Evaluation of the Safety and Efficacy of the OPTIMIZER® System in Subjects With Moderate-to-Severe Heart Failure With Ejection Fraction Between 25% and 45%: FIX-HF-5C
Phase: NA
Conditions: NYHA Class III Heart Failure, NYHA Class IV Heart Failure
Sponsor: Impulse Dynamics

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C  
Protocol version September 25, 2015 
 
        Page 1 of 51 
 
 
 
 
 
 
Evaluation of the Safety and Efficacy of the OPTIMIZER® System  
in Subjects with Moderate-to-Severe Heart Failure  
with Ejection Fraction between 25% and 45%: FIX-HF-5C 
 
 
Protocol ID CP OPT2009-009  
 
ORIGINAL Version:  October 21, 2009* 
Revised March 15, 2010* 
Revised June 2, 2010* 
Revised July 23, 2010 
Revised July 29, 2011 
Revised August 13, 2013* 
FIX-HF-5B => FIX-HF-5C 
November 4, 2013  
July 15, 2015* 
September 25, 2015 
 
Sponsor: 
Impulse Dynamics NV 
Schottegatweg Oost 10 (Unit AIK) 
Curacao,  
Dutch Caribbean 
 
US Sponsor: 
Impulse Dynamics (USA), Inc. 
30 Ramland Road South 
Suite 101 
Orangeburg, New York 10962 
Tel: 
845-359-2389 
Fax: 
845-818-3684 
 
 
* Protocol version sent to FDA only and not to the clinical sites. 
 
 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 2 of 51 
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 --------------------------------------------------------------  
6 
c. Clinical studies ---------------------------------------------------------------------  
8 
C. Summary of the known and potential risks and benefits, if any, to human subjects
 --------------------------------------------------------------------------------------------------  
16 
D. Description of and justification for the route of administration, dosage, dosage 
regimen and treatment period --------------------------------------------------------------  
21 
E. Statement that the trial will be conducted in compliance with the protocol, GCP 
and the applicable regulatory requirements ----------------------------------------------  
22 
F. Description of the population to be studied ----------------------------------------------  
22 
G. References to literature and data that are relevant to the trial and that provide 
background for the trial ---------------------------------------------------------------------  
22 
III. 
Trial Objectives and Purpose -----------------------------------------------------------------  
22 
IV. 
Trial Design ---------------------------------------------------------------------------------------  
23 
A. Primary and secondary endpoints to be measured during the trial -------------------  
23 
B. Description of the type/design of the trial and a schematic diagram of trial 
design, procedures and stages --------------------------------------------------------------  
24 
Figure 1.  Study Overview-------------------------------------------------------------  
25 
Table 1.  Schedule of Events ----------------------------------------------------------  
26 
C. Anticipated Rate of Site and Patient Recruitment --------------------------------------  
27 
D. Data Safety and Monitoring Board (DSMB) --------------------------------------------  
27 
E. Event Adjudication Committee (EAC) ---------------------------------------------------  
27 
F. A description of the measures taken to minimize/avoid bias -------------------------  
27 
G. A description of study treatments, the dosage and the dosage regimen of the 
investigational product ----------------------------------------------------------------------  
29 
H. Expected duration of subject participation -----------------------------------------------  
30 
I. 
Description of the “stopping rules” or “discontinuation criteria” --------------------  
30 
J. Accountability procedures for investigational products -------------------------------  
31 
K. Maintenance of trial treatment randomization codes and procedures for breaking 
codes -------------------------------------------------------------------------------------------  
31 
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 ----------------  
31 
V. 
Selection and Withdrawal of Subjects ------------------------------------------------------  
31 
A. Subject inclusion criteria -------------------------------------------------------------------  
31 
B. Subject exclusion criteria -------------------------------------------------------------------  
33 
C. Subject withdrawal criteria and procedures specifying --------------------------------  
35 
VI. 
Treatment of subjects---------------------------------------------------------------------------  
35 
A. Treatments to be administered -------------------------------------------------------------  
35 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 3 of 51 
Section 
Page 
1. Screening ---------------------------------------------------------------------------------  
36 
2. Baseline Evaluation and Randomization --------------------------------------------  
36 
3. Study Start Date/Optimizer Implantation -------------------------------------------  
39 
4. Week 2 Follow-up Visit------------------------------------------------------------- 
39 
5. Weeks 12 and 24 Follow-up Visits ----------------------------------------------- 
40 
6. Post Study Follow-up --------------------------------------------------------------- 
40 
7. Device retrieval in case of subject death ----------------------------------------- 
41 
B. Medications/treatments permitted (including rescue medication) and not 
permitted before and/or during the trial --------------------------------------------------  
41 
C. Procedures for monitoring subject compliance------------------------------------------  
41 
VII. 
Assessment of efficacy --------------------------------------------------------------------------  
41 
A. Specifications of efficacy parameters  ----------------------------------------------------  
41 
B. Methods and timing for assessing, recording and analyzing efficacy parameters -  
42 
VIII. 
Assessment of safety ----------------------------------------------------------------------------  
42 
A. Specification of safety parameters --------------------------------------------------------  
43 
B. Serious, Device Related and Unanticipated Adverse Event Definitions ------------  
43 
C. Procedures for recording and reporting adverse events and intercurrent illnesses-  
43 
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 and justification of sample 
size ---------------------------------------------------------------------------------------------  
44 
1. Primary efficacy analysis --------------------------------------------------------------  
44 
2. Primary safety analysis-----------------------------------------------------------------  
47 
3. Other efficacy analyses ----------------------------------------------------------------  
47 
B. Number of subjects planned to be enrolled ----------------------------------------------  
48 
C. Study Termination ---------------------------------------------------------------------------  
48 
D. Procedure for accounting for missing, unused and spurious data --------------------  
48 
E. Procedures for reporting deviations from the original statistical plan ---------------  
49 
F. Selection of subjects to be included in the analyses ------------------------------------  
49 
X. 
Direct access to source/data documents ----------------------------------------------------  
49 
XI. 
Quality control and quality assurance ------------------------------------------------------  
49 
XII. 
Ethics -----------------------------------------------------------------------------------------------  
49 
XIII. 
Data handling and record keeping ----------------------------------------------------------  
50 
Appendix A: CCM References 
 
 
Appendix B: Informed Consent template / HIPAA template 
 
 
Appendix C: Template Case Report Forms 
 
 
Appendix D: Device-device Interaction Testing Procedure 
Appendix E: Follow-up of Subjects enrolled during the FIX-HF-5B Protocol 
 
 
 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 4 of 51 
 
 
CLINICAL INVESTIGATION PLAN 
 
I. 
TITLE 
Evaluation of the Safety and Efficacy of the OPTIMIZER® System in Subjects with 
Moderate-to-Severe Heart Failure with Ejection Fraction between 25% and 45%: FIX-
HF-5C  
II. 
BACKGROUND INFORMATION 
A. 
Name and description of investigational product  
The investigational product is the OPTIMIZER IVs 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 four major components: 
1. 
An implantable pulse generator with specialized internal components that 
generate the cardiac contractility modulation (CCM) signal (the OPTIMIZER IVs 
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.   
NOTE: For purposes of this study, any commercially available atrial lead can be 
used.  For the ventricular sensing and CCM delivery leads, the following leads 
may be used: 
 Biotronik Setrox S45, S53 and S60 lead  
 Boston Scientific Dextrus 4135, 4136 and 4137 lead  
 St. Jude Tendril DX 1688T, 1788T, 1888 or 2088  active fixation lead  
 or others as qualified by Impulse Dynamics and approved by FDA   

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 5 of 51 
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 (OMNI II Programmer); 
4. 
A battery charging system, consisting of a charger unit and wand (Mini 
Charger);   
 
The OPTIMIZER IVs is very similar in its design, and is substantially equivalent, to the 
OPTIMIZER III System with regard to its intended use, safety, performance, and design 
characteristics. The design of the OPTIMIZER IVs includes several differences intended 
to offer physicians and patients a smaller IPG, a portable charger and an easier to use 
programmer. Despite these differences the critical aspects of the device design (the device 
algorithms, sensing signals, CCM signal outputs and functionality) all remain identical. 
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, 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 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 6 of 51 
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 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 OPTIMIZER 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 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 7 of 51 
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.  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 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 8 of 51 
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 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. 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 9 of 51 
(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 
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.   

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 10 of 51 
The data indicated that subject symptoms improved during the study.  From Class 
III at entry, NYHA class decreased in three 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 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) 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 11 of 51 
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 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.   

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 12 of 51 
(5)    Prospective, multicenter, randomized double blind study of CCM: the FIX-
CHF-4 study (Europe)  
A multicenter, randomized, double-blinded study (FIX-CHF-4) was 
conducted to evaluate the safety and effectiveness of the OPTIMIZER II and 
OPTIMIZER III systems in subjects with New York Heart Association 
(NYHA) class II and III heart failure. A total of 164 subjects with ischemic 
(60%) or idiopathic (40%) cardiomyopathy, EF<35%, NYHA Class II (24%) 
or III (76%) received a CCM pulse generator. Patients were randomly 
assigned to Group 1 (n=80, CCM treatment 3 months, sham treatment second 
3 months) or Group 2 (n=84, sham treatment 3 months, CCM treatment 
second 3 months). The co-primary endpoints were differences between 
groups of changes in peak oxygen consumption (VO2 peak) and Minnesota 
Living with Heart Failure Questionnaire (MLWHFQ). 164 subjects with 
ejection fraction <35% and NYHA Class II (24%) or III (76%) symptoms 
received a CCM pulse generator. Baseline EF (29.3±0.9% vs. 29.8±1.12%), 
peak oxygen consumption (VO2,peak, 14.1±0.3 vs. 13.6±0.3 ml/kg/min) and 
Minnesota Living with Heart Failure Questionnaire (MLWHFQ, 38.4±2.1 
vs. 36.5±2.11) were similar in both groups. For VO2,peak and MLWHFQ, a 
statistically significant benefit was noted during periods of active treatment 
compared to sham treatment. The mean improvement in patients’ VO2,peak 
during the periods of active treatment was 1.03  2.78 (p=0.03 via t-test) with 
95% confidence interval of (0.09, 1.98).  For MLWHFQ, mean improvement 
during patients’ active treatment was 5.85  16.03 (p=0.03 via t-test) with 
95% confidence interval of (0.59, 11.11).   
There were 6 deaths during the study, two prior to randomization (ventricular 
fibrillation and worsening heart failure), one in Group 1 during the OFF 
period (undetermined cause), one in Group 2 during the OFF period and two 
in Group 2 during the ON period (sudden cardiac death and renal failure).   
In total, there were 48 serious adverse events in 40 patients during CCM OFF 
periods, compared to 45 serious adverse events in 41 patients during CCM 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015 
 
Page 13 of 51 
ON periods.  The most frequently reported events were episodes of 
decompensated heart failure, atrial fibrillation, bleeding at the OPTIMIZER 
System implant site and pneumonia.  There were no significant differences 
between ON and OFF phases in the number or types of adverse events.  
Adverse events specifically related to the device and/or the procedure as 
reported by the investigators included lead dislodgement, device pocket 
infections, bleeding at the insertion site and pericardial effusion.  
Investigators listed several other events as being of “unknown” relationship 
to the device and/or procedure, including atrial fibrillation, episodes of heart 
failure exacerbations, cardiogenic shock, angina, ventricular tachycardia and 
ICD sensing defect. 
Because of the crossover design, hospitalizations and mortality were 
analyzed for the first period only.  In all there were 14 hospitalizations Group 
1 patients (CCM ON phase) compared to 20 hospitalizations in Group 2 
patients (CCM OFF phase).  In addition there was 1 death in a Group 2 
patient versus no deaths in Group 1 patients.  With the relatively small sample 
size the overall event-free survival did not reach statistical significance 
(p=0.31).   
Another safety endpoint in the study was an evaluation of whether the use of 
the OPTIMIZER Systems was associated with changes in the incidence and 
nature of arrhythmias assessed by Holter monitoring.  At baseline, the total 
number of PVCs/hour was balanced between groups with median (range) 
values of 21 (0-511) and 25 (0-712) in Groups 1 and 2, respectively.  During 
ON periods, there was a median of 20 (0-777) and 17 (0-459) PVCs/hour in 
Groups 1 and 2, respectively, compared to 16 (0-1007) and 15 (0-764) during 
the OFF periods.  In addition, there were no significant differences in other 
Holter parameters between baseline and follow up in either group.   
Overall, the results of this study suggested that the device improves quality 
of life and exercise tolerance and appears safe when used over 3 months time. 
(6) 
US Feasibility IDE Trial: The FIX HF-5, Phase I Study (US) 

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Study ID CP OPT2009-009 
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 Protocol version September 25, 2015 
 
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On May 6, 2004, the FDA granted conditional approval for human trials to 
begin in the United States. The US Feasibility Study (also referred to as the 
Phase I Study) was designed to evaluate the safety and effectiveness of the 
OPTIMIZER II System with active fixation leads in subjects with moderate 
and severe heart failure.  The investigation was designed as a multi-center, 
randomized, double-blind study at 10 sites nationwide.  This was a 
randomized, double blind pilot study of the safety and efficacy of CCM in 
heart failure patients with normal QRS duration. Methods:  49 subjects with 
medically refractory NYHA Class III symptoms were successfully implanted 
with a CCM pulse generator and two leads inserted into the RV septum.  
Forty-nine (49) subjects were randomized to have their devices programmed 
to deliver CCM signals (Treatment, n=25) or to remain off (Control, n=24) 
for 6 months.  Evaluations (double blind) included 6-minute hall walk, 
echocardiography, cardiopulmonary stress test and Minnesota Living with 
Heart Failure Questionnaire (MLWHFQ).  Results:  Although most baseline 
features were balanced between groups, ejection fraction (31.4±7.4 vs. 
24.9±6.5%, p=0.003) and peak VO2 (16.0±2.9 vs. 14.3±2.8 ml O2/kg/min, 
p=0.02) were lower in the Treatment group versus the Control.  Nevertheless, 
freedom from hospitalization at 6 months was 65 vs. 80% in Control vs. 
Treatment.  Freedom from death was 100% in both groups at 6-months.  
Compared to baseline, 6MW increased 13.4 meters, peak VO2 increased 0.2 
ml O2/kg/min and anaerobic threshold increased 0.8 ml O2/kg/min more in 
the Treatment group than the Control group.  With the small number of 
subjects none of the differences were statistically significant.  Conclusions:  
Even though the Treatment group was sicker at baseline, event-free survival, 
adverse event profiles and measures of effectiveness trended to be better in 
the treatment group.  These results warrant large scale studies of safety and 
effectiveness of CCM.   
(7) 
 US Pivotal IDE Trial:  The FIX HF-5 Phase II Study (US) 

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Study ID CP OPT2009-009 
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 Protocol version September 25, 2015 
 
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The US Pivotal Trial (also referred to as the Phase II Study) was conducted 
under an IDE granted by the FDA (G030099/S7).  This study tested safety and 
efficacy of CCM in 428 NYHA III or IV heart failure patients on optimal 
medical treatment (OMT) with EF≤35% (as quantified by site 
echocardiographers) and narrow QRS randomized to CCM plus OMT 
(n=215) or OMT alone (n=213). Efficacy was assessed by anaerobic threshold 
(AT, primary endpoint), peak VO2 (pVO2) and Quality of Life (QoL) score at 
6 months; total follow up was 12 months. The primary safety endpoint was a 
test of noninferiority between groups at 12 months of the composite of all-
cause mortality and all cause hospitalizations (12.5% allowable delta).  The 
groups were matched for age (56±14 vs 59±12 yrs), EF (27±6 vs 26±7%), 
pVO2 (14.6±3.3 vs 14.8±3.0 ml/kg/min) and all other characteristics. While 
AT did not improve at 6 months, pVO2 and QoL were improved by CCM (by 
0.65 ml/kg/min, p=0.024 and -9.7 points, p<0.0001, respectively) over OMT. 
48% of OMT and 52%of CCM patients experienced a safety endpoint, which 
satisfied the non-inferiority criteria (p=0.03). In patients with EF≥25% (as 
determined by the echo core lab) and NYHA III (n=185), AT (0.64 ml/kg/min, 
p=0.03), pVO2 (1.31 ml/kg/min, p=0.001) and QoL (10.8 points, p=0.003) 
improved more in the CCM group. Findings were similar at 12 months and 
results of responders analyses applied to all variables were also significant 
(p<0.01) in this group.  Furthermore, when peak VO2 was analyzed as a 
continuous variable, it was observed that for patients with EF≥25% the 
treatment group experienced a statistically and clinically significant 
improvement over controls through 12 months, regardless of NYHA class 
(further details provided below in Statistical Analysis section).  Thus, the 
study showed that when used in patients with narrow QRS and NYHA Class 
III or IV symptoms on OMT, CCM is safe and improves pVO2 and QoL at 6 
months. In the prespecified subgroup analysis, CCM appeared more effective 
in patients with EF≥25% as evidence by significant improvements in pVO2 at 
6 months, findings that were sustained through 12 months. 

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Furthermore, subjects were deemed eligible and enrolled based on the site 
assessment of EF, but since each study was also assessed in an 
echocardiographic core lab, it turned out that 38 of the study subjects (20 in 
OMT and 18 OMT+CCM) had EFs greater than 35% per core lab assessment.  
For this subgroup, the EF average was 38±3% (range 35-45%) and did not 
differ between groups.  At the 6 month endpoint, peak VO2 increased by 
1.66+0.42 ml/kg/min in OMT+CCM versus a 1.30+0.73 ml/kg/min decrease 
in OMT, a difference of 2.96 mlO2/kg/min (p=0.03).  MLWHFQ decreased 
by 19±22 points in OMT+CCM versus 1±29 point in OMT, a mean difference 
of 18 points (p=0.06).  6MW increased by 43±80 meters in OMT+CCM 
versus a decrease of 10±97meters in OMT, a mean difference of 53 meters 
(p=0.11).  The results of this additional hypothesis generating subgroup 
analysis indicate that CCM has the potential to provide clinically significant 
benefits in patients with medically refractory CHF with EF between 35 and 
45%.   
In aggregate, the results of prior studies suggest that the OPTIMIZER System 
functions as intended and preliminary evidence suggests that CCM therapy 
could provide clinical benefit especially in a subset of subjects with ejection 
fraction ≥25%.   
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. 
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 

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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. Invasive aspects and the associated risks of 
the OPTIMIZER implant procedure and device system are described 
below. Additionally, there may be an increased risk of death associated 
with the application of cardiac contractility modulation therapy. Applying 
appropriate subject selection criteria, using meticulous techniques and 
providing attentive post-procedure care will minimize the risks associated 
with these procedures. 
b. 
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. 
c. 
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.   

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d. 
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.   
e. 
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.  
f. 
Thromboembolic Events 
Thrombosis or embolism may occur as a result of the placement of the 
leads for the OPTIMIZER System or as a result of the underlying disease.  
These events may include deep vein thrombosis, renal vein thrombosis, 
pulmonary embolism, transient ischemic attacks (TIA), stroke, 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. 
g. 
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.     
h. 
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 

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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. 
i. 
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 or even cardiac tamponade.  This risk 
can be minimized by using appropriate, standard insertion techniques by 
experienced operators. 
j. 
Vascular laceration and bleeding 
There is a risk of vascular laceration and bleeding as a result of the implant 
procedure.  This may include bleeding in the pulse generator pocket.  This 
risk can be minimized by using appropriate surgical technique. 
k. 
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. 
l. 
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.   
m. 
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 

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ICD leads are used and when both devices are programmed properly.  To 
minimize this risk, all personnel involved with programming the 
OPTIMIZER device are appropriately trained in proper device 
programming. 
n. 
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).   
o. 
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 improved exercise 
tolerance, fewer symptoms of heart failure and increased overall quality 
of life.   
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 

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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 (7.5V) 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 and Phase II of the FIX-HF-5 
studies utilized an intermediate dose of 5 hour/day signal delivery paradigm.  Since the 
safety profile during Phase I and Phase II of the study has been clinically acceptable and 
for consistency, the present study shall continue to use the 5 hour/day dose.   
 
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 other 
region-specific 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 

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investigation will be representative of the patient population with stable, moderate-to-
severe heart failure receiving optimal medical therapy that are most likely to benefit from 
application of CCM signals.  The population is generally characterized by NYHA Class 
III and IV symptoms, an ejection fraction between 25 and 45% (inclusive) and peak VO2 
between 9 and 20 ml O2/kg/min.   
 
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 medically refractory 
moderate-to-severe heart failure characterized by an ejection fraction between 25% and 
45% and peak VO2 between 9 and 20 ml O2/kg/min.  Safety and effectiveness endpoints 
are provided in Section IV below. 
 
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 24 weeks following the date of scheduled implantation, shall consist of the 
following parameter: 

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Improvement in exercise tolerance quantified by peak VO2 measured on 
cardiopulmonary exercise stress testing (CPX) and evaluated by a blinded core 
lab.  The primary endpoint will be a comparison of mean changes from baseline 
to 24-weeks between control and treatment groups. 
2. 
Secondary efficacy endpoints 
a.  
Improvement in quality of life, as assessed by the Minnesota Living with 
Heart Failure (MLWHF) Questionnaire. 
b. 
Comparison of mean changes in peak VO2 between groups with change in 
respiratory exchange ratio (RER) included as a covariate in the analysis. 
c.   
Improvement in heart failure class, as assessed by the New York Heart 
Association (NYHA) classification.  NYHA classification shall be assigned 
by a blinded on site clinician according to their standard clinical practice.  
The analysis of this endpoint will test that hypothesis that the subjects 
treated with the OPTIMIZER will have a greater proportion of subjects that 
improve by at least one NYHA category than the control group.    
d. 
Comparison of mean change in peak VO2 between groups in an analysis that 
only includes tests with a peak RER of ≥1.05 
3. 
Other efficacy endpoints 
a. 
Comparison of mean change in 6 minute hall walk test between baseline and 
24 weeks 
b. 
Comparison of mean change in VE/VCO2 between baseline and 24 weeks 
as measured on a cardiopulmonary stress test.  
4. 
The primary safety endpoint of this trial shall be: 
 
The proportion of subjects experiencing an OPTIMIZER device- or procedure-
related complication through the 24-week follow up period, as determined by an 
independent events committee (Section IV.E.).  Satisfying the primary safety 
endpoint will require demonstrating that the complication-free proportion is 
significantly higher than 70% (using a one-sided significance level of 0.025). 
5. 
Other safety endpoints of this trial will be: 

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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 composite rate of all-cause mortality and all-cause hospitalizations 
d. 
the composite rate of cardiovascular mortality and heart failure-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.  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. 
 
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 230 subjects with symptomatic 
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 subjects will be followed for 24 weeks (Figure 1).  Evaluation of 
subjects will be documented on electronic case report forms and will include the tests and 
procedures listed in Table 1.  The details of the Schedule of Events are provided in 
Section VI.A. 

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Figure 1.  Study Overview
Baseline
Tests
Eligible
Random-
ization
Device Implant
Continued Medical
Therapy
6 Months
Visit 
(primary Safety 
and Eficacy)
3 Months
Visit
Continued
Follow-up
Scheduled 
Implant Date =
Study Start Date

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Table 1.  Schedule of Events 
 
 
 
 
Follow-Up Schedule  
(relative to Study Start Date§) 
Long-term F-up Every 6 Months**  
(relative to Study Start Date§) 
Test or Assessment 
Screening 
Baseline 
OPT 
Implant 
Week 2  
±2 days§ 
+12±2 
Weeks 
+24±2 
Weeks 
US 
Optimizer 
Group 
US 
Control 
Group 
EU OPT 
and 
Control  
Informed Consent 
X 
 
 
 
 
 
 
 
 
1-Year Medical History/Interim History 
X 
  
  
X 
X 
X 
X 
 
 
NYHA Class (blinded site clinician assessment) 
X 
  
  
 
X 
X 
 
 
 
Medications 
X 
  
 
 
X 
X 
 
 
 
Physical Examination 
X 
  
 
 
X 
X 
 
 
 
12-Lead EKG* 
 
X 
 
 
 
 
 
 
 
24 hour Holter Monitor* 
  
X 
  
 
 
 
 
 
 
Echocardiogram* 
  
X 
  
 
 
 
 
 
 
MLWHFQ 
  
X 
  
 
X 
X 
 
 
 
Cardiopulmonary Stress Test 
  
2X 
  
 
2X 
2X 
 
 
 
6 Minute Walk Test 
 
X 
 
 
 
X 
 
 
 
Pregnancy test  
  
X 
  
 
 
X 
 
 
 
Eligibility determination 
  
X 
  
 
 
 
 
 
 
Randomization 
  
X 
 
 
 
 
 
 
 
OPTIMIZER System Implant 
  
  
X 
 
 
 
 
 
 
Chest X-ray (prior to hospital discharge) 
  
  
X 
 
 
 
 
 
 
OPTIMIZER Device Interrogation / 
Programming 
  
  
X 
X 
X 
X 
X 
 
 
Adverse Events, Hospitalizations, and 
Procedures (as needed)/OPTIMZER device-
related SAEs after 24-weeks 
  
X 
X 
X 
X 
X 
X 
 
 
Vital Status  
 
 
 
 
 
 
X 
X 
X 
 § Study Start Date (SSD):  After completion and satisfying all entry criteria and prior to randomization, a date shall be scheduled for OPTIMIZER 
System implantation.  This date shall serve as the start date for all subjects regardless of randomization assignment, from which all future follow-
up visits are scheduled.  
* 12-Lead EKG, 24-Hour Holter Monitor, and Echocardiogram test results (from the study-qualified lab) obtained within 30 days before informed 
consent and performed in accordance with the protocol, testing, and data collection requirements may be used for eligibility determination. 
** US OPTIMIZER subjects are followed every 6 months (+/- 4 weeks) after the 24-week interval for device interrogation and reporting of 
OPTIMIZER Device related SAEs, if any. All other subjects are followed for vital status only, for 2 years following their SSD.

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C. 
Anticipated Rate of Site and Patient Recruitment 
Two hundred and thirty (230) study participants will be recruited from a maximum of 60 
study sites over a period of approximately 2 years from study initiation.  No site will be 
allowed to enroll more than 15% (35 subjects) into the study. 
 
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 independent 
physicians and statisticians not otherwise affiliated with the study.  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 events.  The classification shall include whether the 
event is related to either the OPTIMIZER device or to the OPTIMIZER procedure, and 
whether such an event constitutes a “complication” as defined by the Event Adjudication 
Committee.  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 subject 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.  
1. 
Site selection 

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The trial will be a multi-center study, with up to 60 clinical sites located in the 
United States and in Europe.  A minimum of 115 subjects will be enrolled in the 
US; it is anticipated that approximately 30-50% of the subjects will be recruited 
from European sites.   
3. 
Randomization 
Subjects will be randomly assigned to one of two treatment groups with an 
allocation ratio of 1:1.  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. 
4. 
Objective Primary Efficacy Endpoint 
The primary efficacy endpoints of this study are chosen to provide as objective, 
reliable and practical as possible assessments of clinical and physiologic 
improvements.  With regard to the physiologic assessment, peak VO2 shall be 
used to assess efficacy.  In order to minimize bias, , the subject will complete 2 
tests at each time point and testers will be trained on how to ensure that subjects 
exercise to maximal effort.  The blinded core laboratory will review the raw data 
of each and every test for quality and adequacy of testing requirements.  
1.   In order for a subject to be randomized, they must complete 2 baseline CPX 
tests. If the blinded core lab deems one of the two tests “inadequate”, the data 
from the one “adequate” test shall be used for eligibility determination and 
final analysis.  
2.    Randomized subjects are required to complete two CPX tests at 12 weeks and 
two CPX tests at 24 weeks, also. If the subject refuses or is unable to complete 
one of the two tests, or if the core lab deems one of the two tests “inadequate”,  
the data from the one “adequate” test shall be used for the final analysis.  In 
cases where data from both tests are available, the values will be averaged and 
the resulting value will be used for data analysis.  
3.   Only tests deemed “adequate” by the blinded core lab will be used for study 
eligibility and study endpoint analyses. 
4.   The core lab can deem a test “inadequate” for any one of the following reasons: 

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a.  the subject has an erratic or oscillatory breathing pattern  
b.   data is non-physiologic 
c.   testing equipment issues 
d.   the test is submaximal 
4. 
Core Laboratories 
A Core laboratory shall be used to analyze results of cardiopulmonary exercise 
tests and echocardiograms.  All analyses shall be performed blinded to treatment 
assignment.  Standard operating procedures (SOPs) for the core laboratory 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.  
 
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 24 weeks of the study, with a schedule of one hour ON and three hours 
48 minutes OFF.     

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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 (US requirement only), and that protects the device under 
normal conditions of shipping and handling.  The leads will retain their 
commercial packaging and labeling. 
 
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 7 months.  This will include approximately one month for screening 
and baseline testing and a 24 week primary follow-up period.  Following completion of 
the main portion of the study:  
 Subjects with an OPTIMIZER device in the US shall continue to be followed 
clinically at 6 month intervals until the FDA has made a determination about the 
safety and efficacy of the device.   
 All other subjects (US Control group and all non-US subjects) shall be followed 
for vital status only, every 6 months, until the 2 year vital status has been 
determined.  
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 

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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 in the United States will be trained in the importance of 
accountability of investigational products.  Impulse Dynamics engineers will install any 
OPTIMIZER System hardware required for the implant procedures and follow-up visits 
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 complete the IDE Device 
Accountability Log for the IPG investigational components.  Site clinical representatives 
will complete the IDE Device Accountability Log for all other investigational products 
including the OMNI II programmers, chargers, and Test Device Extension cables shipped 
to, used at, or returned from the clinical site. 
 
K. 
Maintenance of trial treatment randomization codes and procedures for breaking 
codes. 
Trial treatment randomization codes are pre-programmed into the Medidata EDC site. 
There are no procedures for breaking the codes as this is not a blinded clinical trial. 
 
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 (eCRF).  
A listing of the case report forms is located in Appendix C.  A separate source document 
should be available for each eCRF.   
 
V. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Two hundred and thirty (230) 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 

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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.   
3. 
Condition 
a. 
Subjects who have a baseline ejection fraction greater than or equal to 
25% and less than or equal to 45% by echocardiography determined by 
the echocardiography core laboratory.  
NOTE: Echocardiograms performed within 30 days before patient 
informed consent may be used to determine study eligibility if the test was 
performed in accordance with the Echo Study SOP at the study-qualified 
echo laboratory. 
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 subject 
is intolerant) and are in New York Heart Association functional Class III 
and 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 according to the region-
specific guideline recommendations. For patients with EF≤35%, this 
regimen shall consist of the appropriate doses of diuretics, ACE-inhibitor 
or angiotensin II receptor blocker and -blocker1.  Ivabradine may also be 
considered in subjects with a heart rate >70bpm.2 Stable is defined as no 
more than a 100% increase or 50% decrease in dose. 
                                                         
1 The appropriate medical regimen for each subject will be determined by the care provider managing the patient. 
One or more of the “guideline-recommended" medications may not be appropriate for all patients (e.g. intolerance, 
allergy). In particular the use of diuretics is most often used for symptomatic relief, therefore in absence of 
symptoms, a diuretic may not be part of the optimal medical regimen. The use of ACE-I or ARB, beta-blocker, 
aldosterone antagonist, and diuretic should be considered in all subjects, however "appropriate" doses of these 
medications may be zero. 
2 Ivabradine should only be initiated after a stabilisation period of 4 weeks on optimised standard therapy with 
ACE inhibitors, beta-blockers and aldosterone antagonists.  
http://www.servier.co.uk/pdfs/NICE_Guidance_20130617.pdf 
 

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d. 
Subjects who, in the opinion of the Principal Investigator (based on the 
current guidelines for clinical practice3), have a clinical indication for an 
implanted cardiac defibrillator (ICD, e.g., EF≤35%) 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. 
NOTE: ICD implantations, when indicated in accordance with 
Investigator assessment, should be implanted prior to informed consent 
when reasonably possible. However, in the case where the indication for 
the device is only appreciated after informed consent, it must be implanted 
prior to study randomization. Use of the Core Lab LVEF evaluation is not 
required when determining ICD indication. 
e. 
Subjects who are willing and able to return for all follow-up visits. 
 
B. 
Subject exclusion criteria 
1. 
Subjects whose baseline peak VO2 is <9 or >20 ml O2/min/kg. 
NOTE: Each CPX test deemed “adequate” by the Core Lab (one or both) must 
meet the eligibility criterion. 
2. 
Subjects who have a potentially correctible cause of heart failure, such as valvular 
heart disease or congenital heart disease.  
NOTE: This exclusion relates to Mitral Valve Regurgitation as the cause of the 
heart failure. In the event that the physician decides to implant a MV Clip, the 
subject many not be evaluated for the protocol until a minimum of 90 days after 
the procedure.  
3. 
Subjects who have clinically significant angina pectoris, consisting of angina 
during daily life (i.e., Canadian Cardiovascular Society Angina score of II or 
more), an episode of unstable angina within 30 days before enrollment, or angina  
                                                         
3 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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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 before 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.4 
NOTE: 24-Hour Holter monitoring performed within 30 days before patient 
informed consent may be used to determine study eligibility. 
6. 
Subjects having a PR interval greater than 375 ms. 
NOTE: An ECG performed within one month before patient informed consent 
may be used to determine study eligibility. 
7. 
Subjects who have chronic (permanent or persistent) atrial fibrillation or atrial 
flutter or those cardioverted within 30 days of enrollment. 
NOTE: Subjects cardioverted into normal sinus rhythm must be free of atrial 
tachyarrhythmias for a minimum of 30 days before patient informed consent. 
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 perform baseline stress testing. 
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, an accepted indication for such 
a device, or a QRS width of 130ms or greater.    
NOTE: An ECG performed within 30 days before patient informed consent may 
be used to determine study eligibility. 
                                                         
4 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.     
5. Holter readings less than 24 hours (eg., 20-24 hours) may be used to confirm protocol eligibility when the # of PVCs is such that 
extrapolation to 24 hours can reasonably predict a PVC burden less than 8,900 per 24 hours. 

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11. 
Subjects who have had a myocardial infarction within 90 days of enrollment. 
12. 
Subjects who have mechanical tricuspid valve. 
13. 
Subjects who have a prior heart transplant. 
14. 
Subjects on dialysis. 
15. 
Subjects who are participating in another experimental protocol. 
16. 
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 or Ethics Committee 
approved Informed Consent Form.  All subjects who sign Informed Consent will be 
accounted for in the final report of this study.  Subjects may be withdrawn from the study 
for the following reasons: 
a. 
Voluntary decision to withdraw made by the subject. Options for a reduced level of 
participation will be discussed with randomized subjects prior to a decision to 
completely withdraw, if possible. 
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 or circumstance 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 to ascertain their vital status for 2 years following their study start date. Every 
effort will be made to follow all subjects in both cohorts to assure as complete a data set 
as possible for the 24-week study period. 
 
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 for the U. S. sites is located 

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in Appendix B; this document includes a proposed form to authorize making 
information available for the purpose of clinical research in compliance with US 
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 patient privacy laws.  For 
each subject, a medical history (inclusive of collecting 1-year pre-randomization 
history of hospitalizations), physical examination, demographic information and 
current usage of medications will be obtained. 
2. 
Baseline Evaluation and Randomization 
Baseline testing should not be initiated until the subject has been treated for heart 
failure for at least 90 days, and heart failure medications have been stable for a 
minimum of 30 days as outlined in section V.A.3.   
All enrolled subjects will complete a Minnesota Living with Heart Failure 
Questionnaire and undergo an NYHA assessment, ECG, echocardiogram, 6 
minute hall walk test (6MW), two cardiopulmonary stress tests (CPX, which shall 
include assessment of peak VO2, peak RER and VE/VCO2) and a 24-hour Holter 
monitor test (for assessment of the number PVCs).   
Baseline testing details: 
1. An echocardiogram performed within 30 days before informed consent may 
be used as the baseline test and protocol eligibility determination if the 
following criteria can be confirmed: 
o The echo was performed in accordance to the Echo SOP at a lab certified 
for the FIX-HF-5C Study, and 
o The patient was receiving optimal and stable heart failure medications as 
of the date the echo study was performed, and continues to be optimal and 
stable at the time of informed consent, and 
2. A 24-hour Holter test performed within 30 days before informed consent may 
be used as the baseline test and protocol eligibility determination. 
3. An ECG performed within 30 days before informed consent may be used as 
the baseline test and protocol eligibility determination. 

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4. The CPX test will be performed twice, with the second test being performed 
between 1 day (24 hours) and 7 days following the first test.   
5. The 6MW and CPX tests may be performed on the same day, but must be 
performed a minimum of 3 hours apart, with the CPX test performed first.  
6. Females of childbearing potential will undergo a pregnancy test within 7 days 
of the schedule implantation procedure. 
Randomization 
If the results of the baseline tests indicate that the subject is eligible for 
participation, a device implantation date shall be scheduled.  The scheduled 
implant date shall serve as the Study Start Date (SSD) for all subjects.  The subject 
shall then be randomized to one of two groups:   
a. 
Treatment Group, in which case the subject shall undergo device 
implantation on the scheduled implant date.  These subjects shall go on to 
receive CCM treatment for 24 weeks as detailed below.   
b. 
Control Group, in which case the subject will be followed with continued 
medical therapy for 24 weeks.  For subjects randomized to the Control 
group, the scheduled implant date shall be cancelled but will still serve as 
the SSD. 
3. 
Study Start Date/Optimizer Implantation 
a. 
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. 
b. 
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.     

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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 
position and the other in the posterior position 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 
position with a separation of at least ~2 cm.   
Leads that are in place in subjects with a prior ICD and/or pacemaker 
implant will continue to be used for those devices, and may not be 
connected to the OPTIMIZER system.  To ensure that the OPTIMIZER 
System does not interfere with proper functioning of the ICD or 
pacemaker, these devices shall be interrogated during application of CCM 
signals according to the device interaction testing procedure outlined in 
Appendix D.  The main mechanism 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. 
c. 
Predischarge (for Treatment Subjects) 
When each of the implanted subjects is stable and suitable for hospital 
discharge, he or she will undergo a chest X-ray after the implantation and 
prior to hospital discharge and according to hospital policy to rule out 
pneumothorax and to evaluate lead placement.   

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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 
subject has a pacemaker or defibrillator implanted, the pacemaker 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.  At the discretion of the Investigator, the 
subject may be observed for an additional amount of time with CCM 
activated in the hospital prior to discharge. 
Prior to discharge, subjects will be introduced to the battery charging 
system and provided a comprehensive overview on the use of this 
equipment.     
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. 
4. 
Week 2 Follow-up Visit 
At 2 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 and an assessment for the occurrence of 
adverse events.  For subjects randomized to the treatment arm, the OPTIMIZER 
generator will be interrogated to confirm proper functioning and parameters shall 
be adjusted as needed.  In addition, the OPTIMIZER interrogation will include an 
assessment of the subject’s compliance with battery charging to maintain CCM 
therapy ON. These subjects will also be further educated on the use of the 
OPTIMIZER System charger. 
5. 
Weeks 12 and 24 Follow-up Visits 
All subjects will return for follow-up at weeks 12 and 24 following the SSD.  Each 
visit shall include an interim medical history, a medication review, a physical 
examination, an NYHA classification (blinded assessment), two CPX tests, a 
MLWHFQ, and an OPTIMIZER interrogation (for subjects with the device).  The 

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OPTIMIZER interrogation will include an assessment of the subject’s compliance 
with battery charging to maintain CCM therapy ON.  The CPX test will be 
performed twice during both the 12 week and 24 week intervals, with the second 
test being performed between 1 day (24 hours) and 7 days after the first test.  At 
24 weeks, subjects will also undergo a 6MW test.  The 6MW and CPX tests may 
be performed on the same day, but must be performed a minimum of 3 hours 
apart, with the CPX test performed first. 
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. 
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 visit.  If a subject randomized to device treatment 
becomes pregnant the device will be turned off.  Any study subject who becomes 
pregnant will continue to be followed for evaluation of safety endpoints.  
6. 
Post Study Follow-Up 
Following the 24 week follow up visit, all subjects in the Control group and 
Treatment group subjects enrolled in Europe shall resume routine follow-up from 
their primary care providers and shall be discontinued from further active 
participation in the study.  However, subjects will be contacted at ~6 month 
intervals to ascertain their vital status for up to 2 years from the SSD.   
Subjects enrolled in the Treatment group in the United States can continue to 
receive CCM therapy and shall be seen at ~6 month intervals at the investigational 
site until FDA has made a determination of device safety and efficacy.  These 
follow-up visits shall include a medical history, OPTIMIZER device interrogation 
and reporting of any OPTIMIZER device-related serious adverse events and 
deaths.  In the event that the study is terminated prior to approval, or at the request 
of the subject, the device can be removed.  Alternatively, the device can be left in 

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place and deactivated; in this case, the device charger would be retrieved from the 
subject in order to eliminate the possibility of further use of the device. 
7. 
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 OPTIMIZER device.  In such cases, 
the device shall be shipped to the sponsor where it shall be inspected and 
interrogated. 
 
