
183/213 (85.92) 
29/213 (13.62) 
0 (0.0) 
0/215 (0.00) 
196/215 (91.16) 
19/215 (8.84) 
 
0.17202 
1Two-sided Fisher’s exact test. 
2Two-sided Pearson Chi-square test. 
 
The table above demonstrates that there are no statistically significant differences for 
baseline categorical variables indicating good balance between the two study groups.  
The table below presents a comparison of baseline medication use. 
 

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Table VI.3  Baseline Medications 
Medication  
 
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-Value1 
Angiotensin converting enzyme inhibitor (ACEi) 
148/213 (69.48) 
153/215 (71.16) 
0.7512 
Angiotensin receptor blocker (ARB) 
51/213 (23.94) 
52/215 (24.19) 
1.0000 
ACEi or ARB 
195/213 (91.55) 
195/215 (90.70) 
0.8654 
Beta Blocker  
198/213 (92.96) 
202/215 (93.95) 
0.7005 
Loop Diuretic 
194/213 (91.08) 
198/215 (92.09) 
0.7307 
Second Diuretic2 
12/210 (5.71) 
19/212 (8.96) 
0.2629 
Aldosterone Inhibitor 
102/213 (47.89) 
95/215 (44.19) 
0.4973 
Hydralazine 
15/213 (7.04) 
12/215 (5.58) 
0.5574 
Nitrates 
75/213 (35.21) 
73/215 (33.95) 
0.8391 
Calcium Channel Blocker 
9/213 (4.23) 
18/215 (8.37) 
0.1103 
Anti-arrhythmic 
28/213 (13.15) 
37/215 (17.21) 
0.2816 
1Two-sided Fisher’s exact test. 
2Three control patients and three Optimizer patients did not have a second diuretic reponse. 
 
The baseline medication usage is not statistically significantly different for any 
medication.  The baseline core laboratory cardiopulmonary exercise assessments are 
compared in the table below. 
 
Table VI.4 Baseline Cardiopulmonary Exercise (Core Laboratory) 
 Variable 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P –value 
   Duration (minutes)3 
11.50 (3.46) 213 
11.52 (2.73 20.13) 
11.34 (3.20) 214 
11.36 (3.30, 19.57) 
0.48141 
   Peak SBP (mmHg)4 
138.8 (24.6) 212 
140 (72, 210) 
139.7 (27.1) 211 
140 (80, 240) 
0.97141 
   Peak HR (bpm)5 
121.2 (20.5) 212 
121 (72, 176) 
122.1 (20.2) 214 
123 (72, 174) 
0.52231 
   Peak VO2 (ml/kg/min)6 
14.71 (2.92) 211 
15.00 (8.5, 22.6) 
14.74 (3.06) 214 
14.50 (8.4, 23.0) 
0.85751 
   Peak RER7 
1.13 (0.09) 212 
1.12 (0.91, 1.45) 
1.14 (0.10) 214 
1.12 (0.89, 1.57) 
0.51891 
   AT (ml/kg/min)8 
10.97 (2.18) 207 
10.7 (5.4, 17.0) 
10.95 (2.24) 201 
10.6 (5.3, 16.9) 
0.97192 
1Two-sided Wilcoxon rank sum test. 
2Two-sided unequal variance two-sample t-test. 
3One Optimizer patient did not have a core lab report on exercise duration. 
4One Control patient and four Optimizer patients did not have core lab report of baseline peak SBP. 
5One Control patient and one Optimizer patient did not have core lab report of peak heart rate. 
6Two Control patients and one Optimizer patient did not have a core lab report of peak VO2. 
7One Control patient and one Optimizer patient did not have a core lab report of peak RER. 
8Six Control patients and fourteen Optimizer patients did not have a core lab report of AT. 
 
The baseline exercise capacity appears to be balanced between the treatment groups. 
 
The data from all study sites will be pooled based on a clinical justification of pooling 
given in Meinert (1986).  The pooling is based on three principles: that all sites used 
the same protocol, that the sponsor monitored the sites for protocol compliance and 
that the data gathering instruments (case report forms) were the same at all sites. 

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A comparison of the baseline characteristics by study site required by the Food and 
Drug Administration is provided below.  Study sites were combined (to create pseudo 
sites) to allow a study site comparability assessment because a number of sites 
enrolled too few patients for analysis on their own.  The method of forming pseudo-
sites combines sites in numerical order in such a way to provide as much balance 
between treated and control patients within the pseudo site as possible.  This process 
occasionally requires skipping the next site in order to have a better balance in the 
randomized patients between the two groups.  The skipped site was combined with 
one or more sites below it that also provide a good balance for the randomized 
assignments to the control and Optimizer groups.  The pseudo-sites and the original 
sites used to obtain the pseudo-site are presented below. 
 
Table VI.5  Pseudo-site Formation from Original Study Sites 
Pseudo Site 
Number 
Originals Site 
Number(s) 
Number of 
Control Patients 
Number  of 
Optimizer Patients 
Total 
Patients 
101 
01 and 02 
4 
5 
9 
03 
03 
5 
5 
10 
102 
04 and 06 
5 
4 
9 
103 
05 and 08 
4 
5 
9 
09 
09 
13 
13 
26 
12 
12 
5 
5 
10 
13 
13 
10 
9 
19 
104 
10, 14, and 18 
5 
5 
10 
15 
15 
6 
6 
12 
17 
17 
8 
9 
17 
105 
19, 24, and 25 
6 
6 
12 
20 
20 
9 
7 
16 
21 
21 
6 
3 
9 
22 
22 
6 
5 
11 
106 
23 and 28 
4 
6 
10 
26 
26 
11 
12 
23 
27 
27 
25 
25 
50 
107 
29 and 30 
5 
5 
10 
108 
31, 34, 38, and 39 
5 
8 
13 
32 
32 
6 
8 
14 
33 
33 
4 
5 
9 
35 
35 
5 
4 
9 
36 
36 
8 
6 
14 
37 
37 
7 
5 
12 
109 
40, 44, and 48 
7 
7 
14 
41 
41 
17 
17 
34 
110 
42 and 43 
4 
5 
9 
111 
45, 46, and 47 
4 
8 
12 
49 
49 
9 
7 
16 
Total 
213 
215 
428 
    
The analyses below use the general linear models procedure in SAS 9.1.3 to 
determine a site (pseudo-site) effect, treatment group effect, or an interaction for 
quantitative variables.  For categorical variables, each variable was made binary by 
sub-grouping and the analysis of site, treatment and interaction was assessed by 

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logistic regression.  In the tables below, the P-value for site, treatment, and interaction 
are presented.  Any P-value less than 0.05 is to be included as a potential covariate for 
subsequent safety and effectiveness multivariate models.  
 
Table VI.6  Summary of Study Site Comparability1 for Baseline Quantitative Endpoints. 
 Variable 
P-value for 
Treatment 
P-value for Study 
Site2 
P-value for Site 
by TRT 
Interaction 
Age (yrs) 
0.8898 
0.0358 
0.4392 
QRS Duration (ms)    
0.9860 
0.0140 
0.5862 
PR Interval 
0.5946 
0.0671 
0.3618 
Holter (PVCs/24hr) 
0.7084 
0.1963 
0.8410 
LVEF (%) (site) 
0.6279 
0.0080 
0.0407 
LVEDD (mm) (site) 
0.3354 
0.0089 
0.8733 
MLWHFQ 
0.3544 
0.1093 
0.6825 
6MW (meters) 
0.9201 
<0.0001 
0.4810 
CPX (site) 
     Peak VO2 (ml/kg/min) 
0.8181 
0.1801 
0.6258 
     RER 
0.8303 
0.0002 
0.9014 
     Exercise Time (minutes) 
0.3910 
0.0006 
0.3362 
Physical Exam 
  Weight (kg) 
0.2300 
0.7073 
0.8733 
  Height (cm) 
0.4452 
0.4173 
0.0699 
  BMI (kg/m2) 
0.3869 
0.4334 
0.9820 
  HR (bpm) 
0.3611 
0.3479 
0.6336 
  SBP (mmHg) 
0.5761 
0.0204 
0.8225 
  DBP (mmHg) 
0.3488 
0.1249 
0.9863 
  MAP 
0.4041 
0.1620 
0.9602 
1Analysis by general linear models analysis of variance with Type III sums of squares. 
2Pseudo-sites were used in this analysis and are defined in Table 4a. 
 
Table VI.7  Summary of Study Site Comparability1 for Baseline Categorical Endpoints. 
 Variable 
P-value for 
Treatment 
P-value for Study 
Site2 
P-value for 
Site by 
TRT 
Interaction 
Gender  
0.5035 
0.3753 
0.7480 
Ethnicity  (White Versus   Other) 
0.4544 
0.1526 
0.8869 
CHF Etiology 
0.7791 
0.9264 
0.5019 
Prior MI  
0.4954 
0.4563 
0.3030 
Prior CABG  
0.4600 
0.6964 
0.2006 
Prior PCI  
0.5696 
0.7694 
0.5854 
Diabetes  
0.8448 
0.3187 
0.4951 
NYHA (site)  
0.7991 
0.7948 
0.3724 
1Analysis by logistic regression. 
2Pseudo-sites were used in this analysis and are defined in Table 4a. 
 
 
 
 

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Table VI.8  Summary of Study Site Comparability1 for Baseline Medications. 
 Variable 
P-value for 
Treatment 
P-value for Study 
Site2 
P-value for 
Site by 
TRT 
Interaction 
ACEi 
0.1089 
0.5171 
0.0226 
ARB 
0.4673 
0.3345 
0.4238 
ACEi +/- ARB 
0.0518 
0.0191 
0.0261 
B-Blocker 
0.5372 
0.1887 
0.6063 
Diuretic 
0.4026 
0.9576 
0.4637 
Second Diuretic 
0.0122 
0.0035 
0.0161 
Aldosterone Inhibitor 
0.1551 
0.7007 
0.2385 
Antiarrhythmic 
0.2260 
0.3131 
0.5036 
Hydralazine 
0.5334 
0.9813 
0.7634 
Nitrates 
0.8873 
0.3973 
0.6726 
Ca Channel Blocker 
0.2411 
0.3480 
0.9998 
1Analysis by logistic regression. 
2Pseudo-sites were used in this analysis and are defined in Table 4a. 
 
Table VI.9  Summary of Study Site Comparability1 for Baseline Cardiopulmonary Exercise 
 Variable 
P-value for 
Treatment 
P-value for Study 
Site2 
P-value for 
Site by 
TRT 
Interaction 
   Duration (minutes) 
0.4822 
0.0022 
0.2157 
   Peak SBP (mmHg) 
0.7493 
<0.0001 
0.5936 
   Peak HR (bpm) 
0.4134 
0.0223 
0.4897 
   Peak VO2 (ml/kg/min) 
0.9894 
0.6534 
0.5938 
   Peak RER 
0.7288 
0.0020 
0.9477 
  AT (ml/kg/min) 
0.9690 
0.3116 
0.4726 
1Analysis by general linear models analysis of variance with Type III sums of squares. 
2Pseudo-sites were used in this analysis and are defined in Table 4a. 
 
Because several baseline variables were significantly different between study sites, 
study pseudo-site will be used as a possible covariate in multivariate analyses below. 
 
V I I . 
Study Populations 
 
The analysis populations are the intention to treat (ITT) consisting of all subjects 
randomized.  The full analysis set A (FASA), consisting of all randomized patients 
but excluding patients who never received a study treatment (there were 7 Optimizer 
and 1 Control patient excluded in this population). The full analysis set B (FASB) 
consisting of all randomized patients excluding patients who did not receive a study 
treatment or had no study follow-up (there were 7 Optimizer and 6 Control patients 
excluded from this population).  The population of completed cases (CC) consisting 
of all patients with a 24 week endpoint.  The final population is the per protocol (PP) 
consisting of all CC patients who did not have a protocol violation that would 

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substantially affect study outcomes.  Imputation by the methods described below is 
used to provide outcomes for effectiveness for subjects without outcomes in the ITT 
and FAS populations.  
 
V I I I . Comparison of Patient with Missing and Non-Missing Data 
 
A comparison of the baseline characteristics between patients with missing data for 
the primary effectiveness variable and those without missing data are provided below.  
These test are intended to determine if there is evidence of not missing at random and 
if there is, to provide a remedy such that the missing data can be assumed to be 
missing at random for those patients for which imputation is planned.  An initial 
analysis indicated that baseline weight, BMI, and site and core laboratory exercise 
durations were statistically significant.  The weight variable was considered of lower 
importance, but the exercise duration could impact anaerobic threshold (AT, the 
primary effectiveness variable) and therefore indicated that, strictly speaking, the data 
are not missing at random.  A review of the data indicated that the vast majority of 
exercise times exceeded 6-7 minutes and that subjects with short exercise times were 
less likely to show an improved AT regardless of treatment group.  On that basis, any 
patient missing the 24 week PVO2 and/or 24 week AT was assigned a worst case 
score.  This is similar to patients who had an event, i.e, patients who died or had an 
intervention (LVAD, heart transplant, or surgery to correct CHF) at a time that could 
be considered the reason why the data for 24 weeks was missing.  There were 10 
Active and 4 Control patients who had events prior to the 24 week visit and there 
were 3 Active and 6 Control patients who had an event between 24 and 50 weeks 
such that the event was considered the reason for missing the 24 week CPX.  The 
inclusion of patients with missing 24 week data and a baseline core laboratory 
exercise time of less than 6.5 minutes results in 5 Active and 8 Control patients added 
to the worst score assignment list.  The cumulative result is that 18 Active and 18 
control patients had either the lowest AT value from any previous visit assigned, or if 
all AT values were missing for previous visits, the lowest AT value recorded for any 
randomized patient.  These patients are indicated in Table IX.1 below as Imputation 
Case 6.   
 
After removing the 13 cases with missing 24 week data and an exercise time less than 
6.5 minutes, the baseline characteristic comparison between patients with missing and 
non-missing data at 24 weeks or baseline are presented in the following tables. 
 

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Table VIII.1  Baseline Demographics – Quantitative Variables - Compare Patients with Missing 
24 Week AT data with those Not Missing 24 Week Data 
Variable 
Missing 
Mean (SD) N 
Med (Min, Max) 
Non-Missing 
Mean (SD) N 
Med (Min, Max) 
P-value 
Age (yrs) 
55.65 (14.42) 80 
56.5 (19, 82) 
58.93 (11.95) 348 
59 (26, 86) 
0.06732 
QRS Duration (ms)3 
100.11 (14.03) 80 
98.5 (72, 150) 
101.91 (14.12) 346 
102 (60, 150) 
0.13251 
PR Interval4 
175.45 (34.00) 80 
174.0 (24, 248) 
181.70 (31.53) 345 
180.0 (65, 272) 
0.22841 
Holter (PVCs/24hr) 
1521.9 (2160.1) 80 
438.6 (0, 8527.0) 
1303.2 (1916.7) 348 
411.6 (0, 9960.5) 
0.45652 
LVEF (%) (site) 
26.50 (6.42) 80 
27 (11, 35) 
25.78 (6.60) 348 
25.5 (10, 40) 
0.33681 
LVEDD (mm) (site)5 
62.31 (8.58) 80 
62 (42, 89) 
62.80 (8.98) 346 
63 (30,  88) 
0.75551 
MLWHFQ 
58.86 (22.73) 80 
60 (2, 96) 
58.96 (22.90) 348 
63 (0, 102) 
0.83651 
6MW (meters)6 
321.96 (88.40) 79 
334.0 (95, 585) 
325.93 (87.15) 348 
326 (80, 600) 
0.72431 
CPX (site)7 
Peak VO2 (ml/kg/min) 
14.60 (3.36) 79 
14.2 (6.0, 25.9) 
14.80 (2.96) 348 
14.95 (9.0, 22.5) 
0.45831 
RER 
1.14 (0.09) 79 
1.13 (0.91, 1.43) 
1.13 (0.10) 348 
1.12 (0.96, 1.64) 
0.22181 
Exercise Time (minutes) 
11.13 (3.49) 79 
10.53 (4.0, 18.33) 
11.58 (3.38) 348 
11.75 (2.73, 22.00) 
0.21861 
Physical Exam 
Weight (kg) 
90.31 (23.99) 80 
90.00(47.3, 140.9) 
92.67 (22.44) 348 
90.00 (44.7, 184.5) 
0.36561 
Height (cm) 
173.11 (10.84) 80 
174.5 (142.0, 192.0) 
173.02 (9.42) 348 
173.0 (142.0 201.0) 
0.55921 
BMI (kg/m2) 
30.02 (7.37) 80 
28.98 (18.38, 60.99) 
30.85 (6.65) 348 
30.18 (18.63, 61.09) 
0.19551 
Resting HR (bpm)8 
75.76 (12.11) 80 
76.0 (50.0, 107.0) 
73.42 (12.75) 347 
72.0 (46.0, 118.0) 
0.06551 
SBP (mmHg)8 
117.15 (19.03) 80 
118 (78, 178) 
115.89 (18.46) 347 
114 (78, 195) 
0.45321 
DBP (mmHg)8 
71.56 (12.63) 80 
70.0 (48.0, 110.0) 
70.67 (10.97) 347 
70.0 (42.0, 119.0) 
0.71291 
MBP8 
86.76 (13.61) 80 
87.00 (59.33, 132.67) 
85.74 (12.29) 347 
84.67 (54.67, 144.33) 
0.51711 
1Two-sided Wilcoxon rank sum test. 
2Two-sided unequal variance two-sample t-test. 
3Two patients with non-missing data did not report QRS duration. 
4Three patients with non-missing data did not report a PR interval. 
5Two patients with non-missing data did not report LVEDD. 
6One patient with missing data did not have a 6 minute walk time at baseline. 
7One patient with missing data did not have any variable reported for the Site CPX. 
8One patient with non-missing data did not report heart rate or blood pressure at baseline. 