B. 
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. 
 
C. 
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 peak VO2 as assessed by cardiopulmonary stress test as evaluated by a 
blinded core lab.  Subjects shall undergo 2 tests at each time point (baseline, 12 weeks 
and 24 weeks) and the average at each interval shall be the value used in the primary 
analysis.  If only one test is performed or meets testing requirements for a particular 
interval, that single value shall be used in the analysis. 
The secondary efficacy parameters shall include: 
 Change in Quality of Life, as assessed by the Minnesota Living with Heart Failure 
Questionnaire 

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 Comparison of mean changes in peak VO2 between groups with change in respiratory 
exchange ratio (RER) included as a covariate. 
 Change in heart failure class, as assessed by the New York Heart Association 
(NYHA) classification.  NYHA classification shall be assigned by the blinded site 
clinician according to their standard clinical practice. 
 Comparison of mean change in peak VO2 between groups that only includes tests on 
which RER is ≥1.05 
Other efficacy parameters shall include: 
 Comparison of mean changes in 6 minute hall walk test between baseline and 24 
weeks 
 Comparison of mean changes in VE/VCO2 measured on CPX between baseline and 
24 weeks. 
 
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 
baseline, 12 weeks and 24 weeks. 
 
VIII.  Assessment of safety 
A. 
Specification of safety parameters 
The safety of the OPTIMIZER System will be assessed by evaluating the incidence of 
OPTIMIZER device or procedure related complications (see section IX for statistical 
analysis).  The primary safety endpoint shall be the proportion of subjects without 
experiencing either an OPTIMIZER device-related complication or a procedure-related 
complication by 24 weeks.  The safety endpoint will considered to be met if the 
proportion of complication-free subjects is significantly larger than 70% (one-sided 
significance level of 0.025); equivalently, the safety endpoint will be met if the lower 
bound for the 95% confidence interval of the percent of subjects surviving without 
experiencing a primary safety event is not less than 70%.   

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Adverse events shall also be carefully recorded and compared between treatment and 
control groups.   
An adverse event is defined as any undesirable change from the subject’s baseline and 
usual health status (prior to their enrollment into the study) whether or not it is device or 
procedure related.  An adverse event includes device failures that adversely affect the 
subject and/or require an intervention to correct the failure.  
B.
Serious, Device Related and Unanticipated Adverse Event Definitions.
Adverse events that occur during this study may be associated with the OPTIMIZER
implant procedure, or specifically associated with the use of the OPTIMIZER 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 (UADE) 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, if that effect, problem, or death was not previously identified
in nature, severity, or degree of incidence in the investigational plan or application
(including a supplementary plan or application), or any other unanticipated serious
problem associated with a device that relates to the rights, safety, or welfare of subjects.
For purposes of the primary safety analysis, an OPTIMIZER device or OPTIMIZER
implantation procedure-related complication shall be any serious adverse event that is
related to the device or the procedure as classified by the Events Adjudication Committee.
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 or Ethics Committee (EC) (as/if required according to IRB or EC policy).  All device
malfunctions and serious adverse events, including, but not limited to events associated

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with prolongation of hospitalization, and/or a new hospitalization or death shall be 
reported to Impulse Dynamics within 24 hours after the Investigator learns of the event.  
Impulse Dynamics will report UADEs to the DSMB, FDA and all reviewing IRBs and 
ECs as required.    
After the 24-week study period, only deaths and OPTIMIZER device related SAEs shall 
be reported. 
 
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/Ethics 
Committee approval. 
 
IX. STATISTICAL CONSIDERATIONS 
A detailed description of the statistical methods, sample size justifications and 
justifications for safety and efficacy parameters are provided separately in the Statistical 
Analysis Plan (SAP).  Important features of the SAP are reviewed below. 
A.   
Description of the statistical methods to be employed and justification of sample size 
1. 
Primary efficacy analysis 
The primary efficacy analysis will compare differences in the change in peak VO2 
from baseline to 24 week follow-up visit between the Treatment and Control 
groups.  An intent-to-treat analysis based on a Generalized Mixed-Effects Model 
will constitute the primary analysis as detailed in the Statistical Analysis Plan.   
The general statistical hypothesis to be tested is: 
 
H0: βint ≤ 0  vs  HA: βint > 0 
 

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Where βint is the coefficient for the interaction of time and treatment group and 
represents the difference in mean change in peak VO2 24-weeks from baseline in 
the treatment vs. control groups.  As will be detailed in the next section, a 
Bayesian approach will be employed to take advantage of the significant amount 
of data available from the original FIX-HF-5 study.  Superiority of the treatment 
arm will be declared if the posterior probability that the mean change from 
baseline to 24-weeks in peak VO2 in the prospective trial is higher in the treatment 
group (i.e., βint>0) is 97.5% or higher, conditioned on the prospective data and the 
original FIX-HF-5 data. 
Hierarchical Bayesian Design for Borrowing Data from the Original FIX-HF-
5 Study for the Primary Efficacy Analysis 
As noted above, the original FIX-HF-5 study did not meet the primary 
effectiveness endpoint of showing superiority of probability of response for the 
treatment group compared to the control group (average ITT imputation result of 
38/215 = 17.7% Treatment responder versus 28/213 = 13.2% Control responder).   
However, in the subgroup of subjects with EF ≥ 25 subjects (which is the focus 
of the present study), a statistically significant increase in peak VO2 was observed 
in Treatment versus Control.   
FDA released the document “Guidance for the Use of Bayesian Statistics in 
Medical Device Clinical Trials” on February 5, 2010.  This document explicitly 
allows sponsors to employ Bayesian designs in proposals to FDA, but lays out 
some important guidelines that must be satisfied.  In particular, a Bayesian design 
must avoid putting strong priors on favorable outcomes as this will inflate type I 
error far above acceptable levels.  In fact, Bayesian designs are required by this 
guidance document to conform to the same frequentist operating characteristics 
as traditional frequentist designs; usually this means requiring that the probability 
of a type I error will be kept very low.  In order to be able to incorporate favorable 
prior information and yet not inflate type I error, the statistical model must be able 
to borrow in a flexible manner so that more borrowing is done when results for 
the prospective study are consistent with the favorable prior information but 

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relatively little borrowing is done when the prospective results are consistent with 
the null hypothesis.  Hierarchical models are a natural approach to achieving this 
flexible borrowing strategy.   
Statistical Model Used for Effectiveness 
For a Bayesian design in this setting, we regarded the original study as having 
generated normally distributed longitudinal data in the 2 subgroups defined by EF 
≥25 or <25.  The current study will only enroll subjects in the EF ≥25 subgroup.  
If the favorable subgroup result holds up, then a fair amount of borrowing from 
this favorable subgroup should occur (but less than just pooling the prior and 
prospective subgroup data).  If, on the other hand, the favorable subgroup is not 
confirmed than more borrowing will occur from the non-favorable subgroups in 
the previous study.  The model used to achieve this is a hierarchical model 
consistent with one presented in Pennello & Thompson (Pennello G, Thompson 
L. Experience with reviewing Bayesian Medical Device Trials. J Biopharm 
Statistics. 2008;18:81–115).  A detailed model description appears in the 
Statistical Analysis Plan.  Inference for this model centers around the difference 
in mean changes in peak VO2 between the treatment arm and control arm in the 
prospective data set conditional on all of the data both for the prior study (both 
subgroups) and prospective study (focused only on the single subgroup), and it 
will be required that the posterior probability of superiority be 97.5% or higher.  
The design simultaneously gives incremental power above and beyond that of a 
standalone analysis while preserving the low (5%) type I error of a standalone 
analysis.   
Power, Type I Error Tables for Effectiveness and Sample Size 
Operating characteristics for the Bayesian design are determined by simulating a 
large number of possible data sets for a variety of true values of the model 
parameters and then determining the associated posterior inference via Markov 
chain Monte Carlo methods (Lunn D J, Thomas A, Best N and Spiegelhalter D 
(2000) WinBUGS -- A Bayesian modelling framework: Concepts, structure, and 
extensibility. Statistics and Computing. 10, 325-337;  Sturtz S, Ligges U, Gelman 

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A. R2WinBUGS: A Package for Running WinBUGS from R.  Journal of 
Statistical Software 2005;12:1–16).     
The type I error of the design is approximately 5%.  More than adequate (86% or 
better) is ensured if the true interaction term (i.e. difference in mean change from 
baseline to 24 weeks for treatment vs. control arms) is at least 75% of that 
observed in the subgroup in the original study. Further details will be provided in 
the Statistical Analysis Plan 
  2. 
Primary Safety Analysis 
The primary safety analysis shall evaluate the procedure- or device-related 
complication rates through 24-weeks of follow up.  The statistical null hypothesis 
shall be that the proportion of patients in the treatment group without experiencing 
a primary safety event is less than 70%, and the alternative hypothesis shall be 
that the proportion is more than 70%.  This lower limit of 70% was chosen to be 
the same criterion used in several prior studies of CRT (PMAs P010012: Contak 
CD CRT D, P030005: Contak Renewal TR, P030035: St. Jude Frontier, and 
P010012/S37: Contak Renewal 3AVT).  Satisfying the primary safety endpoint 
will require rejecting the null hypothesis at a one-sided significance level of 0.025 
using an exact binomial test.  Equivalently, the endpoint will be met if the lower 
limit of the exact 95% confidence interval is above 70%.  It is noteworthy that 
point estimate of freedom from this composite endpoint at 24-weeks among 
subjects in the subgroup EF≥25% was 88%.   
3.  
Other efficacy analyses 
Other efficacy analyses that will be analyzed in a hierarchical statistical method 
and will include: 
a. 
MLWHFQ: Results will be analyzed both as a comparison between groups 
of the changes from baseline and as a responders analysis with a 10 point 
reduction in MLWHFQ considered as a “responder”.  
b. 
Between group differences in changes in mean peak VO2 with RER 
included as a covariate in the analysis.   

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Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015                                                                                                                                               Page 48 of 51 
c. 
New York Heart Association (NYHA) classification by a blinded on site 
clinicians.  Results will be analyzed both as a comparison between groups 
of the changes from baseline and as a responders analysis with a 1 class 
reduction in NYHA considered as a “responder”. 
d. 
An analysis of between group differences in changes in peak VO2 that only 
includes tests whose RER is ≥1.05. 
These analyses will be conducted on both the prospective data alone and on the 
prospective data pooled with the data from the original FIX-HF-5 study of the 
subgroup of interest (EF ≥25). Pooled models will include a study indicator to 
adjust for differences in overall success rate between studies.  Analysis from the 
pooled data will constitute the analysis upon which success will be determined. 
Since, with regard to efficacy, there are multiple hypotheses to be tested, the 
method of alpha control is the closed form hierarchical method.  Thus in order to 
test endpoints beyond the primary endpoint, the primary endpoint must attain a 
posterior probability of superiority that exceeds the nominal value.  This 
hierarchical approach does not result in additional inflation of the type I error rate. 
The two other efficacy parameters to be tested (changes in 6 minute hall walk test 
and VE/VCO2) will not be included in the hierarchical statistical analysis 
described above. 
 
B. 
Number of subjects planned to be enrolled 
Based upon the power calculations above, 230 subjects will be randomized in a 1:1 ratio 
between the two groups. 
 
C. 
Study Termination 
The study shall be considered complete approximately 24 weeks after the last study 
subject is randomized, when all subjects have completed the Week 24 follow-up.  
Subjects enrolled in the US with an OPTIMIZER implant who choose to continue CCM 
therapy shall continue to be followed every six months until FDA has completed their 
review of this study. 
 

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Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015                                                                                                                                               Page 49 of 51 
D. 
Procedure for accounting for missing, unused and spurious data. 
Subjects must perform 2 baseline measurements of peak VO2 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 safety and efficacy endpoint assessment).  An 
intent-to-treat analysis will be performed on the primary efficacy and safety endpoints 
and will include all subjects randomized, regardless of whether the subject withdrew prior 
to study completion.  The main reason for withdrawal is anticipated to be a voluntary 
decision made by the subject to withdraw from the study.  A Generalized Mixed-Effects 
Model will be performed for the primary analysis as detailed in the Statistical Analysis 
Plan (SAP).  An analysis of missingness patterns between treatment groups will also be 
performed.   
 
E. 
Procedures for reporting deviations from the original statistical plan 
Any deviations from the original statistical plan will be submitted and agreed upon with 
the FDA prior to any implementation.   
 
F. 
Selection of subjects to be included in the analyses 
The primary analysis will be an intent-to-treat analysis and all subjects will be accounted 
for (See Section IX.E.). 
 
X. 
DIRECT ACCESS TO SOURCE/DATA DOCUMENTS 
The investigators and institutions will permit trial-related monitoring, audits, IRB/EC 
review, and regulatory inspections, providing direct access to source/data and regulatory 
documents. 
 
XI. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality control and quality assurance is the responsibility of the Investigator and his/her 
study staff.  Impulse Dynamics clinical representatives will provide training and support 
to ensure that data quality is optimal (accurate, valid, reliable, complete and reported in 
a timely manner). Data will be monitored in accordance with Impulse Dynamic’s 
Monitoring procedures. Data used for publication will not identify the subjects, and 
publications will be generated in accordance with Impulse Dynamic’s publication policy.  

Impulse Dynamics (USA), Inc. 
 
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Study ID CP OPT2009-009 
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 Protocol version September 25, 2015                                                                                                                                               Page 50 of 51 
 
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/EC 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. 
Amendments to the clinical investigation plan will include rationale for the amendment 
and will be approved by IRBs/ECs and the national competent authorities.  
Deviations from the clinical investigational plan will be recorded and will be included in 
the final study report. 
 
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 permissions including data entry, data viewing, data querying and data 
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 

Impulse Dynamics (USA), Inc. 
 
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Study ID CP OPT2009-009 
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 Protocol version September 25, 2015                                                                                                                                               Page 51 of 51 
Part 11, Electronic Records and Electronic Signatures, the FDA’s Guidance: 
Computerized Systems used in Clinical Trials, and the Privacy Rule of the Health 
Insurance Privacy and Portability Act of 1996 (HIPAA) or other privacy laws, as 
applicable. 
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 as required for the study endpoints. The documents will be maintained in the 
Impulse Dynamics Clinical Affairs office in Orangeburg, New York.  Database 
development and management shall be performed by: 
Medidata 
79 Fifth Avenue 
New York, NY, 10003 
Tel: 212 918 1800 
Fax: 212 918 1818 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
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 Mohr, 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, pp 1642-47 (First published January 17, 2002). 
 
7. 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, pp 691-5. 
 
8. Nonexcitatory Stimulation: 2002: A Pace Odyssey Author: Kirstin Ellison, M.D.  Editorial 
Comment, Journal of Cardiovascular Electrophysiology, Volume 13, No. 7, July 2002. 
 

Impulse Dynamics (USA), Inc. 
 
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Study ID CP OPT2009-009 
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 Protocol version September 25, 2015 
 
 
9. 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. 
 
10. 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.  
 
11. 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. 
 
12. 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. 
 
13. 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. 
 
14. 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. 
 
15. 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. 
 
16. 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. 
 
17. 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. 
 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
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 Protocol version September 25, 2015 
 
 
18. 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. 
 
19. Electrical 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. JACC, Vol. 46, No. 
12, 2005, 2230-2236. 
 
20. 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.   European Journal of Heart Failure 8 (2006) 7-15. 
 
21. Treating Heart failure with Cardiac Contractility Modulation Electrical Signals. Authors: Hani N. 
Sabbah, PhD, Ramesh C. Gupta,  PhD, Sharad Rastogi, MD, Sudish Mishra, PhD, Yuval Mika, PhD, 
and Daniel Burkhoff, MD. Current Heart Failure Reports 2006, 3:21-24. 
 
22. Non-Excitatory, Cardiac Contractility Modulation (CCM) Electrical Impulses: Feasibility Study for 
advanced Heart Failure in Patients with Normal QRS Duration  Authors: Suresh B. Neelagaru, 
Javier E. Sanchez, Stanley K. Lau, Steven M. Greenberg, Nirav Y. Raval, Seth Worley, Jill Kalman, 
Andrew D. Merliss, Steven Krueger, Mark Wood, Marc Wish, Daniel Burkhoff, Koonlawee 
Nademanee. Heart Rhythm 3(10), October 2006, 1140-1147. 
 
23. Enhanced Inotropic State of the Failing Left Ventricle by Cardiac Contractility Modulation Electrical 
Signals is Not Associated with Increased Myocardial Oxygen Consumption. Authors:  Christian 
Butter MD, Ernst Wellnhofer MD, Michael Schlegl MD, Georgia Winbeck MD, Eckart Fleck MD 
and Hani N. Sabbah, Ph.D.  Journal of Cardiac Failure. Vol. 13, No. 2, 2007, p 137. 
 
24. Therapy with Cardiac Contractility Modulation Electrical Signals Improves Left Ventricular 
Function and Remodeling in Dogs with Chronic Heart Failure. Authors: Makoto Imai, M.D., Sharad 
Rastogi, M.D., Ramesh C. Gupta, Ph.D. Sudhish Mishra, Ph.D., Victor G. Sharov, M.D., Ph.D., Yuval 
Mika, Ph.D., Benny Rousso, Ph.D., Daniel Burkhoff, M.D., Ph.D., FACC, Shlomo Ben-Haim, M.D., 
Ph.D., Hani N. Sabbah, Ph.D., FACC. Journal of the American College of Cardiology. Vol.49, No.21, 
May 29, 2007, 2120-8. 
 
25. First use of cardiac contractility modulation (CCM) in a patient failing CRT therapy: Clinical and 
technical aspects of combined therapies. Authors: Christian Butter, Jurgen Meyhofer, Martin Seifert, 
Michael Neuss, Hans-Heinrich Minden. European Journal of Heart Failure, 2007, Volume 9, Issue 
9, Pages 955-958. 
 
26. Effects of Chronic Therapy with Cardiac Contractility Modulation Electrical Signals on Cytoskeletal 
Proteins and Matrix Metalloproteinases in Dogs with Heart Failure. Authors: Sharad Rastogi, 
Sudish Mishra, Valerio Zacà, Yuval Mika, Benny Rousso, Hani N. Sabbah. CARDIOLOGY. 2007 
Dec 12;110(4):230-237. 
 
27. Anaesthesia and cardiac contractility modulation Authors: Huschak G, Schmidt-Runke H, Ruffert H. 
Eur J Anaesthesiol 2007; 24:819-25. 
 
28. Randomized, Double Blind Study of Non-Excitatory, Cardiac Contractility Modulation (CCM) 
Electrical Impulses for Symptomatic Heart Failure Authors: Martin M. Borggrefe, Thomas Lawo, 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
Christian Butter, Herwig Schmidinger, Maurizio Lunati, Burkert Pieske, A. Ramdat Misier, Antonio 
Curnis, Dirk Böcker, Andrew Remppis, Joseph Kautzner, Markus Stühlinger, Christophe Leclerq, 
Miloš Táborský, Maria Frigerio, Michael Parides, Daniel Burkhoff, and Gerhard Hindricks. European 
Heart Journal. 2008 Apr;29(8):1019-28. 
 
29. Cardiac Contractility Modulation Electrical Signals Improve Myocardial Gene Expression in 
Patients with Heart Failure Authors: Christian Butter, Sharad Rastogi, Hans-Heinrich Minden, 
Jürgen Meyhöfer, Daniel Burkhoff and Hani N. Sabbah.  J Am Coll Cardiol. 2008 May 
6;51(18):1784-9. 
 
30. A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation 
in   patients with systolic heart failure: Rationale, design, and baseline patient characteristics. 
Authors: William T. Abraham, Daniel Burkhoff, Koonlawee Nademanee, Peter Carson, Robert 
Bourge, Kenneth A. Ellenbogen, Michael Parides, and Alan Kadish, On behalf of the FIX-HF-5 
Investigators and Coordinator.  Am Heart J. 2008 Oct; 156(4):641-648. 
 
31. Cardiac contractility modulation in non-responders to cardiac resynchronization therapy. Authors: 
Nägele H*, Behrens S, Eisermann C.  Europace. 2008; Dec;10(12):1375-80. Epub 2008 Sep 5. 
 
32. Improving left ventricular contractility by stimulation during the absolute refractory period—cardiac 
contractility modulation (CCM). Authors: Seifert M, Hoffmann J, Meyhöfer J, Butter C. 
Herzschrittmacherther Elektrophysiol. 2008 Dec;19 Suppl 1:69-76. German. 
 
33. “Responder Analysis” for Assessing Effectiveness of Heart Failure Therapies based on Measures of 
Exercise Tolerance. Authors: Daniel Burkhoff MD PhD, Michael Parides PhD, Martin Borggrefe 
MD, William T Abraham MD and Alan Kadish MD.  Journal of Cardiac Failure 2009 
Mar;15(2):108-15. Epub 2008 Dec12. 
 
34. Cardiac contractility modulation electrical signals normalize activity, expression, and 
phosphorylation of the Na+-Ca2+ exchanger in heart failure. Authors: Gupta RC, Mishra S, Wang 
M, Jiang A, Rastogi S, Rousso B, Mika Y, Sabbah HN. J Card Fail. 2009 Feb;15(1): 48-56. Epub 
2008 Oct 15.  
 
35. Cardiac contractility modulation: a new option for treating systolic heart failure. Authors: 
Rottlaender D, Michels G, Hoppe UC. Dtsch Med Wochenschr. 2009 Mar;134(13):639-43. Epub 
2009 Mar 17. Review. German. 
 
36. Biventricular and novel pacing mechanisms in heart failure. Authors: Salazar C, Abraham WT. Curr 
Heart Fail Rep. 2009 Mar;6(1):14-8. 
 
37. High sensing integrity counter in a patient with a Sprint Fidelis defibrillation lead: What is the cause? 
Authors: Bich Lien Nguyen, MD, Charles Swedlow, MD, FHRS, Carlo Gaudio, MD, Eli S. Gang, 
MD. Heart Rhythm, Vol 6, No 4, April 2009. 
 
38. Impact of Cardiac Contractility Modulation on Left Ventricular Global and Regional Function and 
Remodeling. Authors: Cheuk-Man Yu, MD, FRCP, FRACP; Joseph Yat-Sun Chan, FHKAM; Qing 
Zhang, MM, PhD; Gabriel WK Yip, MD, FACC; Yat-Yin Lam, MRCP; Anna Chan, FHKAM; Daniel 
Burkhoff, MD, PhD; Pui-Wai Lee, MRCP; Jeffrey Wing-Hong Fung, MD, FRCP. JACC Cardiovasc 
Imaging. 2009 Dec;2(12):1341-9. 
 

Impulse Dynamics (USA), Inc. 
 
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Study ID CP OPT2009-009 
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 Protocol version September 25, 2015 
 
 
39. Clinical trials update from the American College of Cardiology 2009: ADMIRE-HF, PRIMA, STICH, 
REVERSE, IRIS, partial ventricular support, FIX-HF-5, vagal stimulation, REVIVAL-3, pre-RELAX-
AHF, ACTIVE-A, HF-ACTION, JUPITER, AURORA, and OMEGA. Authors:  Cleland JG, Coletta 
AP, Clark AL, Cullington D., Eur J Heart Fail 2009; 11:622-30. 
 
40. Ca2+-Binding Proteins in Dogs with Heart Failure: Effects of Cardiac Contractility Modulation 
Electrical Signals Authors: Ramesh C. Gupta, Sudhish Mishra, Sharad Rastogi, Mengjum Wang, 
Benny Rousso, Yuval Mika, Andrew Remppis, Hani N. Sabbah Clinical and Translational Science, 
Volume 2, Issue 3, Date: June 2009, Pages: 211-215. 
 
41. Progress in cardiac pacing] Authors: Martinez FJ, Fidalgo Andres ML, Barba PR, Sancho-Tello de 
Carranza MJ. Rev Esp Cardiol 2009; 62 Suppl 1:117-28. 
 
42. Cardiac Contractility Modulation by Electrical Signals Applied during the Absolute Refractory 
Period as a Treatment for Chronic Heart Failure Authors: Daniel Burkhoff, Hani N. Sabbah, 
Christian Butter, Yuval Mika and Martin Borggrefe. Chapter 4 (page 44) in the book Heart Failure 
Device Management edited by Arthur M. Feldman. Published by Wiley-Blackwell, January 2010. 
 
43. The ventilatory anaerobic threshold in heart failure: a multicenter evaluation of reliability Authors: 
Myers J, Goldsmith RL, Keteyian SJ, et al. J Card Fail 2010; 16:76-83. 
 
44. Effects of Electric Stimulations Applied during Absolute Refractory Period on Cardiac Function of 
Rabbits with Heart Failure Authors: Haizhu Zhang, Changcong Cui, Dayi Hu.  J. Hauzhong Univ 
Sci Technol. 2010; 30(2): 155-158. 
 
45. A Randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation 
in advanced heart failure Authors: Alan Kadish, MD,a ,s Koonlawee Nademanee, MD,b,s Kent 
Volosin, MD, Steven Krueger, MD, Suresh Neelagaru, MD, Nirav Raval, MD, Owen Obel, MD, 
Stanislav Weiner, MD, Marc Wish, MD, Peter Carson, MD, Kenneth Ellenbogen, MD, Robert 
Bourge, MD, Michael Parides, PhD, Richard P. Chiacchierini, PhD, Rochelle Goldsmith, PhD, 
Sidney Goldstein, MD, Yuval Mika, PhD, Daniel Burkhoff, MD PhD, and William T. Abraham, MD. 
American Heart Journal, Volume 161, Number 2, February 2011, pages 329-337.e2. 
 
46. Subgroup Analysis of a Randomized Controlled Trial Evaluating the Safety and Efficacy of Cardiac 
Contractility Modulation in Advanced Heart Failure. Authors: William T. Abraham, Koonlawee 
Nademanee, Kent Volosin, Steven Krueger, Suresh Neelagaru, Nirav Raval, Owen Obel, Stanislav 
Weiner, Marc Wish, et al. Journal of Cardiac Failure Vol. 17 No. 9 2011. 
 
47. Does Contractility Modulation Have a Role in the Treatment of Heart Failure? Author: Daniel 
Burkhoff. Curr Heart Fail Rep. ePub 09 June 2011.  
 
48. The effect of device-based cardiac contractility modulation therapy on myocardial efficiency and 
oxidative metabolism in patients with heart failure Authors: Georg Goliasch, Aliasghar Khorsand, 
Matthias Schütz, Georgios Karanikas, Cesar Khazen, Heinz Sochor, Herwig Schmidinger, Michael 
wolzt, Senta Graf. Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-011-1977-8 (published online 
15 November 2011). 
 
49. Improvement of left ventricular contractility by stimulation during the absolute refractory period 
(German) Verbesserung der linksventrikulären Kontraktilität durch Stimulation in der absoluten 
Refraktärperiode. Author: Christian Butter. Herzschr Elektrophys 2011; 22: 37-33.  
 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
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 Protocol version September 25, 2015 
 
 
50. Cardiac contractility modulation as new device based therapy option for Heart failure patients 
(German) 
Neue 
apparative 
Therapie 
optionen 
bei 
Herzinsuffiziens 
Kardiale 
Kontraktilitätsmodulation. Authors: Kai Mortensen. Cardiovasc 2011; 2: 51-55.  
 
51. Therapy of chronic heart failure by cardiac contractility modulation (CCM) (German) Therapie der 
chronischen Herzinsuffizienz durch kardiale Kontraktionmodulation (CCM). Authors: Tönnis T, 
Kuck KH. Herz 2011; 36: 600-607.  
 
52. Therapy options for systolic heart failure  by implementing new study results (German) Systolische 
Herzinsuffizienz Therapeutische Möglichketien durch Implementierung neuer Studienergebnisse. 
Author: Rolf Wachter. Klinikarzt 2011; 40(4): 192-195.  
 
53. Clinical effects of cardiac contractility modulation (CCM) as a treatment for chronic heart failure. 
Authors: Martin Borggrefe, Daniel Burkhoff, European Journal of Heart Failure Advance Access 
published June 12, 2012. 
 
54. Comparison of left ventricular reverse remodeling induced by cardiac contractility modulation and 
cardiac resynchronization therapy in heart failure patients with different QRS durations. Authors: 
Qing Zhang, Yat-Sun Chan, Yu-Jia Liang, Fang Fang, Yat-Yin Lam, Chin-Pang Chan, Alex Pui-Wei 
Lee, Karl Chi-Yuen Chan, Eugene B. Wu, Cheuk-Man Yu. International journal of cardiology 2012 
(in press). 
 
55. The Economic Benefit of Cardiac Contractility Modulation Therapy for Heart Failure Patients in the 
United Kingdom. A Market Research Project. Authors: Joao Jorge, Prof. A Noble. Trinity Term 
2012. 
 
56. Electrical therapy of heartfailure (German) Elektrische Therapie der Herzinsuffizienz. Authors: 
Kuschyk J, Borggrefe M. Herzinsuffizienz 2013; up2date 9: 37-53.  
 
57. Inconsistencies in the development of the ESC Clinical Practice Guidelines for Heart Failure. 
Authors: Andrew J. Stewart Coats, Louise G. Shewan. International Journal of Cardiology 2013 (in 
press). 
 
58. A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation 
in patients with moderately reduced left ventricular ejection fraction and a narrow QRS duration: 
study rationale and design. Authors: Abraham WT, Lindenfeld J, Reddy VY, Hasenfuss G, Kuck 
KH, Boscardin J, Gibbons R, Burkhoff D; FIX-HF-5C Investigators and Coordinators. J Card Fail. 
2015 Jan;21(1):16-23. 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
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 
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. 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
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, WalidHaddad, 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 Institute, 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 Haddad, 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, Walid 
Haddad, 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, WalidHaddad, 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 (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
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 HaCarmel, 
Israel. Pacing and Clinical Electrophysiology; Vol. 24, No' 4, Part II; 319 (April, 2001) (NASPE 
Abs.) p.618  
21. Non-Excitatory 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.  

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
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 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, Daniel 
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, 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
D. Burkhoff, J. Wang; Columbia University, New York City, NY, USA. 8th.World Congress on 
Heart Failure: Mechanisms and Management, July 14, 2002 poster session (Abs. # 095).  
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. 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 
44. 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  
45. 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  
46. 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 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
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  
47. 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 
48. 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, Detroit, MI. Supplement III Circulation, Vol 110, 
No 17, Abstract #2808, October 26, 2004.  
49. 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.  
50. 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  
51. 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  
52. 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  
53. 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.  
European Journal of Heart Failure 4:135, (June) 2005. Presented at the European Society of 
Cardiology "Heart Failure 2005" in Lisbon, Portugal, June 13, 2005 
54.  Effect of CCM therapy on contractile function and oxygen consumption in patients with heart 
failure. Authors: S. Graf, A. Khorsand, G. Karanikas*, A. Becherer*, M. Mitterhauser*, K. Kletter*, 
G. Stix, G. Porenta†, H. Schmidinger, M. Wolzt° Department of Cardiology, (*)Department of 
Nuclear Medicine,(†)KH Rudolfinerhaus (°)Department of Clinical Pharmacology, Medical 
University of Vienna. Presented at the congress of the Society of Nuclear Medicine, June 18 - 22, 
2005 in Toronto/USA by Dr. Graf.   
55. Cardiac Contractility Modulation for the Treatment of Severe Heart failure: Hope for patients with 
narrow QRS? Authors: Gerhard Hindricks, Hans Kottkamp (Department of Electrophysiology, 
University Leipzig, Heart Center, Leipzig, Germany). J of the HK College of Cardiol, Vol 14 (Suppl 
1), February 2006, A73 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
 
International Symposium on Cardiovascular & Neurovascular Medicine, Hong Kong Convention & 
exhibition Center, 25 Feb. 2006 – Cardiac Contractility Modulation Symposium: 
“Effects of Cardiac Contractility Modulation Signals Studied in the Canine Model of Chronic 
Heart Failure” - Hani N. Sabbah 
“Application of Cardiac Contractility Modulation Therapy by Non-excitatory Signals in the 
Clinical Setting” – Gerhard Hindricks 
56. Chronic Therapy with cardia Contractility Modulation Electrical Signals Normalizes mRNA 
Expression of the Sodium-Calcium Exchanger and its Modulators GATA-4 and FOG-2 in Dogs With 
Chronic Heart failure.  Authors: Sudish Mishra, Ramesh C. Gupta, Sharad Rastogi, Makoto Imai, 
Omar Habib, Hani N. Sabbah, Henry Ford Health system, Detroit, MI. Supplement to JACC February 
21, 2006, Volume 47, No. 4 (Supplement A), Abstract # 1007-49, Page 76A. (Presented at ACC, 14 
Mar 2006) 
57. Chronic Therapy with Non-Excitatory Cardiac Contractility Modulation Electrical Signals 
Normalizes Cardiac mRNA Expression of the Maladaptive Fetal Gene Program and Up-Regulates 
Sarcoplasmic Reticulum Calcium Cycling Genes in Patients with Chronic Heart Failure. Authors: 
Christian Butter, MD, Sharad Rastogi, MD, Hani N Sabbah, PhD. Poster Session at HRS 2006, 
Supplement to Heart Rhythm, Vol.3, Issue 1S, May 2006, P3-96, Page S209. 
58. Cardiac Contractility Modulation Electrical Signals Combined with β-Blockade Improve LV 
Systolic Function in Dogs with Heart Failure Beyond that seen with β-Blockade Alone. Authors: 
Hani N Sabbah, PhD, Makoto Imai, MD, Valerio Zaca, MD, Mengjun Wang, MD, Alice Jiang, MD. 
Oral Abstract Session at HRS 2006, Supplement to Heart Rhythm, Vol.3, Issue 1S, May 2006, AB42-
4, Page S87. 
59. Chronic Therapy with Non-Excitatory Cardiac Contractility Modulation Electrical Signals 
Normalizes Expression of the Ca2+ - Binding Protein S100A1 in Dogs with Chronic Heart Failure. 
Authors: Ramesh C. Gupta, PhD, Sudhish Mishra, PhD, Remppis Andrew, MD, Hani N Sabbah, 
PhD. Oral Abstract Session at HRS 2006, Supplement to Heart Rhythm, Vol.3, Issue 1S, May 2006, 
AB23-5, Page S48. 
60. Cardiac Contractility Modulation by Non-Excitatory Electrical Currents Might Improve Diastolic 
Function in Patients with Chronic Heart Failure – a Pilot Study. Authors: Turgut Brodherr, MD, 
Matthias Vogt, BS, Leif I. Bösche, MD, Eyal Lebanony, ScD, Benny Rousso, ScD, Yuval Mika, 
PhD, Andreas Mügge, MD, PhD, Thomas Lawo, MD. Poster Session at HRS 2006, Supplement to 
Heart Rhythm, Vol.3, Issue 1S, May 2006, P3-85, Page S205. 
61. Effects of CCM (Cardiac Contractility Modulation) Signal Delivery on Left Ventricular 
Contractility. Authors: Thomas Lawo, MD, Leif I. Bösche, MD, Thomas Deneke, MD, Matthias 
Vogt, MS, Andreas Mügge, MD. Poster Session at HRS 2006, Supplement to Heart Rhythm, Vol.3, 
Issue 1S, May 2006, P4-90, Page S248. 
62. Long-term therapy with non-excitatory cardiac contractility modulation electrical signals 
normalizes expression of maladaptive cardiac genes in patients with chronic heart failure. Authors: 
C. Butter, S. Rastogi, H.N. Sabbah. Poster presentation, World Congress of Cardiology (ESC), 2-6 
September, 2006, Barcelona. 
63. Non-Excitatory, Cardiac Contractility Modulation (CCM) Electrical Impulses: Feasibility Study for 
Advanced Heart failure in Patients with Normal QRS Duration. Authors: Suresh B. Neelagaru, 
Javier E. Sanchez, Steven M. Greenberg, Nirav Y. Raval, Seth Worley, Jill Kalman, Andrew D. 
Merliss, Mark Wood, Marc Wish, Koonlawee Nademanee. Poster presentation at HFSA, Sep. 10-
13, Seattle, WA, Abstract #45. 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
64. Evaluation of the Safety and Efficacy of the OPTIMIZERTM II and III Systems with Active Fixation 
Leads in Subjects with Heart Failure Resulting from Systolic Dysfunction: FIX-CHF-4. Authors: 
Borggrefe on behalf of all FIX 4 PIs.  Accepted for Late Breaking Trials at HFSA 2006, Seattle, 
WA, Sep. 13 
65. Cardiac Contractility Modulation. Martin Borggrefe. AHA Scientific Sessions 12 Nov., 2006, 
Chicago Illinois. Session title: “Device Therapy in Heart Failure”. 
66. Cardiac Contractility Modulation: Fact or Fiction? Carlo Pappone. SJM symposium for “Recent 
Advances in Drug and Device Therapy for Heart Failure”, 13 Nov. 2006, Chicago, Illinois. 
67. Effects of CCM Signal Delivery on Left Ventricular Contractility. Author: Lawo, T. Abstract # 
Abst264, Oral presentation at CardioRthythm 2007 congress, 2-4 February, 2007, Hong Kong.  
68. Chronic Therapy with Cardiac Contractility Modulation Electric Signals Normalizes mRNA and 
Protein Expression of Titin and Tubulin In Dogs With Heart Failure. Authors: Sharad Rastogi, 
Makoto Imai, Menjung Wang Valerio Zaca, Hani N. Sabbah. Accepted for poster presentation at 
ACC.07, March 24-27, 2007, New Orleans. 
69. Improvement of Clinical Status and Cardiac Function by Cardiac Contractility Modulation for 
Patients with Advanced Heart Failure. Authors: Cheuk-Man Yu, MD, FRCP, Joseph Yat-Sun Chan, 
FHKAM; Qing Zhang, PhD; Gabriel WK Yip, MD, Anna Chan, FHKAM; SP Poon, Jeffrey Wing-
Hong Fung, FHKAM.  Accepted for poster(?) presentation at ACC.07, March 24-27, 2007, New 
Orleans. 
70. Randomized, Double Blind Study of Non-Excitatory, Cardiac Contractility Modulation Electrical 
Impulses for Heart Failure (FIX-CHF-4). Author: Borggrefe, M. Accepted for hotline session of 
the “73rd annual meeting of the German Society of Cardiology”, April 14, 2007, Mannheim, 
Germany.  
71. Normalisierung krankhaft veränderter Calcium-Zyklus Gene durch nicht-excitatorische Cardiac 
Contractility Modulation (CCM) bei schwerer Herzinsuffizienz. Author: Butter, C. Accepted for 
Poster presentation at the “73rd annual meeting of the German Society of Cardiology”, April 13, 
2007, Mannheim, Germany. German.  
72. Cardiac Contractility Modulation by non-excitatory electrical currents improves acutely diastolic 
function in patients with chronic systolic heart failure. Authors: Turgut Brodherr, MD, Thomas 
Lawo, MD, Matthias Vogt, MS, Netanel Eizenberg, MS, Benny Russo, MS and Andreas Mügge, 
MD, PhD. Poster presentation at Heart Rhythm 2007, Hamburg, 9 May, 2007. Supplement to Hearth 
Rhythm, page S128, abstract P01-57. 
73. Cardiac Contractility Modulation Electrical Signals Improve LV Diastolic Function in Dogs with 
Heart Failure. Authors: Hani N. Sabbah, PhD, Valerio Zaca, MD, Alice Jiang, MD and Mengjun 
Wang. Poster presentation at Heart Rhythm 2007, Denver, CO, 10 May, 2007. Supplement to Heart 
Rhythm, page S169, abstract P02-74. 
74. Randomized, Double blind study of non-excitatory, cardiac contractility modulation (CCM) 
electrical impulses for advanced heart failure. Authors: Borggrefe M., Lawo T., Butter C., 
Schmidinger H., Lunati M., Pieske B., Ramdat Misier A., Curnis A., Boecker D., Remppis A., 
Kautzner J., Stuhlinger M., Leclercq C., Taborsky M., Burkhoff D., Hindricks G. Accepted as a 
poster presentation at the Cardiologists National Congress in Firenze (ANMCO congress), 4 June, 
2007. 
75. Cardiac contractility modulation electrical signals improve LV diastolic function in dogs with Heart 
Failure. Authors: HN. Sabbah, V. Zaca, M. Wang, A. Jiang, S. Rastogi, B. Rousso, Y. Mika. Poster 
presentation at the European Association of Heart Failure in Hamburg, June 10, 2007 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
76. Randomised double blind study of non-excitatory, cardiac contractility modulation (CCM) electrical 
impulses for advanced heart failure. Authors: B.M. Pieske. Late Breaking Clinical Trials session at 
the European Association of Heart Failure in Hamburg, June 11, 2007.  
77. Cardiac Contractility Modulation (CCM) is equally Effective in Patients with Normal or Prolonged 
QRS Duration: Results of Responder’s Analysis. Authors: M. Borggrefe, G. Hindricks, T. Lawo, C. 
Butter, H. Schmidinger, M. Lunati, B. Pieske, AR. Misier, A. Curnis, R. Gradaus. Accepted as poster 
presentation (#231) at HFSA, September 18, 2007, Washington, DC.  
78. Cardiac Contractility Modulation Electrical Signals combined with β-Blockade Improve Myocardial 
Protein Expression of Phosphorylated Phospholamban in Dogs with Heart Failure beyond That 
Seen with β-Blockade alone. Authors: Sudish Mishra, Ramesh C. Gupta, Mengjun Wang, Alice 
Jiang, Benny Rousso, Yuval Mika, Hani S. Sabbah. Supplement to Journal of Cardiac Failure, Vol. 
13, No. 6, August 2007. Presented at the 11th Annual Scientific Meeting of the Heart Failure Society 
of America (HFSA), September 16-19, 2007, Washington, DC.  
79. Device-based CRT optimization by peak endocardial acceleration on cardiac resynchronization 
therapy. Authors: H. Naegele, P.P. Delnoy, R. Ritter, L. Padeletti, S. Orazi, F. Anselme, F. Renesto, 
V. Magagnin. European Journal of Heart Failure Supplements 2007, Vol. 6(1), p.170. 
80. Cardiac Contractility Modulation Electrical Signals Normalize Expression of the Excitation-
Contraction Coupling Proteins Presenillin-2 and Sorcin in Left Ventricular Myocardium in Dogs 
with Chronic Heart Failure. Authors: Hani N. Sabbah, Ramesh C. Gupta, Sudish Mishra, Mengjun 
Wang, Alice Jiang, Benny Rousso, Yuval Mika, Daniel Burkhoff. Supplement to Journal of Cardiac 
Failure, Vol. 13, No. 6, August 2007. Presented at the 11th Annual Scientific Meeting of the Heart 
Failure Society of America (HFSA), September 16-19, 2007, Washington, DC.  
81. Cardiac Contractility Modulation by Non-Excitatory electrical Current acutely Improves Diastolic 
Function in Patients with Chronic systolic Heart Failure. Authors:  T. Brodherr, M. Vogt, N. 
Eizenberg, B. Rousso, A. Muegge, T. Lawo. Poster presentation at the XIII World Congress on 
Cardiac Pacing and electrophysiology, December 2-6, 2007, Rome, Italy. 
82. Multicenter Randomized Controlled Trial of Cardiac Contractility Modulation in Patients with 
Advanced Heart Failure. Authors:  William T. Abraham, Koonlaawee Nademanee, Kent Volosin, 
Steve Krueger, Suresh Neelagaru, Nirav Raval, Owen Obel, Stanley Weiner, Mark Wish, Peter 
Carson, Kenneth Ellenbogen, Robert Bourge, Mike Parides, Richard Chiacchierini, Rochelle 
Goldsmith, Sidney Goldstein and Alan Kadish on behalf of the FIX-HF-5 investigators and 
coordinators. Presented at the Late Breaking Clinical-Trials session, March 28, 2008, ACC 2008 
(57th Annual Scientific Session), Chicago, IL. 
83. Rapid In-Vitro and In-Vivo Phosphorylation of Phospoholamban by Cardiac Contractility 
Modulation. Authors: HN. Sabbah, S. Mishra, RC. Gupta, S. Rastogi, B. Rousso, Y. Mika. Poster 
presentation at ESC 2008, Munich, Germany, August 30 – September 3, 2008. 
84. Improvement of Left Ventricular Regional Function and Reverse Remodeling in Heart Failure 
Patients Received Cardiac Contractility Modulation Therapy – a comprehensive Assessment by 
Real-Time 3D Echocardiogram and Tissue Doppler Imaging. Authors: Jeffrey WH. Fung, Joseph 
YS. Chan, Qing Zhang, Anna KY. Chan, Chun-yan Ma, Cheuk-man Yu. Heart Rhythm 2008, San 
Francisco, CA, May 14-17, 2008. Heart Rhythm Vol. 5, No.5, May Supplement 2008, p.S84 
(Abstract session AB40-2). 
85. FIX HF-5 TRIAL: Multicenter experience with implantation of a novel heart failure device. Authors: 
Kent J. Volosin, MD, Koonlawee Nademanee, MD, Owen Obel, MBChB, Stan Weiner, MD, Suresh 
Neelagaru, MD, FIX HF-5 Investigators. Presented at 30th annual scientific Sessions of the Heart 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
Rhythm Society, May 13-16, 2009, Boston, MA. Heart Rhythm Vol.6, No.5 May Supplement 2009, 
Abstract AB15-3 
86. Comparison of left ventricular reverse remodeling between cardiac contractility modulation and 
cardiac resynchronization therapy with different QRS durations. Authors: Qing Zhang, PhD, Yat-
sun Chan, MD, Wing-hong Fung, MD, Gabriel Wai-kwok Yip, MD, FRCP, Yu-jia Liang, Anna Kin-
yin Chan, MD and Cheuk-man Yu, Md, FRCP. Poster session at the 30th annual scientific Sessions 
of the Heart Rhythm Society, May 13-16, 2009, Boston, MA. Heart Rhythm Vol.6, No.5 May 
Supplement 2009, Abstract PO02-132. 
87. High sensing integrity counter with a sprint fidelis defibrillation lead and a cardiac contractility 
modulation device: false indication of high voltage lead failure. Authors: Bich Lien Nguyen, MD, 
Charles Swerdlow, MD, Jeffery M. Gillberg, MS, Carlo Gaudio, MD and Eli S. Gang, MD. Poster 
session at the 30th annual scientific Sessions of the Heart Rhythm Society, May 13-16, 2009, Boston, 
MA. Heart Rhythm Vol.6, No.5 May Supplement 2009, Abstract PO02-166. 
88. US Multicenter RCT of Cardiac Contractility Modulation in Patients With Advanced Heart Failure 
(FIX-CHF-5). Presenter: M. Borggrefe.  75 Annual Meeting of the German Cardiac Society – 
Cardiac and Circulation Research, 18.04.2009, Congress Center Rosengarten Mannheim. 
89. Welche CRT-Non-Responder eignen sich für eine zusätzliche Behandlung mit “Cardiac 
Contractility Modulation” (CCM)? Authors: H. Nägele, S. Behrens, I. Ollmann, C. Eisermann, 75 
Annual Meeting of the German Cardiac Society – Cardiac and Circulation Research, 18.04.2009, 
Congress Center Rosengarten Mannheim. 
90. Langzeit-Mortalität 
bei 
fortgeschrittener 
chronischer 
Herzinsuffizienz 
unter 
cardialer 
Contraktionsmodulation (CCM-Therapie). Authors: T. Schau, M. Seifert, J. Meyhöfer, M. Neuss, 
C. Butter, 75 Annual Meeting of the German Cardiac Society – Cardiac and Circulation Research, 
17.04.2009, Congress Center Rosengarten Mannheim. 
91. Clinical outcome of cardiac contractility modulation in patients with drug-refractory chronic heart-
failure. Authors: C. Schukro, M. Wolzt, G. Stix, T. Pezawas, J. Kastner, H. Schmidinger; accepted 
for poster presentation at Europace 2009, 30 Aug – 2 Sep, 2009, Berlin. 
92. The Ventilatory Anaerobic Threshold in Heart Failure: A Multi-Center Evaluation of Reliability. 
Authors: Jonathan Myers, Rochelle Goldsmith, Steven J Keteyian, Clinton A Brawner, Jonathan K 
Ehrman, Derdre Brazil, Heather Aldred, Stacinoel Hallenbeck, Daniel Burkhoff. Accepted for an 
oral presentation at the AHA Scientific Sessions 2009 in Orlando, Florida, November 18, 2009. 
93. Impact of cardiac contractility modulation on symptoms and exercise tolerance in patients with heart 
failure and EF greater than 35%: a subgroup analysis of the FIX-HF-5 study. Authors: Daniel 
Burkhoff MD PhD, Alan Kadish MD and William T Abraham MD on behalf of the FIX-HF-5 
Investigator and Coordinators. Accepted for poster presentations at the Annual ESC Congress 2010, 
Stockholm, Sweden, 30 August, 2010. 
 
 
 
 
 
 
 
 
 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 
 Protocol version September 25, 2015 
 
 
 
 
 
Appendix B 
 
 
Informed Consent Template / 
 
HIPAA Template

Impulse Dynamics (USA), Inc.  
 
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Study ID CP OPT2009-009 
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Protocol version September 25, 2015 
 
Page 1 of 11 
 
Subject ID Number:___  - ________ 
 
Evaluation of the Safety and Efficacy of the OPTIMIZER System  
in Subjects with Moderate-to-Severe Heart Failure  
with Ejection Fraction between 25% and 45%: FIX-HF-5C 
 
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.  An 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.  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 dependent on your randomization assignment described later in 
this informed consent form. You will be expected to come in for study assessments and procedures 
for approximately 7 months.  This will include approximately one month for screening and 

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Study ID CP OPT2009-009 
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Page 2 of 11 
baseline testing with a six month follow-up period.  If you receive an OPTIMIZER System 
implant, you will be asked to return for follow-up every 6 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 3 years.  If you are in the Control group or in the OPTIMIZER 
group but not receiving the test therapy, you will be contacted at approximately 6 month intervals 
to check on your health status for up to 2 years following the start of your study participation. 
Study Procedures  
Certain medical tests and assessments will be performed to determine if you are eligible to 
participate in this study. These tests and assessments include:  
 a physical examination  
 an evaluation of your medications  
 an evaluation of your medical history including all hospitalizations that have occurred in 
the prior year 
 an assessment of your current heart failure symptoms 
 an electrocardiogram (to check the electrical activity in your heart) 
 an echocardiogram (to check the strength of your heart) 
 a questionnaire that asks you about your heart failure symptoms 
 a 24-hour Holter monitor test (a tape recording of your heart rhythm over the course of an 
entire day) 
 two different types of stress tests. The first test is to see how far you can walk on flat ground 
for 6 minutes and the second test is performed on a treadmill while the oxygen in your 
breath is analyzed.  You will repeat the test performed on the treadmill 1-7 days after the 
first test.   
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.  
In some cases, your doctor may be able to use an echocardiogram, 24-hour Holter, or 
electrocardiogram performed within 30 days prior to your consent to enroll in this study.  
Many patients with heart failure develop a need for a device called an implantable cardiac 
defibrillator (ICD) and/or a pacemaker.  If your doctor believes that you have a need for an ICD 
or pacemaker, this may be offer to you at this time. 

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Page 3 of 11 
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 Control 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.   
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.   
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. The 
implantation is performed under sterile conditions on an exam table and an intravenous (IV) line 
is put into your arm. The IV delivers fluids and medication during the procedure. The medication 
will make you relaxed and drowsy but you will remain awake.  
The implant includes three electrical wires (leads) that connect the main component of the 
OPTIMIZER System, the implantable pulse generator (IPG) to your heart through the veins inside 
your chest, very similar to procedures used when implanting a pacemaker device.  The IPG is 
generally implanted under your skin in the shoulder area and contains a battery and components 
that deliver CCM therapy sealed inside. The leads are used to record the normal electrical signals 
generated by your heart and to deliver the CCM treatment to your heart.  The skin is numbed prior 
to making an incision, and the leads are inserted and steered through the blood vessels into your 
heart while the doctor views them with moving x-rays.  
Tests will be performed to ensure that the OPTIMIZER System and if you have one, the ICD 
System, are functioning properly.  This test may require your doctor to make your heart beat 
quickly to see if your ICD will sense and properly treat that condition. 
If you also have an ICD or pacemaker, 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).   

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Page 4 of 11 
Following a device implant, you will have a chest X-ray and the OPTIMIZER System will be 
turned on.  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.  You will be discharged from the hospital, typically the day after the 
implant.   
If you are randomized to the Control group, you will continue to receive optimal medical 
therapy and you shall receive the same study related assessments as detailed below.   
All subjects follow-up (Optimizer group and Control group), will be asked to return to the 
hospital in two weeks after the beginning of the study for a medical history review.  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.  You will also receive additional instruction on when and how 
to use the battery charger.   
You will be asked to return for follow-up visits at 12-weeks and 24-weeks following your study 
start date.  At these visits, you will undergo medication review, medical history, physical 
examination, OPTIMIZER device evaluation, completion of the questionnaire about symptoms 
you have during your daily life, an assessment of your current heart failure symptoms and two 
different types of stress tests. The first stress test is the 6 minute walk test and the second stress 
test is the treadmill test.  You will repeat the treadmill test 1-7 days after the first test.  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 24-week visit. The OPTIMIZER System will be 
turned off in any subject who becomes pregnant. 
Following the 24-week visit, 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 this case, a medical history and OPTIMIZER device interrogation will be performed at 6-
month intervals until the FDA has completed its review of this study.   
 
 

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Study ID CP OPT2009-009 
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Page 5 of 11 
Foreseeable Risks Associated with Study Participation for Subjects with the OPTIMIZER 
System 
If you suspect that you have become pregnant while participating in the study, you must contact 
the study doctor immediately. 
 
Risks Associated with the OPTIMIZER System Implant and CCM Treatment 
The risks associated with implanting the OPTIMIZER System (which includes implantation of the 
pulse generator and the leads that connect the generator to your heart) and applying 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 the tricuspid valve, potentially resulting in tricuspid valve regurgitation 
 damage to specialized tissue in the heart responsible for initiating each heart beat (i.e., the 
heart’s conduction system) 
 transient ischemic attack (TIA) or stroke 
 formation of blood clots 
 chest wall sensations 
 pain at the incision site 
 infection 
 collapsed lung 
 a hole in the heart from the leads 
 lead dislodgement 
 fluid or blood accumulation around the heart 
 death 
 
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 
 
 

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Study ID CP OPT2009-009 
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Page 6 of 11 
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 is possible that the OPTIMIZER 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 suggests this is unlikely to occur. 
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 heartbeat.  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.  However, if you visit any other physician or medical 
center that needs to reprogram either of your implantable devices, please ensure that they are aware 
of possible interaction between the devices. 
 
Risks associated with possible interaction between the ICD and OPTIMIZER charger  
 
If in addition to the OPTIMIZER device, you also have an Implantable Cardioverter Defibrillator 
(ICD), there is the possibility that the ICD may inappropriately deliver therapy (shocks) if you 
place the charger wand over the ICD.  Please make sure that you place the charging wand only 
over the OPTIMIZER implant site. 
 
 

Impulse Dynamics (USA), Inc.  
 
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Study ID CP OPT2009-009 
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Protocol version September 25, 2015 
 
Page 7 of 11 
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.  Malfunctions of system parts or other clinical 
circumstances (e.g., sepsis) may require corrective actions or possibly even surgical repair 
(repositioning, replacement, or removal) of the part or parts that are not working properly.   
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 Subjects 
There is a risk for all subjects 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 the following:  
 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.  
 
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.  If researchers determine that there are benefits, then your participation in this research 

Impulse Dynamics (USA), Inc.  
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
Protocol version September 25, 2015 
 
Page 8 of 11 
study could benefit others who will suffer from heart failure in the future. However, because the 
therapy is not yet proven to be effective, you and others 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).  So you can choose not to participate in the study 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, US FDA and other regulatory agencies 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. 
 
FDA disclosure to all subjects in clinical trials    
A description of this clinical trial will be available on http://www.ClinicalTrials.gov at the 
following link http://www.clinicaltrials.gov/ct2/show/NCT01381172 as required by U.S. 
Law.  This Website will not include information that can identify you.  At most, the Website will 
include a summary of the results.  You can search this Website at any time.  
  
 
 

Impulse Dynamics (USA), Inc.  
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
Protocol version September 25, 2015 
 
Page 9 of 11 
Compensation  
The study sponsor will compensate you for your participation in the 24-week study according to 
the schedule listed below: 
2-week follow-up visit: 
$50 
12-week follow-up visit: 
$250 
24-week follow-up visit: 
$249 
You will receive a single payment that includes compensation for each visit that you completed. 
You will be given that payment after the 24-week follow-up visit.  If you end your participation in 
the study before to the 24-week visit or do not complete one or more of the visits listed above, you 
will still receive a single payment for each visit that you completed.   
Reimbursement 
During the 24-week study, if you live more than 50 miles away, you will be reimbursed for 
reasonable lodging, meals, parking fees and the transportation costs to and from the facility and 
your home.  Reasonable lodging, meals and parking fees will also be reimbursed for subjects that 
require an overnight stay in order to complete the two treadmill stress tests required at the baseline 
visit, 12-week and 24-week follow-up visits.  Car mileage will be reimbursed at the current IRS 
reimbursement rate per mile, which includes the cost of gasoline.  You will be asked to maintain 
and submit expense receipts for reimbursement; reimbursement will be provided according to the 
study sponsor guidelines. 
Costs  
All costs related to the implantation of the OPTIMIZER System will be billed to your insurance 
provider.  These costs include: 
 The OPTIMIZER Device hospitalization 
 The  OPTIMIZER Device 
 The OPTIMIZER  Device procedure, including anesthesia 
 Post implant chest x-ray 
 
You and your insurance provider will be responsible for paying these costs including any co-pays, 
co-insurance or deductibles.  If your insurance provider will not pay (denies payment) for the 
OPTIMIZER implant related expenses, the study sponsor will cover these costs directly. 

Impulse Dynamics (USA), Inc.  
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
Protocol version September 25, 2015 
 
Page 10 of 11 
You or your insurance provider may also be responsible for paying for any treatments or tests that 
your doctor orders for you if those treatments or tests are for standard, clinical care.  You may 
have to pay for these tests if they are not covered by your insurance provider.    
Neither you nor your insurance provider will be charged for any tests that are done solely for the 
purposes of this study other than the OPTIMIZER implant hospitalization as explained earlier.   
The study sponsor will also cover the costs related to the removal of the device in the following 
circumstances: 
 if you would like to leave the study and have the OPTIMIZER System removed 
 if you would like to have the OPTIMIZER System removed at the end of the study 
 if your OPTIMIZER System needs to be removed or replaced due to a device malfunction 
during your study participation 
 
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.___________.    If 
you get ill or injured as the direct result of being in this study, the Sponsor will pay the costs for 
your medical treatment of the illness or injury only if it: 
(a) Is directly caused by the study device;  
(b) is not a medical condition that you had before you started the study; 
(c) is not the result of the natural progress of your disease or condition; 
(d) is not caused by your or the hospital’s failure to follow the study plan or protocol; and   
(e) is not proved to be directly caused by the negligence of a hospital employee.  “Negligence” is 
the failure to follow a standard duty of care.  
The Sponsor will not provide compensation for lost wages or for any other damages, expenses or 
losses, or for medical expenses that have been covered by your medical or other insurance. 
 
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:____________. 

Impulse Dynamics (USA), Inc.  
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
Protocol version September 25, 2015 
 
Page 11 of 11 
 
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.   
If you decide to withdraw from the study after starting to participate, we will keep the information 
we have collected up to that point, but we will not collect any additional information from you 
without your consent.  We may, however, want to determine your vital status after you drop out 
of the study. To be able to determine your vital status (and if deceased, cause of death), we will 
consult sources of information such as the National Death Index. 
 
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, the US FDA and other regulatory agencies to inspect my health data. 
 
 
 
 
Printed Name of Participant 
 
 
 
 
 
 
Signature of Participant 
 
Date 
 
 
 
 
Legally Authorized Representative (if applicable) 
 
Date 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C  
Protocol version September 25, 2015 
 
Page 1 of 2 
HIPAA Clinical Research Authorization 
AUTHORIZATION TO USE AND DISCLOSE HEALTH INFORMATION 
Evaluation of the Safety and Efficacy of the OPTIMIZER System  
in Subjects with Moderate-to-Severe Heart Failure  
with Ejection Fraction between 25% and 45%: FIX-HF-5C 
 
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 FIX-HF-5C OPTIMIZER System 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.  
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
Protocol version September 25, 2015 
 
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.  
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
Protocol version September 25, 2015 
                   Appendix C                                  
Page 1 of 2 
 
APPENDIX C 
TEMPLATE CASE REPORT FORMS for the FIX-HF-5C Study 
 
Data for this study will be recorded into data entry screens using the Medidata electronic data capture 
(EDC) system.  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  
Minnesota Living with Heart Failure Questionnaire 
Echocardiogram 
Cardiopulmonary Stress Test 
6 Minute Walk Test 
12-Lead ECG 
24 Hour Holter Monitor 
Eligibility Determination  
Randomization 
Health Insurance Coverage 
 
Implant Folder (for Subjects Randomized to the OPTIMIZER System): 
Implant Success 
Implant- OPTIMIZER and Lead Information 
Implant- Equipment Notes, & Personnel 
Discharge 
OPTIMIZER IVs Patient Training 
OPTIMIZER Interrogation 
 
 
 

Impulse Dynamics (USA), Inc.  
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
Protocol version September 25, 2015 
                   Appendix C                                  
Page 2 of 2 
 
Follow-up Folders: 
Interim Medical History 
Follow Up Medications 
Follow-Up Physical Examination 
NYHA Classification 
Minnesota Living with Heart Failure Questionnaire 
Cardiopulmonary Stress Test 
6 Minute Walk Test 
Pregnancy Test 
OPTIMIZER Interrogation (for subjects randomized to the OPTIMIZER System) 
 
 
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 
Pre-Randomization Hospitalizations  
 
 

Impulse Dynamics (USA), Inc. 
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C  
Protocol version September 25, 2015 
Appendix D                         
Page 1 of 1 
APPENDIX D 
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 System and the 
concomitant device. The following steps summarize the required testing: 
1. Program the ICD so that it does not deliver antitachycardic therapy during this test. 
2. Program the sensing windows of the OPTIMIZER and ensure that the OPTIMIZER System can be 
programmed to consistently delivery CCM therapy in the presence of the concomitant device. 
3. 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.  
4. 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. 
5. 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. 
6. Program the ICD to detect and convert an induced ventricular tachyarrhythmia. Program the 
OPTIMIZER 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.  
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
Protocol version September 25, 2015 
        Appendix E                                  
Page 1 of 1 
APPENDIX E 
Follow-up of Subjects enrolled during the FIX-HF-5B Protocol 
Background 
FDA approved the FIX-HF-5B Confirmatory Study protocol in 2010 for the enrollment of 230 subjects 
at 30 US sites. The study was designed to prospectively evaluate CCM therapy in a subgroup of the pivotal 
trial (NYHA 3 and LVEF 25-35%) with the OPTIMIZER III System. A FIX-HF-5B protocol revision, 
version July 29, 2011 (G030099/S084), was approved by the FDA in August 2011 that included an 
expanded LVEF criterion of 25-45%. 
Enrollment into the FIX-HF-5B Confirmatory Study started with the first subject consent on February 22, 
2011. A total of 17 subjects were randomized from 2011-2012; 11 to the OPTIMIZER group and 6 to the 
Control group. The FIX-HF-5C Confirmatory Study enrollment began in 2013 with the next generation 
device, the OPTIMIZER IVs System.   
Study Follow-up Procedures 
Subjects enrolled into the FIX-HF-5B protocol shall continue follow-up per the current (FIX-HF-5C) 
protocol.  The FIX-HF-5C protocol is a revision of the FIX-HF-5B protocol, with the study number 
change made primarily to delineate the difference in the index device implanted at the time. All FIX-HF-
5B subjects are in the post-study follow-up phase and being seen every 3 months for a history and device 
interrogation.  
OPTIMIZER III IPG Replacement: 
FIX-HF-5B subjects requiring an exchange of their OPTIMIZER III implantable pulse generator (IPG) 
may receive the OPTIMIZER IVs IPG.  
Consent Materials: 
All FIX-HF-5B subjects have signed the current IRB-approved consent form for the FIX-HF-5B study. 
A template informed consent addendum is attached and should be provided to all FIX-HF-5B subjects 
currently in active follow-up.

Impulse Dynamics (USA), Inc.  
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015  
                        FIX-HF-5B Consent Addendum                                  
Page 1 of 2 
Informed Consent Addendum for Participation in Research Activities 
Impulse Dynamics FIX-HF-5B 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.  
 
CONFIDENTIAL 
Study ID CP OPT2009-009 
FIX-HF-5C 
 Protocol version September 25, 2015  
                        FIX-HF-5B Consent Addendum                                  
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     
 
 

FIX-HF-5C Clinical Report 
                                       Impulse Dynamics USA, Inc. 
                                                                                                                                                                   
 
OPTIMIZER SMART System 
 
Page 1 of 108 
 
PROPRIETARY: This document is proprietary and confidential. No part of this document may be disclosed in any manner to 
a third party without the prior written consent of Impulse Dynamics USA, Inc. 
FIX- HF-5C Clinical Report 
1.1 Introduction 
   
Clinical evidence to support approval of this PMA (M150003) is derived from FIX-HF-5  
series of studies, including: the Phase I FIX-HF-5 Feasibility trial; the Phase II FIX-HF-5 
Pivotal trial; and the FIX-HF-5C Confirmatory trial.    
 
The Feasibility trial (FIX-HF-5, Phase I) examined the OPTIMIZER II System in patients with 
NYHA Class III or IV heart failure and a normal QRS duration. The results provided 
preliminary evidence of device safety and efficacy, which led to the conduct of the Phase II 
FIX-HF-5 Pivotal trial.  
 
The Phase II FIX-HF-5 Pivotal trial was a prospective, randomized study that included 428 
heart failure patients with NYHA functional class III-IV symptoms despite optimal medical 
therapy (OMT), ejection fractions (EF) <35% (or up to 45% per echo core lab reading) and 
QRS duration <130 ms.  Patients were randomized 1:1 to either continue to receive OMT or 
received OMT plus CCM™ treatment delivered by the OPTIMIZER III device.   
 
The primary effectiveness endpoint of the FIX-HF-5 study was ventilatory anaerobic threshold 
(VAT) evaluated by a blinded core lab and assessed by a responder’s analysis.  Comparisons 
between treatment and control in peak VO2 and quality of life were statistically significant  (p 
value 0.024 and <0.0001, respectively).  More importantly, a post hoc sub-group analysis of 
patients with EF > 25% showed significantly greater effect between the treatment and control 
groups for peak VO2 and quality of life than in the cohort as a whole. 
 
After consultation with FDA, Impulse Dynamics conducted an additional confirmatory study 
(FIX-HF-5C) with peak VO2 as the primary effectiveness endpoint in patients with EFs ranging 
from 25% to 45% (inclusive).  A Bayesian statistical approach was employed to take advantage 
of the data available from the FIX-HF-5 Phase II study.  The FIX-HF-5C study was performed 
with the OPTIMIZER IVs device.  It is important to note that at this point, the OPTIMIZER 
System was designated as an expedited access pathway (EAP) device on July 31, 2015, 
indicating that FDA believes the device fills an unmet clinical need and merits priority review. 
 
The 160 patient FIX-HF-5C study forms the primary basis for this PMA and will be thoroughly 
described and discussed in this clinical report.  Data from the FIX-HF-5 Phase II study are 
most relevant in that there was a pre-specified fixed borrowing of data from a subgroup of 
patients from this study for the Bayesian Analysis of the FIX-HF-5C primary endpoint: peak 
VO2. 
 
The results of the FIX-HF-5C study demonstrated a statistically and clinically significantly 
higher improvement in peak VO2 in patients treated with CCM™ for 24 weeks in addition to 
OMT in comparison to patients treated with OMT alone.  Similarly, quality of life as assessed 
by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ), functional class 
(NYHA) and 6 minute walk were all shown to be statistically significantly better in CCM™-
treated patients. 

FIX-HF-5C Clinical Report 
                                       Impulse Dynamics USA, Inc. 
                                                                                                                                                                   
 
OPTIMIZER SMART System 
 
Page 2 of 108 
 
PROPRIETARY: This document is proprietary and confidential. No part of this document may be disclosed in any manner to 
a third party without the prior written consent of Impulse Dynamics USA, Inc. 
 
In parallel, the OPTIMIZER System has been available in Europe and Asia gaining real world 
experience.  Investigator-initiated studies were conducted to examine long term effects of 
CCM™ (Kuschyk et al., 2015; Kloppe et al., 2016 and Liu et al., 2016).  In addition, Impulse 
Dynamics conducted 2 registry studies (CCM-HF and CCM-REG) to further elucidate the use 
of CCM™ in the moderate-to-severe heart failure population.   
 
Once enrollment was completed in the FIX-HF-5C study, a Continued Access Protocol (FIX-
HF-5CA) was submitted and approved by the FDA.  The first patient was enrolled in this study 
on July 3, 2017. The Continued Access Study utilizes the next version of the device, the 
OPTIMIZER SMART with the 3-Lead configuration.  As detailed above, the switch to the 
OPTIMIZER SMART was necessitated due to OPTIMIZER IVs manufacturing constraints 
(i.e., loss of availability of the header material).  The differences between the OPTIMIZER 
IVs and the OPTIMIZER SMART 3-Lead configuration are summarized above in Table 8; the 
main differences are the different epoxy material used for the header and the smoothness of 
the titanium can contour.  Therefore, this PMA application is seeking approval for the 
OPTIMIZER SMART 3-Lead configuration device. 
 
1.2 Clinical Need 
 
CCM™ delivered by the OPTIMIZER SMART System provides a unique therapeutic 
modality for the treatment of patients with moderate to severe heart failure (HF), a life 
threatening and irreversibly debilitating disease for which there is an unmet clinical need.   
 
1.2.1 Unmet clinical need 
 
Despite major advances in drug and device therapies, heart failure remains a cause of 
substantial disability, hospitalizations, and mortality. There is a crucial need for additional safe 
and effective heart failure therapies, in particular in patients with normal QRS where there is 
currently no therapeutic medical device available in the United States.  The OPTIMIZER 
SMART System fulfills an unmet medical need.  
 
1.2.2 Life threatening and irreversibly debilitating disease 
 
The heart is a life sustaining organ.  When it fails, the heart can no longer supply adequate 
cardiac output to meet the body’s metabolic needs, particularly during periods of exertion.  
Thus, heart failure (HF) is both a life threatening and irreversibly debilitating condition.  
Current statistics support this fact.  Approximately 5.7 million people have heart failure in the 
United States according to CDC.1 Fifty percent of people diagnosed with heart failure die 
within 5 years of diagnosis.1  One in 9 deaths in 2009 included HF as a contributing cause1.  In 
2010, there were 1,801,000 physician office visits with a primary diagnosis of HF and 676,000 
emergency department visits and 236,000 outpatient department visits for HF.2  Clearly, 
morbidity and mortality are high in patients with HF.  HF is life threatening since the likelihood 
of death is high unless the course of the disease is interrupted in patients before permanent 
damage is done.  Moreover, heart failure can be considered irreversibly debilitating in that in 

FIX-HF-5C Clinical Report 
                                       Impulse Dynamics USA, Inc. 
                                                                                                                                                                   
 
OPTIMIZER SMART System 
 
Page 3 of 108 
 
PROPRIETARY: This document is proprietary and confidential. No part of this document may be disclosed in any manner to 
a third party without the prior written consent of Impulse Dynamics USA, Inc. 
its moderate to severe stages, morbidity can have a substantial impact on day to day life of 
patients affected.  Indeed, the patient population served by the OPTIMIZER device is 
characterized clinically as NYHA functional Class III and ambulatory IV.  By definition, 
NYHA Class III patients have a marked limitation of physical activity but are reasonably 
asymptomatic at rest; less than ordinary physical activity causes fatigue, palpitation, or 
dyspnea in NYHA Class III heart failure patients.  NYHA Class IV patients are even more 
impaired in that these patients have an inability to carry out any physical activity without 
symptoms; patients have symptoms at rest, which are increased with any amount of physical 
activity.    
 
1.2.3 Lack of Alternative Therapies 
 
Based on the above considerations, it is evident that the OPTIMIZER SMART is intended to 
treat a life threatening, irreversibly debilitating disease:  heart failure.  The OPTIMIZER 
SMART is the only available device that can provide CCM therapy. 
 
 CCM™’s target population is NYHA Class III and ambulatory IV subjects, with normal QRS 
duration and reduced ejection fraction despite appropriate, guideline-directed pharmacologic 
therapies.   There are currently no device therapies available for this sub-group of patients. 
 
Cardiac Resynchronization Therapy (CRT) is also indicated for patients with moderate to 
severe heart failure with prolonged QRS duration.  CRT works by synchronizing the electrical 
activity of the heart and indirectly has an effect on ventricular chamber contractility. However, 
CRT is only indicated for patients with prolonged QRS duration, primarily those with QRS 
duration >150 ms.  Since only ~30% of the patients with heart failure have a wide QRS3, CRT 
is not applicable to 70% of heart failure patients.  In addition, CRT applied to patients with 
systolic heart failure and a QRS duration of less than 130 ms may increase mortality4. 
 
Finally, patients with severe heart failure also have the treatment option of a left ventricular 
assist device (LVAD).  However, even with newer and smaller devices being developed, 
LVADs are fraught with serious complications such as bleeding, stroke, infection, and 
thrombosis. Because of these risks, LVAD use is generally limited to patients with more severe 
heart failure than those qualifying for CCM™ therapy. 
 
 
1.3 Intended Use and Indications for Use 
 
Intended Use: The OPTIMIZER SMART System is intended to deliver CCM™ electrical 
signals to the myocardium of the heart. 
 
Indications for Use:   The OPTIMIZER SMART System, which delivers CCM therapy, is 
indicated for the treatment of NYHA Class III or ambulatory NYHA Class IV heart failure 
patients in normal sinus rhythm with LVEF ranging from 25% to 45% and QRS interval <130 
ms to improve exercise tolerance, quality of life, functional status and reduce heart failure 
hospitalizations. 
 

FIX-HF-5C Clinical Report 
                                       Impulse Dynamics USA, Inc. 
                                                                                                                                                                   
 
OPTIMIZER SMART System 
 
Page 4 of 108 
 
PROPRIETARY: This document is proprietary and confidential. No part of this document may be disclosed in any manner to 
a third party without the prior written consent of Impulse Dynamics USA, Inc. 
1.4 FIX-HF-5C 
 
The FIX-HF-5C study received FDA approval on April 30, 2014 utilizing the then-current 
version of the OPTIMIZER family of devices, the OPTIMIZER IVs System.  The 
investigation was initially limited to 40 sites and 230 subjects.  The first patient was 
randomized on July 28, 2014. Through subsequent discussions with FDA, the OPTIMIZER 
system was granted expedited access pathway (EAP) designation on July 31, 2015.  As a 
result, the final sample size for the FIX-HF-5C study was modified to 160 subjects; this was 
agreed upon with FDA on November 14, 2016.  Enrollment was completed on February 28, 
2017 and 24-week follow up for all subjects concluded in August 2017.  The Continued 
Access Study phase of the FIX-HF-5C study was approved by FDA on April 6, 2017 and 
enrollment began July 3, 2017. 
 
1.4.1 Overview of Study Design for FIX-HF-5C        
                        
 
FIX-HF-5C was a prospective, randomized, third-party blinded (CPX core lab), 
multicenter study. For the primary effectiveness endpoint, longitudinal data from the 
prospective study was analyzed together with 30% fixed borrowing of data from the 
229 subjects with EF > 25% from the FIX- HF-5 Phase II study using a Bayesian 
modeling approach. Subjects (n=160) were randomly assigned to one of two treatment 
groups with an allocation ratio of 1:1. Block randomization by site and etiology of heart 
failure (ischemic versus non-ischemic cardiomyopathy) was used to ensure balanced 
enrollment between the two groups. 
 
 
1.4.2 Overview of Study Methodology 
 
Sites identified potential patients from their clinic’s chronic heart failure population.  
The target patient population consisted of subjects with ejection fractions from 25 to 
45% (inclusive) whose symptoms were consistent with NYHA Class functional class 
III or ambulatory NYHA Class IV.   Informed consent was obtained from potential 
subjects who were then enrolled in the study to undergo baseline screening testing to 
determine eligibility for the study.  Baseline screening exams included: 
cardiopulmonary exercise testing (CPX) to determine peak VO2, echocardiography to 
determine left ventricular ejection fraction (LVEF), 12-Lead ECG, 24-hour Holter 
Monitor, quality of life assessment (MLWHFQ), a blinded assessment of NYHA Class 
and 6 minute walk test.  Each subject performed two CPX tests at baseline, and at the 
12 week, and 24 week follow-up visits.  The CPX tests were evaluated by an 
independent core laboratory.  The core laboratory was blinded to the randomization 
assignment for individual patients. 
 
If patients passed baseline testing, a device implant date was scheduled in the 
electrophysiology laboratory as soon as possible; this scheduled implant date served as 
the study start date (SSD) from which the timing of all future follow-up visits were 
determined. After passing baseline testing and meeting all entry criteria (Table 9), 
subjects were randomized in a 1:1 manner to either the Control Group that received 

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optimal medical therapy (OMT) alone or to the Active Group with OMT plus the 
OPTIMIZER IVs System. Subjects randomized to the Active Group were implanted 
with the device, and the implant date was canceled in subjects randomized to the 
Control group, but the putative implant date was kept as the SSD.  
 
Table 9: Subject Eligibility Criteria 
Inclusion Criteria 
Subjects who are 18 years of age or older 
Subject is male or non-pregnant female 
Subjects have baseline ejection fraction >= 25% and <= 45% as determined by 
the echocardiography core laboratory 
Subjects who have been treated for heart failure for at least 90 days (including 
beta blocker for 90 days) 
Subjects who have NYHA functional Class III or IV heart failure 
Subjects who have been receiving appropriate, stable medical therapy during the 
30 days prior to enrollment (Stable is defined as no more than a 100% increase or 
50% decrease in dose.) 
Subjects have a pre-existing ICD or pacemaker system, if one is clinically 
indicated 
Subjects who are willing to comply with the prescribed course of treatment and 
willing and able to return for all follow-up visits 
 
Exclusion Criteria 
Subjects whose baseline peak VO2 is <9 or >20 ml O2/min/kg 
Subjects who have a potentially correctible cause of heart failure, such as 
valvular heart disease or congenital heart disease. 
Subjects who have clinically significant angina pectoris, consisting of angina 
during daily life, an episode of unstable angina within 30 days before enrollment, 
or angina and/or ECG changes during exercise testing performed during baseline 
evaluation. 
Subjects who have been hospitalized for heart failure which required the use of 
inotropic support within 30 days before enrollment. 
Subjects who have a clinically significant amount of ambient ectopy, defined as 
more than 8,900 PVCs per 24 hours on baseline Holter monitoring. 
Subjects having a PR interval greater than 375 ms. 
Subjects who have chronic (permanent or persistent) atrial fibrillation or atrial 
flutter or those cardioverted within 30 days of enrollment. 
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 perform baseline stress testing. 
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. 
Subjects who have a biventricular pacing system, an accepted indication for such 
a device, or a QRS width of 130ms or greater. 
Subjects who have had a myocardial infarction within 90 days of enrollment 

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Exclusion Criteria 
Subjects who have mechanical tricuspid valve. 
Subjects who have a prior heart transplant. 
Subjects on dialysis. 
Subjects who are participating in another experimental protocol. 
Subjects who are unable to provide informed consent. 
 