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Thus, there are no statistically significant differences in the quantitative baseline 
characteristics between the missing and non-missing patients.  
 
Table VIII.2  Baseline Demographics and Medical History Categorical Variables - Compare 
Patients with Missing 24 Week AT data with those Not Missing 24 Week Data 
Variable 
Missing 
n/N (%) 
Non Missing 
n/N (%) 
P-
value1 
Male     
58/80 (72.50) 
251/348 (72.13) 
1.0000 
Ethnicity (White)                  
52/80 (65.00) 
244/348 (70.11) 
0.4207 
CHF Etiology (Ischemic) 
32/80 (40.00) 
115/348 (33.05) 
0.2426 
Prior MI  
44/80 (55.00) 
207/348 (59.48) 
0.5292 
Prior CABG  
30/80 (37.50) 
138/348 (39.66) 
0.7998 
Prior PCI  
30/80 (37.50) 
139/348 (39.94) 
0.7058 
Diabetes  
38/80 (47.50) 
155/348 (44.54) 
0.7088 
NYHA (site) (Class IV) 
11/80 (13.75) 
37/348 (10.63) 
0.4334 
1Two-sided Fisher’s exact test. 
 
Table VIII.3  Baseline Medications - Compare Patients with Missing 24 Week AT data with 
those Not Missing 24 Week Data 
Medication 
 
Missing 
n/N (%) 
Non-Missing 
n/N (%) 
P-Value1 
Angiotensin converting enzyme inhibitor 
(ACEi) 
58/80 (72.50) 
243/348 (69.83) 
0.6856 
Angiotensin receptor blocker (ARB) 
18/80 (22.50) 
85/348 (24.43) 
0.7733 
ACEi or ARB 
72/80 (90.00) 
318/348 (91.38) 
0.6660 
Beta Blocker  
72/80 (90.00) 
328/348 (94.25) 
0.2060 
Loop Diuretic 
76/80 (95.00) 
316/348 (90.80) 
0.2701 
Second Diuretic 
9/80 (11.25) 
22/348 (6.32) 
0.1489 
Aldosterone Inhibitor 
35/80 (43.75) 
162/348 (46.55) 
0.7096 
Hydralazine 
7/80 (8.75) 
20/348 (5.75) 
0.3122 
Nitrates 
27/80 (33.75) 
121/348 (34.77) 
0.8970 
Calcium Channel Blocker 
4/80 (5.00) 
23/348 (6.61) 
0.7994 
Anti-arrhythmic 
4/80 (5.00) 
61/348 (17.53) 
0.0031 
     1Two-sided Fisher’s exact test. 
 
Only anti-arrhythmic medication use was statistically significantly difference between 
the missing and non-missing groups.  The non-missing group had the higher rate of 
anti-arrhythmic medication use.

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Table VIII.4 Baseline Cardiopulmonary Exercise (Core Laboratory) - Compare Patients with 
Missing 24 Week AT data with those Not Missing 24 Week Data 
Variable 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P –value 
   Duration (minutes)3 
11.22 (3.50) 80 
10.48 (4.92, 18.82) 
11.47 (3.29) 347 
11.65 (2.73, 20.13) 
0.35701 
   Peak SBP (mmHg)4 
139.9 (24.3) 80 
140 (96, 210) 
139.1 (26.2) 343 
140 (72, 240) 
0.71161 
   Peak HR (bpm)5 
124.0 (20.4) 80 
123.5 (72, 173) 
121.1 (20.3) 346 
121 (72, 176) 
0.23721 
   Peak VO2 (ml/kg/min)6 
14.69 (2.99) 78 
14.65 (8.4, 21.7) 
14.73 (3.00) 347 
14.80 (8.5, 23.0) 
0.81891 
   Peak RER7 
1.13 (0.11) 79 
1.12 (0.89, 1.52) 
1.13 (0.09) 347 
1.12 (0.97, 1.57) 
0.77022 
   AT (ml/kg/min)8 
11.00 (1.99) 64 
10.6 (7.4, 15.6) 
10.95 (2.25) 344 
10.7 (5.3, 17.0) 
0.75411 
1Two-sided Wilcoxon rank sum test. 
2Two-sided unequal variance two-sample t-test. 
3One non-missing patient did not have a core lab report on exercise duration. 
4Five non-missing patients did not have core lab report of baseline peak SBP. 
5Two non-missing patients did not have core lab report of peak heart rate. 
6Two missing patients and one non-missing patient did not have a core lab report of peak VO2. 
7One missing patient and one non-missing patient did not have a core lab report of peak RER. 
8Sixteen missing patients and four non-missing patients did not have a core lab report of AT. 
 
Exercise testing was not statistically significantly different between the missing and 
non-missing patients after deleting missing patients with less than 6.5 minute of 
baseline exercise duration.  These tests do not provide evidence that the missing at 
random assumption for the imputations below is violated. 
 
I X. 
I mputation Methods 
 
There are several methods of imputation that could be applied to missing data based 
on what data are missing and the relationships of the missing observations to data that 
are present.  The proposed method of imputation depends on the amount of data that 
are present for any given subject as summarized in the following table, and detailed 
below. 
 

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Table IX.1  Imputation Cases from Statistical Analysis Plan 
CASE 
Baseline 
6 Month Follow-Up 
Imputation 
Method 
Patients in Case 
Peak VO2 
AT 
Peak VO2 
AT 
Treatment 
Control 
0 
Present 
Present 
Present 
Present 
None 
159 
153 
1 
Present 
Present 
Present 
Absent 
Stochastic 
regression based 
on PVO2 and 
RER at 6M 
8 
9 
2 
Present 
Absent 
Present 
Present 
Stochastic 
regression based 
on PVO2 and 
RER at Baseline  
10 
2 
3 
Present 
Absent 
Present 
Absent 
Stochastic 
regression based 
on ΔPVO2 and 
RER 
1 
0 
4 
Present 
Present 
Absent 
Absent 
Propensity 
Matching and 
Random 
Selection 
18 
29 
5 
Present 
Absent 
Absent 
Absent 
Propensity 
Matching and 
Random 
Selection 
1 
2 
6 
Patients died, had an event, or had missing data and baseline 
duration <6.5 minutes1 
18 
18 
1A comparison of exercise duration between patients with missing and non-missing 24 week AT data 
indicated that subjects missing 24 week data with short baseline exercise times (<6.5 minutes) were 
possibly not missing at random.  Assigning these patients worst case values and removing them from 
the missing patient comparison resulted in no statistically significant differences between the patients 
with missing and non-missing 24 week AT values demonstrating that there is no violation in the 
missing at random assumption.     

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a. Regression Imputations 
 
For the patients in groups 1-3 above, the regression analysis of the completed 
cases resulted in the coefficients presented in the table below.   
 
Table IX.2  Regression Results for Imputation 
Imputation   
Case 1 
Intercept 
Coefficient of 
PVO2 (6 Mo.) 
Coefficient of 
RER (6 Mo.) 
Root Residual 
Mean Square 
6-Mo AT Missing 
Control 
9.138 
0.538 
-5.502 
1.170 
6-Mo AT Missing 
Optimizer 
4.163 
0.597 
-1.945 
1.132 
Imputation   
Case 2 
Intercept 
Coefficient of 
PVO2 (BL) 
Coefficient of 
RER (BL) 
Root Residual 
Mean Square 
Baseline AT Missing 
Control 
6.421 
0.619 
-3.888 
1.176 
Baseline AT Missing 
Optimizer 
6.534 
0.613 
-4.096 
1.127 
Imputation  
Case 3  
Intercept 
Coefficient of 
∆PVO2 (6 Mo.) 
Coefficient of 
∆RER (6 Mo.) 
Root Residual 
Mean Square 
Baseline and 6-
Month AT Missing 
Control 
-0.075 
0.571 
-4.212 
1.300 
Baseline and 6-
Month AT Missing 
Optimizer 
-0.118 
0.614 
-1.499 
1.270 
 
The imputed value is obtained by generating a standard normal value, z, and 
then applying the formula below for cases 1 and 2. 
 
 
AT = z*s + a + b1* PVO2 + b2 *RER 
 
Where s is the root mean square from the regression (an estimate of the 
standard deviation of the AT value), a is the intercept, b1is the coefficient for 
PVO2 and b2 is the coefficient for RER.  The equation for case three is similar 
with the difference that the AT term being estimated and the PVO2 and RER 
values are differences between 24 weeks and baseline.  
 
b. Propensity Score Imputation (Imputation Cases 4 and 5) 
 
The patients who had both PVO2 and AT at 24 week missing were assigned to 
Imputation Case 4.  In addition to the one patient missing AT at baseline, and 
PVO2 and AT at 24 weeks, one patient missing PVO2 and AT at baseline and 
PVO2 at 24 weeks and a second patient missing PVO2 and AT at baseline 
were added to Imputation Case 5.  Because there were only three patients in 
Case 5, these were added to Case 4 for propensity score assignment and 
subsequent imputation.  The random selection based on the propensity score 
quintile replaced only the missing values for any patient.  For the purposes of 

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modeling missingness, patients in the combined Cases 4 and 5 were assigned 
a missingness indicator and all other patients were assigned an indicator that 
data were not missing.  The propensity scores were assigned modeling the 
missingness of the combined Cases 4 and 5 by non-parsimonious logistic 
regression.  The model estimates are provided in the table below.  
 
 
Table IX.3  Non-parsimonious Model for Propensity Score Imputation 
Baseline Covariate* 
Estimated Coefficient 
P-value 
Age 
-0.0237 
0.1129 
Treatment Group 
0.2644 
0.0914 
Gender (Female) 
0.00976 
0.9569 
CHF Etiology (Ischemic) 
0.0584 
0.7557 
Diabetic 
-0.1579 
0.3209 
LVEF (Site) 
0.0215 
0.3739 
Baseline MLWHFQ 
-0.0134 
0.0635 
NYHA (Class IV) 
0.0503 
0.8356 
Baseline PVO2 
0.0204 
0.7150 
Baseline RER 
0.5316 
0.7460 
*Only covariates that have date for at least 90% of patients will be used and missing data will 
be imputed by substituting the median by treatment group for the missing variable.  
Propensity score covariates can have no missing values. 
 
The random selection was done from quintiles of patients with actual non-
missing data based on propensity scores and the numbers of missing, assumed 
non-missing (patients not in Case 4 or 5) and actual non-missing patients (the 
subset of patients not in Cases 4 or 5 with non-missing data) are presented in 
the table below. 
 
Table IX.4  Distribution of Patients by Treatment and Propensity Score Quintile 
Quintile 
Missing 
n/N (%) 
Not Case 4 or 5 
Not Missing 
1 
2/50 (4.00) 
84/378 (22.22) 
75/348 (21.55) 
2 
12/50 (24.00) 
74/378 (19.58) 
67/348 (19.26) 
3 
11/50 (22.00) 
74/378 (19.58) 
70/348 (20.11) 
4 
8/50 (16.00) 
78/378 (20.63) 
72/348 (20.69) 
5 
17/50 (34.00) 
68/378 (17.99) 
64/348 (18.39) 
 
This table demonstrates that there is a more than ample set of patients with 
complete data from which the patients with missing data can obtain values in 
each quintile.  The random selection is done with replacement.  

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X. 
Primary Safety Analysis 
 
The primary safety analysis evaluated the composite event rate of all cause mortality 
and all cause hospitalization at 50 weeks.  The statistical hypothesis is that the 
proportion of subjects in the treatment group where an event occurs by the 50 weeks 
will be non-inferior to the proportion of subjects where an event occurs by the 50 
weeks in the control group.  The statistical hypothesis to be tested is: 
 
Η0: πt > πc + δ 
vs. 
 
Η1: πt < πc + δ 
 
where δ=0.125 (clinically insignificant difference) and πc is the event rate in the 
control group and the πt is the event rate in the treatment group.  The statistical test to 
be used shall be the Blackwelder (1982) non-inferiority test and will be evaluated 
based on the intent-to-treat subject population. 
 
The events comprising the composite primary safety endpoints are provided in the 
table below for all patients, for patients grouped by core lab ejection fraction (< 25 or 
≥ 25), and patients grouped by core lab ejection fraction and NYHA (equal to 3 or 
not).   
 
Table X.1  Primary Safety Events (Deaths or All Cause Hospitalizations) for the ITT Population 
Group 
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-Value1 
All 
103/213 (48.36) 
112/215 (52.09) 
0.0348 
BL EF2<25  
50/99 (50.50) 
56/98 (57.14) 
0.2041 
BL EF2≥25  
53/113 (46.90) 
56/117 (47.86) 
0.0399 
BL EF2<25 & NYHA ≠3 
9/14 (64.29) 
7/11 (63.64) 
0.2484 
BL EF2<25 & NYHA=3 
41/85 (48.24) 
49/87 (56.32) 
0.2805 
BL EF2≥25 & NYHA ≠3 
11/16 (68.75) 
4/8 (50.00) 
.0.0696 
BL EF2≥25 & NYHA=3 
42/97 (43.30) 
52/109 (47.70) 
0.1219 
1One-sided Blackwelder’s test for non-inferiority with δ = 0.125 
2One Control patient did not have a baseline core laboratory ejection fraction 
 
There were 103 events in the control group and 112 events in the Optimizer group by 
50 weeks.  If one applies the Blackwelder test to the ITT population, assuming those 
lost to follow-up did not have an event, the rate in the control arm is 103/213 = 
0.4836 and in the test arm is 112/215=0.5209.  The difference is 0.0374 and the 
Blackwelder z-statistic is -1.8143 which corresponds to a P-value of 0.0348.  The 
upper one-sided 95% confidence limit is 11.68 which is below the delta of 12.5.  
Under this test, the primary safety endpoint is met. 
 
Recognizing that 6 control patients and 7 Optimizer patients either died or withdrew 
early with no follow-up beyond the screening examination, the modified ITT 

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population has 207 control and 208 Optimizer patients.  The events in this population 
are presented in the table below. 
 
Table X.2  Primary Safety Events (Deaths or All Cause Hospitalizations) for the m-ITT 
Population 
Group 
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-Value1 
All 
103/207 (49.76) 
112/208 (53.85) 
0.0431 
BL EF2<25  
50/98 (51.02) 
56/96 (58.33) 
0.2334 
BL EF2≥25  
53/108 (49.07) 
56/112 (50.00) 
0.0430 
BL EF2<25 & NYHA ≠3 
9/14 (64.29) 
7/11 (63.64) 
0.2484 
BL EF2<25 & NYHA=3 
41/84 (48.81) 
49/85 (57.65) 
0.3160 
BL EF2≥25 & NYHA ≠3 
11/15 (73.33) 
4/8 (50.00) 
0.0443 
BL EF2≥25 & NYHA=3 
42/93 (45.16) 
52/104 (50.00) 
0.1409 
1One-sided Blackwelder’s test for non-inferiority with δ = 0.125 
2One Control patient did not have a baseline core laboratory ejection fraction 
An analysis of the primary safety endpoint in this population results in 103/207 = 
0.4976 in the control group and 112/208 = 0.5385 in the Optimizer group.  The 
difference is 0.0409 and the Blackwelder z-statistic is -1.7163 which corresponds to a 
P-value of 0.0431.  The upper one-sided 95% confidence limit is 12.15 which is 
below the delta of 12.5.  Under this test in the m-ITT population, the primary safety 
endpoint is met. 
 
There was 1 additional control patient that was a clear protocol violation and 4 
Optimizer patients who refused treatment but continued with study follow-up visits.  
Excluding these additional subjects from the m-ITT population yields the per protocol 
population (PP) for safety of 206 control and 204 Optimizer patients.  The events for 
this population are presented in the table below. 
 