Subjects then returned to the clinic for evaluation at 2 weeks, 12 weeks and 24 weeks 
following the initial implantation or SSD for control patients.  At the 12-week visit, 
subjects completed 2 CPX tests, a blinded NYHA, MLWHFQ, a routine physical exam, 
a medical history and an assessment of adverse events. In addition to evaluations 
performed at the 12-week visit, the 24-week visit also included the 6 minute walk test.  
Data collection for assessment of the study endpoints was concluded with the 24-week 
visit. Table 10 provides the schedule of events for the study. 
 
 
 
 
Table 10:  Schedule of Events 
 
 
 
Follow-Up Schedule  
(relative to Study Start Date§) 
Long-term F-up Every 6 Months**  
(relative to Study Start Date§) 
Test or Assessment 
Screening 
& Baseline 
OPT 
Implant 
Week 2  
±2 days§ 
+12±2 
Weeks 
+24±2 
Weeks 
US 
OPTIMIZER 
Group 
US 
Control 
Group 
EU OPT 
and 
Control  
Informed Consent 
X 
 
 
 
 
 
 
 
1-Year Medical 
History/Interim History 
X 
  
X 
X 
X 
X 
 
 
NYHA Class (site clinician 
assessment) 
X 
  
 
X 
X 
 
 
 
Medications 
X 
 
 
X 
X 
 
 
 
Physical Examination 
X 
 
 
X 
X 
 
 
 
12-Lead ECG* 
X 
 
 
 
 
 
 
 
24 hour Holter Monitor* 
X 
  
 
 
 
 
 
 
Echocardiogram* 
X 
  
 
 
 
 
 
 
MLWHFQ 
X 
  
 
X 
X 
 
 
 
Cardiopulmonary Stress Test 
2X 
  
 
2X 
2X 
 
 
 
6 Minute Walk Test 
X 
 
 
 
X 
 
 
 
Pregnancy test  
X 
  
 
 
X 
 
 
 
Eligibility determination 
X 
  
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
OPTIMIZER System 
Implant 
  
X 
 
 
 
 
 
 
Chest X-ray (prior to hospital 
discharge) 
  
X 
 
 
 
 
 
 
OPTIMIZER Device 
Interrogation / Programming 
  
X 
X 
X 
X 
X 
 
 
Adverse Events, 
Hospitalizations, and 
Procedures (as 
 X 
X 
X 
X 
X 
X 
 
 

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Follow-Up Schedule  
(relative to Study Start Date§) 
Long-term F-up Every 6 Months**  
(relative to Study Start Date§) 
Test or Assessment 
Screening 
& Baseline 
OPT 
Implant 
Week 2  
±2 days§ 
+12±2 
Weeks 
+24±2 
Weeks 
US 
OPTIMIZER 
Group 
US 
Control 
Group 
EU OPT 
and 
Control  
needed)/OPTIMZER device-
related SAEs after 24-weeks 
Vital Status  
 
 
 
 
 
X 
X 
X 
 § Study Start Date (SSD):  After completion and satisfying all entry criteria and prior to randomization, 
a date shall be scheduled for OPTIMIZER System implantation.  This date shall serve as the start date 
for all subjects regardless of randomization assignment, from which all future follow-up visits are 
scheduled.  
* 12-Lead ECG, 24-Hour Holter Monitor, and Echocardiogram test results (from the study-qualified lab) 
obtained within 30 days before informed consent and performed in accordance with the protocol, 
testing, and data collection requirements may be used for eligibility determination. 
** US OPTIMIZER subjects are followed every 6 months (+/- 4 weeks) after the 24-week interval for 
device interrogation and reporting of OPTIMIZER Device related SAEs, if any. All other subjects are 
followed for vital status only, for 2 years following their SSD. 
OPTIMIZER subjects in the US were then followed every 6 months at which time an 
interim medical history was obtained, device interrogation was performed, occurrence 
of adverse events was assessed, and vital status recorded.  Control subjects and 
OPTIMIZER subjects OUS were assessed every 6 months for vital status only, until 2 
years. 
 
A detailed description of all study methodologies, associated criteria and definitions is 
provided in the Study Protocol for the FIX-HF-5C study (Attachment 4). 
 
1.4.2.1 CPX Core Laboratory 
 
We think it important to note that, to the best of our knowledge, no prior study 
has invested as much time, effort and financial resources to ensure the quality of 
every cardiopulmonary stress test (CPX).  Quality measures taken in the FIX-
HF-5C study, included: quality assurance testing at every site to validate 
equipment every 6 months; sending technicians to perform tests upon requests 
of the sites or when the core lab identified issues with test performance; 
mandating two tests at each timepoint; and rapid centralized reads of test quality 
and asking for additional tests when quality metrics were not met.  Similar 
measures were taken in the FIX-HF-5 study with the exception of two tests at 
each timepoint.  Thus, we believe that the data of the current study are valid, and 
reflect what can be expected from serial assessments of exercise tolerance in our 
target population.   
Rigorous procedures were used for the conduct of CPX testing at the sites and 
the evaluation of the tests by a blinded core laboratory to optimize the quality of 
tests and achieve maximal effort from each patient.  These measures included: 
1) on-site training on standardized procedures for conducting CPX testing; 2) 
normal subject validation testing and revalidation every 6 months; 3) providing 
the patient with instructions on how to prepare for the CPX test; 4) rapid 
feedback on quality of every test from the core laboratory and retest requests for 

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inadequate tests; and 5) two tests performed at each time point. 
Tests were deemed inadequate if: 1) the subject had an erratic or oscillatory 
breathing pattern; 2) the data were non-physiologic; 3) an issue was identified 
with the testing equipment; or 4) the test was submaximal, meaning it was 
terminated by either the subject or the supervising clinician/technician prior to 
the subject reaching volitional exhaustion. Reasons for early termination 
included non-heart failure symptoms (e.g., angina, heart rhythm disturbance, or 
leg, foot, or back pain) or the subject was technically challenged to perform the 
test.   
Metabolic data were collected for 2 minutes prior to the start of exercise to 
confirm RER, VO2, and the subject’s ventilation volume were at normal, 
physiologic, and stable resting values before beginning the test. Metabolic data 
were then collected for the duration of the test and for an additional 2 minute 
recovery period following termination of the test. Peak VO2 and peak respiratory 
exchange ratio (RER) were determined by the blinded core lab from averaged 
20 second averaged gas exchange data from the start of exercise to the end of 
exercise.  Tests were deemed to be of maximal effort if RER reached 1.05 or 
greater. 
As noted, two CPX tests were performed for each subject at baseline and at the 
12- and 24-week follow up visits.  A 3rd test could be requested by the core lab 
if both tests were deemed inadequate based on criteria defined above.  If both 
tests were deemed adequate, the average of the 2 tests was used for the value at 
that time point.  If only 1 test was deemed adequate, then only that 1 value was 
used for the analysis.  As in a prior study,5  this approach was used to reduce 
variability of test results with the potential for reducing sample size.  
 
The CPX core lab SOP is provided in Attachment 05. 
 
 
1.4.2.2 Safety Oversight Committees 
 
An Events Adjudication Committee (EAC) was established to review records of 
individual serious adverse events, hospitalizations and deaths.  This committee 
was composed of 3 independent cardiologists experienced in the adjudication 
process.  The committee provided definitions for OPTIMIZER device-related or 
procedure-rated complications, protocol-specified hospitalizations which 
included a hospital admission that resulted in a calendar date change or was 
related to an adverse event that caused a prolongation of the index hospitalization 
for device implantation.  The committee also adjudicated the cardiac and heart 
failure relatedness of deaths and hospitalizations.   
An independent Data and Safety Monitoring Board (DSMB) reviewed aggregate 
safety data and monitored for the emergence of any significant safety concerns.  
The DSMB was composed of 5 members with clinical trial experience in heart 
failure, electrophysiology and statistics not otherwise participating in the study.  

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The DSMB was unblinded to study group assignment.   
  
1.4.3 Overview of Statistical Analyses 
 
Statistical analysis of the FIX-HF-5C study data utilized two distinct statistical 
techniques.  Analysis of the primary effectiveness endpoint, peak VO2, was done using 
Bayesian techniques where fixed borrowing from the previous FIX-HF-5 trial was 
incorporated.  The use of Bayesian methodology improved the statistical power of the 
results.  The remaining effectiveness and safety endpoints were analyzed employing 
typical frequentist statistical methods. A detailed description of the Statistical Analysis 
Plan and the resultant Statistical Report for both Primary Effectiveness Endpoint and 
other endpoints can be found in the following attachments. We provide a brief overview 
here of the Statistical Methods. 
 
Attachment 02    FIX-HF-5C Statistical Analysis Plan 
Attachment 06    Primary Endpoint Analysis Specification 
Attachment 07    Primary & Key Secondary Analyses Impulse Dynamics FIX-HF-5C 
Attachment 03    Statistical Analysis Report of Impulse Dynamics FIX-HF-5C Study. 
 
The primary effectiveness endpoint for the study was serial change in peak VO2 
measured at baseline, 12 weeks and 24 weeks of follow up. Here, we summarize the 
hypothesis for the primary analysis. Let Δ3 be the mean difference in peak VO2 
between device and control groups at the third (24 week) visit, adjusting for baseline 
and 12-week peak VO2 values. The primary analysis corresponds to a test of the 
following hypothesis: 
H0 : Δ3 ≤ 0                                         (1) 
H1 : Δ3  > 0 
A Bayesian model is fitted in order to obtain the posterior distribution of Δ3. If the 
Bayesian posterior probability that Δ3 is positive is greater than 0.975, i.e. 
Pr (Δ3 > 0) > 0.975                             (2) 
the null hypothesis will be rejected and the device will be considered superior to 
control with respect to the primary endpoint. As described in the analysis plan, the 
data from the FIX-HF-5 study that is incorporated into this Bayesian model is given 
by the following table: 
 
Table 11: FIX-HF-5 Treatment Effect Posterior Distributions 
Time 
Posterior Mean 
Posterior SE 
Lower 95% 
Upper 95% 
12 weeks 
         0.232 
      0.343 
      -0.442 
    -0.908 
24 weeks 
         1.080 
      0.344 
        0.413 
     1.759 
 
As detailed in the statistical analysis plan (Attachment 02) and the final report on the 
Primary & Key Secondary Analyses Impulse Dynamics FIX-HF-5C (Attachment 07), 
the primary measure of effectiveness was defined as the change in peak VO2 as 
evaluated by the blinded core laboratory. The primary analysis employed a Bayesian 

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repeated measures linear model to estimate group differences in mean peak VO2 at 24 
weeks from baseline, with 30% borrowing of information (70% down-weighting) from 
the corresponding treatment group difference observed in the FIX-HF-5 study 
subgroup.  
More specifically, the Bayesian linear model incorporated peak VO2 data from 
baseline, 12 weeks, and 24 weeks for each patient, in which a mean treatment difference 
was estimated at 12 and 24 weeks and set equal to zero (no treatment difference) at 
baseline on the premise of randomization.  A random intercept was used to account for 
repeated observations within the same individual.  An informative prior distribution 
was used for the treatment effect at 12 and 24 weeks based on FIX-HF-5 data, using 
the power prior methodology of Ibrahim and Chen6, with a 30% weight or 70% down-
weighting of the FIX-HF-5 subgroup treatment group difference. Non-informative 
prior distributions were specified for all other model parameters. The pre-specified 
primary analysis would conclude superiority of the CCM™ Treatment group versus 
Control if the Bayesian posterior probability of a positive treatment difference in favor 
of CCM™ treatment exceeded 0.975.  In addition, a 95% Bayesian credible interval 
was provided based on the 2.5th and 97.5th percentiles of the Bayesian posterior 
distribution of the treatment difference.  For summary purposes, and similar (non-
Bayesian) repeated measures model was also fitted to the FIX-HF-5 and FIX-HF-5C 
studies (without borrowing) to summarize the treatment differences of each trial 
independently. 
 
Quality of life assessed with the Minnesota Living with Heart Failure Questionnaire 
(MLWHFQ) was a key secondary effectiveness endpoint.  The 21-question scale 
assesses the impact of the signature physical symptoms and signs of heart failure. Other 
questions look at physical and social functioning in the context of heart failure 
symptoms.  Scores on the MLWHFQ can range from 0 to 105.  The tool is validated 
for the heart failure patient population. 
 
Additional secondary effectiveness endpoints include: 
• 
Change in NYHA Class 
• 
Change in Peak VO2 including only tests with RER > 1.05 
 
The primary safety endpoint was the incidence of complications (OPTIMIZER device- 
or procedure-related serious adverse events that requires invasive treatment or results 
in a permanent disability or death). The success criterion for the safety endpoint was 
set such that the therapy would be considered safe if greater than 70% of the implanted 
population was free of such a complication.  This criterion was agreed upon with FDA 
with approval of the final Data Development Plan (DDP) on July 13, 2017.  Secondary 
safety endpoints included mortality, hospitalizations, and SAEs. 
 
1.4.3.1 Analysis Populations 
 
The primary analysis of effectiveness utilized the intent-to-treat (ITT) population, i.e., 
all randomized subjects. All subjects were analyzed in the group to which they were 
randomized. The analysis of the primary safety endpoint utilized the population of all 

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subjects implanted with the OPTIMIZER system. Supporting analyses of the primary 
endpoints were done in completed cases (CC) and the per protocol (PP) population. 
Secondary and additional effectiveness analyses were conducted in completed cases and 
the PP population. Completed cases refer to all available data for the particular endpoint 
of interest. The PP population is defined as subjects who received treatment 
(OPTIMIZER Group), have any follow-up post study start and have no protocol 
violations that would affect endpoint assessment. Secondary and additional safety 
endpoints were assessed in the PP population. The primary effectiveness endpoint was 
evaluated together with the borrowing of information from 229 subjects with EF≥25 
from the original FIX-HF-5 study using a Bayesian modeling approach.  
1.4.3.2 Subject Accountability 
A summary table provides the total number of subjects screened, randomized and 
evaluable, by investigational site. The subjects eligible for and compliant with each 
follow-up visit were summarized descriptively. Subjects withdrawn were tabulated with 
their reasons for withdrawal. 
Each subject screened for the study was accounted for. A subject accountability table 
presents the total number of screened and randomized subjects as well as the total 
number of evaluable subjects and subjects with a violation of specific inclusion or 
exclusion criterion. A tabulation of subjects who were screened but not randomized, and 
their reasons for ineligibility, is provided. Subjects who were ineligible at the 
intraoperative stage with the reason for ineligibility and subjects with a protocol 
violation with the specific violation are also listed. Subjects were grouped into broad 
categories for the purpose of tabulation. 
1.4.3.3 Character of Study Variables 
For continuous variables, the descriptive analyses present the mean, standard deviation, 
median, minimum and maximum. For categorical variables, the number with the 
characteristic, the total number evaluated, the percent and the 95% exact binomial 
confidence intervals are provided. 
 
4.4.3.4 Comparability Analyses 
Comparability analyses were performed to determine the similarity between treatment 
groups and study sites with respect to important demographic or other variables, either 
known or suspected to have an influence on the outcome variables. The absence of 
similarity for any variable identifies that variable as a potential covariate in subsequent 
safety and effectiveness analyses. 
1.4.3.4.1 Treatment Group Comparability 
The demographic and prognostic variables measured at study entry include 
baseline peak VO2 between the OPTIMIZER treated and control groups. 
Continuous variables were compared with two-sample t-test or Wilcoxon rank 
sum test, and categorical variables were compared with Fisher's exact test or 
Chi-square test. 

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1.4.3.4.2 Study Site and Geographic Region Comparability 
A set of important demographic or prognostic variables were compared across 
study sites to determine homogeneity of study sites in subject characteristics. 
Smaller study sites with insufficient numbers of subjects to allow a meaningful 
analysis were combined into one or more pseudo-sites to allow the comparison 
to be done. The size of any pseudo-site created in this way does not exceed the 
size of the study site with the largest enrollment 
Demographic and prognostic variables were not used as a basis for combining 
data across study sites. Rather, the data were combined on a clinical basis, i.e., 
the sites used a common protocol, the sponsor adequately monitored the study 
to assure protocol compliance, and the data gathering and validation 
mechanisms were the same across all study sites.7 
A sensitivity analysis was conducted on the primary outcome to determine if 
the estimated difference in treatments is consistent across pseudo-sites. A 3-
level model with measurement occasions nested within subjects and subjects 
nested within pseudo-sites was performed to obtain an overall estimate of the 
combined treatment effect, allowing for the effect of treatment to vary over 
sites. Site by treatment interactions of a quantitative nature, i.e., all pseudo- sites 
show the treatment to be beneficial, but perhaps to a different degree by pseudo-
site, were not considered to be an impediment to combining data. Site by 
treatment interactions that are qualitative in nature, i.e., the vast majority of 
pseudo-sites show the treatment to be beneficial, but one or more pseudo-sites 
show the treatment to be detrimental, requires extensive evaluation of the 
pseudo-sites with contrary results to attempt to determine what factors at those 
pseudo-sites led to the result.8 
A similar sensitivity analysis was performed to compare a set of important 
demographic or prognostic variables across geographic regions (US vs non-
US). A 3-level model with measurement occasions nested within subjects and 
subjects nested within study regions was performed to obtain an overall estimate 
of the combined treatment effect, allowing for the effect of treatment to vary 
between regions. 
 
1.4.3.5 Primary Effectiveness Endpoint Analysis 
The main effectiveness endpoints of the Impulse Dynamics FIX-HF-5 trial were 
ventilatory anaerobic threshold (VAT primary) and peak VO2 (secondary) at 24 
weeks, using multiple imputations to obtain estimates of missing data. In addition, 
responder analyses were conducted using a variety of arbitrary cut-points (i.e. percent 
improvement) as a basis for dichotomizing the quantitative data and "response rates" 
were compared between treated and control subjects. Results of these analyses 
showed that the effectiveness of the OPTIMIZER System, when assessed by increases 
in peak VO2, is most evident in a subgroup of subjects with an EF>=25% at baseline. 
Several issues were identified with the approaches used in the FIX-HF-5 study. First, 
they did not make full use of the available data, which included measurements at 

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baseline, 12, and 24 weeks. Second, in order to obtain an end-point, values had to be 
imputed for those subjects that had a missing value at 24 weeks. Third, the responder 
analyses were based on dichotomization of the underlying quantitative data using 
arbitrary thresholds which may not be clinically meaningful. 
To overcome these limitations, the FIX-HF-5C study utilized an alternative statistical 
approach to the analysis of these data based on mixed effects regression models9 with 
peak VO2 as the primary endpoint. Unlike the 'pre-specified endpoint analyses using 
propensity score matching for imputation of missing data, the current analysis uses 
all available longitudinal data (baseline, 12 weeks, and 24 weeks from each subject 
). This statistical approach does not require imputation, but still provides the same 
level of robustness to missing values and drop-outs (missing at random - MAR)10 
employed by the previously used multiple imputation procedure. Specifically, we 
model the three repeated measures from each subject as normally distributed with 
arbitrary means. The correlation and variance parameter models used were chosen as 
those that give the best fit (by the Bayesian Information Criterion) to the FIX-HF-5 
data. In particular, we found that an equicorrelation, equal variance model fit the data 
quite well, and was superior by BIC to:  
(i) 
arbitrary variances and correlations; 
(ii) 
random intercepts and slopes with arbitrary variances;  
(iii) 
random intercepts and slopes with equal variances. Error variance was 
allowed to vary by study as the prospective data is expected to have 
lower variability due to averaging of replicated studies.  
The primary effect of interest is the treatment by time-24-weeks interaction. A 
Bayesian approach was used (see next section) to extend this model to allow the 
treatment by time interactions to vary across the 2 subgroups and the 2 studies which 
allows the evidence in this new study to take into account the previous findings in 
FIX­ HF-5. 
 
As a sensitivity analysis with respect to pooling of centers, centers were dummy-
coded and included as a fixed-effect in a model along with center by time, center by 
treatment and center by treatment by time interactions. If a significant center by 
treatment by time interaction is found at the p=0.15 level, then random center effects 
were included in a model which permits the treatment by time interactions to vary 
across centers, and the overall pooled estimate of the treatment by time interaction 
was obtained and tested for significance. This sensitivity analysis was based on FIX-
HF-5C data only and was based on maximum likelihood methods (not Bayesian). 
A similar sensitivity analysis was carried out to test for a region (i.e., US vs non-US) 
by treatment by time interaction. 
Siddiqui, Hung and O'Neill of the FDA Office of Biostatistics conducted a detailed 
simulation study to compare the endpoint analytic approach of last observation carried 
forward (LOCF) to the generalized mixed-effects regression model that we have 
proposed here11. They conducted two extensive simulation studies to examine the 
empirical bias and Type I error rates associated with the estimators and tests of 

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treatment related effects under three missing data assumptions (missing completely 
at random (MCAR), MAR, and missing not at random (MNAR)). The results of these 
studies revealed that LOCF endpoint analysis can lead to substantial biases in 
estimators of treatment effects under all three of the missing data mechanisms 
evaluated, whereas the generalized mixed-model analysis of the available data leads 
to estimators with comparatively small bias, and controls Type I error rates at the 
nominal level in the presence of MCAR, MAR, and some cases of MNAR. In a 
sensitivity analysis of 48 RCTs from 25 NDAs, the generalized mixed model was the 
superior approach in controlling Type I error rates and minimizing biases as compared 
to the endpoint analytic approach. Interestingly, no evidence of MNAR was found in 
these real datasets. 
 
1.4.3.5.1 Bayesian Primary Analysis for Borrowing Strength from the Original 
FIX -HF-5 Study  
Specific details of the primary analysis, including relevant simulations and 
operating characteristics, are given in the "Primary Analysis Specification" 
report provided with the Primary Analysis Report (Attachment 06). 
 
1.4.3.5.2 Supportive Secondary Analyses 
As supportive analyses, we used a correlated repeated measures model identical 
to the primary analysis model to analyze the prospective FIX-HF-5C trial on a 
standalone basis. This model was based on maximum likelihood methods (non-
Bayesian). We also used correlated repeated measures model to test for baseline 
factors that modify the relationship between the changes in peak VO2 associated 
with the OPTIMIZER treatment. We did this for all possible clinically relevant 
variables including age, gender, baseline peak RER, baseline ejection fraction, 
history of diabetes, NYHA class per blinded assessment, primary heart failure 
etiology, pacing or ICD use, baseline Minnesota Living with Heart Failure 
questionnaire score, and study site. Potential covariates were screened by the 
method of Hosmer and Lemeshow.12 The screening was done by forming 
bivariate regression models with treatment, the covariate, and the treatment by 
covariate interaction. If the interaction or the main effect has a p-value of 0.2 or 
less, the covariate was allowed to enter the competition for the final (secondary 
analysis) model. The final supportive model was done by manual backward 
elimination and retained only main effects and interactions that have a p-value 
of 0.025 or less. Recall that if an interaction is statistically significant, the main 
effects for the terms in the interaction must be included in the model regardless 
of their p-values. 
As further supportive secondary analyses, the Bayesian modeling of the 
primary endpoint (with borrowing of FIX-HF-5 data) as well as the above 
standalone secondary analyses (no borrowing) was repeated for the CC and PP 
populations. 

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The results for these analyses are also found in the Primary & Key Secondary 
Analyses Impulse Dynamics FIX-HF-5C report (Attachment 07). 
 
1.4.3.6 Primary Safety Analysis 
The primary safety analysis evaluated the OPTIMIZER procedure- or device-
related complication rates through 24-weeks of follow up. We constructed an exact 
binomial 95% confidence interval for the complication free proportion. 
 
The primary safety endpoint was the percentage of subjects in the OPTIMIZER group 
who experienced either an OPTIMIZER device or OPTIMIZER procedure related 
complication through the 24-week follow-up period, as determined by an 
independent events adjudication committee (EAC). The EAC reviewed all serious 
adverse event reports (SAEs), confirmed the classification of "serious", and 
adjudicated the relationship of the event to the OPTIMIZER System device or 
procedure. SAEs that the EAC determined to be definitely related to either the 
OPTIMIZER System or the OPTIMIZER Procedure were further classified as either 
a Complication or Not a Complication. A "complication" is an OPTIMIZER device 
or OPTIMIZER procedure related event that requires invasive treatment or results in 
a permanent disability or death.  
Satisfying the primary safety endpoint required that the complication-free proportion 
of the population was significantly higher than 70% (using a one-sided significance 
level of 0.025).   
 
1.4.3.7 Justification of Sample Size 
Power calculations for a longitudinal design are normally quite complex, and the 
addition of the Bayesian modeling increases the complexity. We adopted the 
following approach. Data were simulated based on a multivariate normal 
distribution, in which the means, variances, and correlations between time points 
are based on the FIX-HF-5 data. We assumed that all variance components for the 
prospective study were the same as their estimated values in the subgroup of interest 
analysis from the FIX-HF-5 data except we allowed the variances to be lower to 
reflect the 2 independent replicates being averaged together for each measurement, 
and we allowed this general covariance structure to be scaled smaller or larger than 
the FIX-HF-5 study. We also assumed that the control group means at each time 
point are the same as in the subgroup of interest for the original trial. We then 
simulated a large number of prospective datasets under these assumptions for a 
variety of possible true treatment effects (differences in change from baseline to 24 
weeks between control and treatment arm) and calculated the proportion of these 
datasets that would satisfy the Bayesian superiority criterion of the previous section. 
Assuming a true treatment effect of O (that is the slopes in the two arms are 
identical) yields the type I error. Simulations are presented in the "Primary Analysis 
Specification" report (Attachment 06). For 30% borrowing of the FIX-HF-5 data, 
the Type I error was controlled at approximately 0.10, and has power ranging from 
about 0.40 for the smallest effect to 0.99 for the largest effect. 

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1.4.3.8 Secondary effectiveness analysis 
If the null hypothesis was rejected for the primary endpoint, it was planned that the 
secondary effectiveness analyses would be performed. Details of the secondary 
effectiveness analyses are provided in the "Primary Endpoint Analysis 
Specification" report (Attachment 06) provided with the “Primary & Key 
Secondary Analyses Impulse Dynamics FIX-HF-5C” Report (Attachment 07). 
 
1.4.3.9 Supporting Secondary Effectiveness Analyses 
A supporting analysis of the secondary endpoints was done using the combined 
FIX-HF-5C and FIX­ HF-5 subject data with baseline NYHA III-IV and baseline 
EF>25% (to be referred to as the FIX-HF-5 Subset).  
These supporting secondary effectiveness analyses were done in the completed 
cases population from the combined FIX-HF-5 Subset and FIX-HF-5C data sets. 
The analysis of MWLHF and peak VO2 with RER ≥1.05 utilized a repeated 
measures analysis of variance restricted maximum likelihood model that included 
baseline value of the variable being analyzed, treatment group, study visit, and 
etiology used in the randomization. The NYHA analysis of at least one class 
reduction from baseline used the same Mantel-Haenszel method proposed from the 
secondary endpoint applied to the combined study groups. 
 
1.4.3.10 Exploratory Effectiveness Analyses 
As exploratory analyses, all primary and secondary analyses are repeated with 
pooled FIX-HF-5 Subset and FIX-HF-5C data using maximum likelihood methods, 
with adjustment for study where applicable (e.g. a fixed effect for study in 
longitudinal models). 
A series of additional analyses of effectiveness were performed.  Each variable was 
tested with a univariate and multivariate test. The univariate test for categorical 
variables were with Fisher's exact test and the multivariate analysis was done with 
logistic regression. If the variable is ordinal or continuous, the univariate test was a 
two-sample Wilcoxon rank sum test and the multivariate test was done with the 
analysis of variance procedure or equivalent. Screening for all multivariate analyses 
was done to prevent over specification of the model. 
The additional analyses include: 
 
a. Univariate and multivariate evaluation of the primary effectiveness 
endpoint in the per protocol population. 
b. Comparisons of treatment effects separately in subjects whose CHF etiology 
is ischemic or non-ischemic. 
c. Comparison of treatment effects separately in the subjects whose EF is ≥ 
35% 

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d. Comparison of treatment effects in the subjects with NYHA Ill symptoms at 
baseline 
e. Comparison of mean changes in 6 minute hall walk test between baseline 
and 24 weeks. 
f. Comparison of mean changes in VE/VCO2 between baseline and 24 weeks 
g. A comparison of treatment effects between the lead types (i.e., St. Jude, 
Biotronik, and Boston Scientific) utilized during the FIX-HF-5C study 
were performed. 
h. The number of days in and out-of-hospital was analyzed for each study for 
subjects with EF ≥25 and NYHA class of III or IV. 
 
These analyses are supportive or exploratory analyses and are not intended to 
be part of claims for the device. Their purpose is to investigate properties of the 
device that may be used in publications or for planning additional claims in 
future studies. 
 
1.4.3.11 Secondary Safety Analysis 
The nature, frequency, and seriousness of adverse events between the two groups 
were compared using descriptive summary statistics. In addition, the primary safety 
endpoint and hypothesis were tested on the completed cases and per protocol 
populations. 
• 
All-cause mortality 
• 
Cardiac mortality 
• 
Composite rate of all-cause mortality and all-cause hospitalization 
• 
Composite rate of cardiovascular mortality and heart failure-related 
hospitalizations 
• 
Overall incidence and seriousness of adverse events 
 
Kaplan Meier plots and log-rank tests were used to descriptively compare treatment 
groups for each of the above outcomes. Summary statistics were presented for both 
the prospective data alone and on the prospective data pooled with the data from the 
original FIX-HF-5 study in the subgroup of interest (NYHA=III or IV, EF ≥25% 
subgroup). 
 
1.4.3.12 Missing Data 
 
Our primary approach to handling missing endpoint data was the mixed effects 
modeling framework.  Mixed models provide valid inference for the model 
parameters provided that all missing data are "missing at random" (MAR) with 
respect to the data used in the statistical model.  If the MAR assumption does not 
hold, inference can be biased.  In particular, endpoint data missing due to patient 
death or to heart failure hospitalization are not MAR.  To handle these specific cases 
a value of 0 was imputed if the reason for missing was death and the minimum value 

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observed from the cohort at the respective time point was imputed if the reason for 
missing was heart failure hospitalization.  For all other cases, including events 
occurring between enrollment and start date, assumed to be MAR, there are several 
approaches we could potentially use to examine the sensitivity of our results to this 
assumption.13   Our primary presentation employs a tipping point approach.14 We 
constructed a grid showing the effect of filling in a range of pairs of values for missing 
control and treatment arm patients.  The grid ranged from –2 SD's below the average 
(here SD means the standard deviation of the non-missing values of the outcome 
measure of interest) to 2 SD's above the average by increments of 0.1 SD's with one 
axis for treatment group and the other for control group.  For each location in this 
grid, we filled in the indicated control and treatment values for all missing data points 
and then indicated whether our primary endpoint was met or not met by shading the 
grid box different colors.  The grid can be thought of as a way to bridge quasi-
continuously between a worst-case, most likely-case, and best-case analyses.  In 
addition, we compared the patterns of missing data between the treatment and control 
group by constructing a two-way table of all possible missingness patterns (as there 
are 3 time points, there are 8 possible patterns) vs. study arm.   
 
 
1.4.4 Protocol Deviations 
 
Protocol deviations were reported from baseline testing through the end of the 24-week 
study period and are tabulated by category, study interval and randomization assignment 
in Table 12 below. There were no protocol eligibility deviations reported. 
Table 12: Protocol Deviations Number of deviations (number of subjects) 
  
Baseline 
SSD-24 weeks 
Deviation Category 
Control 
Active 
Control 
Active 
Consent and re-consent 
1 
0 
3(3) 
3(3) 
Medication reporting 
1 
0 
0 
0 
Testing 
1 
2(2) 
18(15) 
18(15) 
Implant not done 
  
  
N/A 
3(3) 
dP/dt testing not done 
  
  
N/A 
2(2) 
CCM therapy 
  
  
N/A 
1 
Follow-up visit done out of window 
  
  
22(20) 
16(14) 
2 week visit not done 
  
  
3(3) 
0 
4 week visit not done 
  
  
1 
0 
12 Week follow-up not done 
  
  
2(2) 
0 
24 Week follow-up not done 
  
  
5(5) 
0 
Subject Lost To Follow-up 
  
  
0 
1 

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Baseline 
SSD-24 weeks 
Deviation Category 
Control 
Active 
Control 
Active 
SAE Reporting Delay 
0 
0 
4(4) 
2(2) 
 
Consent and re-consent: The deviation related to consent at baseline was because the 
consent process was not documented in the medical record.  The 6 follow-up re-
consent deviations were for either a delay in providing a revised version of the consent 
form or an extra consent addendum was incorrectly provided to the subject in addition 
to the main consent form.  
Medication reporting: One subject did not have complete reporting of the baseline 
medications. 
Testing: This includes individual tests that were done outside the protocol window, 
were not done at all, the equipment failed during the test, or the test was not done in 
accordance with the testing procedure. 
Implant not done: Subjects that were randomized to the OPTIMIZER System but did 
not receive the device are described in detail in another section of the current report.   
dP/dt testing not done: The September 25, 2015 version of the protocol dropped the 
requirement of dP/dt testing that involved performing a left heart catheterization in the 
patient prior to implanting the device. Two (2) implant cases were done after FDA 
approval with IRB approval documentation pending. 
CCM™ therapy: Subjects are typically discharged with CCM™ therapy programmed 
ON after the index hospitalization. In one case, due to lasting effects from the 
anesthesia, CCM™ was initiated 2 days later. 
Follow-up visit done out of the window: This included study visits that were 
completed but were done either prior to the study window start date or after the study 
window end date.  
2 week or 4 week visits not done: Four visits were not done in Control group subjects. 
These study visits only required a safety assessment and an OPTIMIZER device 
interrogation for subjects that received the device. Control subjects that did not return 
for these visits were assessed for safety over of the phone until they returned for the 
12-week visit. No effectiveness endpoints were required at these two intervals. 
12 week or 24 week visits not done: As with the 1 and 4-week visits, the 12 and 24 
week missed visit deviations were only reported in the Control group. There were 7 
subjects that missed either the 12 week or the 24 week visit.  
Subject Lost To Follow-up: There was one subject that was randomized but was never 
heard from again after that. The details of this case are described in the Subject 
Accountability Section of the current report. 
Study visits performed outside the study window specified in the protocol accounted 
for a majority of the protocol deviations that occurred.  None of the protocol deviations 
were serious enough to cause the associated patient to be removed from the overall 

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analysis of data.  Similarly, none of the protocol deviations were judged to have a 
significant impact on the outcomes achieved in the study, either positive or negative. 
The majority of the “Testing” deviations had to do with the subject being unable to 
do, or refusing to do, the CPX testing at one or both follow-up intervals. All have been 
detailed below for each study group. 
 
There were 18 testing deviation reports in 15 Active subjects. 
 
1. Subject 06-404 (Active, 2 Test Deviations) did not do the CPX testing at 12 or 24 
weeks, due to back pain with ambulation. At the 24 week interval, the subject also 
did not do the 6MW test.  
2. Subject 06-409 (Active, 1 Test Deviation) did the 24 week NYHA assessment out 
of window (2 days late) due to the blinded NYHA coordinator being unexpectedly 
out of the office on the scheduled visit day.  
3. Subject 32-409 (Active, 1 Test Deviation) was unable to have the OPTIMIZER 
device interrogated due to a lead dislodgement.  
4. Subject 51-426 (Active, 1 Test Deviation) did the 6MW test 73 minutes after 
completing the CPX test, when the SOP requires a 3 hour period between the 2 
tests. 
5. Subject 51-456 (Active, 1 Test Deviation) only did one 12-week CPX test and was 
unable to do the second one due to his wife dying that week. 
6. Subject 51-459 (Active, 1 Test Deviation) performed several of the required 12-
week assessments 4 days prior to the visit window starting, including one of the 
two required CPX tests. The second CPX test was performed within the study 
window. 
7. Subject 57-413 (Active, 1 Test Deviation) did the 6MW test prior to the 3 hour 
period required after completing the CPX test. 
8. Subject 65-403 (Active, 1 Test Deviation) did not have a 12-week NYHA 
assessment done, due to a scheduling oversight. 
9. Subject 70-410 (Active, 1 Test Deviation) did the 6MW test prior to the 3 hour 
period required after completing the CPX test. 
10. Subject 72-406 (Active, 1 Test Deviation) did the NYHA assessment outside the 
24-week study visit window (44 days late). 
11. Subject 75-429 (Active, 2 Test Deviations) refused to complete the 12-week and 
24-week CPX testing due to symptoms of nausea experienced after test. 
12. Subject 78-401 (Active, 1 Test Deviation) only did one 24-week CPX test. Test #2 
could not be done do to a hardware failure of the equipment. 
13. Subject 90-405 (Active, 1 Test Deviation) did not have a pre-discharge x-ray taken 
as required per protocol. 
14. Subject 90-406 (Active, 1 Test Deviation) did not have a pre-discharge x-ray taken 
as required per protocol. 
15. Subject 90-422 (Active, 2 Test Deviations) performed both 12-week CPX tests as 
required, however due to an equipment malfunction, the data from test #2 was lost.  
This subject completed all testing required for the 24-week interval, however the 

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6MW test and the MLWHFQ were done outside of the protocol visit window (9 
days late). 
There were 18 testing deviation reports in 15 Control subjects. 
 
1. Subject 08-401 (Control, 1 Test Deviation) completed the 12-week visit, including 
CPX test #1, within the study window. The second of the 2 required CPX tests was 
canceled due to weather and not performed until 28 days later. Only test #1 was 
approved by the core lab. 
2. Subject 41-405 (Control, 2 Test Deviations) refused to do CPX testing at 12 weeks 
and 24 weeks. At the 24 week visit, the subject also refused to do the 6MW test and 
NYHA assessment 
3. Subject 51-432 (Control, 1 Test Deviation) only did one 12-week CPX test and 
refused to do the 2nd one.  
4. Subject 51-438 (Control, 1 Test Deviation) only did one 24-week CPX test and did 
not do the 2nd one due to his travel schedule. 
5. Subject 51-467 (Control, 1 Test Deviation) did not do the 24-week CPX or 6MW 
testing due to a recent pulmonary embolism. All other tests and assessments were 
performed. 
6. Subject 55-408 (Control, 1 Test Deviation) had a foot fracture and was on 
continuous oxygen therapy and was unable to do CPX testing at the 12-week 
interval.  
7. Subject 55-413 (Control, 1 Test Deviation) became ill after the 1st CPX test for the 
24-week interval, so the 2nd test was not performed.  
8. Subject 59-408 (Control, 1 Test Deviation) did not do the 24-week 6MW test due 
to a scheduling oversight and it wasn’t realized until the testing widow had closed. 
9. Subject 65-421 (Control, 2 Test Deviations) refused to complete the 12-week CPX 
testing and also refused the 24-week CPX testing due to orthopedic issues. 
10. Subject 65-431 (Control, 1 Test Deviation) did not complete the 12-week CPX 
testing due to his traveling schedule. 
11. Subject 65-450 (Control, 1 Test Deviation) did the 6MW test prior to the 3 hour 
period required after completing the CPX test. 
12. Subject 65-475 (Control, 1 Test Deviation) performed both 24-week CPX tests as 
required, however due to an equipment malfunction, the data from test #2 was lost.   
13. Subject 70-411 (Control, 1 Test Deviation) refused any study specific testing during 
12-week visit except for the MLWHFQ and NYHA assessment. 
14. Subject 75-424 (Control, 1 Test Deviation) only did one 12-week CPX test and 
refused to do the 2nd one. 
15. Subject 90-408 (Control, 2 Test Deviations) did not perform the 12-week CPX 
testing or the 24-week 6MW test and CPX testing due to a diabetic foot ulcer. 
            Table 13: Testing Deviation Summary 
Testing Deviation 
Control 
Group 
Active 
Group 
Pre-discharge x-ray no done 
N/A 
2 

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OPTIMIZER Interrogation not done 
N/A 
1 
No CPX testing at 12-weeks 
4 
2 
Only 1 CPX test done at 12-weeks 
4 
2 
No NYHA assessment at 12-weeks 
0 
1 
No CPX testing (or 6MW) test at 24-weeks 
5 
2 
Only 1 CPX test done at 24-weeks 
2 
1 
No 6MW test at 24-weeks 
1 
0 
Time between CPX test and 6MW test too 
short 
1 
3 
Testing done late outside of protocol window 
1 
3 
Testing done early outside of protocol 
window 
0 
1 
 
18 (15) 
18 (15) 
 
1.4.5 Ethics Statement 
 
The study followed the Declaration of Helsinki and adhered to good clinical 
practices as defined in ICH-E6.15,16  
 
1.4.6 Results  
The following section summarizes the results of the FIX-HF-5C study and discusses 
the clinical implications of those results for the safety and effectiveness of the 
OPTIMIZER IVs and thus, OPTIMIZER SMART 3-Lead configuration, systems.  
Further detail concerning the statistical aspects of analyses presented are provided in 
Attachments 03 and the Primary & Key Secondary Analyses Impulse Dynamics FIX-
HF-5C (Attachment 07). 
 
1.4.6.1 Study Enrollment 
 
There were 488 subjects that signed informed consent; 480 of those subjects were 
screened for the study and 160 were randomized. 
 
Table 14 below provides a listing of all participating study centers with the number 
of patients screened and ultimately randomized to the OPTIMIZER or Control group 
for the study.   
 
 
Table 14: Distribution of Subjects by Treatment Group and Study Site 
 
Site Number and Name 
Screened1 
Control 
n(%)2 
OPTIMIZER 
n(%)2 
Total 
Randomized 
06 The Ohio State University 
10 
3 (50.00)  
3 (50.00) 
6 
08 Stern Cardiovascular Foundation 
8 
3 (75.00) 
1 (25.00) 
4 
09 Christus Mother Frances Hospital 
17 
2 (50.00)  
2 (50.00) 
4 
15 Aurora Research Institute  
4 
1 (100.00)  
0 (0.00) 
1 
21 The Detroit Medical Center 
13 
1 (50.00)  
1 (50.0) 
2 

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Site Number and Name 
Screened1 
Control 
n(%)2 
OPTIMIZER 
n(%)2 
Total 
Randomized 
31 Advocate Medical Group 
6 
0 (0.00)  
0 (0.00) 
0 
32 Ochsner Clinic Foundation 
12 
2 (50.00) 
2 (50.00) 
4 
36 lnova Research Center 
4 
2 (100.00) 
0 (0.00) 
2 
41 Bryan Heart 
8 
2 (66.67)  
1 (33.33) 
3 
51 VA Dallas Medical Center 
68 
15 (53.57)  
13 (46.43) 
28 
54 Donald Guthrie Foundation 
20 
2 (50.00) 
2 (50.00) 
4 
55 Baptist Health Lexington 
16 
2 (33.33)  
4 (66.67) 
6 
56 Spartanburg Regional Medical 
Center 
5 
1 (50.00)  
1 (50.00) 
2 
57 AZ Heart Rhythm Center 
24 
3 (60 .00)  
2 (40.00) 
5 
58 Florida Hospital Cardiovascular 
Institute 
1 
0 (0.00)  
0 (0.00) 
0 
59 Yale University 
8 
1 (100.00)  
0 (0.00) 
1 
60 Nebraska Heart Institute 
1 
0 (0.00)  
0 (0.00) 
0 
61 The Lindner Center 
1 
0 (0.00)  
0 (0.00) 
0 
63 University of Arizona 
3 
0 (0.00)  
0 (0.00) 
0 
64 University of Maryland 
1 
0 (0.00)  
0 (0.00) 
0 
65 Cardiovascular Associates of Mesa 
80 
13 (52.00)  
12 (48.00) 
25 
67 Washington Adventist Hospital 
3 
0 (0.00)  
0 (0.00) 
0 
69 Orange County Health Institute 
1 
0 (0.00)  
0 (0.00) 
1 
70 Na Homolce Hospital 
27 
3 (75.00)  
1 (25.00) 
4 
71 Asklepios Kliniken 
9 
2 (100.00) 
0 (0.00) 
2 
72 University Medical Center 
Mannheim 
8 
1 (33.33)  
2 (66.67) 
3 
74 Heart and Vascular Center Bad 
Bevensen 
3 
0 (0.00) 
1 (100.0) 
1 
75 Universitat Göttingen 
37 
5 (45.45) 
6 (54.55) 
11 
76 Charité University Hospital Berlin 
CVK 
5 
1 (100.00)  
0 (0.00) 
1 
78 University of Munich 
(Großhadern) 
1 
0 (0.00) 
1 (100.0) 
1 
79 Charité Campus Benjamin Franklin 
4 
0 (0.00) 
1 (100.0) 
1 
80 UKSH (Kiel) 
2 
0 (0.00)  
0 (0.00) 
0 
88 Cardiovascular Consultants 
14 
2 (66.67) 
1 (33.33) 
3 
89 Pima Heart 
11 
2 (66.67) 
1 (33.33) 
3 
90 Chan Heart Rhythm Institute 
53 
16 (50.00)  
16 (50.00) 
32 
Grand Totals 
488 
86(53.75) 
74(46.25) 
160 
Program: Create Patient Data.sas 
1 Of the 488 subjects, 8 subjects did not get screened, and 314 subjects failed inclusion/exclusion criteria at 
screening. 166 passed the inclusion/exclusion criteria at screening, 3 of these subjects withdrew from the study 
prior to randomization, 3 subjects failed criteria other than those at screening, and 160 were randomized  
2 Percentage taken from the site total. 
 
Nine of the 35 sites were OUS and accounted for 24 of the 160 (15%) randomized 
subjects.  The three sites with the most subjects randomized into the study were: 
Dallas VA Center, Cardiovascular Associates of Mesa and Chan Heart Rhythm 
Institute.  These three sites accounted for 85 (53%) of the 160 subjects 
randomized. 

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1.4.6.2 Subject Accountability 
Figure 14 below illustrates the flow of subjects through the FIX-HF-5C study. 
 
 
 
 
 
 
Figure 14: Flow of Subjects through FIX-HF-5C study 
 
 
There were 488 subjects consented for the FIX-HF-5C study; 160 were randomized and 328 
were not randomized. Table 15 lists the reasons for protocol exclusion for each of the 328 
subjects. Investigators were asked to review the patient medical records for obvious exclusion 
criteria, such as the presence of a CRT, LVAD or heart transplant or QRS duration > 130 ms, 
before scheduling the patient for baseline testing.  Baseline testing included 12-Lead EKG, 24-
Hour Holter Monitor, and Echocardiogram and tests performed for clinical care purposes and 
done within 30 days before informed consent could be used for protocol eligibility 

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determination.  
  
 
 
 
 
         Table 15: Summary of reasons for study exclusion 
# of 
Subjects 
Primary reason for study exclusion 
106* 
pVO2 >20 
69** 
LVEF < 25% 
27* 
Submax CPX testing 
26 
Subject withdrew 
19* 
Exercise limited 
18 
NYHA < Class III 
13** 
LVEF >45% 
10 
QRS > 130ms 
8 
More than 8,900 PVCs on 24-Hour Holter Monitor  
6 
CRF revision due to protocol revision  
5 
Baseline medications not stable 
5 
CRT 
2 
Mitral valve related 
2 
Too healthy 
1 
Atrial fibrillation 
1 
Comorbidities 
1* 
CPX test inadequate 
1 
Participating in another research study 
1 
Incomplete testing, overall study protocol enrollment 
completed 
1 
MI within 90 days 
1 
Died prior to randomization 
1 
Subject non-compliance with baseline testing schedule 
1 
Subject too sick and unstable 
1* 
Unable to determine LVEF 
1 
Unstable heart failure 
1 
Venous Occlusion  
*The majority of the reasons for exclusion were related to CPX testing or exercise limitations, 
with the majority of those due to a peak VO2 >20.  
**The second highest reason for exclusion was due to echocardiography testing. LVEF was 
>45% in 13 subjects, <25% in 69 subjects, and indeterminate in 1 subject. 
 
 
Of the 160 subjects randomized in the study, 86 were randomized to the control 
group and 74 were randomized to the OPTIMIZER group. This imbalance in 
patient numbers was a chance occurrence due to the nature of block 

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randomization by site and CHF etiology. 
 
1.4.6.2.1 Control Arm of the Study (Optimal Medical Therapy) 
 
Eighty-six (86) subjects were randomized to the control group; 79 of the 86 
subjects completed the 24-week study. Three (3) control subjects died prior to the 
12-week visit (subjects 90-402, 65-427, 65-422) at 4, 36, and 70 days 
respectively. The causes of death included 2 pump failures and 1 death following 
a VT-ablation procedure.  Another control subject (72-408) died after the 12-
week visit and prior to the 24-week visit at 117 days, due to a pulmonary 
complication following a non-cardiac procedure.  
 
Table 16: Summary on Cause of Death 
Subject 
Time 
Cause of Death 
90-402 
Day 4 
Pump Failure 
65-427 
Day 36 
Pump Failure 
65-422 
Day 70 
VT ablation procedure 
72-408 
Day 117 
Pulmonary Complication following a non-cardiac 
procedure 
 
 
One control subject withdrew prior to the 12-week visit (subject 88-407) at 77 
days and 2 subjects withdrew after the 12-week visit and prior to the 24-week 
(70-411 and 71-401) visit at 86 and 115 days respectively.  
 
Completed case report forms for control and OPTIMIZER treatment patients who 
died or were lost to follow up are found in VOL_007 and VOL_008 of this 
submission. 
 
1.4.6.2.2 OPTIMIZER Treatment Arm of the Study 
 
Seventy-four (74) subjects were randomized to the CCM™ Treatment group; 68 
of these 74 subjects underwent device implantation.  Six (6) subjects did not 
receive an implant. One (subject 65-446) died 2 days prior to the scheduled 
implant date, 1 (subject 57-409) was lost to follow-up prior to the scheduled 
implant date, 1 (subject 08-407) was deemed ineligible (interim assessment 
classified this patient as NYHA Class II) and was withdrawn, 1 (06-404) was 
discovered to have an additional abandoned ICD lead and the implant was 
canceled (follow-up testing through 24-weeks performed) and 2 subjects 
(subjects 51-423 and 51-454)  elected not to undergo the implant procedure but 
follow-up testing through 24-weeks was performed. Thus, 3 of the six patients 
randomized to CCM™ treatment who did not undergo device implantation 
completed the 24-week study follow up visits. 
 
In addition to the subject that died just prior to the implant date, 1 subject (88-
402) died 164 days after the OPTIMIZER implantation due to sepsis following 

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surgery for an incarcerated hernia.  
 
Narratives for lost to follow up (LTF) subjects and subjects who died are found 
in Attachments 08 and 09. 
 
1.4.6.2.3 Visit Accountability 
 
Table 17 illustrates the subject accountability and shows the study visits achieved 
within the window for the OPTIMIZER and Control groups. 
 
Table 17: Subject accountability and Study visit for OPTIMIZER and 
Control Group 
 
 
Interval 
Implant/Study 
Start Date 
(SSD) 
x/n (%) 
 
Week 12 
x/n (%) 
 
Week 24 
x/n (%) 
CONTROL 
Enrolled 
  86 
86 
86 
Died1 
   0 
35 
45 
Withdrawn1 
   0 
16 
36 
LTFLJ 1 2 
                 0 
            0 
            0 
Eligible3 
     86/86 (100.00) 
82/86 (95.35) 
79/86 (91.86) 
Visit in Window 
NA 
72/82 (87.80) 
67/79 (84.81) 
Visit Outside 
Window 
NA 
8/82 (9.88) 
10/79 (12.66) 
No Visit 
NA 
2/82 (2.44) 
2/79 (2.53) 
OPTIMIZER 
Enrolled 
744 
744 
744 
Died1 
15 
15 
25 
Withdrawn1 
16 
16 
16 
LTFLJ 1 2 
               1 
           1 
           1 
Eligible3 
71/74 (95.55) 
72/74 (97.30) 
71/74 (95.95) 
Visit in Window 
71/71 (100.00) 
65/72 (90.28) 
64/71 (90.14) 
Visit Outside 
Window 
    0 (0.00) 
6/72 (8.33) 
6/71 (8.45) 
No Visit 
         3/74 (4.05) 
1/72 (1.39) 
1/71 (1.41) 
Program: Create Patient Data.sas 
1 Deaths, intervention, withdrawn subjects, and LTFU subjects are cumulative over time. 
2 Lost to Follow-up 
3 The number eligible is the number enrolled minus the number that died and the number that withdrew or were intervened 
except for discharge. For Discharge examination, the subject had to have had an implant attempt (0 Control subjects and 58 
OPTIMIZER subjects. 
4 Six OPTIMIZER subjects did not get an implant: subject 05-404 RCW had an abandoned lead that could not be 
explanted, subject 08-407MAJ improved and was no longer eligible, subject 51-423 M-W refused implant, subject 51-

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454 MJP was a clinician decision due to health status of subject, subject 57-409 GJD was the LTFU who did not return 
after randomization, and subject 55-445 GDN died prior to implantation. 
5 Control subjects 55-422 RTH, 55-427 BAC, and 90-402 M-O died prior to the 12-week visit and subject 72- 408 HHH died 
prior to the 24-week visit. OPTIMIZER subject 55-445 GDN died prior to implant and subject 88-402 SET died prior to the 24-
week visit. 
6 One subject assigned to the Control (88-407 WMR) withdrew prior to the 12-week visit and two Control subjects (70-411 M-
K and 71-401 XXX) withdrew before the 24-week visit. One subject assigned to the OPTIMIZER (08-407 MAJ) improved and 
was no longer eligible for the study after randomization but prior to the discharge visit. 
 
 
Table 18: Withdrawn Subjects with Reason for Withdrawal by Study Group 
CONTROL  
Subject 
Study Days1 
Reason for Discontinuation or Withdrawal  
70-411 M-K 
86 
Subject withdrew from the study without providing a 
reason. No further information is available. 
71-401 XXX 
115 
Subject withdrew from the study during phone call with 
investigator, but the reason for withdrawal was not 
provided and no further information is available. 
88-407 WMR 
77 
A physician treating the subject, but not involved as an 
investigator in the study protocol, advised the subject 
to withdraw from the study. No reason for withdrawal 
was provided. 
OPTIMIZER 
Subject 
Study Days 
Reason for Discontinuation or Withdrawal  
08-407 MAJ 
0 
Due to time lapse between randomization and implant, 
an improvement of health status was noted (NYHA III 
to NYHA II) and the subject was no longer eligible. 
Program: Create Patient Data.sas 
 
1 Study days relative to study start date (SSD), which is the scheduled day of device implantation. 
1.4.6.3 Analysis Populations 
The following subjects are excluded from per-protocol analyses along with reasons 
for exclusion; since several of the secondary efficacy analyses involve pooling of 
data from the FIX-HF-5C and original FIX-HF-5 studies, these details are provided 
for both populations. 
Table 19: Subjects excluded from per-protocol population  
Study 
Subject 
Group 
Reason for Exclusion 
FIX-HF-5C 
06-404 RCW 
OPTIMIZER 
no device, not implanted 
08-407 MAJ 
OPTIMIZER 
no device, not implanted, WD 
prior to SSD 
51-423 M-W 
OPTIMIZER 
no device, not implanted 
51-454 MJP 
OPTIMIZER 
no device, not implanted 
57-409 GJD 
OPTIMIZER 
no device, LTF 
65-446 GDN 
OPTIMIZER 
no device, died prior to SSD 
FIX-HF-5 
08-212 J-G 
OPTIMIZER 
no device, died prior to SSD 
13-204STD 
Control 
WD prior to SSD 

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Study 
Subject 
Group 
Reason for Exclusion 
13-206 WSD 
OPTIMIZER 
no device, WD prior to SSD 
13-212 JWG 
Control 
No follow-up, NYHA II, Not 
willing, cognitive impairment 
13-215 PJV 
Control 
WD prior to SSD 
17-221 JAW 
Control 
WD due to Control Group prior to 
follow-up 
20-227 LRM 
OPTIMIZER 
no device 
25-206 J-P 
Control 
no follow-up, HF meds not stable 
27-217 JBG 
OPTIMIZER 
no device, died prior to SSD 
28-203 B-C 
OPTIMIZER 
no device 
29-204 M-V 
OPTIMIZER 
no device, WD prior to SSD 
36-204 BTB 
OPTIMIZER 
no device 
36-206 RKG 
OPTIMIZER 
no device, WD prior to SSD 
 
Complete case analyses are conducted for all secondary and supportive analyses.  
That is, all available data is used without imputation. Analyses are conducted for 
complete cases and for complete cases in the per protocol population. 
 
1.4.6.4 Baseline Demographics 
Tables 20 (continuous variables) and 21 (categorical variables) present 
comparisons of baseline variables between the Control and OPTIMIZER groups 
of the FIX-HF-5C study. There are no statistically significant differences between 
the groups in any of the variables, thus demonstrating that randomization of 
subjects produced balanced groups with respect to baseline characteristics. 
 
 
Table 20: Baseline Demographics - Continuous Variables 
 Variable  
OPTIMIZER  
Mean (SD) N 
Med (Min, Max) 
Control 
Mean (SD) N 
Med (Min, Max) 
P-value 
Age (yrs) 
63.09 (10.89) 74 
63.6 (38.0, 86.8) 
62.79 (11.38) 86 
62.4 (30.7, 89.2) 
0.71091 
QRS Duration (ms)  
102.50 (12.58) 74 
100 (76, 128) 
103.62 (12.10) 86 
104 (80, 129) 
0.58671 
PR Interval (ms) 
183.37 (36.86) 74 
180.0 (114, 288) 
184.57 (43.93) 86 
178.0 (28, 320) 
0.98091 
Holter (PVCs/24hr) 
1599.5 (2009.0) 74 
668 (0, 7370) 
1176.8 (1712.4) 86 
277.5 (0, 8514) 
0.43341 
LVEF (%) (Core Lab) 
33.08 (5.55) 74 
32 (25, 45) 
32.55 (5.18) 86 
32 (25, 45) 
0.57471 
LVEDD (mm) (Core Lab) 
58.47 (7.17) 74 
59 (40, 75) 
60.20 (7.01) 82 
59 (44, 77) 
0.19841 
MLWHFQ 
56.42 (22.95) 74 
60.5 (1, 96) 
57.35 (23.36) 86 
60 (5, 99) 
0.73651 
6MW (meters) 
316.85 (88.37) 74 
324.07 (89.71) 86 
0.87241 

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 Variable  
OPTIMIZER  
Mean (SD) N 
Med (Min, Max) 
Control 
Mean (SD) N 
Med (Min, Max) 
P-value 
308 (75, 462) 
315 (120, 579) 
CPX (Core Lab) 
  Peak VO2 (ml/kg/min) 
15.49 (2.61) 733 
15.70 (9.75, 19.70) 
15.36 (2.82) 86 
15.85 (9.10, 19.90) 
0.80111 
  Peak RER 
1.15 (0.064) 733 
1.140 (1.015, 1315) 
1.14 (0.074) 86 
1.125 (0.975, 1.480) 
0.44691 
  Exercise Time (minutes) 
11.38 (3.08) 733 
11.800 (3.208, 18.500) 
10.58 (3.09) 86 
11.163 (3.133, 18.033) 
0.12861 
Physical Exam 
  Weight (kg) 
99.60 (20.72) 74 
98.0 (52.7, 167.8) 
100.33 (23.32) 86 
96.8 (49.0, 155.1) 
0.84421 
  Height (cm) 
174.77 (9.58) 74 
175.0 (150.0 208.0) 
174.40 (8.97) 86 
175.0 (142.0, 201.0) 
0.90191 
  BMI (kg/m2) 
32.49 (5.63) 74 
32.0 (20.6, 46.6) 
32.90 (6.90) 86 
32.2 (19.1, 50.0) 
0.77281 
  Resting HR (bpm) 
74.42 (11.35) 74 
73.0 (54.0, 112.0) 
76.45 (14.84) 86 
76.5 (45.0, 137.0) 
0.32812 
  SBP (mmHg) 
122.66 (17.66) 74 
124 (88, 165) 
126.04 (18.83) 86 
122.(91, 196) 
0.48701 
  DBP (mmHg) 
74.42 (11.35) 74 
72.5 (54.0, 112.0) 
76.45 (14.84) 86 
76.5 (45.0, 137.0) 
0.74271 
Program: Baseline.sas 
1 Two-sided Wilcoxon rank sum test.        
2 Two-sided unequal variance two-sample t-test. 
3 One subject in the OPTIMIZER group did not have valid readings for the CPX testing. 
 
 
Baseline parameters illustrate that subjects included in the FIX-HF-5C study met 
intended inclusion criteria and are generally representative of the US heart failure 
population with moderately severe heart failure (i.e., 25≤EF≤45).  The typical 
subject in the study was in their early 60’s with a narrow QRS duration and LVEF 
within the 25-45% inclusion criteria range.  Peak VO2 on CPX testing in the 
randomized group of subjects was approximately 15 ml/kg/min which is 
moderately reduced compared to the normal population.  With BMI of 
approximately 32 kg/m2, subjects were moderately obese but demonstrated 
mostly normotensive blood pressures at baseline 
 
Table 21: Baseline Demographics and Medical History Categorical 
Variables 
 Variable 
OPTIMIZER  
n/N (%) 
Control 
n/N (%) 
P-value 
Male     
54/74 (73.0) 
68/86 (79.1) 
0.45651 
Ethnicity   
                White 
                Black 
                Hispanic 
 
55/74 (74.3) 
14/74 (18.9) 
0/74 (0.0) 
 
61/86 (70.9) 
15/86 (17.4) 
1/86 (1.2) 
 
0.92442 

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 Variable 
OPTIMIZER  
n/N (%) 
Control 
n/N (%) 
P-value 
                Native American 
                Other 
1/74 (1.4) 
4/74 (5.4) 
2/86 (2.3) 
7/86 (8.1) 
CHF Etiology   
               Ischemic 
               Idiopathic 
               Other 
 
46/74 (62.2) 
22/74 (29.7) 
6/74 (8.1) 
 
51/86 (59.3) 
29/86 (33.7) 
6/86 (7.0) 
 
0.84972 
Prior MI  
36/74 (48.6) 
51/86 (59.3) 
0.20431 
Prior CABG  
18/74 (24.3) 
23/86 (26.7) 
0.85611 
Prior PTCA 
36/74 (48.6) 
43/86 (50.0) 
0.87541 
ICD/PM System 
65/74 (87.8) 
73/86 (84.9) 
0.65021 
Angina 
5/74 (6.8) 
6/86 (7.0) 
1.00001 
Diabetes  
38/74 (51.4) 
42/86 (48.8) 
0.87411 
History of Atrial Arrhythmias 
25/74 (66.2) 
35/86 (59.3) 
0.41471 
Atrial Flutter 
8/74 (10.8) 
6/86 (7.0) 
0.41541 
Atrial Fibrillation 
20/74 (27.0) 
27/86 (31.4) 
0.60351 
Frequent PACs 
3/74 (4.1) 
1/86 (1.2) 
0.33651 
Other Atrial 
Abnormalities 
2/74 (2.7) 
3/86 (3.5) 
1.00001 
History of Ventricular 
Arrhythmias 
26/74 (35.1) 
28/86 (32.6) 
0.74061 
Ventricle Fibrillation 
5/74 (6.8) 
8/86 (9.3) 
0.77291 
Ventricular Tachycardia 
19/74 (25.7) 
19/86 (22.1) 
0.7098 
Frequent PVCs 
8/74 (10.8) 
7/86 (8.1) 
0.59671 
NYHA (site)  
               Class III 
               Class IV 
64/74 (86.5) 
10/74 (13.5) 
78/86 (90.7) 
8/86 (9.3) 
 
0.45751 
Program: Baseline.sas 
1 Two-sided Fisher’s exact test. 
2 Two-sided Fisher-Freeman-Halton test. 
 
The majority of subjects enrolled in the FIX-HF-5C study were white males, 
which is typical of a large recent heart failure study (e.g., the PARADIGM 
study.)17  
 
The etiology of heart disease was ischemic in ~60% of the subjects.  This finding 
is also consistent with a recent study of heart failure (e.g., the PARADIGM 
study.)17  The history of atrial arrhythmias presented in the Table 21 represents 
remote history because subjects with recent persistent or permanent atrial 
fibrillation or atrial flutter were excluded from the study.  The presence of 
ventricular arrhythmias as shown here is common for patients with predominantly 
ischemic heart failure.  Approximately 90% of the randomized subjects in FIX-
HF-5C were NYHA Class III at baseline assessment consistent with the target 
patient population.  
 
1.4.6.5 Baseline Medications 
Table 22 provides a comparison of baseline medications between the Control and 

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OPTIMIZER groups of the study.  There were no statistically significant 
differences between the groups for any category of cardiovascular medication 
evaluated, so the groups were again shown to be well balanced after 
randomization.  In both groups, approximately 83% of subjects were on ACE-I 
or ARB medications while over 95% of subjects in both groups were receiving 
beta blocker medication at baseline. Seventy-five percent of subjects were taking 
diuretics and approximately 35% of subjects were on an aldosterone inhibitor.  
The rate of diuretic therapy in FIX-HF-5C is similar to the rate reported in the 
PARADIGM study17 which was ~80%.  
 
Table 22: Baseline Medication 
Medication  
 
OPTIMIZER 
n/N (%) 
Control 
n/N (%) 
P-Value1 
ACEi or ARB 
61/74 (82.4) 
72/86 (83.7) 
0.8358 
Angiotensin 
converting 
enzyme 
inhibitor (ACEi) 
40/74 (54.1) 
49/86 (57.0) 
0.7511 
Angiotensin receptor blocker (ARB) 
21/74 (28.4) 
25/86 (29.1) 
1.0000 
Beta Blocker  
72/74 (97.3) 
82/86 (95.3) 
0.6870 
Diuretic 
56/74 (75.7) 
68/86 (79.1) 
0.7049 
Second Diuretic2 
5/74 (6.8) 
8/86 (9.3) 
0.7729 
Ivabradine 
2/74 (2.7) 
4/86 (4.7) 
0.6870 
Digoxin 
10/74 (13.5) 
8/86 (9.3) 
0.4575 
Aldosterone Inhibitor 
25/74 (33.8) 
32/86 (37.2) 
0.7410 
Hydralazine 
4/74 (5.4) 
10/86 (11.6) 
0.2615 
Nitrates 
18/74 (24.3) 
26/86 (30.2) 
0.4786 
Entresto 
2/74 (2.7) 
3/86 (3.5) 
1.0000 
Calcium Channel Blocker 
9/74 (12.2) 
8/86 (9.3) 
0.6132 
Anti-arrhythmic 
13/74 (17.6) 
12/86 (14.0) 
0.6630 
Aspirin 
54/74 (73.0) 
59/86 (68.6) 
0.6035 
Coumadin 
7/74 (9.5) 
5/86 (5.8) 
0.5490 
Clopidogrel 
15/74 (20.3) 
25/86 (29.1) 
0.2719 
Program: Baseline.sas 
1Two-sided Fisher’s exact test. 
1.4.6.6 Lead Type 
 
Three lead types were employed in the study: St. Jude Medical, Biotronik, and 
Boston Scientific/Guidant.  The frequency of use is shown in the Table 23. 
 
Table 23: Number of Subjects with leads used in the study 
Type of Lead 
St. Jude Medical 
N 
Biotronik 
N 
BSC/Guidant 
N 
Number of Subjects with each 
type of lead 
37 
20 
11 
 
1.4.6.7 Site Comparability Analyses 
Comprehensive statistical analyses were conducted to demonstrate the 

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comparability of sites enrolling subjects in the study and to identify any 
differences between OUS and US sites that enrolled subjects.  These detailed 
analyses are provided in their entirety in Attachment 03, the Statistical Analysis 
Report of Impulse Dynamics FIX-HF-5C Study.  The formation of pseudo-sites 
by combining sites with low numbers of patients is outlined in Table 24 below. 
 
 
Table 24: Pseudo-site Formation from Original Study Sites 
Pseudo 
Site 
Number 
Originals Site Number(s) 
Number 
of 
Control 
Subjects 
Number 
of 
Optimizer 
Subjects 
Total 
Subjects 
1 
6, 8, 9, 15, 21, 32, 32, 36, and  88 
16 
10 
26 
2 
41, 54, 55, 56, 57, 59, 69, and  89 
14 
11 
25 
3 
51 
15 
13 
28 
4 
65 
13 
12 
25 
5 
70, 71, 72, 74, 75, 76, 78, and 79 
12 
12 
24 
6 
90 
16 
16 
32 
Total 
86 
74 
160 
Program: Create Patient Data.sas 
 
The following two tables provide summaries of the significant differences found 
between pseudo-sites. 
 
Table 25: Summary of Study Pseudo-Site Comparability1 for Baseline 
Quantitative Endpoints 
 Variable 
P-value for Study Pseudo-Site2 
Age (yrs) 
0.1015 
QRS Duration (ms)    
0.0937 
PR Interval (ms) 
0.6832 
Holter (PVCs/24hr) 
0.0184 
LVEF (%) (Core Lab) 
0.5187 
LVEDD (mm) (Core Lab) 
0.3244 
MLWHFQ 
0.0004 
6MW (meters) 
<0.0001 
CPX (Core Lab) 
     Peak VO2 (ml/kg/min) 
0.8917 
     RER 
0.0082 
     Exercise Time (minutes) 
0.0790 
  Weight (kg) 
0.2585 
  Height (cm) 
0.2424 
  BMI (kg/m2) 
0.4117 
  HR (bpm) 
0.0016 
  SBP (mmHg) 
0.0046 
  DBP (mmHg) 
0.0316 
Program: By Site Analyses.sas 
 

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1 Analysis by general linear model analysis of variance with Type III sums of squares. 
2 Pseudo-sites were used in this analysis and are defined in Table 21 
     p-value-2 sided 
 
Subjects at Pseudo-site 3 (Study Site 51) appear to have a higher mean baseline 
Holter PVC than the subjects at the other pseudo-sites. Similarly, it appears that 
subjects at Pseudo-site 3 (Study Site 51) have a higher mean baseline score for the 
MLWHFQ than subjects at the other pseudo-sites. Subjects at Pseudo-site 5 
(combined sites 70-79) appear to have a lower mean baseline Peak RER than 
subjects at the other pseudo-sites. 
Pseudo-site 6 (Study Site 90) appears to have a higher mean baseline heart rate 
than the subjects at the other pseudo-sites. Similarly, subjects at Pseudo-site 6 
(study Site 90) have a higher mean systolic blood pressure than subjects at the 
other pseudo-sites. Subjects at Pseudo-sites 1, 2, and 6 appear to have a higher 
mean baseline diastolic blood pressure than subjects at the other three pseudo-
sites. 
Table 26: Summary of Study Pseudo-Site by Baseline Categorical Endpoints 
 
Pseudo-Site 
 
 
1 
2 
3 
4 
5 
6 
P-value1 
Females 
12/26 
(46.2) 
7/25 
(28.0) 
0/28 
(0.0) 
7/25 
(28.0) 
9/24 
(37.5) 
3/32 
(9.4) 
<0.0001 
Males 
14/26 
(53.8) 
18/25 
(72.0) 
28/28 
(100.0) 
18/25 
(72.0) 
15/24 
(62.5) 
29/32 
(90.6) 
 
White 
16/26 
(61.54) 
22/25 
(88.00) 
15/28 
(53.57) 
23/25 
(92.00) 
22/24 
(91.67) 
18/32 
(56.25) 
0.0002 
Non-white 
10/26 
(38.46) 
3/25 
(12.00) 
13/28 
(46.43) 
2/25 
(8.00) 
2/24 
(8.33) 
14/32 
(43.75) 
 
Ischemic 
14/26 
(53.85) 
17/25 
(68.00) 
21/28 
(75.00) 
16/25 
(64.00) 
17/24 
(70.83) 
12/32 
(37.50) 
0.0415 
Non-Ischemic 
12/26 
(46.15) 
8/25 
(32.00) 
7/28 
(25.00) 
9/25 
(36.00) 
7/24 
(29.17) 
20/32 
(62.50) 
 
No History of   
  PTCA 
14/26 
(53.85) 
17/25 
(68.00) 
9/28 
(32.14) 
9/25 
36.00) 
10/24 
(41.67) 
22/32 
(68.75) 
0.0152 
History of 
PTCA 
12/26 
(46.15) 
8/25 
(32.00) 
19/28 
(67.86) 
16/25 
(64.00) 
14/24 
(58.33) 
10/32 
(31.25) 
 
No History of 
  Other Atrial 
26/26 
(100.00) 
25/25 
(100.00) 
27/28 
(96.43) 
21/25 
(84.00) 
24/24 
(100.00) 
32/32 
(100.00) 
0.0056 
History of 
Other 
  Atrial 
0/26 
(0.00) 
0/25 
(0.00) 
1/28 
(3.57) 
4/25 
(16.00) 
0/24 
(0.00) 
0/32 
(0.00) 
 
No History of 
VA 
9/26 
(34.62) 
10/25 
(40.00) 
10/28 
(35.71) 
16/25 
(64.00) 
3/24 
(12.50) 
6/32 
(18.75) 
0.0021 
History of VA 
17/26 
(65.38) 
15/25 
(60.00) 
18/28 
(64.29) 
9/25 
(36.00) 
21/24 
(87.50) 
26/32 
(81.25) 
 
  No History of 
VT 
20/26 
(76.92) 
16/25 
(64.00) 
22/28 
(78.57) 
13/25 
(52.00) 
23/24 
(95.83) 
28/32 
(87.50) 
0.0031 

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OPTIMIZER SMART System 
 
Page 35 of 108 
 
PROPRIETARY: This document is proprietary and confidential. No part of this document may be disclosed in any manner to 
a third party without the prior written consent of Impulse Dynamics USA, Inc. 
 
Pseudo-Site 
 
 
1 
2 
3 
4 
5 
6 
P-value1 
History of VT 
6/26 
(33.08) 
9/25 
(36.00) 
6/28 
(21.43) 
12/25 
(48.00) 
1/24 
(4.17) 
4/32 
(12.50) 
 
NYHA 3 
24/26 
(92.31) 
24/25 
(96.00) 
22/28 
(78.57) 
25/25 
(100.00) 
24/24 
(100.00) 
23/32 
(71.88) 
0.0008 
NYHA 4 
2/26 
(7.69) 
1/25 
(4.00) 
6/28 
(21.43) 
0/25 
(0.00) 
0/24 
(0.00) 
9/32 
(28.13) 
 
Program: By Site Analyses.sas 
1 
Analysis by two-sided Fisher-Freeman-Halton test. 
Note the following:  
• There were no female subjects at Pseudo-site 3 whereas all of the other pseudo-
sites had female subjects.  
• Pseudo-sites 1, 3, and 6 had a higher percentage of non-white subjects than the 
remaining pseudo-sites. 
• There was a much higher percentage of subjects with non-ischemic etiology at 
Pseudo-site 6 than at the other pseudo-sites. 
• Subjects at Pseudo-sites 3, 4, and 5 have a higher percentage of subjects with 
prior PTCA than the other pseudo-sites. 
• Subjects at Pseudo-sites 3 and 4 have subjects with some history of atrial 
abnormalities but the other four pseudo-sites have none. 
• Subjects at Pseudo-site 4 have a much lower rate of ventricular arrhythmias 
than the subjects at the other pseudo-sites. 
• Subjects at Pseudo-site 5 have a much lower rate of ventricular tachycardia than 
the subjects at the other pseudo-sites. 
• Pseudo-sites 3 and 6 have a higher percentage of subjects in NYHA class 4 than 
the other pseudo-sites. 
 
Table 27: Summary of Study Pseudo-Site by Baseline Medication Use  
 
Pseudo-Site 
 
 
1 
2 
3 
4 
5 
6 
P-value 
(2-
sided) 
No ACEi Use 
7/26 
(26.92) 
9/25 
(36.00) 
10/28 
(35.71) 
18/25 
(72.00) 
9/24 
(37.50) 
18/32 
(56.25) 
0.0117 
ACEi Use 
19/26 
(73.08) 
16/25 
(64.00) 
18/28 
(64.29) 
7/25 
(28.00) 
15/24 
(62.50) 
14/32 
(43.75) 
 
No 
Diuretic 
Use 
5/26 
(19.23) 
6/25 
(24.00) 
3/28 
(10.71) 
7/25 
(28.00) 
1/24 
(4.17) 
14/32 
(43.75) 
0.0072 
Diuretic Use 
21/26 
(80.77) 
19/25 
(76.00) 
25/28 
(89.29) 
18/25 
(72.00) 
23/24 
(95.83) 
18/32 
(56.25) 
 
No 
Ivabradine 
Use 
25/26 
(96.15) 
25/25 
(100.00) 
28/28 
(100.00) 
24/25 
(96.00) 
20/24 
(83.33) 
32/32 
(100.00) 
0.0111 

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Page 36 of 108 
 
PROPRIETARY: This document is proprietary and confidential. No part of this document may be disclosed in any manner to 
a third party without the prior written consent of Impulse Dynamics USA, Inc. 
 
Pseudo-Site 
 
 
1 
2 
3 
4 
5 
6 
P-value 
(2-
sided) 
Ivabradine 
Use 
1/26 
(3.85) 
0/25 
(0.00) 
0/28 
(0.00) 
1/25 
(4.00) 
4/24 
(16.67) 
0/32 
(0.00) 
 
No 
Digoxin 
Use 
21/26 
(80.77) 
23/25 
(92.00) 
28/28 
(100.00) 
18/25 
(72.00) 
23/24 
(95.83) 
29/32 
90.63) 
0.0141 
Digoxin Use 
5/26 
(19.23) 
2/25 
(8.00) 
0/28 
(0.00) 
7/25 
(28.00) 
1/24 
(4.17) 
3/32 
(9.38) 
 
No 
Aldosterone 
Inhibitor Use 
14/26 
(53.85) 
20/25 
(80.00) 
19/28 
(67.86) 
16/25 
(64.00) 
5/24 
(20.83) 
29/32 
(90.63) 
<0.0001 
Aldosterone 
Inhibitor Use 
12/26 
(46.15) 
5/25 
(20.00) 
9/28 
(32.14) 
9/25 
(36.00) 
19/24 
(79.17) 
3/32 
(9.38) 
 
No 
Hydralazine 
Use 
20/26 
(76.92) 
23/25 
(92.00) 
24/28 
(85.71) 
24/25 
96.00) 
24/24 
(100.00) 
31/32 
(96.88) 
0.0369 
Hydralazine 
Use 
6/26 
(23.08) 
2/25 
(8.00) 
4/28 
(14.29) 
1/25 
(4.00) 
0/24 
(0.00) 
1/32 
(3.12) 
 
No 
Nitrates 
Use 
10/26 
(38.46) 
19/25 
(76.00) 
20/28 
(71.43) 
16/25 
(64.00) 
23/24 
(95.83) 
28/32 
(87.50) 
<0.0001 
Nitrates Use 
16/26 
(61.54) 
6/25 
(24.00) 
8/28 
(28.57) 
9/25 
(36.00) 
1/24 
(4.17) 
4/32 
(12.50) 
 
Program: By Site Analyses.sas 
Note the following: 
• Subjects at Pseudo-sites 4 and 6 have a lower percentage using ace inhibitors 
than the subjects at the other pseudo-sites. 
• Subjects at Pseudo-sites 4 and 6 have a lower percentage using diuretics than 
the subjects at the other pseudo-sites. 
• Pseudo-sites 2, 3, and 6 have no subjects using Ivabradine but the other pseudo-
sites have at least one subject with baseline Ivabradine use. 
• Subjects at Pseudo-sites 1 and 4 have higher rates of digoxin use than subjects 
at the other pseudo-sites. 
• Subjects at Pseudo-site 5 have a much higher rate of Aldosterone inhibitor use 
than subjects at the other pseudo sites. 
• Subjects at Pseudo-sites 1 and 3 have a higher use of Hydralazine that subjects 
at the other pseudo-sites. 
• Subjects at Pseudo-sites 5 and 6 have a much lower baseline rate of nitrate use 
than subjects at the other pseudo-sites. 
 