Table X.3  Primary Safety Events (Deaths or All Cause Hospitalizations) for the PP Population 
Group 
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-Value1 
All 
102/206 (49.51) 
109/204 (53.43) 
0.0409 
BL EF2<25  
49/97 (50.52) 
55/95 (57.89) 
0.2376 
BL EF2≥25  
53/108 (49.07) 
54/109 (49.54) 
0.0381 
BL EF2<25 & NYHA ≠3 
9/14 (64.29) 
7/11 (63.64) 
0.2484 
BL EF2<25 & NYHA=3 
40/83 (48.19) 
48/84 (57.14) 
0.3223 
BL EF2≥25 & NYHA ≠3 
11/15 (73.33) 
4/8 (50.00) 
0.0443 
BL EF2≥25 & NYHA=3 
42/93 (45.16) 
50/101 (49.50) 
0.1276 
1One-sided Blackwelder’s test for non-inferiority with δ = 0.125 
2One Control patient did not have a baseline core laboratory ejection fraction 
 
The one control and 3 of the 4 Optimizer patients experienced events so the number 
of events for the PP population is 102 in the control group and 109 in the Optimizer 
group.  An analysis of the primary endpoint with the PP population yields 102/206 = 
0.4951 in the control group and 109/204 = 0.5343 in the Optimizer group.  The 
difference is 0.0392 and the Blackwelder z-statistic for this test is -1.7400 which 
corresponds to a P-value of 0.0409.  The upper one-sided 95% confidence limit is 

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12.03 which is below the delta of 12.5.  Under this test in the PP population, the 
primary safety endpoint is met. 
 
Thus the primary safety null hypothesis is rejected under any of the three test 
conditions, ITT, m-ITT, or PP. 
 
XI . 
Secondary Safety Analyses 
 
Kaplan-Meier (KM) analyses were done for the composite for all patients in the ITT, 
m-ITT, and PP populations.  The KM analysis for all ITT subjects appear in the 
figure below.  The freedom from event curves with not statistically different from 
each other with a log-rank P-value = 0.2229. 
 
 
 
Figure 1.  Kaplan Meier Analysis of the Composite Primary Safety Endpoint of Death of 
Hospitalization in 350 days for the ITT Population,. 
 
 
The table below presents the freedom from even rates and 95% confidence intervals. 
 
Table XI.1  Estimated Rates of Freedoms from Primary Safety Event through 350 Days  (ITT) 
Treatment 
Group 
Month 
Patients 
Remaining 
Proportion Free 
from AE 
Lower 
95% CL 
Upper 
95% CL 
Control 
0 
212 
1 
-- 
-- 
1 
193 
0.9239 
0.8880 
0.9598 
3 
169 
0.8177 
0.7652 
0.8702 
6 
131 
0.6424 
0.5769 
0.7079 
12 
67 
0.4988 
0.4302 
0.5674 
Optimizer 
0 
209 
1 
-- 
-- 
1 
181 
0.8270 
0.7756 
0.8784 
3 
147 
0.7109 
0.6492 
0.7726 
6 
120 
0.5803 
0.5131 
0.6475 
12 
92 
0.4630 
0.3950 
0.5310 
 

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The KM analysis of the m-ITT population is presented in the figure and table below.  
The two curves were not significantly different from each other with a log-rank P-
value of 0.2134. 
 
Figure 2.  Kaplan Meier Analysis of the Composite Primary Safety Endpoint of Death of 
Hospitalization in 350 days for the m-ITT Population.  
 
 
The table below presents the freedom from even rates and 95% confidence intervals. 
 
Table XI.2  Estimated Rates of Freedoms from Primary Safety Event through 350 Days (m-ITT) 
Treatment 
Group 
Month 
Patients 
Remaining 
Proportion Free 
from AE 
Lower 
95% CL 
Upper 
95% CL 
Control 
0 
207 
1 
-- 
-- 
1 
191 
0.9227 
0.8862 
0.9592 
3 
168 
0.8169 
0.7640 
0.8698 
6 
131 
0.6407 
0.5752 
0.7062 
12 
67 
0.4974 
0.4288 
0.5660 
Optimizer 
0 
208 
1 
-- 
-- 
1 
171 
0.8221 
0.7702 
0.8740 
3 
147 
0.7067 
0.6448 
0.7686 
6 
120 
0.5769 
0.5097 
0.6441 
12 
92 
0.4603 
0.3925 
0.5281 
 
The KM curve for the PP population is presented in the figure and table below.  Two 
freedom from event curves are not statistically significantly different from each other 
with a log-rank P-value of 0.2460.  
 

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Figure 3.  Kaplan Meier Analysis of the Composite Primary Safety Endpoint of Death of 
Hospitalization in 350 days for the PP Population.  
 
 
 
The table below presents the freedom from even rates and 95% confidence intervals. 
 
Table XI.3  Estimated Rates of Freedoms from Primary Safety Event through 350 Days (PP) 
Treatment 
Group 
Month 
Patients 
Remaining 
Proportion Free 
from AE 
Lower 
95% CL 
Upper 
95% CL 
Control 
0 
206 
1 
-- 
-- 
1 
190 
0.9223 
0.8858 
0.9588 
3 
168 
0.8199 
0.7674 
0.8724 
6 
131 
0.6438 
0.5781 
0.7095 
12 
67 
0.4999 
0.4311 
0.5687 
Optimizer 
0 
208 
1 
-- 
-- 
1 
169 
0.8284 
0.7767 
0.8801 
3 
146 
0.7157 
0.6538 
0.7776 
6 
119 
0.5833 
0.5157 
0.6509 
12 
91 
0.4644 
0.3958 
0.5330 
 
A Cox regression multivariate analysis was done on the primary safety endpoint (all 
cause mortality and hospitalization) for events through 350 days. 
 
Variables were screened by the method of Hosmer and Lemeshow (2000) with a P-
value for admission into competition for the final model of 0.2.  Univariate Cox 
models including the covariate of interest and its interaction with treatment were used 
for screening.  If the interaction term with treatment is not significant, a second model 
was done without the interaction to screen for the main effect.   
 
The variables that were screened and their corresponding P-values are presented in 
the table below. 
 
Table XI.4  Univariate Cox Regression  Model Screening of Covariates for Primary Safety 
Events through 350 Days from Study Start Date (m-ITT) 
Characteristic 
P-value1 
Age 
0.0785 
Age by Optimizer Treatment Interaction 
0.8009 

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Gender 
0.3246 
Gender by Optimizer Treatment Interaction 
0.4149 
Baseline PVO2 
0.9940 
Baseline PVO2 by Optimizer Treatment Interaction 
0.4311 
Baseline AT 
0.8637 
Baseline AT by Optimizer Treatment Interaction 
0.7270 
Baseline Peak RER 
0.5796 
Baseline Peak RER by Optimizer Treatment Interaction 
0.8730 
Baseline Ejection Fraction (Quantitative) 
0.6542 
Baseline Ejection Fraction by Optimizer Treatment Interaction 
0.9854 
Baseline Ejection Fraction (Categorical Cut at 25) 
0.4676 
Baseline Ejection Fraction by Optimizer Treatment Interaction 
0.6737 
Diabetes 
0.0982 
Diabetes by Optimizer Treatment Interaction 
0.2642 
Baseline NYHA (Site) 
0.0779 
Baseline NYHA by Optimizer Treatment Interaction 
0.2845 
Baseline NYHA (Site) (NYHA = 3 or Not) 
0.0779 
Baseline NYHA by Optimizer Treatment Interaction 
0.2845 
CHF Etiology 
--2 
CHF Etiology by Optimizer Treatment Interaction 
--2 
Baseline MLWHFQ 
0.0445 
Baseline MLWHFQ by Optimizer Treatment Interaction 
0.2504 
BMI 
0.7600 
BMI by Optimizer Treatment Interaction 
0.8891 
Race (White) 
0.7382 
Race by Optimizer Treatment Interaction 
0.0506 
PTCA or CABG 
0.3363 
PTCA or CABG by Optimizer Treatment Interaction 
0.2056 
Baseline Core Lab Exercise Duration 
0.0912 
Baseline Core Lab Exercise Duration by Optimizer Treatment Interaction 
0.3932 
Pseudo-Site 
0.5091 
Pseudo-Site by Optimizer Treatment Interaction 
0.7444 
1Covariates with P-values ≤0.20 are allowed to enter the competition for the final model (bold face in 
table).  If the interaction is not significant, the P-value reported is for the model with the main effect 
only. 
2The model for CHF etiology did not have a solution so no P-value is reported. 
 
The final model appears was determined by manual backward elimination and the 
result is presented in the table below.  Eight variables were included in the 
competition for the final model including age, diabetes, baseline NYHA (continuous 
or categorical), baseline MLWHFQ, race, and race by treatment interaction.     
 
 
Table 2.2.6  Multivariate Cox Regression Final Model Results for Mortality 
Factor 
Hazard 
Ratio 
95% CL on HR 
P-Value* 
Race (White) 
0.712 
0.535-0.947 
0.0197 
The treatment term was the last term removed from the model and its P-value at 
removal was 0.1627.  This analysis implies that the only covariate associated with the 
primary safety composite endpoint of all cause death or hospitalization is race with 
Caucasians having a lower risk of death or hospitalization than non-Caucasians.  
Stepwise regression was applied to provide a verification of this models and the same 
model resulted from that application.  
 

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XI I . 
Primary Effectiveness Analysis 
 
For the primary effectiveness analysis, imputation was necessary to obtain study 
outcomes for patients that did not have an endpoint at 24 weeks.  The imputation was 
done by the methods described in Section IX above.  Ten imputations for the ITT 
patients appear in the tables below.  First the means are presented and then the 
responder analysis (with a responder defined a subject whose AT increased by 
≥20%). 
 

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Table XII.1a  Mean AT at Study Time Points  
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
ITT1 
Baseline 
10.90 (2.29) 213 
10.56 (4.10, 17.05) 
10.89 (2.32) 215 
10.60 (4.10, 16.92) 
0.98401 
24 Week3 
10.74 (2.27) 213 
10.78 (4.10, 19.61) 
10.81 (2.44) 214 
10.40 (4.10, 19.82) 
0.75051 
24 Week Difference 
From Baseline 
-0.15 (2.25) 213 
-0.17 (-7.29, 9.34) 
-0.08 (2.35) 215 
-0.09 (-6.91, 9.17) 
0.36702 
ITT2 
Baseline 
10.90 (2.26) 213 
10.65 (4.10, 17.05) 
10.87 (2.34) 215 
10.59 (4.10, 16.92) 
0.89661 
24 Week3 
10.74 (2.25) 213 
10.72 (4.10, 19.61) 
10.80 (2.49) 214 
10.42 (4.10, 19.82) 
0.78551 
24 Week Difference 
From Baseline 
-0.16 (2.25) 213 
-0.17 (-5.68, 9.34) 
-0.08 (2.29) 215 
-0.11 (-6.55, 8.94) 
0.34842 
ITT3 
Baseline 
10.92 (2.28) 213 
10.72 (4.10, 17.05) 
10.88 (2.30) 215 
10.60 (4.10, 16.92) 
0.85761 
24 Week3 
10.79 (2.28) 213 
10.61 (4.10, 19.61) 
10.78 (2.46) 214 
10.40 (4.10, 19.82) 
0.96881 
24 Week Difference 
From Baseline 
-0.12 (2.27) 213 
-0.17 (-6.10, 9.34) 
-0.09 (2.29) 215 
-0.09 (-6.47, 8.94) 
0.44442 
ITT4 
Baseline 
10.90 (2.27) 213 
10.73 (4.10, 17.05) 
10.88 (2.29) 215 
10.59 (4.10, 16.92) 
0.93821 
24 Week3 
10.72 (2.30) 213 
10.53 (4.10, 19.61) 
10.81 (2.51) 214 
10.42 (4.10, 19.82) 
0.31221 
24 Week Difference 
From Baseline 
-0.19 (2.27) 213 
-0.12 (-6.03, 9.34) 
-0.08 (2.35) 215 
-0.09 (-6.47, 8.94) 
0.68782 
ITT5 
Baseline 
10.93 (2.28) 213 
10.73 (4.10, 17.05) 
10.89 (2.30) 215 
10.59 (4.10, 16.92) 
0.84921 
24 Week3 
10.69 (2.31) 213 
10.53 (4.10, 19.61) 
10.81 (2.42) 214 
10.49 (4.10, 19.82) 
0.60811 
24 Week Difference 
From Baseline 
-0.24 (2.19) 213 
-0.13 (-8.59, 9.34) 
-0.08 (2.28) 215 
-0.09 (-6.88, 8.94) 
0.23902 
ITT6 
Baseline 
10.89 (2.27) 213 
10.65 (4.10, 17.05) 
10.87 (2.29) 215 
10.59 (4.10, 16.92) 
0.91701 
24 Week3 
10.69 (2.28) 213 
10.64 (4.10, 19.61) 
10.74 (2.56) 214 
10.39 (4.10, 19.82) 
0.83891 
24 Week Difference 
From Baseline 
-0.21 (2.23) 213 
-0.17 (-5.13, 9.34) 
-0.14 (2.41) 215 
-0.14 (-8.23, 8.94) 
0.38982 
ITT7 
Baseline 
10.88 (2.30) 213 
10.65 (4.10, 17.05) 
10.90 (2.33) 215 
10.60 (4.10, 16.92) 
0.92531 
24 Week3 
10.81 (2.29) 213 
10.80 (4.10, 19.61) 
10.78 (2.46) 214 
10.42 (4.10, 19.82) 
0.90881 
24 Week Difference 
From Baseline 
-0.07 (2.32) 213 
-0.10 (-6.65, 9.34) 
-0.12 (2.33) 215 
-0.07 (-7.99, 8.94) 
0.59482 
ITT8 
Baseline 
10.95 (2.28) 213 
10.73 (4.10, 17.05) 
10.83 (2.33) 215 
10.59 (4.10, 16.92) 
0.59651 
24 Week3 
10.68 (2.27) 213 
10.53 (4.10, 19.61) 
10.70 (2.49) 214 
10.38 (4.10, 19.82) 
0.92481 
24 Week Difference 
From Baseline 
-0.27 (2.23) 213 
-0.22 (-6.71, 9.34) 
-0.13 (2.40) 215 
-0.16 (-6.91, 8.94) 
0.27112 
 
 

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Table XII.1a  Mean AT at Study Time Points (Continued) 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
ITT9 
Baseline 
10.94 (2.28) 213 
10.73 (4.10, 17.05) 
10.89 (2.30) 215 
10.59 (4.10, 16.92) 
0.84021 
24 Week3 
10.72 (2.21) 213 
10.72 (4.10, 19.61) 
10.80 (2.50) 214 
10.40 (4.10, 19.82) 
0.70001 
24 Week Difference 
From Baseline 
-0.22 (2.14) 213 
-0.23 (-5.04, 9.34) 
-0.08 (2.26) 215 
-0.14 (-6.51, 8.94) 
0.26452 
ITT10 
Baseline 
10.89 (2.28) 213 
10.56 (4.10, 17.05) 
10.88 (2.29) 215 
10.57 (4.10, 16.92) 
0.94621 
24 Week3 
10.69 (2.33) 213 
10.64 (4.10, 19.61) 
10.79 (2.45) 214 
10.46 (4.10, 19.82) 
0.65471 
24 Week Difference 
From Baseline 
-0.21 (2.34) 213 
-0.13 (-8.59, 9.34) 
-0.08 (2.25) 215 
-0.17 (-6.47, 8.94) 
0.28452 
1Two-sided equal variance Student’s t-test. 
2One-sided equal variance Student’s t-test 
3One patient in the Optimizer group had a difference imputed but did not have a 24 week AT imputed. 
 
The responder analysis for the 10 imputations appears below. 
 
Table XII.1b  Univariate Primary Effectiveness Endpoint Results (≥20% Improvement) for ITT 
Patients  
 Population  
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
ITT1 
28/213 (13.15) 
37/215 (17.21) 
0.1500 
ITT2 
31/213 (14.55) 
37/215 (17.21) 
0.2681 
ITT3 
29/213 (13.62) 
38/215 (17.67) 
0.1533 
ITT4 
26/213 (12.21) 
39/215 (18.14) 
0.0573 
ITT5 
27/213 (12.68) 
40/215 (18.60) 
0.0598 
ITT6 
26/213 (12.21) 
36/215 (16.74) 
0.1157 
ITT7 
30/213 (14.08) 
36/215 (16.74) 
0.2652 
ITT8 
24/213 (11.27) 
39/215 (18.14) 
0.0304 
ITT9 
27/213 (12.68) 
40/215 (18.60) 
0.0598 
ITT10 
33/213 (15.49) 
38/215 (17.67) 
0.3169 
1One-sided Fisher’s exact test 
 
Rubin (1987) indicates that the data from multiple imputations can be combined to 
get an overall test of significance.  The method is the basis of Proc MIANALYZE in 
SAS and is described in the online manual SAS OnlineDoc Version 8, Chapter 10 
(Proc MIANALYZE), page 211. 
 