Thus, as anticipated in a study with a relatively small sample size, several 
differences between pseudo sites emerge.  Accordingly, for purposes of 
poolability, it is appropriate to assess if treatment effects differ among pseudo sites 
as will be detailed in the next section. 

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Page 37 of 108 
 
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a third party without the prior written consent of Impulse Dynamics USA, Inc. 
1.4.6.8 Analysis of Poolability of Data 
To determine if the data can be pooled in estimation of the primary effectiveness 
endpoint, two analyses were conducted below per the SAP: one for the presence 
of a pseudo-site by treatment interaction and one for the presence of a geographic 
region by pseudo-site interaction. Additional exploration of the heterogeneity of 
the treatment effect by site and region can be found in the Primary & Key 
Secondary Analyses Report (Attachment 07). 
 
1.4.6.8.1 Analysis of Poolability by Pseudo-site 
The evaluation of a pseudo-site by treatment interaction was evaluated using 
the primary effectiveness mixed model specification adding pseudo-site as a 
random component along with the interaction of pseudo-site by treatment 
group.  If the interaction of pseudo-site by treatment group has a P-value 
<0.15, the data were considered not poolable and required a model that 
includes pseudo-site as a random component. 
The results of the pseudo-site poolability model are presented in the table 
below. 
Table 28: Repeated Measures Analysis of Variance Pooling Analysis of 
Pseudo-Site  
Effect 
Numerator 
Degrees of 
Freedom 
Denominator 
Degrees of 
Freedom 
F-value 
P-value1 
Interaction Treatment Group by Pseudo-
Site 
6 
279 
0.43 
0.8576 
Program: By Site Analyses.sas 
 
1The P-value is a two-sided Type III F-test from mixed model procedure.   
Because the P-value for the interaction is greater than 0.15, the data can be 
pooled by site. 
1.4.6.8.2 Analysis of Poolability by Geographic Region 
         The results of the geographic region poolability model are presented in the 
table below. 
Table 29: Repeated Measures Analysis of Variance Pooling Analysis of 
Geographic Region 
 Effect 
Numerator 
Degrees of 
Freedom 
Denominator 
Degrees of 
Freedom 
F-value 
P-value1 
Interaction Treatment Group by Region 
2 
279 
0.25 
0.7771 
Program: By Site Analyses.sas 
1 
The P-value is a two-sided Type III F-test from mixed model procedure.    

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Because the P-value for the interaction is greater than 0.15, from the perspective 
of geographic region, the data can be pooled. 
 
1.4.6.9 Analysis of Medication Dose Changes 
Information on both baseline and 24-week medications and doses were available 
from 152 patients among the FIX-HF-5C population, 81 in the Control group and 
71 in the ACTIVE group.  For each class of drug (ACE-inhibitors, ARBs, β-
blockers, diuretics, second diuretic, or aldosterone inhibitor), we determined the 
total number of patients in each group in which the drug was changed, in addition 
to the number in which doses were increased and the number in which doses were 
decreased.  Finally, the percentage of patients with increases and decreases in 
each drug class was determined and compared statistically (Fisher’s Exact Test).  
As detailed in the tables below, there were no significant differences between 
groups in the percentage of patients with increases or decreases in any category. 
 
 

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Table 30: Summary of Medication dose changes  
ACE-Inhibitor 
Control 
Active 
P-value 
Total Number with Change 
17 
13 
 
Number with Increase 
8 
8 
 
Number with Decrease 
9 
5 
 
% with Increase 
9.9% 
11.3% 
0.7974 
% with Decrease 
11.1% 
7.0% 
0.4167 
 
ARB 
Control 
Active 
P-value 
Total Number with Change 
9 
8 
 
Number with Increase 
2 
4 
 
Number with Decrease 
7 
4 
 
% with Increase 
2.5% 
5.6% 
0.5438 
% with Decrease 
8.6% 
5.6% 
0.4187 
 
β-Blocker 
Control 
Active 
P-value 
Total Number with Change 
28 
22 
 
Number with Increase 
18 
12 
 
Number with Decrease 
10 
10 
 
% with Increase 
22.2% 
16.9% 
0.7299 
% with Decrease 
12.3% 
14.1% 
0.5406 
 
Diuretic 
Control 
Active 
P-value 
Total Number with Change 
14 
18 
 
Number with Increase 
8 
11 
 
Number with Decrease 
6 
7 
 
% with Increase 
9.9% 
15.5% 
0.3331 
% with Decrease 
7.4% 
9.9% 
0.7726 
 
Second Diuretic 
Control 
Active 
P-value 
Total Number with Change 
10 
6 
 
Number with Increase 
6 
5 
 
Number with Decrease 
4 
1 
 
% with Increase 
7.4% 
7.0% 
1.000 
% with Decrease 
4.9% 
1.4% 
0.3722 
 
Aldosterone Inhibitor 
Control 
Active 
P-value 
Total Number with Change 
7 
4 
 
Number with Increase 
4 
3 
 
Number with Decrease 
3 
1 
 
% with Increase 
4.9% 
4.2% 
1.000 
% with Decrease 
3.7% 
1.4% 
0.6233 
P-value is two-sided from Fisher’s Exact Test.  

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1.4.6.10 Primary Effectiveness Result 
160 patients contributed 442 peak VO2 observations across baseline, 12-week and 
24-week follow-up visits.  Imputation was performed such that if the reason for 
missing peak VO2 values was death, zeroes were imputed for the missing values.  
If the reason for missing values was heart failure hospitalization, the missing peak 
VO2 values were imputed as the minimum value from the cohort.  There were no 
cases missing for heart failure hospitalization in the data set. 
 
The following is a list of all 160 FIX-HF-5C subjects on order of Peak VO2 
from greatest positive change to greatest negative change. 

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Dynamics USA, Inc. 
Table 31a: Summary of the peak VO2 values for the FIX-HF-5C study (Control Group) 
 
  
  
  
  
Complete Case 
0's Imputed for Deaths 
Sr. no 
Patient ID 
Treatment 
Group 
Baseline 
12 Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
12 
Weeks 
24 
Weeks 
Change from 
Baseline to 
24 Weeks 
1 
65-413 J-R 
CONTROL 
10.5 
15.3 
15.4 
4.9 
15.3 
15.4 
4.9 
2 
65-470 JTH 
CONTROL 
16.9 
20.3 
21.05 
4.15 
20.3 
21.05 
4.15 
3 
51-419 DJG 
CONTROL 
14.1 
14.95 
18.25 
4.15 
14.95 
18.25 
4.15 
4 
06-406 MJP 
CONTROL 
16 
17 
19.7 
3.7 
17 
19.7 
3.7 
5 
51-452 KCH 
CONTROL 
19.1 
20.5 
22.65 
3.55 
20.5 
22.65 
3.55 
6 
71-406 AAA 
CONTROL 
18.65 
21.55 
21.9 
3.25 
21.55 
21.9 
3.25 
7 
65-431 KET 
CONTROL 
15.55 
Not Done 
18.55 
3 
Not Done 
18.55 
3 
8 
09-407 GMW 
CONTROL 
16.85 
19 
19.6 
2.75 
19 
19.6 
2.75 
9 
65-429 EDC 
CONTROL 
15.35 
17.85 
18.1 
2.75 
17.85 
18.1 
2.75 
10 
57-408 DDM 
CONTROL 
16.15 
17.3 
18.7 
2.55 
17.3 
18.7 
2.55 
11 
59-408 FJS 
CONTROL 
19.9 
21.9 
22.05 
2.15 
21.9 
22.05 
2.15 
12 
65-480 SLR 
CONTROL 
12.05 
13 
14.15 
2.1 
13 
14.15 
2.1 
13 
09-408 DPM 
CONTROL 
12.1 
13.5 
14.1 
2 
13.5 
14.1 
2 
14 
51-455 E-B 
CONTROL 
12.9 
14.15 
14.45 
1.55 
14.15 
14.45 
1.55 
15 
70-426 K-S 
CONTROL 
16.1 
16.45 
17.5 
1.4 
16.45 
17.5 
1.4 
16 
65-402 JAD 
CONTROL 
18.8 
Inadequate 
19.9 
1.1 
Inadequate 
19.9 
1.1 
17 
55-413 SLS 
CONTROL 
12.2 
12.35 
13.2 
1 
12.35 
13.2 
1 
18 
08-405 BLB 
CONTROL 
12.5 
13.7 
13.3 
0.8 
13.7 
13.3 
0.8 
19 
51-427 ABG 
CONTROL 
19.5 
20.3 
20.2 
0.7 
20.3 
20.2 
0.7 
20 
55-408 WSG 
CONTROL 
13 
Not Done 
13.6 
0.6 
Not Done 
13.6 
0.6 
21 
65-450 VGH 
CONTROL 
18.65 
15 
19.1 
0.45 
15 
19.1 
0.45 

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Dynamics USA, Inc. 
  
  
  
  
Complete Case 
0's Imputed for Deaths 
Sr. no 
Patient ID 
Treatment 
Group 
Baseline 
12 Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
12 
Weeks 
24 
Weeks 
Change from 
Baseline to 
24 Weeks 
22 
32-408 WJJ 
CONTROL 
15 
17.35 
15.45 
0.45 
17.35 
15.45 
0.45 
23 
75-409 CCC 
CONTROL 
12.8 
14.35 
13 
0.2 
14.35 
13 
0.2 
24 
90-434 D-P 
CONTROL 
19.75 
20.5 
19.95 
0.2 
20.5 
19.95 
0.2 
25 
90-446 MJB 
CONTROL 
16.8 
19.4 
17 
0.2 
19.4 
17 
0.2 
26 
51-448 KAL 
CONTROL 
11.85 
12.1 
11.9 
0.05 
12.1 
11.9 
0.05 
27 
51-438 RKT 
CONTROL 
12.65 
13 
12.7 
0.05 
13 
12.7 
0.05 
28 
88-405 PAS 
CONTROL 
14.4 
14.05 
14.4 
0 
14.05 
14.4 
0 
29 
15-403 CAW 
CONTROL 
16.45 
16.4 
16.45 
0 
16.4 
16.45 
0 
30 
51-432 RAT 
CONTROL 
14.55 
12.2 
14.5 
-0.05 
12.2 
14.5 
-0.05 
31 
51-453 JRB 
CONTROL 
17.7 
15.75 
17.6 
-0.1 
15.75 
17.6 
-0.1 
32 
51-433 BSG 
CONTROL 
11.1 
11.7 
10.7 
-0.4 
11.7 
10.7 
-0.4 
33 
90-404 L-L 
CONTROL 
17.2 
18.9 
16.8 
-0.4 
18.9 
16.8 
-0.4 
34 
08-403 J-O 
CONTROL 
15.85 
15.5 
15.4 
-0.45 
15.5 
15.4 
-0.45 
35 
65-457 SAB 
CONTROL 
15.65 
14 
15.1 
-0.55 
14 
15.1 
-0.55 
36 
54-415 TPC 
CONTROL 
15.85 
15.9 
15.05 
-0.8 
15.9 
15.05 
-0.8 
37 
90-450 DAR 
CONTROL 
11.1 
11.2 
10.05 
-1.05 
11.2 
10.05 
-1.05 
38 
57-414 E-A 
CONTROL 
16.3 
17.8 
15.2 
-1.1 
17.8 
15.2 
-1.1 
39 
90-429 R-R 
CONTROL 
17.65 
19.1 
16.45 
-1.2 
19.1 
16.45 
-1.2 
40 
65-475 LPW 
CONTROL 
18.6 
18.9 
17.4 
-1.2 
18.9 
17.4 
-1.2 
41 
57-416 LAB 
CONTROL 
17.2 
14.8 
15.9 
-1.3 
14.8 
15.9 
-1.3 
42 
08-401 D-F 
CONTROL 
14.3 
13.6 
13 
-1.3 
13.6 
13 
-1.3 
43 
90-444 JSR 
CONTROL 
10.4 
10.9 
9.1 
-1.3 
10.9 
9.1 
-1.3 
44 
89-406 A-M 
CONTROL 
16.3 
15.3 
14.9 
-1.4 
15.3 
14.9 
-1.4 

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Complete Case 
0's Imputed for Deaths 
Sr. no 
Patient ID 
Treatment 
Group 
Baseline 
12 Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
12 
Weeks 
24 
Weeks 
Change from 
Baseline to 
24 Weeks 
45 
75-423 FFF 
CONTROL 
13.5 
13.5 
12.05 
-1.45 
13.5 
12.05 
-1.45 
46 
90-415 J-M 
CONTROL 
15.45 
13.3 
14 
-1.45 
13.3 
14 
-1.45 
47 
90-403 B-L 
CONTROL 
15.8 
14.1 
14.25 
-1.55 
14.1 
14.25 
-1.55 
48 
06-403 GAB 
CONTROL 
13.25 
9.9 
11.55 
-1.7 
9.9 
11.55 
-1.7 
49 
56-402 CES 
CONTROL 
10.5 
11.2 
8.8 
-1.7 
11.2 
8.8 
-1.7 
50 
76-404 DDD 
CONTROL 
18 
17.7 
16.3 
-1.7 
17.7 
16.3 
-1.7 
51 
75-430 KKK 
CONTROL 
18.05 
19.3 
16.3 
-1.75 
19.3 
16.3 
-1.75 
52 
41-401 RBF 
CONTROL 
13.05 
12.75 
11.15 
-1.9 
12.75 
11.15 
-1.9 
53 
36-404 EHT 
CONTROL 
18.4 
17.8 
16.45 
-1.95 
17.8 
16.45 
-1.95 
54 
89-411 JFB 
CONTROL 
18.4 
17.75 
16.25 
-2.15 
17.75 
16.25 
-2.15 
55 
06-410 SNJ 
CONTROL 
16.2 
Not Done 
13.8 
-2.4 
Not Done 
13.8 
-2.4 
56 
65-464 GLW 
CONTROL 
17.5 
16.75 
15.1 
-2.4 
16.75 
15.1 
-2.4 
57 
90-414 J-P 
CONTROL 
15.9 
13.6 
13.45 
-2.45 
13.6 
13.45 
-2.45 
58 
51-403 O-J 
CONTROL 
11.8 
10.5 
9.1 
-2.7 
10.5 
9.1 
-2.7 
59 
90-447 TLG 
CONTROL 
19.75 
18.2 
17.05 
-2.7 
18.2 
17.05 
-2.7 
60 
75-404 BBB 
CONTROL 
15.1 
15.5 
12.3 
-2.8 
15.5 
12.3 
-2.8 
61 
51-462 JPL 
CONTROL 
18.1 
17 
15.3 
-2.8 
17 
15.3 
-2.8 
62 
69-401 M-K 
CONTROL 
15.05 
12.6 
12.25 
-2.8 
12.6 
12.25 
-2.8 
63 
36-401 RLQ 
CONTROL 
19.15 
16.9 
16.25 
-2.9 
16.9 
16.25 
-2.9 
64 
51-457 CAR 
CONTROL 
17.55 
15.5 
14.2 
-3.35 
15.5 
14.2 
-3.35 
65 
51-418 C-R 
CONTROL 
19.1 
14.45 
15.35 
-3.75 
14.45 
15.35 
-3.75 
66 
51-461 RGB 
CONTROL 
17.1 
14.8 
13 
-4.1 
14.8 
13 
-4.1 
67 
90-435 L-S 
CONTROL 
13.1 
8.5 
8.95 
-4.15 
8.5 
8.95 
-4.15 

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OPTIMIZER SMART System 
 
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Complete Case 
0's Imputed for Deaths 
Sr. no 
Patient ID 
Treatment 
Group 
Baseline 
12 Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
12 
Weeks 
24 
Weeks 
Change from 
Baseline to 
24 Weeks 
68 
90-407 A-S 
CONTROL 
17.4 
14.1 
13 
-4.4 
14.1 
13 
-4.4 
69 
54-409 DMD 
CONTROL 
15.65 
10.95 
11.05 
-4.6 
10.95 
11.05 
-4.6 
70 
90-423 M-C 
CONTROL 
17.5 
11.4 
10.65 
-6.85 
11.4 
10.65 
-6.85 
71 
21-402 A-C 
CONTROL 
14.3 
14.05 
Inadequate 
  
14.05 
Inadequate 
  
72 
32-402 R-P 
CONTROL 
15.7 
14.65 
Not Done 
  
14.65 
Not Done 
  
73 
41-405 ACW 
CONTROL 
9.1 
Not Done 
Not Done 
  
Not Done 
Not Done 
  
74 
51-467 TDD 
CONTROL 
16.15 
11.6 
Not Done 
  
11.6 
Not Done 
  
75 
65-421 DTJ 
CONTROL 
14.7 
Not done 
Not done 
  
Not done 
Not done 
  
76 
65-422 RTH 
CONTROL 
17.8 
Died 
Died 
  
0 
0 
-17.8 
77 
65-427 BAC 
CONTROL 
13.7 
Died 
Died 
  
0 
0 
-13.7 
78 
70-411 M-K 
CONTROL 
17.7 
Withdrawn 
Withdrawn 
  
Withdrawn 
Withdrawn 
  
79 
70-415 A-H 
CONTROL 
17.45 
Inadequate 
Inadequate 
  
Inadequate 
Inadequate 
  
80 
71-401 XXX 
CONTROL 
18.05 
Withdrawn 
Withdrawn 
  
Withdrawn 
Withdrawn 
  
81 
72-408 HHH 
CONTROL 
10.15 
Inadequate 
Death 
  
Inadequate 
0 
-10.15 
82 
75-424 GGG 
CONTROL 
10.5 
Inadequate 
Not Done 
  
Inadequate 
Not Done 
  
83 
88-407 WMR 
CONTROL 
10.2 
Withdrawn 
Withdrawn 
  
Withdrawn 
Withdrawn 
  
84 
90-402 M-O 
CONTROL 
10.7 
Death 
Death 
  
0 
0 
-10.7 
85 
90-408 G-M 
CONTROL 
17.85 
Not Done 
Not Done 
  
Not Done 
Not Done 
  
86 
90-437 K-J 
CONTROL 
10.35 
9.65 
Not Done 
  
9.65 
Not Done 
  
Mean 
  
  
15.361 
15.211 
15.162 
-0.504 
14.586 
14.343 
-1.184 
 
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        Table 31b: Summary of the peak VO2 values for the FIX-HF-5C study (Optimizer Group) 
 
  
  
  
  
Complete Case 
0's Imputed for Deaths 
Sr. no 
Patient ID 
Treatment 
Group 
Baseline 
12 Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
12 
Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
1 
51-411 J-B 
ACTIVE 
13.9 
16.95 
19.8 
5.9 
16.95 
19.8 
5.9 
2 
79-402 BBB 
ACTIVE 
14.75 
20.7 
20.4 
5.65 
20.7 
20.4 
5.65 
3 
90-424 H-F 
ACTIVE 
17.35 
21.9 
22.85 
5.5 
21.9 
22.85 
5.5 
4 
65-408 HDF 
ACTIVE 
17.85 
20.3 
22.3 
4.45 
20.3 
22.3 
4.45 
5 
06-409 DKW 
ACTIVE 
13.45 
15.4 
17.4 
3.95 
15.4 
17.4 
3.95 
6 
51-417 CWJ 
ACTIVE 
9.75 
12.3 
13.4 
3.65 
12.3 
13.4 
3.65 
7 
51-464 V-S 
ACTIVE 
19.6 
23.25 
23.2 
3.6 
23.25 
23.2 
3.6 
8 
51-435 KLA 
ACTIVE 
18.1 
16.9 
20.85 
2.75 
16.9 
20.85 
2.75 
9 
90-442 GSG 
ACTIVE 
16.95 
18.45 
19.65 
2.7 
18.45 
19.65 
2.7 
10 
78-401 AAA 
ACTIVE 
16.7 
19.55 
19.3 
2.6 
19.55 
19.3 
2.6 
11 
90-449 HES 
ACTIVE 
14.5 
17.1 
17 
2.5 
17.1 
17 
2.5 
12 
41-404 JJE 
ACTIVE 
17.55 
18.45 
19.9 
2.35 
18.45 
19.9 
2.35 
13 
65-409 DTA 
ACTIVE 
14.3 
15.9 
16.6 
2.3 
15.9 
16.6 
2.3 
14 
72-402 BBB 
ACTIVE 
18.4 
19.05 
20.6 
2.2 
19.05 
20.6 
2.2 
15 
54-404 JAS 
ACTIVE 
18.5 
19.45 
20.55 
2.05 
19.45 
20.55 
2.05 
16 
54-420 JFK 
ACTIVE 
15.75 
17.3 
17.65 
1.9 
17.3 
17.65 
1.9 
17 
51-454 MJP 
ACTIVE 
12.1 
15.25 
13.95 
1.85 
15.25 
13.95 
1.85 
18 
65-432 BRB 
ACTIVE 
18.55 
20.8 
20.15 
1.6 
20.8 
20.15 
1.6 
19 
75-402 AAA 
ACTIVE 
14.85 
15.8 
16.3 
1.45 
15.8 
16.3 
1.45 

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Complete Case 
0's Imputed for Deaths 
Sr. no 
Patient ID 
Treatment 
Group 
Baseline 
12 Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
12 
Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
20 
56-405 CFR 
ACTIVE 
11.15 
12.7 
12.45 
1.3 
12.7 
12.45 
1.3 
21 
65-403 STP 
ACTIVE 
13.15 
12.2 
14.4 
1.25 
12.2 
14.4 
1.25 
22 
75-420 EEE 
ACTIVE 
13.2 
15.4 
14.25 
1.05 
15.4 
14.25 
1.05 
23 
65-471 SLC 
ACTIVE 
16.35 
15.7 
17.4 
1.05 
15.7 
17.4 
1.05 
24 
90-406 H-R 
ACTIVE 
16.05 
19.3 
16.8 
0.75 
19.3 
16.8 
0.75 
25 
65-466 JWS 
ACTIVE 
17.9 
15.7 
18.6 
0.7 
15.7 
18.6 
0.7 
26 
90-413 G-G 
ACTIVE 
10.2 
10.45 
10.9 
0.7 
10.45 
10.9 
0.7 
27 
74-401 AAA 
ACTIVE 
15.95 
16.5 
16.65 
0.7 
16.5 
16.65 
0.7 
28 
75-427 HHH 
ACTIVE 
15.5 
17 
16.2 
0.7 
17 
16.2 
0.7 
29 
65-406 PAT 
ACTIVE 
15.45 
13.25 
15.85 
0.4 
13.25 
15.85 
0.4 
30 
51-446 JEW 
ACTIVE 
10.9 
12.5 
11.25 
0.35 
12.5 
11.25 
0.35 
31 
32-404 LMD 
ACTIVE 
16.9 
13.7 
17.2 
0.3 
13.7 
17.2 
0.3 
32 
09-402 JWA 
ACTIVE 
14.7 
14.25 
14.9 
0.2 
14.25 
14.9 
0.2 
33 
55-407 CRS 
ACTIVE 
13.4 
14.3 
13.6 
0.2 
14.3 
13.6 
0.2 
34 
51-444 JAF 
ACTIVE 
13.95 
16.75 
14.1 
0.15 
16.75 
14.1 
0.15 
35 
51-426 SLS 
ACTIVE 
10.2 
9.25 
10.3 
0.1 
9.25 
10.3 
0.1 
36 
21-404 D-C 
ACTIVE 
10.05 
10.05 
10.05 
0 
10.05 
10.05 
0 
37 
90-431 JCP 
ACTIVE 
13.6 
14.4 
13.6 
0 
14.4 
13.6 
0 
38 
51-423 M-W 
ACTIVE 
18.1 
15.4 
17.9 
-0.2 
15.4 
17.9 
-0.2 
39 
57-413 DEB 
ACTIVE 
16.3 
16.7 
15.95 
-0.35 
16.7 
15.95 
-0.35 
40 
51-456 WFC 
ACTIVE 
12.9 
13.9 
12.45 
-0.45 
13.9 
12.45 
-0.45 

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Complete Case 
0's Imputed for Deaths 
Sr. no 
Patient ID 
Treatment 
Group 
Baseline 
12 Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
12 
Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
41 
65-447 SLG 
ACTIVE 
18.15 
17.9 
17.6 
-0.55 
17.9 
17.6 
-0.55 
42 
65-460 RDB 
ACTIVE 
13.8 
13.7 
13.2 
-0.6 
13.7 
13.2 
-0.6 
43 
55-409 GLF 
ACTIVE 
15.7 
16.65 
15.05 
-0.65 
16.65 
15.05 
-0.65 
44 
65-445 GIC 
ACTIVE 
12.9 
12.8 
11.85 
-1.05 
12.8 
11.85 
-1.05 
45 
65-451 G-G 
ACTIVE 
14.75 
12.45 
13.35 
-1.4 
12.45 
13.35 
-1.4 
46 
75-435 PPP 
ACTIVE 
18.2 
16.85 
16.8 
-1.4 
16.85 
16.8 
-1.4 
47 
55-404 DBG 
ACTIVE 
18.3 
18.4 
16.8 
-1.5 
18.4 
16.8 
-1.5 
48 
90-405 M-R 
ACTIVE 
19.4 
19.25 
17.85 
-1.55 
19.25 
17.85 
-1.55 
49 
32-409 AMD 
ACTIVE 
16.9 
18.1 
15.3 
-1.6 
18.1 
15.3 
-1.6 
50 
89-402 DJB 
ACTIVE 
18.95 
18.2 
17.25 
-1.7 
18.2 
17.25 
-1.7 
51 
90-453 DSG 
ACTIVE 
17.65 
17.5 
15.9 
-1.75 
17.5 
15.9 
-1.75 
52 
06-402 PAS 
ACTIVE 
18.85 
17.9 
17.05 
-1.8 
17.9 
17.05 
-1.8 
53 
90-417 T-T 
ACTIVE 
14.2 
13.35 
12.25 
-1.95 
13.35 
12.25 
-1.95 
54 
90-411 RHJ 
ACTIVE 
12.85 
12.75 
10.6 
-2.25 
12.75 
10.6 
-2.25 
55 
51-459 CDS 
ACTIVE 
14.7 
13.3 
12.4 
-2.3 
13.3 
12.4 
-2.3 
56 
51-434 RLM 
ACTIVE 
18.4 
19.7 
15.75 
-2.65 
19.7 
15.75 
-2.65 
57 
75-416 DDD 
ACTIVE 
13.15 
12.2 
10.4 
-2.75 
12.2 
10.4 
-2.75 
58 
09-401 DLH 
ACTIVE 
11.9 
10.35 
8.9 
-3 
10.35 
8.9 
-3 
59 
90-451 CLC 
ACTIVE 
14.55 
12.45 
11.3 
-3.25 
12.45 
11.3 
-3.25 
60 
90-432 E-C 
ACTIVE 
17.9 
16.75 
13.95 
-3.95 
16.75 
13.95 
-3.95 
61 
90-422 G-W 
ACTIVE 
19.7 
15.6 
15.5 
-4.2 
15.6 
15.5 
-4.2 

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Dynamics USA, Inc. 
  
  
  
  
Complete Case 
0's Imputed for Deaths 
Sr. no 
Patient ID 
Treatment 
Group 
Baseline 
12 Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
12 
Weeks 
24 
Weeks 
Change from 
Baseline to 24 
Weeks 
62 
55-410 BGS 
ACTIVE 
16.3 
8.95 
11.75 
-4.55 
8.95 
11.75 
-4.55 
63 
90-420 D-G 
ACTIVE 
17.25 
13.4 
12.5 
-4.75 
13.4 
12.5 
-4.75 
64 
90-428 T-K 
ACTIVE 
15.65 
10.45 
10.2 
-5.45 
10.45 
10.2 
-5.45 
65 
51-420 KAS 
ACTIVE 
17.7 
15.9 
12 
-5.7 
15.9 
12 
-5.7 
66 
90-426 S-G 
ACTIVE 
17.3 
12.75 
10 
-7.3 
12.75 
10 
-7.3 
67 
06-404 RCW 
ACTIVE 
14 
Not Done 
Not Done 
  
Not Done 
Not Done 
  
68 
08-407 MAJ 
ACTIVE 
18.15 
Withdrawn 
Withdrawn 
  
Withdrawn 
Withdrawn 
  
69 
57-409 GJD 
ACTIVE 
16.45 
LTF 
LTF 
  
LTF 
LTF 
  
70 
65-446 GDN 
ACTIVE 
10.85 
Died 
Died 
  
0 
0 
-10.85 
71 
70-410 V-P 
ACTIVE 
  
Inadequate 
Inadequate 
  
Inadequate 
Inadequate 
  
72 
72-406 FFF 
ACTIVE 
15.2 
Inadequate 
Inadequate 
  
Inadequate 
Inadequate 
  
73 
75-429 JJJ 
ACTIVE 
18.8 
Not Done 
Not Done 
  
Not Done 
Not Done 
  
74 
88-402 SET 
ACTIVE 
13.35 
12.45 
Death 
  
12.45 
0 
-13.35 
Mean 
  
  
15.489 
15.586 
15.487 
-0.027 
15.357 
15.032 
-0.027 
 
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a third party without the prior written consent of Impulse Dynamics USA, Inc. 
 
The primary effectiveness outcome measures by treatment group over time are 
summarized in Figure 15 and Table 32.  The model-based estimated mean 
difference in peak VO2 at 24 weeks between CCM™ Treatment and Control 
groups was 0.836 ml/kg/min (15.042 vs. 14.206 mlO2/kg/min, respectively), with 
a 95% Bayesian credible interval of (0.123, 1.552 mlO2/kg/min). The probability 
that CCM™ treatment is superior to Control is 0.989, which exceeds the 0.975 
criteria required for statistical significance of the primary endpoint. 
 
 
Figure 15: Bayesian Modeled Treatment Mean Difference (Δ) Peak VO2 by Time* 
*N’s for each time point are shown in Table 32 below 
 
                Table 32: “Bayesian Primary Analysis Results (with Borrowing)” 
Borrowing (Bayes) 
Time 
TmtDiff 
LL 
UL 
SE 
P(Superior) 
12 Weeks 
0.675 
-0.037 
1.387 
0.363 
0.968 
24 Weeks 
0.836 
0.123 
1.552 
0.364 
0.989 
Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
Summarizing the FIX-HF-5 and FIX-HF-5C studies separately (Figure 16), the 
model-based estimated treatment differences at 24 weeks in FIX-HF-5 and FIX-
HF-5C studies are 1.080 mlO2/kg/min (0.413, 1.759 mlO2/kg/min) and 0.793 
mlO2/kg/min (-0.099, 1.684 mlO2/kg/min), respectively.  The primary analysis 
for FIX-HF-5C (with borrowing) appropriately leverages information from both 
studies to provide a more robust estimate of the treatment difference. 

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Figure 16: “24-Week Modeled Mean PVO2 Treatment Difference by Study” 
 
 For reference, the mean and SD of peak VO2 observed in the FIX-HF-5C study 
alone by group and time are summarized in Table 33a and 33b below. 
 
Table 33a: Number of Observations, Mean, SD of Peak VO2 by Group and Time 
 
Nobs(observed) 
Nobs(missing) 
Mean 
Standard 
Deviation 
 
Control 
Active 
Control 
Active 
Control 
Active 
Control 
Active 
Baseline 
86 
73 
0 
1 
15.36 
15.49 
2.81 
2.61 
12 Weeks 
73 
68 
10 
4 
14.93 
15.48 
3.33 
3.28 
24 Weeks 
74 
68 
6 
4 
14.79 
15.28 
3.54 
3.66 
                            Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
 
 
 
Table 33b: Number of Observations, Mean, SD of Peak VO2 by Group and Time 
(FIX-HF-5) 
 
 
Nobs(observed) 
Nobs(missing) 
Mean 
Standard 
Deviation 
 
Control 
Active 
Control 
Active 
Control 
Active 
Control 
Active 
Baseline 
112 
117 
1 
0 
14.95 
14.60 
2.83 
2.95 
12 Weeks 
93 
103 
7 
6 
14.62 
14.54 
3.12 
3.30 
24 Weeks 
89 
99 
8 
9 
14.21 
14.99 
3.02 
3.48 
Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
Thus, the results of the analysis of the primary effectiveness endpoint of peak 
VO2 demonstrate superiority of CCM treatment over Control in the primary 
endpoint.  This allows us to conclude that the primary effectiveness endpoint has 
been met and that CCM™ therapy has successfully demonstrated effectiveness 
-1
0
1
2
3
FIX-HF-5C
FIX-HF-5
Mean pVO2 Treatment Difference (ml/kg/min)
Bayesian

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in this study.  
 
The following data confirm the adequacy of CPX tests employed in the 
determinations of peak VO2 and RER. 
 
Eighty-six (86) subjects were randomized to Control and 74 were randomized to 
OPTIMIZER. All have been accounted for in the table below, with regard to their 
24-week CPX testing adequacy determinations. Seventy-two (72) Control 
subjects and 68 OPTIMIZER subjects performed the 24-week CPX testing. 
77.8% of the Control subjects that performed the 24-week CPX testing had 2 
adequate tests done and similarly, 77.9% of the OPTIMIZER subjects had 2 
adequate tests.  The subjects that had only one or zero adequate tests were 
generally not willing or able to perform a third test, and in some cases, they were 
unable to perform a second test as indicated in the table below.  Only one of these 
subjects performed 2 inadequate tests, a third test was requested and performed, 
and that third test was deemed adequate.   
Table 34: CPX test summary in Control and OPTIMIZER group 
 
24 Week CPX Tests 
CONTROL (86 subjects) 
OPTIMIZER (74 subjects) 
Both tests adequate  
56 (65.1%) 
53 (71.6%) 
One test adequate 
14 (16.3) 
- 
2 of the 14 subjects only 
performed 1 test 
13 (17.6%)    
- 
1 of the 13 subjects only 
performed 1 test 
Zero tests adequate 
2 (2.3%)     
- 
3rd test could not be done 
2 (2.7%) 
- 
3rd test could not be done 
Third test  
0 
1   (included in the 13 above 
with 1 adequate test listed 
above) 
No testing performed 
14 (16.3%) 
• 
4 deaths 
• 
3 early withdrawal 
• 
7 patients refused or 
unable  
6 (8.1%) 
• 
2 deaths 
• 
1 LTF 
• 
1 early withdrawal 
• 
2 patients refused or unable 
 
                     Discussion of pVO2 results 
 
The studies primary endpoint, a difference in peak VO2 between groups, was met.  
This difference was arrived at by a reduction of peak VO2 in the control group 
and a maintenance of peak VO2 in the treatment group after 6-month follow-up.  
Thus, it can be concluded that in this study and included cohort, CCM prevented 
worsening of exercise tolerance.  It is typically expected in such a clinical trial 
that exercise tolerance would be maintained in the Control group and would 
increase in the treatment group; for example, such expected findings have 
generally been identified in prior studies of cardiac resynchronization therapy 

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a third party without the prior written consent of Impulse Dynamics USA, Inc. 
(CRT).  It is therefore relevant to further discuss the current findings.   
 
First, the purpose of a randomized trial is to be able to account for (i.e., balance) 
unanticipated confounding factors and behaviors between groups.  Clinical trials 
and trial programs enroll unique populations based on unique eligibility criteria. 
In the FIX-HF-5 / FIX-HF-5C trials, we enrolled a group of patients who 
remained substantially symptomatic despite contemporary guideline-directed 
medical therapies. If left alone, these patients demonstrate disease progression as 
is evident by the progressive fall in peak VO2. Observing this is part of the beauty 
of the randomized parallel-control trial design. As detailed further below, the 
consistency between FIX-HF-5 and FIX-HF-5C supports that this observation is 
population-based, real, and not methodological. Preventing disease progression 
is an acknowledged goal of heart failure therapy. 
Second, it is important to note that, to the best of our knowledge, no prior study 
has invested as much time, effort and financial resources to ensure the quality of 
every cardiopulmonary stress test (CPX).  Quality measures taken in the FIX-HF-
5C study, included: quality assurance testing at every site to validate equipment 
every 6 months; sending technicians to perform tests upon requests of the sites or 
when the core lab identified issues with test performance; mandating two tests at 
each timepoint; and rapid centralized reads of test quality and asking for 
additional tests when quality metrics were not met.  Similar measures were taken 
in the FIX-HF-5 study with the exception of two tests at each timepoint.  Thus, 
we believe that the data of the current study are valid in that they reflect what can 
be expected from serial assessments of exercise tolerance in the target population.   
To provide a perspective on the impact of the quality metrics, from among the 
160 patients enrolled in FIX-HF-5C (86 Control patients; 74 CCM treated 
patients) ~880 CPX tests were conducted.  Strict, prospectively defined criteria 
were applied by a blinded core lab to assess test “adequacy” and only “adequate” 
tests were included for analysis.  It turned out that ~90% of tests were deemed 
adequate and included in the final analysis.  We believe these methods further 
contribute importantly to the reliability of the CPX results obtained in FIX-HF-
5C study. 
Third, the finding of decreased peak VO2 in the control group was very similar to 
what was observed in the original FIX-HF-5 study and now confirmed 
prospectively in the stand-alone data of the FIX-HF-5C study.  This provides 
confidence in the robustness of the observation when studies are performed with 
the type of oversight detailed above. 
Finally, regarding exercise physiology, it is important to consider the impact of 
treatment on exercise duration.  In the pooled FIX-HF-5 and FIX-HF-5C dataset, 
peak VO2 decreased but exercise duration was constant in the Control group (147 
paired observations, 11.2 vs 11.5 min, p=0.84).  In contrast, in the CCM treatment 

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group, peak VO2 was relatively constant, but exercise duration increased 
significantly by almost 1 min (11.3 vs 12.2 min, 159 paired observations, 
p<0.001).  Please refer to the following Figure and Table (data pooled from FIX-
HF-5 and FIX-HF-5C; error bars are SEMs) for further details.  Thus, we identify 
another difference between the groups.  Importantly, since values of RER are 
constant across time, this does not appear to be a result of differences in patient 
effort between groups. 
 
Considering that a continuous treadmill ramp protocol was used in the conduct of 
the exercise tests, exercise time is directly related to workload.  Therefore, the 
ratio of exercise time (a surrogate of work performed) to peak VO2 (energy 
utilization) can be considered as an index of overall metabolic efficiency.  
Improved metabolic efficiency is commonly expected on repeat exercise testing 
due to habituation (i.e., patient familiarity with the test) and possibly some degree 
of physical conditioning. Interestingly, this efficiency ratio increased from 
baseline to 6 months by similar amounts in both groups:  44.5 vs 47.0 
[sec/(mlO2/min), 
p=0.001] 
in 
controls 
compared 
to 
45.7 
vs 
48.5 
[sec/(mlO2/min), p=0.007] in CCM treatment (p=ns between groups).  These 
findings are summarized in the next Figure.  As noted above, this is also in the 
context of no change of RER values between baseline and 6-months such that 
changes in patient effort are considered to be accounted for.   
 