The procedure computes the mean difference across all imputations by the following 
formula 
 
 
 
∑
=
=
m
i
i
Q
m
Q
1
ˆ
1
 
where Qi is the difference between the Optmizer proportion and the control 
proportion for the ith imputation and m is the number of imputations (M=10 here) 

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The variance is computed as a function of the within imputation variance and the 
between imputation variance.  The estimate of the within imputation variance is given 
by the following. 
∑
=
=
m
i
i
U
m
U
1
ˆ
1
 
 
 
 
where Ui is the variance of the difference in the ith imputation and is given by the 
following. 
 
 
 
(
)
(
)
231
1
229
1
ic
ic
it
it
i
p
p
p
p
U
−
+
−
=
 
 
and pit and pic are the proportions of patient with serious or significant adverse events 
in the Optimizer and Control groups respectively. 
 
The between imputation variance is obtained by the following formula. 
 
(
)
∑
=
−
−
=
m
i
i
Q
Q
m
B
1
2
ˆ
1
1
 
 
The total variance in given by the following formula. 
 
B
m
U
T
)
1
1( +
+
=
 
 
and the z-statistic is given by the following. 
 
 
 
( )
T
Q
z =
 
 
When these imputations are combined the z = -0.4839 with a corresponding P-value 
of 0.3142. 
 
The mean values for the ITT ten imputations for patients with baseline EF≥25 are 
presented below. 
 
 
 
 
 
 
 
 
 
 

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Table XII.2a  Mean AT at Study Time Points with EF ≥25 at Baseline 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
ITT1 
Baseline 
11.14 (2.31) 113 
10.73 (5.40, 17.05) 
10.76 (2.12) 117 
10.44 (5.29, 16.08) 
0.19091 
24 Week 
10.69 (2.09) 113 
10.64 (4.79, 15.50) 
10.95 (2.38) 117 
10.50 (5.01, 19.82) 
0.37631 
24 Week Difference 
From Baseline 
-0.45 (2.02) 113 
-0.33 (-7.29, 5.64) 
0.19 (2.45) 117 
-0.08 (-4.65, 9.17) 
0.01522 
ITT2 
Baseline 
11.17 (2.29) 113 
10.76 (5.40, 17.05) 
10.74 (2.18) 117 
10.44 (5.29, 16.09) 
0.14921 
24 Week 
10.73 (2.09) 113 
10.64 (6.24, 15.50) 
10.83 (2.44) 117 
10.39 (5.01, 19.82) 
0.73321 
24 Week Difference 
From Baseline 
-0.44 (2.12) 113 
-0.33 (-5.68, 5.64) 
0.09 (2.35) 117 
-0.14 (-4.65, 8.94) 
0.03743 
ITT3 
Baseline 
11.14 (2.31) 113 
10.73 (5.40, 17.05) 
10.73 (2.09) 117 
10.52 (5.29, 16.08) 
0.16201 
24 Week 
10.75 (2.12) 113 
10.47 (5.99, 15.50) 
10.83 (2.37) 117 
10.41 (4.97, 19.82) 
0.78121 
24 Week Difference 
From Baseline 
-0.39 (2.12) 113 
-0.31 (-6.10, 5.64) 
0.10 (2.44) 117 
-0.08 (-4.65, 8.94) 
0.05333 
ITT4 
Baseline 
11.14 (2.31) 113 
10.73 (5.40, 17.05) 
10.75 (2.12) 117 
10.52 (5.29, 16.08) 
0.18641 
24 Week 
10.66 (2.15) 113 
10.33 (6.24, 15.79) 
10.83 (2.45) 117 
10.39 (4.10, 19.82) 
0.57461 
24 Week Difference 
From Baseline 
-0.48 (2.23) 113 
-0.31 (-6.03, 6.60) 
0.08 (2.33) 117 
-0.11 (-4.65, 8.94) 
0.03283 
ITT5 
Baseline 
11.17 (2.29) 113 
10.76 (5.40, 17.05) 
10.74 (2.14) 117 
10.44 (5.29, 16.08) 
0.13971 
24 Week 
10.70 (2.14) 113 
10.35 (4.78, 15.50) 
10.93 (2.32) 117 
10.57 (5.01, 19.82) 
0.43341 
24 Week Difference 
From Baseline 
-0.47 (2.03) 113 
-0.27 (-5.17, 5.64) 
0.20 (2.31) 117 
-0.07 (-4.65, 8.94) 
0.01063 
ITT6 
Baseline 
11.14 (2.31) 113 
10.73 (5.40, 17.05) 
10.74 (2.10) 117 
10.44 (5.29, 16.08) 
0.17261 
24 Week 
10.61 (2.12) 113 
10.47 (6.24, 15.50) 
10.82 (2.52) 117 
10.39 (4.10, 19.82) 
0.49331 
24 Week Difference 
From Baseline 
-0.53 (2.10) 113 
-0.48 (-5.13, 5.64) 
0.08 (2.38) 117 
-0.11 (-4.65, 8.94) 
0.02033 
ITT7 
Baseline 
11.14 (2.31) 113 
10.73 (5.40, 17.05) 
10.77 (2.19) 117 
10.44 (5.29, 16.84) 
0.21061 
24 Week 
10.82 (2.12) 113 
10.78 (6.24, 15.50) 
10.85 (2.39) 117 
10.41 (5.01, 19.82) 
0.91611 
24 Week Difference 
From Baseline 
-0.32 (2.14) 113 
-0.27 (-5.51, 5.64) 
0.08 (2.34) 117 
-0.07 (-4.65, 8.94) 
0.08763 
ITT8 
Baseline 
11.20 (2.30) 113 
10.76 (5.40, 17.05) 
10.67 (2.13) 117 
10.39 (5.29, 16.08) 
0.07361 
24 Week 
10.62 (2.15) 113 
10.35 (5.37, 15.50) 
10.79 (2.50) 117 
10.39 (4.22, 19.82) 
0.57031 
24 Week Difference 
From Baseline 
-0.58 (2.21) 113 
-0.33 (-6.71, 5.85) 
0.12 (2.48) 117 
-0.14 (-5.36, 8.94) 
0.01243 
 
 

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Table XII.2a  Mean AT at Study Time Points with EF ≥25 at Baseline Continued 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
ITT9 
Baseline 
11.20 (2.30) 113 
10.76 (5.40, 17.05) 
10.75 (2.14) 117 
10.44 (5.29, 16.08) 
0.12531 
24 Week 
10.68 (2.02) 113 
10.53 (6.24, 15.50) 
10.91 (2.44) 117 
10.42 (5.01, 19.82) 
0.43724 
24 Week Difference 
From Baseline 
-0.51 (2.08) 113 
-0.38 (-5.04, 5.64) 
0.17 (2.39) 117 
-0.08 (-4.65, 8.94) 
0.01123 
ITT10 
Baseline 
11.14 (2.31) 113 
10.73 (5.40, 17.05) 
10.73 (2.14) 117 
10.39 (5.29, 16.08) 
0.16481 
24 Week 
10.62 (2.14) 113 
10.35 (5.92, 15.50) 
10.78 (2.38) 117 
10.39 (5.01, 19.82) 
0.60031 
24 Week Difference 
From Baseline 
-0.52 (2.26) 113 
-0.38 (-6.17, 5.64) 
0.05 (2.32) 117 
-0.14 (-4.65, 8.94) 
0.03143 
1Two-sided equal variance Student’s t-test. 
2One-sided unequal variance Student’s t-test 
3One-sided equal variance Student’s t-test 
 
The responder analysis for the 10 imputations appears below. 
 
Table XII.2b  Univariate Primary Effectiveness Endpoint Results (≥20% Improvement) for ITT 
Patients with EF ≥25  
Population  
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
ITT1 
9/113 (7.96) 
23/117 (19.66) 
0.0083 
ITT2 
14/113 (12.39) 
23/117 (19.66) 
0.0930 
ITT3 
12/113 (10.62) 
24/117 (20.51) 
0.0292 
ITT4 
10/113 (8.85) 
24/117 (20.51) 
0.0100 
ITT5 
11/113 (9.73) 
26/117 (22.22) 
0.0078 
ITT6 
10/113 (8.85) 
23/117 (19.66) 
0.0151 
ITT7 
13/113 (11.50) 
23/117 (19.66) 
0.0637 
ITT8 
10/113 (8.85) 
25/117 (21.37) 
0.0065 
ITT9 
11/113 (9.73) 
27/117 (23.08) 
0.0050 
ITT10 
14/113 (12.39) 
24/117 (20.51) 
0.0689 
1One-sided Fisher’s exact test 
 
The combination of the 10 ITT imputations in sub-groups by EF, the resulting z =  
-1.9432 with a corresponding P-value of 0.0260. 
 
The means for the ITT ten imputations with baseline EF≥25 and NYHA=3 are 
presented below. 
 
 
 
 
 
 
 
 

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Table XII.3a  Mean AT at Study Time Points with EF ≥25 and NYHA=3 at Baseline 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
ITT1 
Baseline 
11.19 (2.19) 97 
10.73 (7.22, 16.72) 
10.72 (2.11) 109 
10.44 (5.29, 16.05) 
0.11991 
24 Week 
10.70 (2.14) 97 
10.47 (4.79, 15.50) 
10.98 (2.43) 109 
10.57 (5.01, 19.82) 
0.37831 
24 Week Difference From 
Baseline 
-0.49 (1.97) 97 
-0.38 (-7.29, 4.62) 
0.27 (2.51) 109 
-0.02 (-4.65, 9.17) 
0.00862 
ITT2 
Baseline 
11.22 (2.17) 97 
10.76 (7.22, 16.72) 
10.71 (2.17) 109 
10.44 (5.29, 16.09) 
0.09161 
24 Week 
10.77 (2.11) 97 
10.53 (6.24, 15.50) 
10.89 (2.48) 109 
10.42 (5.01, 19.82) 
0.71091 
24 Week Difference From 
Baseline 
-0.45 (2.06) 97 
-0.38 (-5.68, 4.62) 
0.18 (2.38) 109 
-0.08 (-4.65, 8.94) 
0.02183 
ITT3 
Baseline 
11.19 (2.19) 97 
10.73 (7.22, 16.72) 
10.68 (2.07) 109 
10.44 (5.29, 16.05) 
0.08841 
24 Week 
10.76 (2.18) 97 
10.33 (5.99, 15.50) 
10.84 (2.41) 109 
10.42 (4.97, 19.82) 
0.80431 
24 Week Difference From 
Baseline 
-0.42 (2.11) 97 
-0.31 (-6.10, 4.62) 
0.16 (2.45) 109 
-0.02 (-4.65, 8.94) 
0.03363 
ITT4 
Baseline 
11.19 (2.19) 97 
10.73 (7.22, 16.72) 
10.70 (2.11) 109 
10.44 (5.29, 16.05) 
0.10671 
24 Week 
10.76 (2.16) 97 
10.35 (6.24, 15.79) 
10.85 (2.51) 109 
10.42 (4.10, 19.82) 
0.76731 
24 Week Difference From 
Baseline 
-0.43 (2.16) 97 
-0.27 (-6.03, 6.60) 
0.15 (2.38) 109 
-0.07 (-4.65, 8.94) 
0.03443 
ITT5 
Baseline 
11.22 (2.17) 97 
10.76 (7.22, 16.72) 
10.69 (2.13) 109 
10.39 (5.29, 16.05) 
0.07791 
24 Week 
10.77 (2.10) 97 
10.35 (6.24, 15.50) 
10.93 (2.37) 109 
10.62 (5.01, 19.82) 
0.59461 
24 Week Difference From 
Baseline 
-0.45 (1.92) 97 
-0.31 (-5.17, 4.62) 
0.24 (2.34) 109 
-0.02 (-4.65, 8.94) 
0.00992 
ITT6 
Baseline 
11.19 (2.19) 97 
10.73 (7.22, 16.72) 
10.70 (2.09) 109 
10.44 (5.29, 16.05) 
0.10751 
24 Week 
10.65 (2.10) 97 
10.35 (6.24, 15.50) 
10.83 (2.58) 109 
10.41 (4.10, 19.82) 
0.58724 
24 Week Difference From 
Baseline 
-0.54 (2.08) 97 
-0.49 (-5.13, 5.36) 
0.12 (2.42) 109 
-0.08 (-4.65, 8.94) 
0.01893 
ITT7 
Baseline 
11.19 (2.19) 97 
10.73 (7.22, 16.72) 
10.74 (2.17) 109 
10.44 (5.29, 16.84) 
0.14521 
24 Week 
10.81 (2.12) 97 
10.82 (6.24, 15.50) 
10.87 (2.41) 109 
10.42 (5.01, 19.82) 
0.87031 
24 Week Difference From 
Baseline 
-0.37 (2.14) 97 
-0.30 (-5.51, 5.11) 
0.13 (2.34) 109 
-0.02 (-4.65, 8.94) 
0.05783 
ITT8 
Baseline 
11.25 (2.19) 97 
10.76 (7.22, 16.72) 
10.64 (2.10) 109 
10.39 (5.29, 16.05) 
0.04301 
24 Week 
10.66 (2.16) 97 
10.35 (5.37, 15.50) 
10.79 (2.50) 109 
10.41 (4.22, 19.82) 
0.69151 
24 Week Difference From 
Baseline 
-0.59 (2.19) 97 
-0.33 (-6.71, 5.85) 
0.14 (2.44) 109 
-0.11 (-5.36, 8.94) 
0.01213 
 
 

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Table XII.3a  Mean AT at Study Time Points with EF ≥25 and NYHA=3 at Baseline (Continued) 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
ITT9 
Baseline 
11.25 (2.19) 97 
10.76 (7.22, 16.72) 
10.72 (2.11) 109 
10.44 (5.29, 16.05) 
0.07991 
24 Week 
10.73 (2.02) 97 
10.47 (6.24, 15.50) 
10.91 (2.48) 109 
10.50 (5.01, 19.82) 
0.58104 
24 Week Difference 
From Baseline 
-0.52 (1.98) 97 
-0.48 (-5.04, 5.11) 
0.18 (2.43) 109 
-0.08 (-4.65, 8.94) 
0.01182 
ITT10 
Baseline 
11.19 (2.19) 97 
10.73 (7.22, 16.72) 
10.70 (2.12) 109 
10.39 (5.29, 16.05) 
0.11061 
24 Week 
10.66 (2.14) 97 
10.30 (6.24, 15.50) 
10.83 (2.42) 109 
10.42 (5.01, 19.82) 
0.59171 
24 Week Difference 
From Baseline 
-0.53 (2.21) 97 
-0.48 (-6.17, 5.50) 
0.12 (2.36) 109 
-0.08 (-4.65, 8.94) 
0.02133 
1Two-sided equal variance Student’s t-test. 
2One-sided unequal variance Student’s t-test 
3One-sided equal variance Student’s t-test 
4Two-sided unequal variance Student’s t-test. 
 
The responder analysis for the 10 imputations appears below. 
 
Table XII.3b  Univariate Primary Effectiveness Endpoint Results (≥20% Improvement) for ITT 
Patients with EF ≥25 and NYHA=3 at Baseline 
Population  
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
ITT1 
7/97 (7.22) 
23/109 (21.10) 
0.0037 
ITT2 
11/97 (11.34) 
23/109 (21.10) 
0.0440 
ITT3 
10/97 (10.31) 
23/109 (21.10) 
0.0265 
ITT4 
8/97 (8.25) 
24/109 (22.02) 
0.0050 
ITT5 
9/97 (9.28) 
25/109 (22.94) 
0.0065 
ITT6 
8/97 (8.25) 
22/109 (20.18) 
0.0120 
ITT7 
11/97 (11.34) 
22/109 (20.18) 
0.0613 
ITT8 
8/97 (8.25) 
23/109 (21.10) 
0.0078 
ITT9 
8/97 (8.25) 
25/109 (22.94) 
0.0032 
ITT10 
11/97 (11.34) 
24/109 (22.02) 
0.0311 
1One-sided Fisher’s exact test 
 
Combining the sub-groups from the ten imputations for EF ≥ 25 with NYHA=3 we 
get a z = -2.2624 with at corresponding P-value of 0.0118.  
 
For the FASA population, the ten imputations for the whole population, EF ≥ 25, and 
EF ≥ 25 with NYHA=3 are presented in the tables below.  The means are presented in 
the table below. 
 

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Table XII.4a  Mean AT at Study Time Points  
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASA1 
Baseline 
10.90 (2.29) 212 
10.60 (4.10, 17.05) 
10.90 (2.33) 208 
10.62 (4.10, 16.92) 
0.97981 
24 Week3 
10.75 (2.27) 212 
10.79 (4.10, 19.61) 
10.81 (2.46) 207 
10.40 (4.10, 19.82) 
0.77631 
24 Week Difference 
From Baseline 
-0.15 (2.26) 212 
-0.20 (-7.29, 9.34) 
-0.08 (2.38) 208 
-0.12 (-6.91, 9.17) 
0.37842 
FASA2 
Baseline 
10.90 (2.27) 212 
10.69 (4.10, 17.05) 
10.89 (2.36) 208 
10.60 (4.10, 16.92) 
0.95161 
24 Week3 
10.74 (2.25) 212 
10.73 (4.10, 19.61) 
10.80 (2.51) 207 
10.41 (4.10, 19.82) 
0.82091 
24 Week Difference 
From Baseline 
-0.16 (2.25) 212 
-0.20 (-5.68, 9.34) 
-0.10 (2.32) 208 
-0.14 (-6.55, 8.94) 
0.39362 
FASA3 
Baseline 
10.92 (2.29) 212 
10.72 (4.10, 17.05) 
10.90 (2.32) 208 
10.72 (4.10, 16.92) 
0.91381 
24 Week3 
10.80 (2.29) 212 
10.62 (4.10, 19.61) 
10.81 (2.48) 207 
10.42 (4.10, 19.82) 
0.96861 
24 Week Difference 
From Baseline 
-0.12 (2.28) 212 
-0.20 (-6.10, 9.34) 
-0.09 (2.32) 208 
-0.10 (-6.47, 8.94) 
0.44042 
FASA4 
Baseline 
10.91 (2.27) 212 
10.73 (4.10, 17.05) 
10.90 (2.31) 208 
10.60 (4.10, 16.92) 
0.96611 
24 Week3 
10.72 (2.30) 212 
10.57 (4.10, 19.61) 
10.81 (2.50) 207 
10.42 (4.10, 19.82) 
0.72221 
24 Week Difference 
From Baseline 
-0.19 (2.28) 212 
-0.13 (-6.03, 9.34) 
-0.10 (2.34) 208 
-0.12 (-6.47, 8.94) 
0.34472 
FASA5 
Baseline 
10.94 (2.28) 212 
10.73 (4.10, 17.05) 
10.92 (2.31) 208 
10.61 (4.10, 16.92) 
0.92931 
24 Week3 
10.70 (2.31) 212 
10.57 (4.10, 19.61) 
10.82 (2.44) 207 
10.49 (4.10, 19.82) 
0.61611 
24 Week Difference 
From Baseline 
-0.24 (2.20) 212 
-0.15 (-8.59, 9.34) 
-0.11 (2.29) 208 
-0.14 (-6.88, 8.94) 
0.27782 
FASA6 
Baseline 
10.90 (2.27) 212 
10.69 (4.10, 17.05) 
10.89 (2.31) 208 
10.59 (4.10, 16.92) 
0.94371 
24 Week3 
10.70 (2.28) 212 
10.67 (4.10, 19.61) 
10.74 (2.55) 207 
10.39 (4.10, 19.82) 
0.84341 
24 Week Difference 
From Baseline 
-0.21 (2.23) 212 
-0.20 (-5.13, 9.34) 
-0.15 (2.44) 208 
-0.14 (-8.23, 8.94) 
0.40522 
FASA7 
Baseline 
10.89 (2.31) 212 
10.69(4.10, 17.05) 
10.91 (2.34) 208 
10.66 (4.10, 16.92) 
0.92391 
24 Week3 
10.82 (2.29) 212 
10.81 (4.10, 19.61) 
10.78 (2.48) 207 
10.40 (4.10, 19.82) 
0.87561 
24 Week Difference 
From Baseline 
-0.07 (2.32) 212 
-0.11 (-6.65, 9.34) 
-0.13 (2.36) 208 
-0.10 (-7.99, 8.94) 
0.61402 
FASA8 
Baseline 
10.95 (2.28) 212 
10.74 (4.10, 17.05) 
10.86 (2.34) 208 
10.60 (4.10, 16.92) 
0.66831 
24 Week3 
10.68 (2.28) 212 
10.56 (4.10, 19.61) 
10.71 (2.51) 207 
10.38 (4.10, 19.82) 
0.90271 
24 Week Difference 
From Baseline 
-0.27 (2.23) 212 
-0.23 (-6.71, 9.34) 
-0.15 (2.43) 208 
-0.17 (-6.91, 8.94) 
0.29472 
 
 

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Table XII.4a  Mean AT at Study Time Points (Continued) 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASA9 
Baseline 
10.94 (2.28) 212 
10.73 (4.10, 17.05) 
10.91 (2.32) 208 
10.60 (4.10, 16.92) 
0.88061 
24 Week3 
10.72 (2.22) 212 
10.73 (4.10, 19.61) 
10.83 (2.52) 207 
10.41 (4.10, 19.82) 
0.65821 
24 Week Difference From 
Baseline 
-0.22 (2.15) 212 
-0.23 (-5.04, 9.34) 
-0.08 (2.29) 208 
-0.15 (-6.51, 8.94) 
0.26122 
FASA10 
Baseline 
10.90 (2.28) 212 
10.60 (4.10, 17.05) 
10.91 (2.30) 208 
10.59 (4.10, 16.92) 
0.97481 
24 Week3 
10.69 (2.33) 212 
10.67 (4.10, 19.61) 
10.79 (2.46) 207 
10.42 (4.10, 19.82) 
0.68201 
24 Week Difference From 
Baseline 
-0.21 (2.34) 212 
-0.15 (-8.59, 9.34) 
-0.11 (2.23) 208 
-0.24 (-6.47, 8.94) 
0.33372 
1Two-sided equal variance Student’s t-test. 
2One-sided equal variance Student’s t-test 
3One patient in the Optimizer group had a difference imputed but did not have a 24 week AT imputed. 
 
The responder analysis for the 10 imputations appears below. 
 
Table XII.4b  Univariate Primary Effectiveness Endpoint Results (≥20% Improvement) for 
FASA Patients  
 Population  
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
FASA1 
28/212 (13.21) 
37/208 (17.79) 
0.1224 
FASA2 
31/212 (14.62) 
35/208 (16.83) 
0.3133 
FASA3 
29/212 (13.68) 
37/208 (17.79) 
0.1532 
FASA4 
26/212 (12.26) 
37/208 (17.79) 
0.0736 
FASA5 
27/212 (12.74) 
39/208 (18.75) 
0.0593 
FASA6 
26/212 (12.26) 
35/208 (16.83) 
0.1173 
FASA7 
30/212 (14.15) 
36/208 (17.31) 
0.2253 
FASA8 
24/212 (11.32) 
38/208 (18.27) 
0.0305 
FASA9 
27/212 (12.74) 
39/208 (18.75) 
0.0593 
FASA10 
33/212 (15.57) 
36/208 (17.31) 
0.3632 
1One-sided Fisher’s exact test 
 
The combined imputations for the FASA patients resulted in a z = -0.4745 with a 
corresponding P=0.3176.  
 
The means for the FASA ten imputations with baseline EF≥25 are presented below. 
 
 
 
 
 
 
 
 
 
 

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Table XII.5a  Mean AT at Study Time Points with EF ≥25 at Baseline 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASA1 
Baseline 
11.16 (2.31) 112 
10.74 (5.40, 17.05) 
10.73 (2.13) 112 
10.42 (5.29, 16.08) 
0.14851 
24 Week 
10.70 (2.09) 112 
10.71 (4.79, 15.50) 
10.92 (2.41) 112 
10.42 (5.01, 19.82) 
0.46261 
24 Week Difference 
From Baseline 
-0.45 (2.03) 112 
-0.36 (-7.29, 5.64) 
0.20 (2.49) 112 
-0.08 (-4.65, 9.17) 
0.01632 
FASA2 
Baseline 
11.19 (2.29) 112 
10.79 (5.40, 17.05) 
10.74 (2.21) 112 
10.42 (5.29, 16.09) 
0.14291 
24 Week 
10.74 (2.10) 112 
10.71 (6.24, 15.50) 
10.82 (2.48) 112 
10.37 (5.01, 19.82) 
0.79731 
24 Week Difference 
From Baseline 
-0.44 (2.13) 112 
-0.36 (-5.68, 5.64) 
0.08 (2.40) 112 
-0.15(-4.65, 8.94) 
0.04343 
FASA3  
Baseline 
11.16 (2.31) 112 
10.74 (5.40, 17.05) 
10.73 (2.12) 112 
10.48 (5.29, 16.08) 
0.15461 
24 Week 
10.76 (2.13) 112 
10.49 (5.99, 15.50) 
10.84 (2.41) 112 
10.42 (4.97, 19.82) 
0.78781 
24 Week Difference 
From Baseline 
-0.40 (2.13) 112 
-0.32 (-6.10, 5.64) 
0.11 (2.47) 112 
-0.09(-4.65, 8.94) 
0.05123 
FASA4 
Baseline 
11.16 (2.31) 112 
10.74 (5.40, 17.05) 
10.74 (2.14) 112 
10.48 (5.29, 16.08) 
0.16261 
24 Week 
10.67 (2.16) 112 
10.34 (6.24, 15.79) 
10.83 (2.43) 112 
10.40 (4.10, 19.82) 
0.61301 
24 Week Difference 
From Baseline 
-0.49 (2.24) 112 
-0.32 (-6.03, 6.60) 
0.09 (2.33) 112 
-0.12(-4.65, 8.94) 
0.03143 
FASA5 
Baseline 
11.19 (2.29) 112 
10.79 (5.40, 17.05) 
10.75 (2.17) 112 
10.48 (5.29, 16.08) 
0.14361 
24 Week 
10.71 (2.14) 112 
10.41 (4.78, 15.50) 
10.91 (2.35) 112 
10.46 (5.01, 19.82) 
0.50381 
24 Week Difference 
From Baseline 
-0.47 (2.03) 112 
-0.29 (-5.17, 5.64) 
0.17 (2.32) 112 
-0.09(-4.65, 8.94) 
0.01483 
FASA6 
Baseline 
11.16 (2.31) 112 
10.74 (5.40, 17.05) 
10.73 (2.13) 112 
10.42 (5.29, 16.08) 
0.14991 
24 Week 
10.62 (2.13) 112 
10.50 (6.24, 15.50) 
10.79 (2.51) 112 
10.37 (4.10, 19.82) 
0.59211 
24 Week Difference 
From Baseline 
-0.54 (2.11) 112 
-0.49 (-5.13, 5.64) 
0.06 (2.40) 112 
-0.12 (-4.65, 8.94) 
0.02503 
FASA7 
Baseline 
11.16 (2.31) 112 
10.74 (5.40, 17.05) 
10.74 (2.20) 112 
10.42 (5.29, 16.84) 
0.16931 
24 Week 
10.83 (2.13) 112 
10.80 (6.24, 15.50) 
10.82 (2.41) 112 
10.37 (5.01, 19.82) 
0.97571 
24 Week Difference 
From Baseline 
-0.32 (2.15) 112 
-0.28 (-5.51, 5.64) 
0.08 (2.38) 112 
-0.09 (-4.65, 8.94) 
0.09083 
FASA8 
Baseline 
11.21 (2.31) 112 
10.79 (5.40, 17.05) 
10.68 (2.15) 112 
10.42 (5.29, 16.08) 
0.07641 
24 Week 
10.63 (2.16) 112 
10.41 (5.37, 15.50) 
10.80 (2.53) 112 
10.37 (4.22, 19.82) 
0.59921 
24 Week Difference 
From Baseline 
-0.58 (2.22) 112 
-0.33 (-6.71, 5.85) 
0.11 (2.53) 112 
-0.15 ( -5.36, 8.94) 
0.01483 
 
 

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Table XII.5a  Mean AT at Study Time Points with EF ≥25 at Baseline 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASA9 
Baseline 
11.21 (2.31) 112 
10.79 (5.40, 
17.05) 
10.74 (2.17) 112 
10.42 (5.29, 16.08) 
0.11301 
24 Week 
10.70 (2.02) 112 
10.58 (6.24, 
15.50) 
10.92 (2.47) 112 
10.42 (5.01, 19.82) 
0.45994 
24 Week Difference From 
Baseline 
-0.52 (2.09) 112 
-0.43 (-5.04, 5.64) 
0.18 (2.41) 112 
-0.09 (-4.65, 8.94) 
0.01062 
FASA10 
Baseline 
11.16 (2.31) 112 
10.74 (5.40, 
17.05) 
10.74 (2.17) 112 
10.42 (5.29, 16.08) 
0.16871 
24 Week 
10.64 (2.14) 112 
10.39 (5.92, 
15.50) 
10.78 (2.40) 112 
10.39 (5.01, 19.82) 
0.64521 
24 Week Difference From 
Baseline 
-0.52 (2.27) 112 
-0.43 (-6.17, 5.64) 
0.03 (2.31) 112 
-0.16(-4.65, 8.94) 
0.03583 
1Two-sided equal variance Student’s t-test. 
2One-sided unequal variance Student’s t-test 
3One-sided equal variance Student’s t-test 
4Two-sided unequal variance Student’s t-test 
 
The responder analysis for the 10 imputations appears below. 
 
Table XII.5b  Univariate Primary Effectiveness Endpoint Results (≥20% Improvement) for 
FASA Patients with EF ≥25  
Population  
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
FASA1 
9/112 (8.04) 
23/112 (20.54) 
0.0061 
FASA2 
14/112 (12.50) 
22/112 (19.64) 
0.1012 
FASA3 
12/112 (10.71) 
23/112 (20.54) 
0.0323 
FASA4 
10/112 (8.93) 
23/112 (20.54) 
0.0113 
FASA5 
11/112 (9.82) 
25/112 (22.32) 
0. 0086 
FASA6 
10/112 (8.93) 
22/112 (19.64) 
0.0172 
FASA7 
13/112 (11.61) 
23/112 (20.54) 
0. 0503 
FASA8 
10/112 (8.93) 
24/112 (21.43) 
0. 0073 
FASA9 
11/112 (9.82) 
26/112 (23.21) 
0. 0055 
FASA10 
14/112 (12.50) 
23/112 (20.54) 
0. 0747 
1One-sided Fisher’s exact test 
 
Combining these ten imputations for EF≥25 a z = -1.9292 with a P-value of 0.0269. 
 
The means for the FASA ten imputations with baseline EF≥25 and NYHA=3 are 
presented below. 
 
 
 
 

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Table XII.6a  Mean AT at Study Time Points with EF ≥25 and NYHA=3 at Baseline 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASA1 
Baseline 
11.21 (2.19) 96 
10.74 (7.22, 16.72) 
10.68 (2.11) 104 
10.42 (5.29, 16.05) 
0. 08771 
24 Week 
10.72 (2.14) 96 
10.50 (4.79, 15.50) 
10.96 (2.46) 104 
10.46 (5.01, 19.82) 
0. 46461 
24 Week Difference 
From Baseline 
-0.49 (1.98) 96 
-0.40 (-7.29, 4.62) 
0.27 (2.56) 104 
-0.01 (-4.65, 9.17) 
0.00942 
FASA2 
Baseline 
11.24 (2.17) 96 
10.79 (7.22, 16.72) 
10.71 (2.20) 104 
10.42 (5.29, 16.09) 
0. 08611 
24 Week 
10.78 (2.11) 96 
10.67 (6.24, 15.50) 
10.88 (2.52) 104 
10.42 (5.01, 19.82) 
0. 77291 
24 Week Difference 
From Baseline 
-0.46 (2.07) 96 
-0.43 (-5.68, 4.62) 
0.17 (2.43) 104 
-0.09 (-4.65, 8.94) 
0.02513 
FASA3 
Baseline 
11.21 (2.19) 96 
10.74 (7.22, 16.72) 
10.68 (2.10) 104 
10.42 (5.29, 16.05) 
0. 08221 
24 Week 
10.78 (2.18) 96 
10.34 (5.99, 15.50) 
10.86 (2.44) 104 
10.46 (4.97, 19.82) 
0.81271 
24 Week Difference 
From Baseline 
-0.43 (2.12) 96 
-0.35 (-6.10, 4.62) 
0.18 (2.49) 104 
-0.05 (-4.65, 8.94) 
0.03223 
FASA4 
Baseline 
11.21 (2.19) 96 
10.74 (7.22, 16.72) 
10.68 (2.13) 104 
10.42 (5.29, 16.05) 
0.08921 
24 Week 
10.77 (2.17) 96 
10.39 (6.24, 15.79) 
10.85 (2.50) 104 
10.46 (4.10, 19.82) 
0.81061 
24 Week Difference 
From Baseline 
-0.43 (2.17) 96 
-0.29 (-6.03, 6.60) 
0.17 (2.39) 104 
-0.07 (-4.65, 8.94) 
0.03223 
FASA5 
Baseline 
11.24 (2.17) 96 
10.79 (7.22, 16.72) 
10.70 (2.16) 104 
10.42 (5.29, 16.05) 
0.07911 
24 Week 
10.78 (2.10) 96 
10.41 (6.24, 15.50) 
10.91 (2.40) 104 
10.53 (5.01, 19.82) 
0.67851 
24 Week Difference 
From Baseline 
-0.46 (1.93) 96 
-0.34 (-5.17, 4.62) 
0.21 (2.35) 104 
-0.05 (-4.65, 8.94) 
0.01453 
FASA6 
Baseline 
11.21 (2.19) 96 
10.74 (7.22, 16.72) 
10.69 (2.11) 104 
10.42 (5.29, 16.05) 
0.08971 
24 Week 
10.66 (2.11) 96 
10.41 (6.24, 15.50) 
10.79 (2.57) 104 
10.40 (4.10, 19.82) 
0.70101 
24 Week Difference 
From Baseline 
-0.54 (2.09) 96 
-0.49 (-5.13, 5.36) 
0.10 (2.44) 104 
-0.09 (-4.65, 9.17) 
0.02273 
FASA7 
Baseline 
11.21 (2.20) 96 
10.74 (7.22, 16.72) 
10.71 (2.18) 104 
10.42 (5.29, 16.09) 
0.11131 
24 Week 
10.83 (2.13) 96 
10.83 (6.24, 15.50) 
10.84 (2.43) 104 
10.40 (5.01, 19.82) 
0.98101 
24 Week Difference 
From Baseline 
-0.38 (2.16) 96 
-0.30 (-5.51, 5.11) 
0.13 (2.38) 104 
-0.07 (-4.65, 8.94) 
0.06023 
FASA8 
Baseline 
11.27 (2.19) 96 
10.79 (7.22, 16.72) 
10.66 (2.13) 104 
10.42 (5.29, 16.05) 
0.04421 
24 Week 
10.67 (2.17) 96 
10.41 (5.37, 15.50) 
10.79 (2.53) 104 
10.40 (4.22, 19.82) 
0.72521 
24 Week Difference 
From Baseline 
-0.60 (2.20) 96 
-0.35 (-6.71, 5.85) 
0.14 (2.49) 104 
-0.12 (-5.36, 8.94) 
0.01453 
 