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The fact that this efficiency index improved as expected, and comparably in both 
groups speaks to the equal treatment of study subjects in both groups and, we 
believe, also speaks to the blindness of the core lab interpretations. 
Thus, patients in the CCM group were able to do more work than Controls (as 
evidenced by the significant increase in exercise duration.  However, due to the 
apparent increase in metabolic efficiency in the context of a high degree of 
oversight during the conduct of the tests, increased work was able to be performed 
at the same peak VO2.   
In summary, the finding that peak VO2 declined in controls in the FIX-HF-5C 
study is prospective confirmation of what was generally observed in our prior 
FIX-HF-5 study and speaks to the robustness of the observation. 
The tests were performed with strict oversight by blinded core lab and “as 
needed” traveling exercise physiologist to ensure the highest possible test quality 
and inclusion only of “adequate” tests. 
Although peak VO2 stayed relatively constant, exercise duration (an index of total 
workload in our continuous ramp study) increased significantly in the treatment 
group. In Controls, duration stayed constant but peak VO2 decreased.  Apparent 
metabolic efficiency improved comparably in both groups.  Overall, a significant 
treatment effect of CCM is demonstrated. 
 
1.4.6.11 Sensitivity Analyses  
The conclusion of CCM™ superiority with respect to mean peak VO2 was 
consistent across all sensitivity analyses (detailed in Attachment 07 Primary & 
Key Secondary Analyses Report). These included various methods of imputation 
for missing data (missing data due to death imputed as 0, imputed as the lowest 
pVO2 at any visit, or no imputation), as well as an assessment of site-to-site 
heterogeneity of the treatment effect.  The conclusion of CCM™ superiority with 
respect to mean pVO2 was consistent across all sensitivity analyses.  In addition, 
it was noted that the primary analysis would achieve statistical significance with 

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any borrowing weight of 0.11 or larger (as noted above, 0.30 was pre-specified 
in the analysis plan). 
 
In addition to the sensitivity analyses, there are two additional potential 
limitations of the Bayesian analysis: 
a.  The analysis of the FIX-HF-5 data used for borrowing in the Bayesian analysis 
included one patient with a baseline NYHA class II. The primary outcome 
(peak VO2) was missing at 12 and 24 weeks for this patient, so impact of 
including this patient on the FIX-HF-5 analysis was minimal. 
 
b. There was no imputation of missing data in the FIX-HF-5 analysis submitted 
to the FDA in the FIX-HF-5C simulations (i.e. all simulations used a 
“completed case” analysis of FIX-HF-5 for borrowing). However, a FIX-HF-
5 “complete case” analysis (for borrowing) is inconsistent with the primary 
analysis of FIX-HF-5C, which imputes missing data due to death in FIX- 
HF-5C as 0’s. There are a total of 6 patients in the FIX-HF-5 study who are 
missing peak VO2 due to death, of which 5 are in the active treatment group 
and 1 is in the control group. 
Given these considerations, we repeated the FIX-HF-5C primary analysis with 
30% borrowing of FIX- HF-5 data, in which the FIX-HF-5 analysis excludes 
the one patient with NYHA class II and imputes missing peak VO2 data due 
to death as 0’s for the above 6 patients. This involves fitting a Bayesian model 
on the FIX-HF-5 data, then performing the FIX-HF-5C analysis (with and 
without borrowing of FIX-HF-5 data). 
 
1.4.6.12 Comparison of Baseline Characteristics between Subjects Showing 
Improvement vs. Worsening or No Change on the Primary Endpoint 
(pVO2)  
Baseline characteristics including medications were compared between 
OPTIMIZER subjects who exhibited a worsening or no change in peak VO2 
values to those who demonstrated an improvement in peak VO2 values of greater 
than or equal to 2 ml/kg/min.  Changes were assessed relative to the median value 
of peak VO2 for the control group.  Results for FIX-HF-5C and FIX-HF-5 pooled 
are shown in Table 35 below.  The only parameter which differentiated patients 
between these two subgroups was a higher prevalence of diabetes in 
nonresponders. 
 

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Table 35:  Baseline Characteristics by Change in Peak VO2 at 24 weeks 
(compared to control group median change, ACTIVE subjects only). 
FIX-HF-5C and FIX-HF-5 Pooled, Median (M)=-0.8 ml/kg/min 
Variable 
<=M ml/kg/min 
Mean (SD) or n 
(%) 
N=58 
>=M+2 ml/kg/min 
Mean (SD) or n 
(%) 
N=56 
p-value 
(2-sided) 
Age (yrs) 
61.4 (11.5) 
60.0 (12.0) 
0.5157 
Male 
41 (70.7%) 
43 (76.8%) 
0.5264 
Ethnicity (White) 
46 (79.3%) 
44 (78.6%) 
1.0000 
CHF Etiology (Ischemic) 
43 (74.1%) 
37 (66.1%) 
0.4146 
Prior MI 
37 (63.8%) 
35 (62.5%) 
1.0000 
Prior ICD 
51 (87.9%) 
47 (83.9%) 
0.5974 
Diabetes 
35 (60.3%) 
22 (39.3%) 
0.0389 
QRS Duration (ms) 
100.5 (13.0) 
100.6 (14.0) 
0.9884 
LVEF (%) (core lab) 
31.5 (5.1) 
31.6 (4.9) 
0.9181 
LVEDD (mm) (core lab) 
57.9 (7.1) 
58.1 (6.1) 
0.8763 
   Weight (kg) 
95.7 (21.5) 
90.8 (24.8) 
0.2644 
   Height (cm) 
173.7 (8.6) 
174.1 (11.0) 
0.7920 
   BMI (kg/m2) 
31.6 (6.4) 
29.6 (6.3) 
0.0981 
   Resting HR (bpm) 
70.7 (11.2) 
70.0 (11.8) 
0.7625 
   Systolic 
119.6 (18.0) 
120.0 (16.7) 
0.8948 
   Diastolic 
71.4 (10.5) 
70.8 (9.9) 
0.7634 
ACEi or ARB 
52 (89.7%) 
49 (87.5%) 
0.7747 
   ACE inhibitor 
40 (69.0%) 
39 (69.6%) 
1.0000 
   ARB 
13 (22.4%) 
12 (21.4%) 
1.0000 
Beta Blocker 
56 (96.6%) 
53 (94.6%) 
0.6763 
Diuretic 
43 (74.1%) 
47 (83.9%) 
0.2526 
Second Diuretic 
4 (6.9%) 
4 (7.1%) 
1.0000 

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Table 35:  Baseline Characteristics by Change in Peak VO2 at 24 weeks 
(compared to control group median change, ACTIVE subjects only). 
FIX-HF-5C and FIX-HF-5 Pooled, Median (M)=-0.8 ml/kg/min 
Variable 
<=M ml/kg/min 
Mean (SD) or n 
(%) 
N=58 
>=M+2 ml/kg/min 
Mean (SD) or n 
(%) 
N=56 
p-value 
(2-sided) 
Ivabradine 
0 (0.0%) 
1 (1.8%) 
0.4912 
Digoxin 
15 (25.9%) 
12 (21.4%) 
0.6618 
ENTRESTO 
1 (1.7%) 
0 (0.0%) 
1.0000 
Aldosterone Inhibitor 
25 (43.1%) 
20 (35.7%) 
0.4487 
Hydralazine 
2 (3.4%) 
2 (3.6%) 
1.0000 
Nitrates 
21 (36.2%) 
16 (28.6%) 
0.4277 
Calcium Channel Blocker 
4 (6.9%) 
7 (12.5%) 
0.3569 
Anti-arrhythmic 
9 (15.5%) 
9 (16.1%) 
1.0000 
Aspirin 
39 (67.2%) 
45 (80.4%) 
0.1382 
Coumadin 
8 (13.8%) 
8 (14.3%) 
1.0000 
Clopidogrel 
16 (27.6%) 
12 (21.4%) 
0.5168 
Program: Responders.sas 
 
1.4.6.13 Secondary Effectiveness Endpoints 
 
1.4.6.13.1 MLWHFQ  
 
Given that the null hypothesis was rejected for the primary effectiveness 
endpoint, we proceed to the first pre-specified secondary endpoint, MLWHFQ. 
As described in the SAP, a linear mixed model (non-Bayesian) is fitted on the 
MLWHFQ endpoint.  There are a total of 160 patients and 443 non-missing 
MLWHFQ observations in FIX-HF-5C for this analysis. 
 
 

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 Table 36: Number of Observations, Mean, SD of MLWHFQ by Group 
and Time 
 
Nobs(observed) 
Nobs(missing) 
Mean 
Standard 
Deviation 
 
Control 
Active 
Control 
Active 
Control 
Active 
Control 
Active 
1 
(Baseline) 
86 
74 
0 
0 
57.35 
56.42 
23.36 
22.95 
2 (12 wks) 
80 
71 
3 
1 
49.71 
38.34 
24.72 
23.55 
3 (24 wks) 
76 
70 
4 
2 
47.47 
35.26 
25.65 
24.63 
             Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
 
Table 37: MLWHFQ Treatment Differences 
Time 
Estimate 
SE 
Lower 
95% 
Upper 
95% 
P-value 
(1-sided) 
12 weeks 
-10.33 
2.95 
-16.12 
-4.55 
<0.001 
24 weeks 
-11.73 
2.99 
-17.60 
-5.86 
<0.001 
                                  Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw  
 
The p-value for the comparison of mean MLWHFQ at 24 weeks for active 
treatment vs. control is <0.001. The null hypothesis is rejected, and active 
treatment is superior to control with respect to mean MLWHFQ at 24 weeks. 
 
1.4.6.13.2 Change in NYHA from Baseline 
 
Given that the first secondary null hypothesis was rejected, we proceed to the 
second secondary effectiveness endpoint, which is improvement in heart failure 
class, as assessed by the New York Heart Association (NYHA) classification. 
The analysis of this endpoint tests the hypothesis that the subjects treated with the 
device have greater odds of improving by at least one NYHA category compared 
to the control group. 
 
Table 38: NYHA: Baseline vs. 24 Weeks 
Treatment 
Group 
Baseline 
NHYA 
NYHA at 24 Weeks 
Total 
1 
2 
3 
4 
Active 
3 
23 (38%) 
25 (42%) 
12 (20%) 
0 (0%) 
60 
4 
3 (30%) 
4 (40%) 
2 (20%) 
1 (10%) 
10 
Control 
3 
12 (18%) 
16 (24%) 
39 (57%) 
1 (1%) 
68 
4 
0 (0%) 
0 (0%) 
4 (57%) 
3 (3%) 
7 
        Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
The p-value for the stratified Cochran Mantel-Haenzel test is < 0.001. The null 
hypothesis is rejected, and the Active arm is superior to Control. 
 
 
Table 39: NYHA: Improvement in NYHA, FIX-HF-5C 

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Etiology 
Active 
Control 
Odds Ratio 
P-Value 
(1-sided) 
Ischemic 
34/43 (79%) 
18/43 (42%) 
5.97 
< 0.001 
Non-Ischemic 
23/27 (85%) 
14/32 (44%) 
 
 
           Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
 A stratified Cochran Mantel-Haenzel test (with strata defined by etiology of 
heart failure) is used to compute a p-value at the one-sided 0.025 level. 
 
1.4.6.13.3 PeakVO2 with RER>1.05 Subset 
 
Given that the null hypothesis for NYHA was rejected, we proceed to the third 
secondary effectiveness endpoint, which is mean peak VO2 among observations 
with RER > 1.05. A linear mixed model (non-Bayesian) is fitted on the peak VO2 
endpoint. 
 
There are a total of 160 patients and 420 non-missing peak VO2 observations in 
FIX-HF-5C for this analysis. 
 
      Table 40: Number of Observations, Mean, SD of Peak VO2 by Group and 
Time 
 
Nobs(observed) 
Nobs(missing) 
Mean 
Standard 
Deviation 
 
Control 
Active 
Control 
Active 
Control 
Active 
Control 
Active 
1 
(Baseline) 
83 
71 
3 
3 
15.35 
15.52 
2.82 
2.64 
2 (12 wks) 
68 
64 
12 
7 
15.24 
15.67 
3.07 
3.22 
3 (24 wks) 
69 
65 
7 
5 
15.25 
15.56 
3.21 
3.47 
                               Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
         
               Table 41: pVO2 Treatment Differences with RER≥1.05 
Time 
Estimate 
SE 
Lower 95% 
Upper 
95% 
P-value 
(1-sided) 
12 weeks 
0.35 
0.35 
-0.33 
1.04 
0.1570 
24 weeks 
0.43 
0.35 
-0.25 
1.11 
0.1100 
                                   Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw  
 
As seen in Table 40 the trend of the treatment effect is in favor of CCM™ 
treatment.  However, the p-value for the comparison of mean peak VO2 at 24 
weeks for active treatment vs. control among observations with RER >1.05 is 
0.099. The null hypothesis is not rejected, and there is insufficient evidence to 
claim a difference in mean peak VO2 among observations with RER >1.05 with 
FIX-HF-5C data alone. However, as will be shown in section 4.4.6.14.3 (pVO2 
with RER≥1.05 Subset by Study) when data were pooled from the FIX-HF-5 and 
FIX-HF-5C studies, the treatment effect was estimated as 0.62 ml/kg/min with a 
p value of 0.009. 

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Table 33a shows results from Completed Cases. For this analysis there are a total 
of 160 patients and 442 non-missing peak VO2 observations from FIX-HF-5C 
patients.  Also, in this analysis, zeros are imputed for deaths in accordance with 
the prospective statistical analysis plan. 
In Table 40, which is an analysis of peak VO2 for tests in which RER is ≥1.05, 
there are a total of 160 patients and 420 non-missing values for peak VO2 
observations; 22 subjects less than in Table 33a. In this analysis, zeros are NOT 
imputed for deaths, which certainly had an important influence on the findings 
since there were more deaths in Control and Active treatment groups. 
In addition to the 10 tests missing due to deaths, there were 12 addition patients 
in which tests were deemed adequate but in which the RER was <1.05 (6 in the 
Control group and 6 CCM group). 
This accounts for the differences in the number of observations.  There are several 
additional important points for discussion. 
First, despite the reduced number of observations in the analysis that includes 
only tests with RER≥1.05, the treatment effect still trends in the direction of 
benefit of CCM treatment. In fact, the sensitivity analysis on the completed cases 
analysis without any imputation (Table 20) showed treatment benefit with the 
Bayesian borrowing, and the 24-week difference between treatments in this 
population is similar to the RER≥1.05 subset.  This is further illustrated in the 
following graph (FIX-HF-5C data) which shows that at each timepoint and both 
groups, elimination of tests with RER<1.05 has very small effects on the impact 
of changes in peak VO2 values. 
 

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More generally, inclusion of an analysis that only uses tests with RER ≥1.05 was 
required by FDA over counter-arguments of IMPULSE and consultants as was 
documented in the meeting notes of teleconferences with FDA (Attachment 10).   
We remain concerned about the physiological and statistical validity of such an 
analysis.  Firstly, a 1.05 RER cutoff is arbitrary and assumes that a patient 
achieving a lower RER value cannot have reached their exercise limit.  Impulse 
provided a reference showing, from independent analysis, that low RER values 
are associated with a patient’s maximum effort and that increases of RER may 
themselves reflect improvements in patient conditions.  Accordingly, this analysis 
throws away one side of the distribution that contributes to the assessment of the 
treatment effect.  Furthermore, all the unprecedented safeguards introduced in the 
conduct, data collection and interpretation of test results discussed were geared 
to minimizing (if not eliminating) possible placebo effects on peak VO2.  As 
evidence of the success of the approach, please refer to the following graph of 
data from the FIX-HF-5C, which shows the average RER of tests at each 
timepoint by group.  As seen, there is no difference over time or between groups 
(p>0.4 for all comparisons). 
 
Thus, using RER as in an index, there is no evidence of change of effort during 
exercise testing in either group. 
In summary, the impact of removing test results with RER <1.05 has only a small 
effect on the time course of change of peak VO2 in both groups.  We have further 
shown that based on the FDA-specified index (i.e., RER) there is no evidence of 
change in effort on exercise testing over time in either group, which is likely a 
result of the unprecedented and extreme measures taken to ensure test quality in 
this study.  We reiterate concerns stated during deliberations with FDA that 
throwing out valid data with RER values between 1.00 and 1.05 is not the proper 
way to handle the question of change in patient effort from physiological or 
statistical perspectives.  Finally, we are not aware of any prior study in which 

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such criteria have been applied to the analysis of clinical trial results; there is no 
precedent for performing or interpreting the results of such an analysis.   
 
1.4.6.13.4 Effectiveness Endpoint Summary 
 
Results demonstrate superiority of the OPTIMIZER group over the control 
group with respect to peak VO2, quality of life (MLWHFQ), and NYHA Class.  
All three are important indicators of heart failure severity and improvement in 
these parameters in the subject population of moderately severe heart failure 
patients is strong evidence for a physiologic effect of CCM™ therapy.  
 
 1.4.6.14 Secondary Sensitivity Analyses by Study 
1.4.6.14.1 MLWHFQ Sensitivity by Study 
Estimates of changes in MLWHFQ in the FIX-HF-5 and FIX-HF-5C studies 
alone and combined (i.e., data pooled from both studies) are summarized in 
Tables 42-44 and Fig. 17.  MLWHFQ improved more in the Treatment group 
of each of the studies (by approximately 11 points) as well as in the pooled data. 
 
Table 42: MLWHFQ Treatment Differences, FIX-HF-5 
Time 
Estimate 
SE 
Lower 
95% 
Upper 
95% 
P-value 
(1-sided) 
12 weeks 
-12.59 
2.45 
-17.38 
-7.79 
<0.001 
24 weeks 
-10.82 
2.42 
-15.57 
-6.07 
<0.001 
                                   Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw  
 
Table 43: MLWHFQ Treatment Differences, FIX-HF-5C 
Time 
Estimate 
SE 
Lower 
95% 
Upper 
95% 
P-value 
(1-sided) 
12 weeks 
-10.33 
2.95 
-16.12 
-4.55 
<0.001 
24 weeks 
-11.73 
2.99 
-17.60 
-5.86 
<0.001 
             Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw  
 
Table 44: MLWHFQ Treatment Differences, FIX-HF-5/5C, Combined 
Time 
Estimate 
SE 
Lower 
95% 
Upper 
95% 
P-value 
(1-sided) 
12 weeks 
-11.44 
1.89 
-15.15 
-7.74 
<0.001 
24 weeks 
-10.90 
1.89 
-14.61 
-7.19 
<0.001 
                                Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 

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Figure 17: 24-Week Modeled MLWHFQ Treatment Difference by Study 
 
1.4.6.14.2 NYHA Sensitivity by Study 
Estimates of changes in NYHA in the FIX-HF-5 and FIX-HF-5C studies alone 
and combined (i.e., data pooled from both studies) are summarized in Tables 
45-47.  In each study, and in the combined dataset, a greater proportion of 
patients NYHA improved by 1 or more classes in the Treatment group 
compared to Controls as well as in the pooled data.  This was the case for both 
Ischemic and Non-Ischemic heart failure etiology.  From the pooled data, 
Treatment patients were 2.85 times more likely to experience an improved 
NYHA than Controls. 
 
Table 45:  Improvement in NYHA, FIX-HF-5 
Etiology 
Active 
Control 
OddsRatio 
P-value 
(1-sided) 
Ischemic 
37/73 (51%) 
11/61 (18%) 
2.05 
0.01 
Non-Ischemic 
10/30 (33%) 
16/33 (48%) 
 
 
                   Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
Table 46:  Improvement in NYHA, FIX-HF5C 
Etiology 
Active 
Control 
OddsRatio 
P-value 
(1-sided) 
Ischemic 
34/43 (79%) 
18/43 (42%) 
5.97 
< 0.001 
Non-Ischemic 
23/27 (85%) 
14/32 (44%) 
                   Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
 
 

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Table 47:  Improvement in NYHA, FIX-HF 5/5C Combined 
 
Etiology 
Active 
Control 
OddsRatio 
P-value 
(1-sided) 
Ischemic 
71/116 (61%) 29/104 (28%) 
2.85 
< 0.001 
Non-Ischemic 
33/57 (58%) 
30/65 (46%) 
 
 
 
Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
1.4.6.14.3 pVO2 with RER≥1.05 Subset by Study 
Estimates of changes in peak VO2 in the subset of tests in which RER was ≥1.05 
in the FIX-HF-5 and FIX-HF-5C studies alone and combined (i.e., data pooled 
from both studies) are summarized in Tables 48-50 and Fig. 18.  In this subset 
of tests, peak VO2 trended to improve more in the Treatment group of each of 
the studies and was statistically significant in the FIX-HF-5 study alone.  In 
addition, this parameter was significantly improved by 0.62 ml/kg/min in the 
pooled data. 
Table 48: pVO2 Treatment Differences with RER ≥ 1.05, FIX-HF-5 
Time 
Estimate 
SE 
Lower 95% 
Upper 
95% 
P-value 
(1-sided) 
12 weeks 
0.00 
0.40 
-0.79 
0.78 
0.5020 
24 weeks 
0.83 
0.39 
0.06 
1.61 
0.0170 
                                  Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
Table 49: pVO2 Treatment Differences with RER ≥ 1.05, FIX-HF-5C 
Time 
Estimate 
SE 
Lower 95% 
Upper 
95% 
P-value 
(1-sided) 
12 weeks 
0.35 
0.35 
-0.33 
1.04 
0.1570 
24 weeks 
0.43 
0.35 
-0.25 
1.11 
0.1100 
           Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
Table 50: pVO2 Treatment Differences with RER ≥ 1.05, FIX-HF-5/5C, 
Combined 
Time 
Estimate 
SE 
Lower 95% 
Upper 
95% 
P-value 
(1-sided) 
12 weeks 
0.18 
0.27 
-0.35 
0.70 
0.2530 
24 weeks 
0.62 
0.26 
0.11 
1.14 
0.0090 
       Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 

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        Figure 18: 24-Week Modeled Mean pVO2 Treatment Difference with 
RER≥1.05 subset by Study 
 
1.4.6.15 Secondary Sensitivity Analyses: Per Protocol Population 
 
1.4.6.15.1 MLWHFQ Sensitivity: Per Protocol (PP) Population 
 
There was a total of 154 patients and 445 non-missing MLWHFQ observations 
in FIX-HF-5C for this analysis as summarized in Table 51.  The treatment effect 
in the PP population was -12.32 points (Table 52). 
Table 51: Number of Observations, Mean, SD of MLWHFQ 
by Group and Time 
 
Nobs(observed) 
Nobs(missing) 
Mean 
Standard 
Deviation 
 
Control 
Active 
Control Active 
Control 
Active Control 
Active 
1 
(Baseline) 
86 
68 
0 
0 
57.35 
55.40 
23.36 
23.42 
2 (12 wks) 
80 
68 
3 
0 
49.71 
37.13 
24.72 
23.21 
3 (24 wks) 
76 
67 
4 
1 
47.47 
34.18 
25.65 
24.44 
                             Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
Table 52: MLWHFQ Treatment Differences 
Time 
Estimate 
SE 
Lower 95% 
Upper 
95% 
P-value 
(1-sided) 
12 weeks 
-11.05 
3.01 
-16.95 
-5.16 
<0.001 
24 weeks 
-12.32 
3.05 
-18.29 
-6.35 
<0.001 
 

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1.4.6.15.2 NYHA Sensitivity: Per Protocol Population 
The number and percentage of patients in each NYHA class at 24 weeks as a 
function of baseline NYHA is summarized in Table 53.  As summarized in 
Table 54, patients in the Treatment group were significantly more likely to 
experience an improved NYHA class than patients in the Control group. 
 
        Table 53:  NYHA: Baseline vs.  24 Weeks 
Treatment 
Group 
Baseline 
NHYA 
NYHA at 24 Weeks 
Total 
1 
2 
3 
4 
Active 
3 
23 (40%) 
24 (41%) 
11 (19%) 
0 (0%) 
58 
4 
3 (33%) 
4 (44%) 
1 (11%) 
1 (11%) 
9 
Control 
3 
12 (18%) 
16 (24%) 
39 (57%) 
1 (1%) 
68 
4 
0 (0%) 
0 (0%) 
4 (57%) 
3 (43%) 
7 
                              Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
                    Table 54:  Improvement in NYHA 
Etiology 
Active 
Control 
OddsRatio 
P-value 
(1-sided) 
Ischemic 
33/41 (80%) 
18/43 (42%) 
6.21 
< 0.001 
Non-Ischemic 
22/26 (85%) 
14/32 (44%) 
 
 
                             Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
1.4.6.15.3 pVO2 with RER≥1.05 Subset Sensitivity: Per Protocol Population 
There was a total of 154 patients and 410 non-missing Peak VO2 
observations with RER≥1.05 in FIX-HF-5C PP population for this analysis 
(Table 55).  Results in the PP population are similar to those of the Intent to 
Treat population (Table 56). 
Table 55: Number of Observations, Mean, SD of Peak VO2 with 
RER≥1.05 by Group and Time 
 
Nobs(observed) 
Nobs(missing) 
Mean 
Standard 
Deviation 
 
Control Active 
Control 
Active Control Active Control 
Active 
1 
(Baseline) 
83 
65 
3 
3 
15.35 
15.57 
2.82 
2.61 
2 (12 wks) 
68 
62 
12 
6 
15.24 
15.68 
3.07 
3.27 
3 (24 wks) 
69 
63 
7 
4 
15.25 
15.55 
3.21 
3.51 
                                    Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 
Table 56: pVO2 Treatment Differences with RER ≥ 1.05 
Time 
Estimate 
SE 
Lower 
95% 
Upper 
95% 
P-value 
(1-sided) 
12 weeks 
0.35 
0.35 
-0.34 
1.04 
0.1610 
24 weeks 
0.40 
0.35 
-0.28 
1.09 
0.1250 
      Program: FIX5C-Analysis-ImpulseDynamics-UpdatedDataRev.Rnw 
 

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1.4.6.16 Primary Safety Endpoint 
 
The primary safety endpoint is the composite endpoint of the percentage of subjects 
in the OPTIMIZER group who experienced either an OPTIMIZER device or 
OPTIMIZER procedure related complication through the 24-week follow-up 
period, as determined by an independent events adjudication committee (EAC).  
The EAC reviewed all serious adverse event reports (SAEs), confirmed the 
classification of “serious”, and adjudicated the relationship of the event to the 
OPTIMIZER System device or procedure.  SAEs that the EAC determined to be 
definitely related to either the OPTIMIZER System or the OPTIMIZER Procedure 
were further classified as either a Complication or Not a Complication.  A 
“complication” was defined as an OPTIMIZER device or OPTIMIZER procedure 
related event that requires invasive treatment or results in a permanent disability or 
death.  Satisfying the primary safety endpoint required that the complication-free 
proportion of patients was significantly higher than 70% (using a one-sided 
significance level of 0.025).  
Only those subjects that underwent the OPTIMIZER implant procedure could 
experience an OPTIMIZER procedure related complication and only those subjects 
who receive the OPTIMIZER device could experience an OPTIMIZER device 
related complication. Thus, the “As Treated” cohort is the primary cohort for 
analysis.  The per protocol population is also presented, however, this population 
is identical to the as treated population for OPTIMIZER subjects in the FIX-HF-5C 
study.  For completeness, results in the intent to treat population are also provided. 
 Table 57: Primary Safety Endpoint1 Analysis (OPTIMIZER Group Only) 
Population 
Complication Free Rate 
x/n (%) 
95% LCL 
(%) 
95% UCL 
(%) 
As Treated 
61/68 (89.7%) 
79.9% 
95.8% 
Per Protocol 
61/68 (89.7%) 
79.9% 
95.8% 
ITT 
67/74 (90.5%) 
81.5% 
96.1% 
                                               Program: Safety Primary.sas 
1 OPTIMIZER subjects experiencing a device related and or procedure related adverse event. 
 
Thus, the complication free proportion in the as treated study group is 89.7% 
(61/68) with lower confidence limit of 79.9% (one-sided alpha=0.025).  As this is 
greater than the pre-defined threshold of 70%, the primary safety endpoint was 
met.  The ITT analysis yields similar results (90.5% (67/74) with lower confidence 
limit of 81.5%) and the PP analysis was identical.   
 
 
1.4.6.17 Secondary Safety Endpoints 
There are five secondary safety endpoints: overall survival through 24 weeks, 
cardiac death survival through 24 weeks, freedom from all-cause mortality or all-

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cause hospitalization through 24 weeks, freedom from cardiac death and worsening 
heart failure hospitalization through 24 weeks and adjudicated serious adverse 
events by treatment group through 24 weeks. The survival analyses and freedom 
from event analysis were based on Kaplan-Meier analysis and the adverse events 
are tabulated by seriousness and treatment group with testing by Fisher's exact test. 
 1.4.6.17.1 Survival Analyses 
 
The following section (section 4.4.6.17.1.a) provides results of various 
survival analyses performed on data derived exclusively on the FIX-HF-5C 
study cohort.  Pooling data from the FIX-HF-5 subgroup and the FIX-HF-5C 
study resulted in a significantly larger sample size.  Results from the 
combined population are provided in section 4.4.6.17.1.b. below. 
 
a. Survival Analyses through 24 Weeks (FIX-HF-5C PP Population) 
The plot of the Kaplan-Meier analysis of overall survival in the FIX-HF-5C 
study is presented in the figure below and results are summarized in Table 58.  
The two-groups are similar with respect to overall survival from baseline 
through 24 weeks (98% in Treatment vs 95% in Control, log-rank P= 0.2549). 
   
Program: Safety Survival Analyses.sas 
P-value: 2-sided 
 

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Figure 19: Overall Survival through 24 Weeks by Treatment Group by Kaplan-Meier 
Analysis 
 
Table 58: Overall Survival through 24 Weeks 
Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 95% 
Confidence 
Limit 
Upper 95% 
Confidence 
Limit 
Active 
0 Weeks 
68 
0 
1.0000 
-- 
-- 
12 Weeks 
68 
0 
1.0000 
-- 
-- 
24 Weeks 
54 
1 
0.9828 
0.8838 
0.9976 
Controls 
0 Weeks 
86 
0 
1.0000 
-- 
-- 
12 Weeks 
81 
3 
0.9648 
0.8949 
0.9885 
24 Weeks 
62 
4 
0.9529 
0.8794 
0.9821 
Log-rank P= 0.2549 (2-sided) 
             Program: Safety Survival Analyses.sas 
The Kaplan-Meier plot of freedom from cardiac death in the FIX-HF-5C 
study is presented in the figure below and summarized in Table 59.  Similar 
to the overall survival, the two-groups are similar with respect to survival free 
of cardiac death from baseline through 24 weeks (100% in Treatment vs 96% 
in Control, log-rank P= 0.1198). 

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                                       Program: Safety Survival Analyses.sas 
P-value: 2-sided 
 
Figure 20: Survival from Cardiac Death through 24 Weeks by Treatment Group by 
Kaplan-Meier Analysis 
 
 
 
Table 59: Survival Free of Cardiac Death through 24 Weeks 
Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 95% 
Confidence 
Limit 
Upper 95% 
Confidence 
Limit 
Active 
0 Weeks 
68 
0 
1.0000 
-- 
-- 
12 Weeks 
68 
0 
1.0000 
-- 
-- 
24 Weeks 
54 
0 
1.0000 
-- 
-- 
Controls 
0 Weeks 
86 
0 
1.0000 
-- 
-- 
12 Weeks 
81 
3 
0.9648 
0.8949 
0.9885 
24 Weeks 
62 
3 
0.9648 
0.8949 
0.9885 
Log-rank P= 0.1198 (2-sided) 
             Program: Safety Survival Analyses.sas 

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The Kaplan-Meier plot of the freedom from all-cause mortality or all-cause 
hospitalization in the FIX-HF-5C study is presented in Figure 21 and 
summarized in Table 60.  The proportion surviving was similar for the two 
groups through 24 weeks (78% in Treatment vs 78% in Control, log-rank P= 
0.9437). 
 
               Program: Safety Survival Analyses.sas 
P-value: 2-sided 
Figure 21: Survival from All Cause Death or Hospitalization through 24 Weeks by 
Treatment Group by Kaplan-Meier Analysis 
 
 

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Table 60: Survival from All Cause Death or Hospitalization through 24 Weeks 
Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 95% 
Confidence 
Limit 
Upper 95% 
Confidence 
Limit 
Active 
0 Weeks 
68 
0 
1.0000 
-- 
-- 
12 Weeks 
62 
6 
0.9118 
0.8141 
0.9594 
24 Weeks 
40 
15 
0.7769 
0.6571 
0.8591 
Controls 
0 Weeks 
84 
0 
1.0000 
-- 
-- 
12 Weeks 
72 
11 
0.869 
0.776 
0.9252 
24 Weeks 
38 
18 
0.7814 
0.6754 
0.8563 
Log-rank P= 0.9437 (2-sided) 
             Program: Safety Survival Analyses.sas 
 
The Kaplan-Meier plot of freedom from cardiac death or worsening heart 
failure hospitalization in the FIX-HF-5C study is presented in the figure 
below and summarized in Table 61.  OPTIMIZER Treatment patients had a 
trend towards better survival from cardiac death or heart failure 
hospitalizations from baseline through 24 weeks (log-rank P= 0.0665) as can 
be seen in the figure above and table below, but the result was not statistically 
significant.  
Comparing the Kaplan-Meier rates at 24 weeks, 97.1% versus 89.2%, and 
using Greenwood’s formula for the variance, the difference between 
treatment and control is 7.9% (95% CI: 0.08%, 15.6%, p=0.048). 
 

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                                            Program: Safety Survival Analyses.sas 
P-value: 2-sided 
Figure 22: Survival from Cardiac Death or Heart Failure Hospitalization through 24 
Weeks by Treatment Group by Kaplan-Meier Analysis 
 
Table 61: Survival Free of Cardiac Death or Heart Failure Hospitalization through 24 
Weeks 
Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 95% 
Confidence 
Limit 
Upper 95% 
Confidence 
Limit 
Active 
0 Weeks 
68 
0 
1.0000 
-- 
-- 
12 Weeks 
66 
2 
0.9706 
0.8875 
0.9926 
24 Weeks 
50 
2 
0.9706 
0.8875 
0.9926 
Controls 
0 Weeks 
84 
0 
1.0000 
-- 
-- 
12 Weeks 
76 
7 
0.9167 
0.8331 
0.9594 
24 Weeks 
43 
9 
0.8920 
0.8027 
0.9423 
Log-rank P= 0.0665 (2-sided) 
         Program: Safety Survival Analyses.sas 

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Importantly, it was determined that the total number of days alive free of hospitalization for 
heart failure (DAOOHHF) was significantly greater in the CCM™ Active treatment group 
compared with Controls during the 24-week (168 day) study period. This analysis accounted 
for minor differences in duration of follow-up (due to the ±2 week window for the final visit 
at 24 weeks) by first expressing DAOOHHF as a percentage of total “follow-up days,” where 
the number of follow-up days was defined as the number of days between the study start date 
to the date of the final follow-up visit; for patients who died before the end of the study, 168 
days was used as the total days of follow up.  Final results were then obtained by multiplying 
the percent DAOOHHF by 168.  As summarized above, in the FIX-HF-5C study population, 
there were very few deaths or heart failure hospitalizations.  Accordingly, DAOOHHF in the 
CCM Treatment group was 167.7±2.2 days, versus 158.3±35.8 days in the Control group 
(p=0.011), for a difference of 9.4 days.  
In addition to DAOOHHF, we also explored the rates of hospitalizations for the year prior to 
study enrollment to the rate during the 24-week study period.  The results expressed as events 
per patient-year are summarized in the following table for both non-heart failure cardiovascular 
(“CARDIAC”) and heart failure (HF) hospitalizations are summarized in the following table.  
As summarized in the table, although there were imbalances in the event-rates between groups 
at baseline, both CARDIAC and HF event rates were significantly and substantially reduced 
during the study period compared to the event rates prior to the study in the Active treatment 
group but were unchanged in Control group. 
Table 62: Summary of cardiovascular and heart failure hospitalizations 
  
  
PRE-Study 
POST Study Start Date 
Type 
Group 
Patient-
Yrs 
Number 
of 
Events 
Event-
Rate 
Patient-
Yrs 
Number 
of Events 
Event-
Rate 
p-value 
(2-sided) 
CARDIAC 
ACTIVE 
(n=72) 
72.0 
80 
1.11 
31.8 
14 
0.44 
0.0036 
  
CONTROL 
(n=81) 
81.0 
53 
0.65 
35.6 
14 
0.39 
0.1256 
HF 
ACTIVE 
(n=72) 
72.0 
58 
0.81 
31.8 
4 
0.13 
0.0014 
  
CONTROL 
(n=81) 
81.0 
30 
0.37 
35.6 
11 
0.31 
0.6155 
Program: Pre versus Post Hospitalizations.sas 
This analysis was only possible for the FIX-HF-5C study since information about 
hospitalizations prior to randomization was not available for the FIX-HF-5 study. 
b. 
Survival Analyses through 24 Weeks (PP Population) – Pooled 
The plot of the Kaplan-Meier analysis of overall survival in the pooled FIX-
HF-5 and FIX-HF-5C data is presented in the figure below. The two-groups 
are similar with respect to overall survival from baseline through 24 weeks 
(log-rank P= 0.8138). 

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          Program: Safety Survival Analyses.sas 
P-value: 2-sided 
Figure 23: Overall Survival through 24 Weeks by Treatment Group by Kaplan-Meier 
Analysis 
 
Table 63: Overall Survival through 24 Weeks 
Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 95% 
Confidence 
Limit 
Upper 95% 
Confidence 
Limit 
Active 
0 Weeks 
177 
0 
1.0000 
-- 
-- 
12 Weeks 
175 
2 
0.9887 
0.9556 
0.9972 
24 Weeks 
160 
4 
0.9771 
0.9400 
0.9913 
Controls 
0 Weeks 
193 
0 
1.0000 
-- 
-- 
12 Weeks 
185 
4 
0.9791 
0.9453 
0.9921 
24 Weeks 
165 
5 
0.9738 
0.9382 
0.989 
Log-rank P= 0.8138 (2-sided) 
               Program: Safety Survival Analyses.sas  
The Kaplan-Meier plot of cardiac death survival in the pooled FIX-HF-5 and FIX-HF-5C 
data is presented in the figure below. 

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          Program: Safety Survival Analyses.sas 
P-value: 2-sided 
Figure 24: Survival from Cardiac Death through 24 Weeks by Treatment Group by 
Kaplan-Meier Analysis 
Similar to overall survival, the two-groups are similar with respect to survival from cardiac 
death from baseline through 24 weeks (log-rank P= 0.7786).  
Table 64: Survival from a Cardiac Death through 24 Weeks 
Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 95% 
Confidence 
Limit 
Upper 95% 
Confidence 
Limit 
Active 
0 Weeks 
177 
0 
1.0000 
-- 
-- 
12 Weeks 
175 
2 
0.9887 
0.9556 
0.9972 
24 Weeks 
160 
3 
0.9831 
0.9484 
0.9945 
Controls 
0 Weeks 
193 
0 
1.0000 
-- 
-- 
12 Weeks 
185 
4 
0.9791 
0.9453 
0.9921 
24 Weeks 
165 
4 
0.9791 
0.9453 
0.9921 
Log-rank P= 0.7786 (2-sided) 
             Program: Safety Survival Analyses.sas 

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The Kaplan-Meier plot of the freedom from all-cause mortality or all-cause hospitalization 
in the pooled FIX-HF-5 and FIX-HF-5C data is presented in the figure below. The survival 
proportions for the two treatment groups are similar through 24 weeks (log-rank P= 0.8615) as 
further summarized in Table 65. 
 
          Program: Safety Survival Analyses.sas 
P-value: 2-sided 
Figure 25: Survival from All Cause Death or Hospitalization through 24 Weeks by 
Treatment Group by Kaplan-Meier Analysis 
 
Table 65: Survival from All Cause Death or Hospitalization through 24 Weeks 
Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 95% 
Confidence 
Limit 
Upper 95% 
Confidence 
Limit 
Active 
0 Weeks 
177 
4 
0.9774 
0.9409 
0.9915 
12 Weeks 
144 
33 
0.8136 
0.748 
0.8636 
24 Weeks 
110 
54 
0.6938 
0.6199 
0.7561 
Controls 
0 Weeks 
191 
2 
0.9895 
0.9588 
0.9974 
12 Weeks 
161 
27 
0.8581 
0.7999 
0.9004 
24 Weeks 
104 
57 
0.6928 
0.6207 
0.754 

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Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 95% 
Confidence 
Limit 
Upper 95% 
Confidence 
Limit 
Log-rank P= 0.8615 (2-sided) 
          Program: Safety Survival Analyses.sas 
  
The Kaplan-Meier plots for the freedom from cardiovascular death or 
worsening heart failure hospitalization in the pooled FIX-HF-5 and FIX-
HF-5C data is presented in the figure below. 
 