 

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Table XII.6a  Mean AT at Study Time Points with EF ≥25 and NYHA=3 at Baseline (Continued) 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASA9 
Baseline 
11.27 (2.19) 96 
10.79 (7.22, 16.72) 
10.72 (2.14) 104 
10.42 (5.29, 16.05) 
0.07021 
24 Week 
10.75 (2.02) 96 
10.50 (6.24, 15.50) 
10.91 (2.51) 104 
10.46 (5.01, 19.82) 
0.60904 
24 Week Difference From 
Baseline 
-0.53 (1.99) 96 
-0.49 (-5.04, 5.11) 
0.20 (2.46) 104 
-0.09 (-4.65, 8.94) 
0.01212 
FASA10 
Baseline 
11.21 (2.20) 96 
10.74 (7.22, 16.72) 
10.72 (2.14) 104 
10.42 (5.29, 16.05) 
0.11221 
24 Week 
10.67 (2.15) 96 
10.32 (6.24, 15.50) 
10.83 (2.44) 104 
10.42 (5.01, 19.82) 
0.63551 
24 Week Difference From 
Baseline 
-0.54 (2.22) 96 
-0.49 (-6.17, 5.50) 
0.11 (2.35) 104 
-0.12 (-4.65, 8.94) 
0.02402 
1Two-sided equal variance Student’s t-test. 
2One-sided unequal variance Student’s t-test 
3One-sided equal variance Student’s t-test 
4Two-sided unequal variance Student’s t-test. 
 
The responder analysis for the 10 imputations appears below. 
 
Table XII.6b  Univariate Primary Effectiveness Endpoint Results (≥20% Improvement) for 
FASA Patients with EF ≥25 and NYHA=3 at Baseline 
Population  
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
FASA1 
7/96 (7.29) 
23/104 (22.12) 
0.0027 
FASA2 
11/96 (11.46) 
22/104 (21.15) 
0.0481 
FASA3 
10/96 (10.42) 
22/104 (21.15) 
0.0294 
FASA4 
8/96 (8.33) 
23/104 (22.12) 
0.0057 
FASA5 
9/96 (9.38) 
24/104 (23.08) 
0.0072 
FASA6 
8/96 (8.33) 
21/104 (20.19) 
0.0137 
FASA7 
11/96 (11.46) 
22/104 (21.15) 
0.0481 
FASA8 
8/96 (8.33) 
22/104 (21.15) 
0.0089 
FASA9 
8/96 (8.33) 
24/104 (23.08) 
0.0036 
FASA10 
11/96 (11.46) 
23/104 (22.12) 
0.0338 
1One-sided Fisher’s exact test 
 
The combination of the 10 imputations for the sub-group of FASA EF≥25 and 
NYHA=3 yields a z = -2.2512 with a P = 0.0121. 
 
For the FASB population, the ten imputations for the whole population, EF ≥ 25, and 
EF ≥ 25 with NYHA=3 are presented in the tables below.  The means are presented in 
the table below. 
 
 
 

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Table XII.7a  Mean AT at Study Time Points  
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASB1 
Baseline 
10.87 (2.30) 207 
10.54 (4.10, 17.05) 
10.90 (2.33) 208 
10.62 (4.10, 16.92) 
0.89751 
24 Week3 
10.74 (2.27) 207 
10.78 (4.10, 19.61) 
10.81 (2.46) 207 
10.40 (4.10, 19.82) 
0.74191 
24 Week Difference From 
Baseline 
-0.13 (2.23) 207 
-0.17 (-7.29, 9.34) 
-0.08 (2.38) 208 
-0.12 (-6.91, 9.17) 
0.42082 
FASB2 
Baseline 
10.87 (2.28) 207 
10.56 (4.10, 17.05) 
10.89 (2.36) 208 
10.60 (4.10, 16.92) 
0.92571 
24 Week3 
10.76 (2.26) 207 
10.78 (4.10, 19.61) 
10.80 (2.51) 207 
10.41 (4.10, 19.82) 
0.89441 
24 Week Difference From 
Baseline 
-0.11 (2.24) 207 
-0.12 (-5.68, 9.34) 
-0.10 (2.32) 208 
-0.14 (-6.55, 8.94) 
0.49202 
 FASB3 
Baseline 
10.89 (2.30) 207 
10.65 (4.10, 17.05) 
10.90 (2.32) 208 
10.72 (4.10, 16.92) 
0.96421 
24 Week3 
10.80 (2.28) 207 
10.64 (4.10, 19.61) 
10.81 (2.48) 207 
10.42 (4.10, 19.82) 
0.95331 
24 Week Difference From 
Baseline 
-0.09 (2.22) 207 
-0.17 (-6.10, 9.34) 
-0.09 (2.32) 208 
-0.10 (-6.47, 8.94) 
0.49202 
FASB4 
Baseline 
10.87 (2.28) 207 
10.65 (4.10, 17.05) 
10.90 (2.31) 208 
10.60 (4.10, 16.92) 
0.91051 
24 Week3 
10.72 (2.32) 207 
10.53 (4.10, 19.61) 
10.81 (2.50) 207 
10.42 (4.10, 19.82) 
0.70241 
24 Week Difference From 
Baseline 
-0.16 (2.27) 207 
-0.13 (-6.03, 9.34) 
-0.10 (2.34) 208 
-0.12 (-6.47, 8.94) 
0.39362 
FASB5 
Baseline 
10.91 (2.29) 207 
10.65 (4.10, 17.05) 
10.92 (2.31) 208 
10.61 (4.10, 16.92) 
0.95001 
24 Week3 
10.73 (2.28) 207 
10.61 (4.10, 19.61) 
10.82 (2.44) 207 
10.49 (4.10, 19.82) 
0.69931 
24 Week Difference From 
Baseline 
-0.18 (2.10) 207 
-0.13 (-5.17, 9.34) 
-0.11 (2.29) 208 
-0.14 (-6.88, 8.94) 
0.37462 
FASB6 
Baseline 
10.87 (2.28) 207 
10.56 (4.10, 17.05) 
10.89 (2.31) 208 
10.59 (4.10, 16.92) 
0.93191 
24 Week3 
10.70 (2.30) 207 
10.70 (4.10, 19.61) 
10.74 (2.55) 207 
10.39 (4.10, 19.82) 
0.86461 
24 Week Difference From 
Baseline 
-0.17 (2.23) 207 
-0.13 (-5.13, 9.34) 
-0.15 (2.44) 208 
-0.14 (-8.23, 8.94) 
0.47612 
FASB7 
Baseline 
10.85 (2.31) 207 
10.56 (4.10, 17.05) 
10.91 (2.34) 208 
10.66 (4.10, 16.92) 
0.80301 
24 Week3 
10.81 (2.28) 207 
10.80 (4.10, 19.61) 
10.78 (2.48) 207 
10.40 (4.10, 19.82) 
0.89361 
24 Week Difference From 
Baseline 
-0.04 (2.30) 207 
-0.10 (-6.65, 9.34) 
-0.13 (2.36) 208 
-0.10 (-7.99, 8.94) 
0.66262 
 FASB8 
Baseline 
10.92 (2.29) 207 
10.73 (4.10, 17.05) 
10.86 (2.34) 208 
10.60 (4.10, 16.92) 
0.78201 
24 Week3 
10.71 (2.29) 207 
10.61 (4.10, 19.61) 
10.71 (2.51) 207 
10.38 (4.10, 19.82) 
0.99861 
24 Week Difference From 
Baseline 
-0.21 (2.20) 207 
-0.17 (-6.71, 9.34) 
-0.15 (2.43) 208 
-0.17 (-6.91, 8.94) 
0.39362 
 
 

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Table XII.7a  Mean AT at Study Time Points (Continued) 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASB9 
Baseline 
10.91 (2.29) 207 
10.65 (4.10, 17.05) 
10.91 (2.32) 208 
10.60 (4.10, 16.92) 
0.99911 
24 Week3 
10.72 (2.23) 207 
10.72 (4.10, 19.61) 
10.83 (2.52) 207 
10.41 (4.10, 19.82) 
0.63951 
24 Week Difference 
From Baseline 
-0.19 (2.14) 207 
-0.23 (-5.04, 9.34) 
-0.08 (2.29) 208 
-0.15 (-6.51, 8.94) 
0.30522 
FASB10 
Baseline 
10.87 (2.29) 207 
10.54 (4.10, 17.05) 
10.91 (2.30) 208 
10.59 (4.10, 16.92) 
0.85221 
24 Week3 
10.76 (2.29) 207 
10.72 (4.10, 19.61) 
10.79 (2.46) 207 
10.42 (4.10, 19.82) 
0.89811 
24 Week Difference 
From Baseline 
-0.11 (2.22) 207 
-0.12 (-6.03, 9.34) 
-0.11 (2.23) 208 
-0.24 (-6.47, 8.94) 
0.50792 
1Two-sided equal variance Student’s t-test. 
2One-sided equal variance Student’s t-test 
3One patient in the Optimizer group had a difference imputed but did not have a 24 week AT imputed. 
 
The responder analysis for the 10 imputations appears below. 
 
Table XII.7b  Univariate Primary Effectiveness Endpoint Results (≥20% Improvement) for 
FASB Patients  
 Population  
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
FASB1 
27/207 (13.04) 
37/208 (17.79) 
0.1145 
FASB2 
31/207 (14.98) 
35/208 (16.83) 
0.3516 
FASB3 
28/207 (13.53) 
37/208 (17.79) 
0.1447 
FASB4 
26/207 (12.56) 
37/208 (17.79) 
0.0888 
FASB5 
27/207 (13.04) 
39/208 (18.75) 
0.0726 
FASB6 
26/207 (12.56) 
35/208 (16.83) 
0.1381 
FASB7 
30/207 (14.49) 
36/208 (17.31) 
0.2580 
FASB8 
24/207 (11.59) 
38/208 (18.27) 
0.0381 
FASB9 
27/207 (13.04) 
39/208 (18.75) 
0.0726 
FASB10 
30/207 (15.94) 
36/208 (17.31) 
0.4046 
1One-sided Fisher’s exact test 
 
The total FASB population results in a combined z = -0.4959 with corresponding P-
value of 0.3100. 
 
The means for the FASB ten imputations with baseline EF≥25 are presented below. 
 
 
 
 
 
 
 
 
 
 

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Table XII.8a  Mean AT at Study Time Points with EF ≥25 at Baseline 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASB1 
Baseline 
11.12 (2.33) 108 
10.73 (5.40, 17.05) 
10.73 (2.13) 112 
10.42 (5.29, 16.08) 
0.19701 
24 Week 
10.65 (2.08) 108 
10.58 (4.79, 15.50) 
10.92 (2.41) 112 
10.42 (5.01, 19.82) 
0.36981 
24 Week Difference 
From Baseline 
-0.46 (1.99) 108 
-0.36 (-7.29, 5.64) 
0.20 (2.49) 112 
-0.08 (-4.65, 9.17) 
0.01522 
FASB2 
Baseline 
11.15 (2.31) 108 
10.74 (5.40, 17.05) 
10.74 (2.21) 112 
10.42 (5.29, 16.09) 
0.18841 
24 Week 
10.77 (2.10) 108 
10.80 (6.24, 15.50) 
10.82 (2.48) 112 
10.37 (5.01, 19.82) 
0.86761 
24 Week Difference 
From Baseline 
-0.38 (2.12) 108 
-0.29 (-5.68, 5.64) 
0.08 (2.40) 112 
-0.15 (-4.65, 8.94) 
0.06883 
 FASB3 
Baseline 
11.12 (2.33) 108 
10.73 (5.40, 17.05) 
10.73 (2.12) 112 
10.48 (5.29, 16.08) 
0.20451 
24 Week 
10.72 (2.11) 108 
10.49 (5.99, 15.50) 
10.84 (2.41) 112 
10.42 (4.97, 19.82) 
0.69581 
24 Week Difference 
From Baseline 
-0.39 (2.05) 108 
-0.32 (-6.10, 5.64) 
0.11 (2.47) 112 
-0.09 (-4.65, 8.94) 
0.05123 
FASB4 
Baseline 
11.12 (2.33) 108 
10.73 (5.40, 17.05) 
10.74 (2.14) 112 
10.48 (5.29, 16.08) 
0.21391 
24 Week 
10.68 (2.19) 108 
10.34 (6.24, 15.79) 
10.83 (2.43) 112 
10.40 (4.10, 19.82) 
0.62991 
24 Week Difference 
From Baseline 
-0.44 (2.23) 108 
-0.32 (-6.03, 6.60) 
0.09 (2.33) 112 
-0.12 (-4.65, 8.94) 
0.04433 
FASB5 
Baseline 
11.15 (2.31) 108 
10.74 (5.40, 17.05) 
10.75 (2.17) 112 
10.48 (5.29, 16.08) 
0.18961 
24 Week 
10.70 (2.16) 108 
10.41 (4.78, 15.50) 
10.91 (2.35) 112 
10.46 (5.01, 19.82) 
0.48951 
24 Week Difference 
From Baseline 
-0.44 (1.99) 108 
-0.29 (-5.17, 5.64) 
0.17 (2.32) 112 
-0.09 (-4.65, 8.94) 
0.01933 
FASB6 
Baseline 
11.12 (2.33) 108 
10.73 (5.40, 17.05) 
10.73 (2.13) 112 
10.42 (5.29, 16.08) 
0.19861 
24 Week 
10.62 (2.16) 108 
10.50 (6.24, 15.50) 
10.79 (2.51) 112 
10.37 (4.10, 19.82) 
0.60161 
24 Week Difference 
From Baseline 
-0.49 (2.12) 108 
-0.43 (-5.13, 5.64) 
0.06 (2.40) 112 
-0.12 (-4.65, 8.94) 
0.03583 
FASB7 
Baseline 
11.11 (2.33) 108 
10.73 (5.40, 17.05) 
10.74 (2.20) 112 
10.42 (5.29, 16.84) 
0.22151 
24 Week 
10.80 (2.08) 108 
10.77 (6.24, 15.50) 
10.82 (2.41) 112 
10.37 (5.01, 19.82) 
0.94481 
24 Week Difference 
From Baseline 
-0.31 (2.13) 108 
-0.28 (-5.51, 5.64) 
0.08 (2.38) 112 
-0.09 (-4.65, 8.94) 
0.09753 
 FASB8 
Baseline 
11.17 (2.33) 108 
10.74 (5.40, 17.05) 
10.68 (2.15) 112 
10.42 (5.29, 16.08) 
0.10511 
24 Week 
10.67 (2.17) 108 
10.49 (5.37, 15.50) 
10.80 (2.53) 112 
10.37 (4.22, 19.82) 
0.69071 
24 Week Difference 
From Baseline 
-0.51 (2.18) 108 
-0.32 (-6.71, 5.85) 
0.11 (2.53) 112 
-0.15 (-5.36, 8.94) 
0.02683 
 
 

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Table XII.8a  Mean AT at Study Time Points with EF ≥25 at Baseline 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASB9 
Baseline 
11.17 (2.33) 108 
10.74 (5.40, 17.05) 
10.74 (2.17) 112 
10.42 (5.29, 16.08) 
0.15091 
24 Week 
10.71 (2.05) 108 
10.58 (6.24, 15.50) 
10.92 (2.47) 112 
10.42 (5.01, 19.82) 
0.49281 
24 Week Difference 
From Baseline 
-0.46 (2.07) 108 
-0.36 (-5.04, 5.64) 
0.18 (2.41) 112 
-0.09 (-4.65, 8.94) 
0.01713 
FASB10 
Baseline 
11.11 (2.33) 108 
10.73 (5.40, 17.05) 
10.74 (2.17) 112 
10.42 (5.29, 16.08) 
0.22111 
24 Week 
10.70 (2.13) 108 
10.45 (5.92, 15.50) 
10.78 (2.40) 112 
10.39 (5.01, 19.82) 
0.80301 
24 Week Difference 
From Baseline 
-0.42 (2.19) 108 
-0.36 (-6.03, 5.64) 
0.03 (2.31) 112 
-0.16 (-4.65, 8.94) 
0.07023 
1Two-sided equal variance Student’s t-test. 
2One-sided unequal variance Student’s t-test 
3One-sided equal variance Student’s t-test 
 
The responder analysis for the 10 imputations appears below. 
 
Table XII.8b  Univariate Primary Effectiveness Endpoint Results (≥20% Improvement) for 
FASB Patients with EF ≥25  
Population  
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
FASB1 
8/108 (7.41) 
23/112 (20.54) 
0.0041 
FASB2 
14/108 (12.96) 
22/112 (19.64) 
0.1236 
FASB3 
11/108 (10.19) 
23/112 (20.54) 
0.0257 
FASB4 
10/108 (9.26) 
23/112 (20.54) 
0.0150 
FASB5 
11/108 (10.19) 
25/112 (22.32) 
0.0116 
FASB6 
10/108 (9.26) 
22/112 (19.64) 
0.0224 
FASB7 
13/108 (12.04) 
23/112 (20.54) 
0.0636 
FASB8 
10/108 (9.26) 
24/112 (21.43) 
0.0099 
FASB9 
11/108 (10.19) 
26/112 (23.21) 
0.0076 
FASB10 
14/108 (12.96) 
23/112 (20.54) 
0.0929 
1One-sided Fisher’s exact test 
 
Combining the ten imputations for FASB (EF≥25), the resulting z = -1.9045 with P-
value equal to 0.0284. 
 
The means for the FASB ten imputations with baseline EF≥25 and NYHA=3 are 
presented below. 
 
 
 
 
 
 
 
 

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Table XII.9a  Mean AT at Study Time Points with EF ≥25 and NYHA=3 at Baseline 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASB1 
Baseline 
11.18 (2.21) 93 
10.73 (7.22, 16.72) 
10.68 (2.11) 104 
10.42 (5.29, 16.05) 
0.10721 
24 Week 
10.65 (2.12) 93 
10.35 (4.79, 15.50) 
10.96 (2.46) 104 
10.46 (5.01, 19.82) 
0.34461 
24 Week Difference 
From Baseline 
-0.54 (1.95) 93 
-0.43 (-7.29, 4.62) 
0.27 (2.56) 104 
-0.01 (-4.65, 9.17) 
0.00652 
FASB2 
Baseline 
11.22 (2.19) 93 
10.76 (7.22, 16.72) 
10.71 (2.20) 104 
10.42 (5.29, 16.09) 
0.10431 
24 Week 
10.84 (2.12) 93 
10.85 (6.24, 15.50) 
10.88 (2.52) 104 
10.42 (5.01, 19.82) 
0.90001 
24 Week Difference 
From Baseline 
-0.38 (2.04) 93 
-0.31 (-5.68, 4.62) 
0.17 (2.43) 104 
-0.09 (-4.65, 8.94) 
0.04353 
 FASB3 
Baseline 
11.18 (2.21) 93 
10.73 (7.22, 16.72) 
10.68 (2.10) 104 
10.42 (5.29, 16.05) 
0.10081 
24 Week 
10.73 (2.15) 93 
10.33 (5.99, 15.50) 
10.86 (2.44) 104 
10.46 (4.97, 19.82) 
0.69561 
24 Week Difference 
From Baseline 
-0.46 (2.04) 93 
-0.38 (-6.10, 4.62) 
0.18 (2.49) 104 
-0.05 (-4.65, 8.94) 
0.02633 
FASB4 
Baseline 
11.18 (2.21) 93 
10.73 (7.22, 16.72) 
10.68 (2.13) 104 
10.42 (5.29, 16.05) 
0.10881 
24 Week 
10.76 (2.20) 93 
10.35 (6.24, 15.79) 
10.85 (2.50) 104 
10.46 (4.10, 19.82) 
0.79061 
24 Week Difference 
From Baseline 
-0.42 (2.17) 93 
-0.31 (-6.03, 6.60) 
0.17 (2.39) 104 
-0.07 (-4.65, 8.94) 
0.03673 
FASB5 
Baseline 
11.22 (2.19) 93 
10.76 (7.22, 16.72) 
10.70 (2.16) 104 
10.42 (5.29, 16.05) 
0.09651 
24 Week 
10.75 (2.11) 93 
10.35 (6.24, 15.50) 
10.91 (2.40) 104 
10.53 (5.01, 19.82) 
0.61861 
24 Week Difference 
From Baseline 
-0.46 (1.91) 93 
-0.38 (-5.17, 4.62) 
0.21 (2.35) 104 
-0.05 (-4.65, 8.94) 
0.01352 
FASB6 
Baseline 
11.18 (2.21) 93 
10.73 (7.22, 16.72) 
10.69 (2.11) 104 
10.42 (5.29, 16.05) 
0.10951 
24 Week 
10.66 (2.13) 93 
10.35 (6.24, 15.50) 
10.79 (2.57) 104 
10.40 (4.10, 19.82) 
0.69874 
24 Week Difference 
From Baseline 
-0.52 (2.10) 93 
-0.49 (-5.13, 5.36) 
0.10 (2.44) 104 
-0.09 (-4.65, 8.94) 
0.02823 
FASB7 
Baseline 
11.18 (2.22) 93 
10.73 (7.22, 16.72) 
10.71 (2.18) 104 
10.42 (5.29, 16.84) 
0.13421 
24 Week 
10.84 (2.11) 93 
10.82 (6.24, 15.50) 
10.84 (2.43) 104 
10.40 (5.01, 19.82) 
0.99661 
24 Week Difference 
From Baseline 
-0.34 (2.13) 93 
-0.30 (-5.51, 5.11) 
0.13 (2.38) 104 
-0.07 (-4.65, 8.94) 
0.07433 
 FASB8 
Baseline 
11.25 (2.21) 93 
10.76 (7.22, 16.72) 
10.66 (2.13) 104 
10.42 (5.29, 16.05) 
0.05501 
24 Week 
10.71 (2.17) 93 
10.47 (5.37, 15.50) 
10.79 (2.53) 104 
10.40 (4.22, 19.82) 
0.81631 
24 Week Difference 
From Baseline 
-0.54 (2.16) 93 
-0.33 (-6.71, 5.85) 
0.14 (2.49) 104 
-0.12 (-5.36, 8.94) 
0.02243 
 
 

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Table XII.9a  Mean AT at Study Time Points with EF ≥25 and NYHA=3 at Baseline 
Imputation 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
FASB9 
Baseline 
11.25 (2.21) 93 
10.76 (7.22, 16.72) 
10.72 (2.14) 104 
10.42 (5.29, 16.05) 
0.08541 
24 Week 
10.74 (2.05) 93 
10.47 (6.24, 15.50) 
10.91 (2.51) 104 
10.46 (5.01, 19.82) 
0.60644 
24 Week Difference 
From Baseline 
-0.51 (2.00) 93 
-0.48 (-5.04, 5.11) 
0.20 (2.46) 104 
-0.09 (-4.65, 8.94) 
0.01412 
FASB10 
Baseline 
11.18 (2.22) 93 
10.73 (7.22, 16.72) 
10.72 (2.14) 104 
10.42 (5.29, 16.05) 
0.13531 
24 Week 
10.73 (2.13) 93 
10.33 (6.24, 15.50) 
10.83 (2.44) 104 
10.42 (5.01, 19.82) 
0.76431 
24 Week Difference 
From Baseline 
-0.46 (2.15) 93 
-0.48 (-6.03, 5.50) 
0.11 (2.35) 104 
-0.12 (-4.65, 8.94) 
0.04083 
1Two-sided equal variance Student’s t-test. 
2One-sided unequal variance Student’s t-test 
3One-sided equal variance Student’s t-test 
4Two-sided unequal variance Student’s t-test. 
 
The responder analysis for the 10 imputations appears below. 
 
Table XII.9b Univariate Primary Effectiveness Endpoint Results (≥20% Improvement) for 
FASB Patients with EF ≥25 and NYHA=3 at Baseline 
Population  
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
FASB1 
6/93 (6.45) 
23/104 (22.12) 
0.0015 
FASB2 
11/93 (11.83) 
22/104 (21.15) 
0.0587 
FASB3 
9/93 (9.68) 
22/104 (21.15) 
0.0210 
FASB4 
8/93 (8.60) 
23/104 (22.12) 
0.0073 
FASB5 
9/93 (9.68) 
24/104 (23.08) 
0.0093 
FASB6 
8/93 (8.60) 
21/104 (20.19) 
0.0172 
FASB7 
11/93 (11.83) 
22/104 (21.15) 
0.0587 
FASB8 
8/93 (8.60) 
22/104 (21.15) 
0.0113 
FASB9 
8/93 (8.60) 
24/104 (23.08) 
0.0047 
FASB10 
11/93 (11.83) 
23/104 (22.12) 
0.0419 
1One-sided Fisher’s exact test 
 
The analysis of the combined imputations for FASB (EF≥25 and NYHA=3) resulted 
in a z=-2.1549 with corresponding P=0.0156. 
 
Theses imputation analyses by ITT, FASA, or FASB all resulted in similar outcomes.  
The whole population does not demonstrate statistical significance at a 0.025.  The 
sub group of patients with baseline EF≥25 results in a P-value less than 0.05, but 
slightly above the 0.025 value and the sub-group with EF≥25 and NYHA=3 achieves 
statistical significance with P<0.025. 
  
XI I I . Secondary Effectiveness Analyses 
 

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The mean AT and PVO2 at Baseline, 24 weeks and 50 weeks for the CC population 
are given in the table below. 
 
Table XIII.1a  Mean AT and PVO2 at Study Time Points  
Variable 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
AT 
Baseline 
10.97 (2.18) 207 
10.73 (5.40, 17.05) 
10.95 (2.24) 201 
10.60 (5.29, 16.92) 
0.95281 
24 Week 
10.96 (2.20) 158 
10.83 (6.24, 19.61) 
10.87 (2.45) 169 
10.49 (5.01, 19.82) 
0.73461 
24 Week Difference 
From Baseline 
-0.14 (2.14) 154 
-0.23 (-4.99, 9.34) 
-0.14 (2.23) 159 
-0.25 (-6.47, 8.94) 
0.50403 
50 Week 
10.92 (2.49) 148 
10.78 (4.10, 20.93) 
11.10 (2.56) 163 
10.92 (5.40, 21.83) 
0.54711 
50 Week Difference 
From Baseline 
-0.14 (2.64) 146 
-0.35 (-6.45, 10.66) 
0.01 (2.59) 156 
-0.30 (-5.43, 12.25) 
0.31583 
PVO2 
Baseline 
14.71 (2.92) 211 
15.02 (8.54, 22.61) 
14.73 (3.06) 214 
14.48 (8.43, 23.02) 
0.92451 
24 Week 
14.54 (3.56) 169 
14.47 (6.30, 27.95) 
14.94 (3.62) 179 
14.47 (7.63, 27.49) 
0.30081 
24 Week Difference 
From Baseline 
-0.41 (2.90) 168 
-0.50 (-7.68, 11.60) 
0.24 (3.16) 179 
-0.04 (-8.17, 11.69) 
0.02423 
50 Week 
14.59 (3.87) 159 
14.47 (6.88, 29.75) 
14.72 (3.51) 172 
14.47 (8.12, 30.67) 
0.73941 
50 Week Difference 
From Baseline 
-0.44 (3.01) 152 
-0.58 (-7.80, 12.06) 
-0.08 (3.47) 164 
-0.21 (-6.87, 17.45) 
0.23303 
1Two-sided equal variance Student’s t-test. 
2Two-sided unequal variance Student’s t-test 
3One-sided equal variance Student’s t-test 
 
The responder analyses for the CC population at 24 and 50 weeks are provided in the 
table below.  
 
Table XIII.1b  Responder Analysis (20% or Greater improvement from Baseline) at Study Time 
Points 
 Variable 
Time 
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
AT 
24 Week 
18/154 (11.69) 
28/159 (17.61) 
0.0932 
50 Week 
21/146 (14.38) 
37/156 (23.72) 
0.0275 
PVO2 
24 Week 
23/168 (13.69) 
31/179 (17.32) 
0.2169 
50 Week 
24/158 (15.19) 
31/172 (18.02) 
0.2944 
1One-sided Fisher’s exact test 
 
Note that the responder analysis for 24 weeks has a P-value of less than 0.1 and for 50 weeks 
has a P-value that is near 0.025. 
 
XI V . Additional Analyses 
 

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Analyses of additional endpoints are presented below.  The means for the quality of 
life instrument, the MLWHFQ, the NYHA, and the 6 minute walk test (MWT) are 
provided at 24 and 50 weeks below. 
  
Table XIV.1a  Mean AT and PVO2 at Study Time Points  
Variable 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
MLWHFQ 
Baseline 
57.38 (22.62) 213 
59.0 (1.0, 102.0) 
60.49 (23.00) 215 
64.0 (0.0, 100.0) 
0.15951 
24 Week 
52.08 (23.84) 184 
53.5 (0.0, 105.0) 
45.33 (24.43) 196 
46.0 (0.0, 97.0) 
0.00681 
24 Week Difference 
From Baseline 
-5.72 (21.03) 184 
-6.0 (-74.0, 68.0) 
-15.38 (19.55) 196 
-12.5 (-81.0, 25.0) 
<0.00013 
50 Week 
51.10 (23.57) 173 
53.0 (1.0, 101.0) 
42.75 (25.66) 183 
42.0 (0.0, 101.0) 
0.00151 
50 Week Difference 
From Baseline 
-7.32 (20.66) 173 
-6.0 (-81.0, 87.0) 
-17.60 (22.68) 183 
-15.0 (-81.0, 43.0) 
<0.00013 
NYHA 
Baseline 
3.13 (0.35) 213 
3.0 (2.0, 4.0) 
3.09 (0.28) 215 
3.0 (3.0, 4.0) 
0.16502 
24 Week 
2.81 (0.71) 183 
3.0 (1.0, 4.0) 
2.53 (0.73) 191 
3.0 (1.0, 4.0) 
0.00022 
24 Week Difference 
From Baseline 
-0.32 (0.73) 183 
0.0 (-2.0, 1.0) 
-0.54 (0.72) 191 
0.0 (-3.0, 1.0) 
0.00153 
50 Week 
2.67 (0.78) 174 
3.0 (1.0, 4.0) 
2.48 (0.85) 185 
3.0 (1.0, 4.0) 
0.02322 
50 Week Difference 
From Baseline 
-0.47 (0.83) 173 
0.0 (-3.0, 1.0) 
-0.61 (0.86) 185 
-1.0 (-3.0, 1.0) 
0.05983 
6 MWT 
Baseline 
323.99 (92.44) 212 
321.0 (80.0, 600.0) 
326.38 (82.10) 215 
330.0 (95.0, 525.0) 
0.77711 
24 Week 
335.13 (106.99) 
173 
340.0 (75.0, 730.0) 
347.68 (95.47) 190 
349.0 (90.0, 585.0) 
0.23841 
24 Week Difference 
From Baseline 
8.61 (85.08) 173 
7.0 (-375.0, 457.0) 
19.41 (80.62) 190 
15.0 (-316.0, 301.0) 
0.10793 
50 Week 
337.31 (109.49) 
162 
342.0 (80.0, 823.0) 
348.97 (98.34) 181 
357.0 (55.0, 615.0) 
0.29961 
50 Week Difference 
From Baseline 
10.51 (87.16) 162 
14.0 (-375.0, 
365.0) 
20.22 (83.14) 181 
13.0 (-220.0, 285.0) 
0.14493 
1Two-sided equal variance Student’s t-test. 
2Two-sided unequal variance Student’s t-test 
3One-sided equal variance Student’s t-test 
 
A responder analysis with response being defined as -10 or more points for the 
MLWHFQ, -1 or more classes for the NYHA, and 40 meters or more for the 6 MWT. 
 
 
 
 
 

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Table XIV.1b  Responder Analysis at Study Time Points 
 Variable 
Time 
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
MLWHFQ2 
24 Week 
77/184 (41.85) 
110/196 (56.12) 
0.0037 
50 Week 
73/173 (42.20) 
112/183 (61.20) 
0.0002 
NYHA3 
24 Week 
63/183 (34.43) 
94/191 (49.21) 
0.0026 
50 Week 
80/174 (45.98) 
97/185 (52.43) 
0.1320 
6 MWT4 
24 Week 
51/173 (29.48) 
65/190 (34.21) 
0.1970 
50 Week 
51/162 (31.48) 
69/181 (38.12) 
0.1201 
1One-sided Fisher’s Exact Test 
2Responder is a 10 or more point improvement from baseline. 
3Responder is a 1 or more point improvement from baseline. 
4Responder is a 40 or more meters improvement from baseline. 
 
Note that there are higher proportions of  responders in the Optimizer group for all of the 
endpoints and time periods.  The P-value for patients experiencing a 10 or more point decline 
in the MLWHFQ at both 24 and 50 weeks are highly statistically significant and NYHA at 24 
weeks. 
 
The means for the 24 and 50 week changes in AT and PVO2 are presented for the sub-group 
with EF≥25 for the CC population in the table below. 
 
Table XIV.2a  Mean AT and PVO2 at Study Time Points in Sub-group with Baseline EF≥25  
Variable 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
AT 
Baseline 
11.17 (2.30) 112 
10.74 (5.40, 17.05) 
10.68 (2.12) 110 
10.39 (5.29, 16.08) 
0.10351 
24 Week 
10.89 (2.11) 80 
10.80 (6.24, 15.50) 
11.00 (2.45) 94 
10.46 (5.01, 19.82) 
0.75421 
24 Week Difference 
From Baseline 
-0.44 (1.93) 79 
-0.38 (-3.79, 5.64) 
0.04 (2.32) 88 
-0.15 (-4.65, 8.94) 
0.07452 
50 Week 
11.00 (2.31) 77 
10.97 (4.10, 17.54) 
11.11 (2.36) 95 
11.16 (5.40, 20.62) 
0.75251 
50 Week Difference 
From Baseline 
-0.27 (2.38) 77 
-0.39 (-5.32, 6.62) 
0.23 (2.41) 91 
0.09 (-5.05, 8.31) 
0.08782 
PVO2 
Baseline 
14.95 (2.83) 112 
15.09 (8.68, 22.61) 
14.59 (2.95) 117 
14.48 (8.43, 20.96) 
0.35391 
24 Week 
14.21 (3.02) 89 
14.10 (6.30, 20.37) 
14.99 (3.48) 99 
14.84 (7.63, 27.49) 
0.10201 
24 Week Difference 
From Baseline 
-1.00 (2.47) 89 
-0.96 (-6.54, 6.01) 
0.32 (3.04) 99 
-0.03 (-6.58, 11.69) 
0.00063 
50 Week 
14.63 (3.46) 81 
14.43 (6.88, 24.51) 
14.73 (3.23) 100 
14.75 (8.12, 27.19) 
0.84461 
50 Week Difference 
From Baseline 
-0.68 (2.93) 81 
-0.55 (-6.40, 7.05) 
0.08 (3.00) 100 
-0.00 (-6.36, 11.38) 
0.04362 
1Two-sided equal variance Student’s t-test. 
2One-sided equal variance Student’s t-test 
3One-sided unequal variance Student’s t-test 
 

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The responder analysis for this sub-group in the CC population is presented in the 
following table. 
  
Table XIV.2b.  Responder Analysis (20% or Greater improvement from Baseline) at Study Time 
Points in Sub-group with Baseline EF≥25 
 Variable 
Time 
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
AT 
24 Week 
6/79 (7.59) 
17/88 (19.32) 
0.0230 
50 Week 
10/77 (12.99) 
24/91 (23.53) 
0.0240 
PVO2 
24 Week 
4/89 (4.49) 
18/99 (18.18) 
0.0028 
50 Week 
10/81 (12.35) 
19/100 (19.00) 
0.1563 
1One-sided Fisher’s Exact Test 
 
For this sub-group of CC patients, both at 24 and 50 weeks the AT responders were 
significantly greater in Optimizer patients both with P-values below 0.025.  
 
The means for the other variables for the CC sub-group with EF≥25 are presented below. 
 

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Table XIV.3a  Mean AT and PVO2 at Study Time Points in Sub-group with Baseline EF≥25 
Variable 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value1 
MLWHFQ 
Baseline 
56.57 (23.59) 113 
59.0 (1.0, 102.0) 
59.73 (23.23) 117 
64.0 (4.0, 99.0) 
0.30721 
24 Week 
52.38 (24.29) 97 
54.0 (0.0, 101.0) 
43.93 (24.41) 108 
44.5 (0.0, 97.0) 
0.01391 
24 Week Difference 
From Baseline 
-5.52 (21.68) 97 
-5.0 (-74.0, 68.0) 
-16.34 (20.19) 108 
-17.0 (-67.0, 24.0) 
0.00013 
50 Week 
53.71 (23.60) 90 
55.0 (1.0, 101.0) 
42.98 (25.75) 103 
41.0 (0.0, 101.0) 
0.00301 
50 Week Difference 
From Baseline 
-4.50 (21.23) 90 
-6.0 (-66.0, 87.0) 
-17.65 (22.61) 103 
-17.0 (-78.0, 43.0) 
<0.00013 
NYHA 
Baseline 
3.12 (0.36) 113 
3.0 (2.0, 4.0) 
3.07 (0.25) 117 
3.0 (3.0, 4.0) 
0.17662 
24 Week 
2.88 (0.65) 94 
3.0 (1.0, 4.0) 
2.54 (0.65) 103 
3.0 (1.0, 4.0) 
0.00031 
24 Week Difference 
From Baseline 
-0.24 (0.67) 94 
0.0 (-2.0, 1.0) 
-0.51 (0.68) 103 
0.0 (-3.0, 1.0) 
0.00283 
50 Week 
2.73 (0.79) 91 
3.0 (1.0, 4.0) 
2.41 (0.81) 106 
2.5 (1.0, 4.0) 
0.00591 
50 Week Difference 
From Baseline 
-0.43 (0.83) 91 
0.0 (-3.0, 1.0) 
-0.66 (0.83) 106 
-1.0 (-3.0, 1.0) 
0.02573 
6 MWT 
Baseline 
326.83 (94.49) 112 
330.0 (120.0, 600.0) 
325.80 (84.24) 117 
321.0 (95.0, 525.0) 
0.93081 
24 Week 
333.73 (97.67) 91 
340.0 (89.0, 644.0) 
344.91 (99.17) 104 
346.0 (90.0, 585.0) 
0.42961 
24 Week Difference 
From Baseline 
3.88 (80.19) 91 
4.0 (-375.0, 255.0) 
18.75 (82.49) 104 
15.5 (-316.0, 225.0) 
0.10283 
50 Week 
334.64 (103.60) 83 
352.0 (85.0, 514.0) 
345.51 (100.48) 103 
358.0 (55.0, 615.0) 
0.47011 
50 Week Difference 
From Baseline 
2.89 (90.81) 83 
15.0 (-375.0, 225.0) 
20.29 (87.37) 103 
19.0 (-210.0, 285.0) 
0.09263 
1Two-sided equal variance Student’s t-test. 
2Two-sided unequal variance Student’s t-test 
3One-sided equal variance Student’s t-test 
 
For the responders in this sub-group of the CC population the following table gives 
the results.  
 
 
 
 
 
 
 
 
 
 
 
 

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Table XIV.3b  Responder Analysis at Study Time Points in Sub-group with Baseline EF≥25 
 Variable 
Time 
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
MLWHFQ2 
24 Week 
40/97 (41.24) 
63/108 (58.33) 
0.0105 
50 Week 
34/90 (37.78) 
64/103 (62.14) 
0.0006 
NYHA3 
24 Week 
27/94 (28.72) 
47/103 (45.63) 
0.0105 
50 Week 
42/91 (46.15) 
57/106 (53.77) 
0.1779 
6 MWT4 
24 Week 
24/91 (26.37) 
38/104 (36.54) 
0.0856 
50 Week 
27/83 (32.53) 
37/103 (35.92) 
0.3718 
1One-sided Fisher’s Exact Test 
2Responder is a 10 or more point improvement from baseline. 
3Responder is a 1 or more point improvement from baseline. 
4Responder is a 40 or more meters improvement from baseline. 
 
These results show that MLWFHQ (at 24 and 50 weeks) and NYHA (at 24 weeks) 
demonstrate statistically significant results with P<0.025. 
 
The means AT and PVO2 for the CC sub-group with EF≥25 and NYHA =3 appear in 
the table below. 
 
Table XIV.4a  Mean AT and PVO2 at Study Time Points in Sub-group with Baseline EF≥25 and 
NYHA = 3 
Variable 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
AT 
Baseline 
11.22 (2.18) 96 
10.74 (7.22, 16.72) 
10.63 (2.09) 103 
10.38 (5.29, 16.05) 
0.05211 
24 Week 
10.87 (2.15) 70 
10.67 (6.24, 15.50) 
11.03 (2.49) 88 
10.53 (5.01, 19.82) 
0.67501 
24 Week Difference 
From Baseline 
-0.54 (1.83) 69 
-0.49 (-3.79, 4.62) 
0.10 (2.36) 83 
-0.11 (-4.65, 8.94) 
0.03103 
50 Week 
10.91 (2.25) 66 
10.95 (4.10, 17.54) 
11.18 (2.40) 90 
11.21 (5.40, 20.62) 
0.47361 
50 Week Difference 
From Baseline 
-0.44 (2.27) 66 
-0.48 (-5.32, 4.81) 
0.28 (2.43) 86 
0.12 (-5.05, 8.31) 
0.03173 
PVO2 
Baseline 
15.06 (2.72) 96 
15.09 (9.30, 22.61) 
14.56 (2.91) 109 
14.48 (8.43, 20.88) 
0.20741 
24 Week 
14.44 (2.96) 76 
14.39 (8.61, 20.37) 
14.94 (3.49) 94 
14.67 (7.63, 27.49) 
0.31881 
24 Week Difference 
From Baseline 
-0.97 (2.31) 76 
-0.81 (-6.35, 4.16) 
0.34 (3.11) 94 
0.01 (-6.58, 11.69) 
0.00103 
50 Week 
14.65 (3.42) 69 
14.43 (6.88, 24.51) 
14.82 (3.27) 93 
14.93 (8.12, 27.19) 
0.74251 
50 Week Difference 
From Baseline 
-0.79 (2.79) 69 
-0.73 (-6.40, 7.05) 
0.20 (3.04) 93 
0.07 (-6.36, 11.38) 
0.01743 
1Two-sided equal variance Student’s t-test. 
2One-sided equal variance Student’s t-test 
3One-sided equal variance Student’s t-test 
 
The responder analysis for this sub-group appears in the table below. 
 

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Table XIV.4b  Responder Analysis (20% or Greater improvement from Baseline) at Study Time 
Points in Sub-group with EF≥25 and NYHA = 3 
 Variable 
Time 
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
AT 
24 Week 
4/69 (5.80) 
17/83 (20.48) 
0.0073 
50 Week 
8/66 (12.12) 
23/86 (26.74) 
0.0205 
PVO2 
24 Week 
3/76 (3.95) 
18/94 (19.15) 
0.0020 
50 Week 
8/69 (11.59) 
19/93 (20.43) 
0.0993 
1One-sided Fisher’s Exact Test 
 
The responders in AT for both 24 and 50 weeks demonstrate an advantage for 
Optimizer patients with P-values less than 0.025 and the responders with PVO2 
demonstrate an advantage for Optimizer patients at 24 weeks with a P<0.025.   
 
The means for the remaining effectiveness variables for the sub-group of CC patients 
with EF≥25 and NYHA = 3 are in the table below.   
 

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Table XIV.5a  Mean AT and PVO2 at Study Time Points in Sub-group with EF≥25 and NYHA = 
3 
Variable 
Time 
Control 
Mean (SD) N 
Med (Min, Max) 
Optimizer 
Mean (SD) N 
Med (Min, Max) 
P-value 
MLWHFQ 
Baseline 
53.92 (23.59) 97 
58.0 (1.0, 93.0) 
59.80 (22.97) 109 
64.0 (4.0, 99.0) 
0.07161 
24 Week 
49.20 (23.60) 84 
51.0 (0.0, 95.0) 
43.89 (23.63) 101 
44.0 (0.0, 97.0) 
0.12951 
24 Week 
Difference From 
Baseline 
-5.98 (21.85) 84 
-4.5 (-74.0, 68.0) 
-16.76 (20.23) 101 
-18.0 (-67.0, 24.0) 
0.00032 
50 Week 
51.63 (22.70) 76 
54.5 (1.0, 93.0) 
42.05 (25.45) 97 
40.0 (0.0, 101.0) 
0.01091 
50 Week 
Difference From 
Baseline 
-3.68 (19.07) 76 
-5.5 (-62.0, 87.0) 
-18.25 (22.26) 97 
-18.0 (-78.0, 32.0) 
<0.00013 
NYHA 
Baseline 
3.0 (0.0) 97 
3.0 (3.0, 3.0) 
3.0 (0.0) 109 
3.0 (3.0, 3.0) 
-- 
24 Week 
2.83 (0.64) 82 
3.0 (1.0, 4.0) 
2.54 (0.61) 97 
3.0 (1.0, 4.0) 
0.00221 
24 Week 
Difference From 
Baseline 
-0.17 (0.64) 82 
0.0 (-2.0, 1.0) 
-0.46 (0.61) 97 
0.0 (-2.0, 1.0) 
0.00112 
50 Week 
2.69 (0.77) 77 
3.0 (1.0, 4.0) 
2.38 (0.80) 99 
2.0 (1.0, 4.0) 
0.01181 
50 Week 
Difference From 
Baseline 
-0.31 (0.77) 77 
0.0 (-2.0, 1.0) 
-0.62 (0.80) 99 
-1.0 (-2.0, 1.0) 
0.00603 
6 MWT 
Baseline 
333.59 (87.82) 96 
340.0 (122.0, 600.0) 
330.61 (79.14) 109 
330.0 (134.0, 525.0) 
0.79862 
24 Week 
341.19 (98.81) 79 
346.0 (89.0, 644.0) 
352.93 (96.00) 97 
360.0 (100.0, 585.0) 
0.42701 
24 Week 
Difference From 
Baseline 
0.84 (82.58) 79 
0.0 (-375.0, 255.0) 
21.54 (77.54) 97 
16.0 (-305.0, 225.0) 
0.04453 
50 Week 
342.44 (101.77) 70 
356.0 (85.0, 514.0) 
351.15 (95.41) 95 
358.0 (105.0, 615.0) 
0.57421 
50 Week 
Difference From 
Baseline 
0.91 (96.20) 70 
12.0 (-375.0, 225.0) 
20.45 (87.28) 95 
20.0 (-210.0, 285.0) 
0.08793 
1Two-sided equal variance Student’s t-test. 
2One-sided unequal variance Student’s t-test 
3One-sided equal variance Student’s t-test 
 
The responder analysis corresponding to the table above appears in the table below. 
 
 
 
 
 
 
 

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Table XIV.5b  Responder Analysis at Study Time Points in Sub-group with EF≥25 and NYHA = 
3 
 Variable 
Time 
Control 
n/N (%) 
Optimizer 
n/N (%) 
P-value1 
MLWHFQ2 
24 Week 
35/84 (41.67) 
60/101 (59.41) 
0.0119 
50 Week 
28/76 (36.84) 
61/97 (62.89) 
0.0006 
NYHA3 
24 Week 
19/82 (23.17) 
43/97 (44.33) 
0.0023 
50 Week 
32/77 (41.56) 
51/99 (51.52) 
0.1229 
6 MWT4 
24 Week 
20/79 (25.32) 
36/97 (37.11) 
0.0652 
50 Week 
22/70 (31.43) 
35/95 (36.84) 
0.2895 
1One-sided Fisher’s Exact Test 
2Responder is a 10 or more point improvement from baseline. 
3Responder is a 1 or more point improvement from baseline. 
4Responder is a 40 or more meters improvement from baseline. 
 
These analyses indicate that for CC patients with EF≥25 and NYHA = 3, Optimizer 
patients have greater response than control patients and it is significantly greater for 
MLWHFQ and NYHA at 24 weeks and for MLWHFQ at 50 weeks with a P<0.025. 
 
These additional analyses indicate that Optimizer patients had greater changes from 
baseline than control patients across all measures.  Statistical significance in 
responder analyses with P-values less than 0.025 was achieved for all Optimizer CC 
patients for MLWHFQ overall at 24 and 50 weeks and NYHA for 24 weeks.  For 
patient sub-grouped with EF≥25 whether or not the NYHA =3, the AT responder 
analysis demonstrated superiority for the Optimizer patients with P-values less than 
0.025 at both 24 and 50 weeks.  In these patients, the PVO2 demonstrated a 
significant advantage for Optimizer patients at 24 weeks. 
 
References: 
 
1. Meinert, C. (1986). Clinical Trials: Design, Conduct, and Analysis.  Oxford 
University Press, New York. 
2. Hosmer, D. and Lemeshow, S. (2000). Applied Logistic Regression (Second Edition).  
John Wiley and Sons, New York. 
3. Rubin, D.  (1987).  Multiple Imputation for Nonresponse in Surveys.  John Wiley and 
Sons, New York.