Program: Safety Survival Analyses.sas 
P-value: 2-sided 
Figure 26: Survival from Cardiovascular Death or Heart Failure Hospitalization through 
24 Weeks by Treatment Group by Kaplan-Meier Analysis 
 
OPTIMIZER subjects had better survival from cardiovascular death or heart 
failure from baseline through 24 weeks (log-rank P= 0.0419) as can be seen 
in the figure above and Table 66 below.  

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Comparing the Kaplan-Meier rates at 24 weeks 95.5% versus 89.8% and 
using Greenwood’s formula for the variance, the difference between 
treatment and control is 5.7% (95% CI: 0.4%, 11.0%, p=0.036). 
Table 66: Survival from Cardiovascular Death or Heart Failure Hospitalization through 
24 Weeks 
Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 95% 
Confidence 
Limit 
Upper 95% 
Confidence 
Limit 
Active 
0 Weeks 
177 
0 
1.0000 
-- 
-- 
12 Weeks 
172 
5 
0.9718 
0.9335 
0.9881 
24 Weeks 
153 
8 
0.9548 
0.9117 
0.9771 
Controls 
0 Weeks 
194 
0 
1.0000 
-- 
-- 
12 Weeks 
181 
9 
0.9527 
0.9110 
0.9751 
24 Weeks 
148 
19 
0.8982 
0.8450 
0.9338 
Log-rank P= 0.0419 (2-sided) 
               Program: Safety Survival Analyses.sas 
Similar to findings in the FIX-HF-5C study on its own, DAOOHHF was 
significantly greater in the CCM Active treatment group compared with 
Controls during the 24-week (168 day) study period. For the CCM Treatment 
group, DAOOHHF averaged 165.8±16.1 in the Treatment group compared to 
162.0±28.1 days in Controls (p=0.035), for an average difference of 3.9 days. 
c. 
Summary of Kaplan-Meier Survival Analyses to Compare Freedom 
from Specific Events: Control vs. OPTIMIZER  
 
There were no statistically significant differences between the active 
OPTIMIZER group and the control OMT group with respect to overall 
survival or freedom from cardiac death. Freedom from the composite of 
cardiac death and heart failure hospitalization was 7.9% higher in treatment 
compared to control (p=0.048 using Greenwood’s formula for the variance) in 
the FIX-HF-5C population alone and was 5.7% higher in the combined FIX-
HF-5 and FIX-HF-5C population (p=0.036 using Greenwood’s formula for the 
variance and p=00419 by log-rank test).  In the pooled population, patients 
experienced an overall 3.9 greater number of days alive out of the hospital for 
any reason, and the same number of more days alive not hospitalized for heart 
failure.  Even in the FIX-HF-5C study alone CCM™ patients experienced a 
greater number of days alive not hospitalized for heart failure. Finally, the rates 
of cardiac and heart failure hospitalizations were significantly reduced in the 
FIX-HF-5C population (the population for which data were available) vs. the 
rates prior to implant. 
 
1.4.6.17.2 Adverse Event Analyses 
The final secondary safety endpoint in this study was an analysis of the 
incidence of serious adverse events observed during the 24-week study.  All 
serious events reported have been adjudicated by the study’s EAC. The EAC 

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was comprised of subject matter experts in cardiology. SAE narratives are 
provided in Attachment 11.   
As summarized in Table 67 (for all subjects) and in Table 68, for the PP 
population, there were no statistically significant differences between the 
Control and OPTIMIZER groups for any serious adverse event tabulated. 
 
Table 67: All Adverse Events and Adjudicated Serious Adverse Events by Treatment 
Group Occurring from Study Start to 24 Weeks (all subjects) 
 
All AE 
Adjudicated Serious AE 
Event 
Optimizer  
x/n (%)  
(LCL, UCL)  
# Events 
Control  
x/n (%)  
(LCL, UCL) 
# Events 
P-
value 
Optimizer  
x/n (%)  
(LCL, UCL) 
# Events 
Control  
x/n (%)  
(LCL, UCL) 
# Events 
P-
value 
(2-
sided) 
All 
35/74 (47.3) 
(35.6, 59.3) 
73 
36/86 (41.9) 
(31.3, 53.0) 
61 
0.5258 
20/74 (27.0) 
(17.4, 38.6)  
29 
19/86 (22.1) 
(13.9, 32.3) 
27 
0.5800 
Arrhythmia 
4/74 (5.4) 
(1.5, 13.3)  
4 
5/86 (5.8) 
(1.9, 13.0)  
5 
1.0000 
3/74 (4.1) 
(0.8, 11.4)  
3 
2/86 (2.3) 
(0.3, 8.1)  
2 
0.6631 
Worsening 
Heart Failure 
9/74 (12.2) 
(5.7, 21.8)  
11 
10/86 (11.6) 
(5.7, 20.3)  
12 
1.0000 
3/74 (4.1) 
(0.8, 11.4)  
4 
7/86 (8.1) 
(3.3, 16.1)  
8 
0.3424 
General 
Cardiopulmo
nary 
7/74 (9.5) 
(3.9, 18.5)  
9 
6/86 (7.0) 
(2.6, 14.6)  
6 
0.5779 
3/74 (4.1) 
(0.8, 11.4)  
4 
2/86 (2.3) 
(0.3, 8.1)  
2 
0.6631 
Bleeding 
2/74 (2.7) 
(0.3, 9.4)  
2 
1/86 (1.2) 
(0.0, 6.3)  
1 
0.5963 
0/74 (0.0) 
(4.9, 0.0)  
0 
1/86 (1.2) 
(0.0, 6.3)  
1 
1.0000 
Neurologic 
1/74 (1.4) 
(0.0, 7.3)  
1 
0/86 (0.0) 
(4.2, 0.0)  
0 
0.4625 
0/74 (0.0) 
(4.9, 0.0)  
0 
0/86 (0.0) 
(4.2, 0.0)  
0 
-- 
Thromboemb
olism 
1/74 (1.4) 
(0.0, 7.3)  
1 
1/86 (1.2) 
(0.0, 6.3) 
1 
1.0000 
1/74 (1.4) 
(0.0, 7.3)  
1 
1/86 (1.2) 
(0.0, 6.3)  
1 
1.0000 
Local 
Infection 
5/74 (6.8) 
(2.2, 15.1)  
5 
6/86 (7.0) 
(2.6, 14.6)  
6 
1.0000 
1/74 (1.4) 
(0.0, 7.3)  
1 
4/86 (4.7) 
(1.3, 11.5)  
4 
0.3743 
Sepsis 
1/74 (1.4) 
(0.0, 7.3)  
1 
1/86 (1.2) 
(0.0, 6.3)  
1 
1.0000 
1/74 (1.4) 
(0.0, 7.3)  
1 
1/86 (1.2) 
(0.0, 6.3)  
1 
1.0000 
ICD/PM 
Malfunction 
2/74 (2.7) 
(0.3, 9.4)  
2 
0/86 (0.0) 
(4.2, 0.0)  
0 
0.2123 
2/74 (2.7) 
(0.3, 9.4)  
2 
0/86 (0.0) 
(4.2, 0.0)  
0 
0.2123 
Optimizer 
Malfunction 
8/74 (10.8) 
(4.8, 20.2)  
9 
-- 
-- 
6/74 (8.1) 
(3.0, 16.8)  
6 
-- 
-- 

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All AE 
Adjudicated Serious AE 
Event 
Optimizer  
x/n (%)  
(LCL, UCL)  
# Events 
Control  
x/n (%)  
(LCL, UCL) 
# Events 
P-
value 
Optimizer  
x/n (%)  
(LCL, UCL) 
# Events 
Control  
x/n (%)  
(LCL, UCL) 
# Events 
P-
value 
(2-
sided) 
General 
Medical 
18/74 (24.3) 
(15.1, 35.7) 
28 
17/86 (19.8) 
(12.0, 29.8) 
29 
0.5663 
7/74 (9.5) 
(3.9, 18.5)  
7 
7/86 (8.1) 
(3.3, 16.1)  
8 
0.7864 
                                                       Program: Safety Adverse Events.sas 
Table 68: All Adverse Events and Adjudicated Serious Adverse Events by Treatment 
Group Occurring from Study Start to 24 Weeks (PP population) 
 
All AE 
Adjudicated Serious AE 
Event 
Optimizer  
x/n (%)  
(LCL, UCL)  
# Events 
Control  
x/n (%)  
(LCL, UCL) 
# Events 
P-value 
Optimizer  
x/n (%)  
(LCL, UCL) 
# Events 
Control  
x/n (%)  
(LCL, UCL) 
# Events 
P-value 
(2-
sided) 
All 
34/68 (45.9) 
(34.3, 57.9) 
70 
36/86 (41.9) 
(31.3, 53.0) 
61 
0.6342 
19/68 (27.9) 
(17.7, 40.1)  
28 
19/86 (22.1) 
(13.9, 32.3) 
27 
0.4539 
Arrhythmia 
4/68 (5.4) 
(1.5, 13.3)  
4 
5/86 (5.8) 
(1.9, 13.0)  
5 
1.0000 
3/68 (4.4) 
(0.9, 12.4)  
3 
2/86 (2.3) 
(0.3, 8.1)  
2 
0.6551 
Worsening 
Heart 
Failure 
8/68 (10.8) 
(4.8, 20.2)  
10 
10/86 (11.6) 
(5.7, 20.3)  
12 
1.0000 
3/68 (4.4) 
(0.9, 12.4)  
4 
7/86 (8.1) 
(3.3, 16.1)  
8 
0.5138 
General 
Cardiopulm
onary 
7/68 (9.5) 
(3.9, 18.5)  
9 
6/86 (7.0) 
(2.6, 14.6)  
6 
0.5779 
3/68 (4.4) 
(0.9, 12.4)  
4 
2/86 (2.3) 
(0.3, 8.1)  
2 
0.6551 
Bleeding 
2/68 (2.7) 
(0.3, 9.4)  
2 
1/86 (1.2) 
(0.0, 6.3)  
1 
0.5963 
0/68 (0.0) 
(0.0, 5.3)  
0 
1/86 (1.2) 
(0.0, 6.3)  
1 
1.0000 
Neurologic 
1/68 (1.4) 
(0.0, 7.3)  
1 
0/86 (0.0) 
(4.2, 0.0)  
0 
0.4625 
0/68 (0.0) 
(0.0, 5.3)  
0 
0/86 (0.0) 
(0.0, 4.2)  
0 
-- 
Thromboem
bolism 
1/68 (1.4) 
(0.0, 7.3)  
1 
1/86 (1.2) 
(0.0, 6.3)  
1 
1.0000 
1/68 (1.5) 
(0.0, 7.9)  
1 
1/86 (1.2) 
(0.0, 6.3)  
1 
1.0000 
Local 
Infection 
5/68 (6.8) 
(2.2, 15.1)  
5 
6/86 (7.0) 
(2.6, 14.6)  
6 
1.0000 
1/68 (1.5) 
(0.0, 7.9)  
1 
4/86 (4.7) 
(1.3, 11.5)  
4 
0.3842 
Sepsis 
1/68 (1.4) 
(0.0, 7.3)  
1 
1/86 (1.2) 
(0.0, 6.3)  
1 
1.0000 
1/68 (1.5) 
(0.0, 7.9)  
1 
1/86 (1.2) 
(0.0, 6.3)  
1 
1.0000 
ICD/PM 
Malfunction 
2/68 (2.7) 
(0.3, 9.4)  
2 
0/86 (0.0) 
(4.2, 0.0)  
0 
0.2123 
2/68 (2.9) 
(0.4, 10.2)  
2 
0/86 (0.0) 
(0.0, 4.2)  
0 
0.1934 
Optimizer 
Malfunction 
8/68 (10.8) 
(4.8, 20.2)  
-- 
0.0017 
6/68 (8.8) 
(3.3, 18.2)  
-- 
-- 

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All AE 
Adjudicated Serious AE 
Event 
Optimizer  
x/n (%)  
(LCL, UCL)  
# Events 
Control  
x/n (%)  
(LCL, UCL) 
# Events 
P-value 
Optimizer  
x/n (%)  
(LCL, UCL) 
# Events 
Control  
x/n (%)  
(LCL, UCL) 
# Events 
P-value 
(2-
sided) 
9 
6 
General 
Medical 
17/68 (23.0) 
(14.0, 34.2) 
26 
17/86 (19.8) 
(12.0, 29.8) 
29 
0.6996 
6/68 (8.8) 
(3.3, 18.2)  
6 
7/86 (8.1) 
(3.3, 16.1)  
8 
1.0000 
Program: Safety Adverse Events PP.sas 
The total number of adjudicated SAEs was 36. However only 29 occurred 
within the 24-week study period. Each of the 29 events are detailed below and 
a complete summary of each event has been provided in Attachment 11 –SAE 
Narratives 
Table 69: Listing Serious Adverse Events / Primary Safety Events (OPTIMIZER Group 
Only) 
Patient ID 
Treated 
Adverse Event 
Category/Description 
Days to 
Onset 
Device 
Related 
Procedure 
Related 
Complicatio
n 
(1° Safety 
Event) 
06-402 PAS 
Yes 
OPTIMIZER generator 
reposition (protruding from 
pocket) with lead replacement 
76 
Definitely Possibly 
Y 
06-404 RCW 
No 
General Medical - Hypertension 
168 
N 
N 
N 
32-409 AMD 
Yes 
OPTIMIZER Lead 
dislodgement 
80 
Possibly Definitely 
Y 
51-411 J-B 
Yes 
OPTIMIZER Lead 
dislodgement 
0 
N 
Definitely 
Y 
51-420 KAS 
Yes 
Worsening Heart Failure - 
Dyspnea 
49 
N 
N 
N 
51-420 KAS 
Yes 
General Medical - Abdominal 
Pain 
59 
N 
N 
N 
51-420 KAS 
Yes 
Worsening Heart Failure - 
Dyspnea 
89 
N 
N 
N 
51-426 SLS 
Yes 
OPTIMIZER Lead 
dislodgement 
14 
Possibly Definitely 
Y 
51-456 WFC 
Yes 
General Cardiopulmonary - 
Myocardial Infarction 
5 
N 
N 
N 
51-459 CDS 
Yes 
Deep Vein Thrombosis 
8 
Possibly Definitely 
Y 
65-403 STP 
Yes 
General Medical - Esophagitis 
151 
N 
N 
N 
65-445 GIC 
Yes 
Worsening Heart Failure - 
Dyspnea 
64 
N 
N 
N 
65-445 GIC 
Yes 
General Cardiopulmonary - 
worsening coronary artery 
disease 
102 
N 
N 
N 
65-471 SLC 
Yes 
OPTIMIZER Lead 
dislodgement 
0 
Possibly Definitely 
Y 

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Table 69: Listing Serious Adverse Events / Primary Safety Events (OPTIMIZER Group 
Only) 
Patient ID 
Treated 
Adverse Event 
Category/Description 
Days to 
Onset 
Device 
Related 
Procedure 
Related 
Complicatio
n 
(1° Safety 
Event) 
70-410 V-P 
Yes 
General Medical - 
choledocholithiasis 
112 
N 
N 
N 
75-416 DDD 
Yes 
General Cardiopulmonary - 
Angina 
79 
N 
N 
N 
75-416 DDD 
Yes 
General Medical - 
hypoglycemia 
116 
N 
N 
N 
75-416 DDD 
Yes 
General Cardiopulmonary - 
Worsening CAD 
127 
N 
N 
N 
79-402 BBB 
Yes 
Inappropriate ICD fire due to 
ICD lead failure 
6 
N 
N 
N 
88-402 SET 
Yes 
General Medical - Sigmoid 
stricture with incarcerated 
hernia 
144 
N 
N 
N 
88-402 SET 
Yes 
Localized Infection - 
Pneumonia 
147 
N 
N 
N 
88-402 SET 
Yes 
Sepsis 
161 
N 
N 
N 
90-413 G-G 
Yes 
Atrial flutter 
162 
N 
N 
N 
90-424 H-F 
Yes 
ICD lead fracture 
52 
N 
N 
N 
90-424 H-F 
Yes 
General Medical - Mood 
Disorder Psychosis 
168 
N 
N 
N 
90-428 T-K 
Yes 
Worsening Heart Failure - 
Dyspnea 
45 
N 
N 
N 
90-442 GSG 
Yes 
Atrial fibrillation 
12 
N 
N 
N 
90-451 CLC 
Yes 
OPTIMIZER Lead 
dislodgement 
2 
Possibly Definitely 
Y 
90-451 CLC 
Yes 
Brady Arrhythmia – Junctional 
Rhythm 
9 
N 
N 
N 
                          Program: SAE Listing.sas 
 
a. OPTIMIZER Malfunction 
 Per the case report form reporting instructions, an adverse event category called 
“OPTIMIZER Malfunction” is reported for any of the following occurrences: 
• 
OPTIMIZER lead dislodgement  
• 
OPTIMIZER lead fracture  
• 
OPTIMIZER pulse generator  
• 
OPTIMIZER sensing defect  
• 
Other- To be specified 
There were 6 events classified as an “OPTIMIZER Malfunction” reported 
during the 24-week study occurring in 6 subjects.  Five (5) of the six events 

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were lead dislodgements and 1 was a lead extraction/replacement with a pocket 
revision due to increasing pain and discomfort at the IPG suture line with 
prominent exposure of the lead. None of these events were as a result of 
product quality issues or failures. 
b. ICD/Pacemaker Malfunction 
 
There were 2 ICD/Pacemaker malfunctions in the OPTIMIZER group.  One 
incident was an ICD/ lead dislodgment.  The other incident was an inappropriate 
firing of the ICD; testing at the time of the incident proved it was not due to 
crosstalk between the ICD and OPTIMIZER devices. There were no 
ICD/Pacemaker related SAEs in the Control group. 
c. Arrhythmias 
There were 5 serious AEs classified as an arrhythmia; 3 occurred in the 
OPTIMIZER group and 2 occurred in the Control group. 
 
             Table 70: Adjudicated Serious Adverse Events 
Adjudicated Serious AE 
OPTIMIZER 
x/n (%)  
(LCL, UCL) 
# Events 
Control  
x/n (%)  
(LCL, UCL) 
# Events 
P-value 
(2-sided) 
3/74 (4.1) 
(0.8, 11.4)  
3 
2/86 (2.3) 
(0.3, 8.1)  
2 
0.6631 
                                            Program: SAE Listing.sas 
 
     The following details the 3 arrhythmia SAEs in the OPTIMIZER group: 
  
 Sixty-nine (69) year old female (Subject 90-413) with idiopathic 
cardiomyopathy and ICD (2011).  The subject was randomized to the 
OPTIMIZER group on September 1, 2016 and was successfully implanted on 
September 10, 2016.  The subject presented to the ER on February 19, 2017 
(AE3- Arrhythmia: Atrial fibrillation) and was found to be in atrial flutter with 
a heart rate of 130 bpm. The subject remained in the hospital and underwent an 
ablation on February 22nd and was discharged on February 23rd. The AE was 
adjudicated and classified as “Not a Complication.” The SAE was also re-
categorized as “Arrhythmia: Atrial flutter” by the adjudication committee. 
  
 Seventy (70) year old male (Subject 90-442) with idiopathic cardiomyopathy, 
a history of atrial fibrillation and ventricular tachycardia, and a dual-chamber 
ICD.  The subject was randomized to the OPTIMIZER group on December 15, 
2016 and was successfully implanted on December 17, 2016.  When the subject 
was seen for the 2-week follow-up visit on December 29, 2016 (AE1- Atrial 
fibrillation), he was in atrial fibrillation. The subject’s Eliquis dose was 

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increased with a plan to initiate Sotalol in 3 weeks. The subject underwent a 
successful cardioversion under sedation on January 27, 2017. The AE was 
adjudicated and classified as “Not a Complication.” 
  
 Eighty-two (82) year old male (Subject 90-451) with ischemic cardiomyopathy, 
CABG (2001) and a history of atrial fibrillation.  The subject was randomized to 
the OPTIMIZER group on February 16, 2017 and was implanted on March 4, 
2017.  The subject developed evidence of sick sinus syndrome with SOB, 
dizziness and lightheadedness, and a long first-degree AV-block. On March 13, 
2017 (AE1- Junctional rhythm) the Investigator decided the subject required a 
pacemaker and a dual-chamber pacemaker was implanted on March 17, 2017. 
The AE was adjudicated and classified as “Not a Complication.”                         
 
      None of the 3 events were reported as device related. 
      
      The following details the 2 arrhythmia SAEs in the Control group: 
  
 Fifty-one (51) year old male (Subject 09-407) with idiopathic cardiomyopathy, 
MI on July 17, 2015, frequent PVCs, and a history of atrial fibrillation, which 
was well managed on amiodarone but medication was discontinued due to 
concern about side effects. The subject had previously declined an ICD implant 
due to his employment as a truck driver.  The subject was randomized to the 
Control group on December 9, 2015 with a study start date (SSD) of January 
11, 2016.  On May 4, 2016 (AE2- Atrial Fibrillation) recurrent, persistent, 
symptomatic atrial fibrillation was reported.  On May 13, 2016, he was admitted 
for a same day TEE cardioversion and discharged in normal sinus rhythm.  This 
event was adjudicated and classified as “Not a Complication”. 
 Sixty-one (61) year old male (Subject 65-422) with ischemic cardiomyopathy, 
MI and PTCA (November 1, 2006), a history of atrial fibrillation and 
ventricular tachycardia, and a dual-chamber ICD implant (2013). The subject 
was randomized to the Control group on December 9, 2015 with a study start 
date of January 11, 2016.  The subject had been experiencing palpitations and 
presyncope related to sustained ventricular tachycardia requiring multiple 
bursts of ATP from his defibrillator and was scheduled for catheter 
ablation.  Sotalol was prescribed on February 28th pending the ablation.  On 
March 21, 2016 (AE2-Sustained Ventricular Tachycardia) the subject was 
admitted for an ablation procedure.  An Impella device was placed for 
temporary ventricular support during the procedure; mapping and the extensive 
ablation procedure took several hours and the subject was transferred to 
recovery in the ICU.  This event was adjudicated and classified as “Not a 
Complication”. The SAE onset date was reported as March 21, 2016 by the 
EAC instead of the site reported date of January 2, 2016. 
       

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d. Infection/Sepsis 
There were 5 local infection serious AEs reported; 1 reported in the 
OPTIMIZER group and 4 in the Control group. There were 2 reports of 
sepsis; 1 in each group.  
 
Table 71: Local infection reported as serious adverse events 
 
Adjudicated Serious AE 
Event 
OPTIMIZER 
x/n (%)  
(LCL, UCL) 
# Events 
Control  
x/n (%)  
(LCL, UCL) 
# Events 
P-value 
(2-sided) 
Local Infection 
1/74 (1.4) 
(0.0, 7.3)  
1 
4/86 (4.7) 
(1.3, 11.5)  
4 
0.3743 
Sepsis 
1/74 (1.4) 
(0.0, 7.3)  
1 
1/86 (1.2) 
(0.0, 6.3)  
1 
1.0000 
                                                     Program: SAE Listing.sas 
 
The following details the 1 report of infection and 1 report of sepsis in the 
OPTIMIZER group, both events occurred in the same subject: 
 
Seventy-three (73) year old female (subject 88-402) with ischemic 
cardiomyopathy, MI (April 29, 2016), PTCA (May 1, 2016) and diabetes. The 
subject was randomized to the OPTIMIZER group on December 19, 2016 and 
the device was implanted on January 5, 2017. The subject presented to the 
hospital on May 29, 2017 (AE1- General Medical: Sigmoid stricture with 
incarcerated hernia) with nausea, diarrhea and vomiting. CT scan showed a 
distal sigmoid stricture and multiple ventral hernias. The subject underwent 
surgery on May 30th, which included lower ventral resection with loop 
ileostomy, lysis of adhesions, and hernia repair with biologic mesh. The subject 
was left intubated when they transferred her to the recovery room.  The subject 
developed acute hypoxic and hypercapnic respiratory failure, secondary to 
pneumonia and was placed on Bi-PAP, O2 and antibiotics (for pneumonia and 
post-surgical purposes). She was diagnosed on June 1, 2017 (AE12-Localized 
Infection: Pneumonia) with bilateral pneumonia with secondary acute hypoxic 
and hypercapnic respiratory failure. The subject was scheduled to move to a 
skilled nursing facility (SNF) but on June 9, 2017 the colostomy bag leaked into 
the surgical incision with some dehiscence and erythema. Antibiotics were 
continued and a wound VAC placed. With the wound VAC in place and the 
incision and abdominal pain improving, the subject was discharged to a SNF 
on June 12th. The AE was adjudicated and classified as “Not a Complication.” 
 
The subject was presented to the ER and was readmitted to the hospital on June 
15, 2017 (AE13-Sepsis) with pain, redness and swelling around the ileostomy 

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tube. She was septic and hypertensive; IV antibiotics and analgesics were 
initiated. The AE was adjudicated and classified as “Not a Complication.” 
 
The following details the 4 reports of infection and 1 report of sepsis in the 
Control group: 
 
1. 
Fifty-five (55) year old female (Subject 55-413) with ischemic 
cardiomyopathy, MI (2006), PTCA (2012) and a dual-chamber ICD implant 
(2007). The subject was randomized to the Control group on August 24, 2015 
with a study start date of September 10, 2015.  The subject began experiencing 
symptoms of worsening dysuria on September 16, 2015 (AE3-General 
Medical - UTI) and presented to the ER and admitted to the hospital on 
September 20, 2015.  She developed fever, rigors, nausea, vomiting, and 
myalgia; 
tested 
positive 
for 
urinary 
tract 
infection 
and 
pyelonephritis.  Antibiotics, IV hydration, analgesic and antiemetics were 
administered. A cystoscopy was performed with a double J stent placed on 
September 22, 2015.  Pyridium was provided for dysuria and bladder spasms. 
Symptoms improved and the subject was discharged on September 26th.  
2. 
Sixty-two (62) year old female (Subject 56-402) with idiopathic 
cardiomyopathy, diabetes, hypertension, and hyperlipidemia. The subject was 
randomized to the Control group on April 23, 2015 with a study start date of 
May 13, 2015.  On May 21, 2015 (AE2- Sepsis: UTI) the subject presented to 
the ER with symptoms of generalized weakness; admitted with urinary tract 
infection, sepsis, hypertension, and acute renal failure. Treated with IV 
Rocephin and IV fluids and discharged home in good condition; the antibiotic 
was transitioned to cephalexin. The subject’s blood pressure, renal failure and 
sepsis improved and the patient was discharged on May 26, 2015.   
 
3. 
Seventy-two (71) year old male (Subject 70-426) with idiopathic 
cardiomyopathy, diabetes, and a single-chamber ICD implanted on April 20, 
2016. The subject was randomized to the Control group on September 19, 2016 
with a study start date of September 29, 2016.  The subject was admitted to the 
hospital on January 4, 2017 (AE2- Localized Infection: Pneumonia) and 
treated with IV diuretics and antibiotics and discharged on January 11, 2017. 
4. 
Sixty (60) year old male (Subject 90-408) with idiopathic 
cardiomyopathy, diabetes, a history of atrial flutter and an ICD implanted on 
April 16, 2016. The subject was randomized to the Control group on August 
17, 2016 with a study start date of August 20, 2016.  As of October 28, 2016 
(AE1 – Localized Infection: Diabetic foot ulcer) the subject developed a 
diabetic foot ulcer that was drained and beaded on November 28, 2016. 
 
5. 
Fifty-one (51) year old male (Subject 90-435) with idiopathic 
cardiomyopathy, diabetes, a history of atrial fibrillation, and a dual-chamber 

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ICD (April 26, 2016). The subject was randomized to the Control group on 
October 26, 2016 and with a study start date of November 12, 2016.  The 
subject was hospitalized on January 12, 2017 for chest pain and shortness of 
breath. IV Lasix, Losartan and amiodarone were prescribed. While there, he 
developed pneumonia (January 22, 2017, AE7-Localized infection: 
Pneumonia) and was treated with antibiotics.  The admission was further 
complicated with renal failure and the subject was put on dialysis on January 
30. The subject was discharged on February 2, 2017.  
There was one additional adjudicated serious adverse event (worsening of heart 
failure) not reported in the table above.  When the adjudication committee 
reviewed the event, they classified it as non-serious. Since this is the only non-
serious adverse event, a separate table of non-serious events is not presented. 
1.4.6.18 Summary of Safety Endpoints 
 
The primary safety endpoint for the FIX-HF-5C study was met since the proportion 
of patients who were complication free exceeded 70% in the ITT population.   
There were no statistically significant differences between the active OPTIMIZER 
group and the control OMT group with respect to overall survival or freedom from 
cardiac death. Freedom from the composite of cardiovascular death and heart failure 
hospitalization was 7.9% higher in treatment compared to control (p=0.048 using 
Greenwood’s formula for the variance) in the FIX-HF-5C population alone and was 
5.7% higher in the combined FIX-HF-5 and FIX-HF-5C population (p=0.036 using 
Greenwood’s formula for the variance and p=0.0419 by log-rank test).  In the pooled 
population, patients experienced an overall 3.9 greater number of days alive out of the 
hospital for any reason, and the same number of more days alive not hospitalized for 
heart failure.  Even in the FIX-HF-5C study alone CCM patients experienced a greater 
number of days alive not hospitalized for heart failure. Finally, the rates of cardiac and 
heart failure hospitalizations were significantly reduced in the FIX-HF-5C population 
(the population for which data were available) vs. the rates prior to implant. 
 
The incidence of adverse events in this study was in general relatively low.  
Comparisons between the treatment groups did not show any statistical differences 
between Control and OPTIMIZER groups with respect to any adverse event tabulated 
for the analysis.  The data presented here allows us to conclude that the OPTIMIZER 
IVs, and therefore the OPTIMIZER SMART 3-Lead configuration by association, is 
safe for use in the population of patients with moderate-to-severe heart failure. 
 
1.4.6.19 Exploratory Analyses 
1.4.6.19.1 Evaluation of the primary effectiveness endpoint in the per 
protocol population 
   This Bayesian analysis is contained in the Primary & Key Secondary Analyses 
Impulse Dynamics FIX-HF-5C Report (Attachment 07). 
 

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1.4.6.19.2 Comparison of Peak VO2 by Heart Failure Etiology (complete case 
analysis) 
The unadjusted mean change from baseline at 24 weeks is presented in the table 
below by heart failure etiology. Significant treatment effects are seen in both 
groups. 
Table 72: Unadjusted Mean Changes from Baseline in Peak VO2 Scores at 24 Weeks 
(complete case analysis)  
 
Ischemic Etiology 
Mean (SD) N 
Med (Min, Max) 
P-
value1 
Non-Ischemic Etiology 
Mean (SD) N 
Med (Min, Max) 
P-
value1 
(1-
sided) 
Study 
OPTIMIZER 
Control 
 
OPTIMIZER 
Control 
 
FIX-HF-
5C 
0.34 (2.69) 40     
0.28 (-4.75, 5.9) 
-0.31 (2.69) 41     
-0.55 (-6.85, 4.9) 
0.1429 
-0.58 (2.79) 26    
-0.1 (-7.3, 4.45) 
-0.77 (1.81) 29     
-1.2 (-4.4, 2.75) 
0.2447 
FIX-HF-5 
-0.08 (2.78) 72    
-0.2 (-6.6, 8.1) 
-0.97 (2.39) 57     
-1 (-6.4, 4.2) 
0.0450 
1.36 (3.48) 27     
0.8 (-4.8, 11.7) 
-1.05 (2.66) 32     
-0.8 (-6.6, 6) 
0.0037 
Pooled 
0.07 (2.74) 112    
0 (-6.6, 8.1) 
-0.7 (2.53) 98      
-0.9 (-6.85, 4.9) 
0.0293 
0.41 (3.28) 53     
0.3 (-7.3, 11.7) 
-0.92 (2.28) 61     
-0.8 (-6.6, 6) 
0.0063 
                                     Program: Additional Exploratory.sas 
1Two-sample Wilcoxon (one-sided) for difference between treatment groups. 
The primary model of the completed cases data was refit separately by etiology.  In 
addition, a term for etiology and the interaction between treatment groups and 
etiology was included in the primary model to examine the overall interaction 
between etiology and treatment effect. 
Table 73: Least Squares Means from Repeated Measures Analysis of Variance for Peak 
VO2 over Study Visits by Heart Failure Etiology (complete case analysis) 
 
 
Ischemic Etiology 
Non-Ischemic Etiology 
 
Study 
Visit 
Treatment 
Difference (LCL, 
UCL) 
P-
value1 
Treatment 
Difference (LCL, 
UCL) 
P-
value1 
Interaction 
P-value2 
FIX-HF-5C 
12 Weeks 
0.670 (-0.224, 1.564) 
0.0704 
-0.012 (-1.076, 1.053) 
0.5080 
0.5979 
24 Weeks 
0.601 (-0.298, 1.500) 
0.0944 
0.247 (-0.818, 1.312) 
0.3232 
0.3415 
FIX-HF-5 
12 Weeks 
-0.186 (-0.959, 0.588) 
0.6806 
1.440 (0.133, 2.746) 
0.0156 
0.3182 
24 Weeks 
0.653 (-0.138, 1.444) 
0.0522 
2.377 (1.059, 3.695) 
0.0003 
0.3369 
Pooled 
12 Weeks 
0.113 (-0.476, 0.702) 
0.3521 
0.759 (-0.102, 1.620) 
0.0416 
0.3205 
24 Weeks 
0.599 (0.001, 1.197) 
0.0247 
1.336 (0.472, 2.201) 
0.0013 
0.2470 
                                 Program: Additional Exploratory.sas 
1 One sided P-value for difference in least squares means from mixed model by Etiology. 
2 Two sided for interaction between treatment and etiology from mixed model containing a main effect for etiology and visit by 
treatment by Etiology interaction. 
 

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While there are trends in differences in treatment effects by etiology, there is not 
a significant interaction between etiology and treatment effect at any time point 
for either study or for pooled studies. Thus, we can conclude that there is not a 
difference in treatment effects based on etiology.  The overall conclusions by 
etiology remain consistent. 
1.4.6.19.3 Comparison of Peak VO2 for Subjects with Baseline EF ≥ 35 
This analysis is contained in the Statistical Analysis Report of Impulse Dynamics 
FIX-HF-5C Study (Attachment 03). 
1.4.6.19.4 Comparison of Peak VO2 by Baseline NYHA Class (complete case 
analysis) 
The unadjusted mean change from baseline at 24 weeks is presented in the table 
below. 
Table 74: Unadjusted Mean Changes from Baseline in Peak VO2 Scores at 24 Weeks 
(complete case analysis)  
 
NYHA III 
Mean (SD) N 
Med (Min, Max) 
P-
value1 
NYHA IV 
Mean (SD) N 
Med (Min, Max) 
P-
value
1 
Study 
OPTIMIZER 
Control 
 
OPTIMIZER 
Control 
 
FIX-HF-C 
0.2 (2.61) 56      
0.33 (-7.3, 5.9) 
-0.51 (2.33) 63    
-0.55 (-6.85, 4.9) 
0.0345 
-1.29 (3.28) 10    
-1.75 (-5.7, 3.95) 
-0.41 (2.8) 7  
-1.2 (-4.15, 4.15) 
0.232
1 
FIX-HF 
0.34 (3.11) 94     
0.05 (-6.6, 11.7) 
-0.97 (2.31) 76    
-0.8 (-6.4, 4.2) 
0.0040 
-0.08 (1.19) 5     
-0.2 (-1.2, 1.9) 
-1.18 (3.37) 13     
-1.3 (-6.6, 6) 
0.162
1 
Pooled 
0.29 (2.92) 150    
0.2 (-7.3, 11.7) 
-0.76 (2.32) 139   
-0.8 (-6.85, 4.9) 
0.0009 
-0.89 (2.77) 15    
-0.8 (-5.7, 3.95) 
-0.92 (3.13) 20     
-1.25 (-6.6, 6) 
0.447
0 
                                   Program: Additional Exploratory.sas 
1Two-sample Wilcoxon (one-sided) for difference between treatment groups. 
Next, the primary model applied to completed cases data was refit separately by 
etiology.  In addition, a term for etiology and the interaction between treatment 
group and etiology was included in the primary model to examine the overall 
interaction between etiology and treatment effect. 
 
 

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Table 75: Least Squares Means from Repeated Measures Analysis of Variance for Peak 
VO2 over Study Visits by Heart Failure Etiology (complete case analysis) 
 
 
NYHA III 
NYHA IV 
 
Study 
Visit 
Treatment 
Difference (LCL, 
UCL) 
P-
value1 
Treatment 
Difference (LCL, 
UCL) 
P-
value1 
Interaction 
P-value2 
FIX-HF-C 
12 Weeks 
0.509 (-0.203, 1.221) 
0.0799 
-0.066 (-2.481, 2.349) 0.5237 
0.9154 
 
24 Weeks 
0.719 (0.004, 1.434) 
0.0244 
-0.956 (-3.37, 1.459) 
0.7878 
0.7090 
FIX-HF 
12 Weeks 
0.15 (-0.562, 0.861) 
0.3410 
0.203 (-2.268, 2.675) 
0.4330 
0.2786 
 
24 Weeks 
0.998 (0.275, 1.722) 
0.0035 
1.564 (-1.045, 4.173) 
0.1156 
0.4838 
Pooled 
12 Weeks 
0.288 (-0.223, 0.799) 
0.1337 
0.265 (-1.343, 1.873) 
0.3712 
0.3138 
 
24 Weeks 
0.871 (0.354, 1.388) 
0.0005 
0.239 (-1.393, 1.871) 
0.3864 
0.6519 
                               Program: Additional Exploratory.sas 
1 One sided P-value for difference in least squares means from mixed model by Etiology. 
2 Two sided for interaction between treatment and etiology from mixed model containing a main effect for etiology and visit by 
treatment by Etiology interaction. 
 
While there are trends for differences in treatment effects by baseline NYHA score, 
there is not a significant interaction between baseline NYHA score and treatment 
effect at any time point for either study or for the pooled studies. Thus, we can 
conclude that there is not a difference in treatment effects based on baseline NYHA 
score.  The numbers with NYHA score equal 4 are small and thus interpretation of 
the results is difficult. 
1.4.6.19.5 Comparison of Mean Changes from Baseline in the 6 Minute Walk 
The unadjusted means and changes from baseline at 24 weeks in the 6-minute walk 
distances in meters are presented in the table below. 
Table 76: Means and Mean Changes from Baseline in 6-Minute Walk Distance (m) at 24 
Weeks (complete case analysis) 
 
 
Mean (SD) N 
Med (Min, Max) 
P-value1 
Study 
Visit 
OPTIMIZER 
Control 
 
FIX-HF-
5C 
Baseline 
316.85 (88.37) 74    
308 (75, 462) 
324.07 (89.71) 86    
315 (120, 579) 
0.8722 
24 Weeks 
362.01 (100.6) 69    
336 (170, 602) 
332 (86.27) 72      
324 (160, 552) 
0.0981 
Change from Baseline 
to 24 Weeks 
43.04 (80.73) 69     
46 (-147, 350) 
9.33 (87.43) 72      
15.5 (-261, 152) 
0.0234 
FIX-HF-5 
Baseline 
325.8 (84.24) 117    
321 (95, 525) 
324.5 (91.64) 111    
329 (120, 600) 
0.9096 
24 Weeks 
344.91 (99.17) 104   
346 (90, 585) 
333.73 (97.67) 91    
340 (89, 644) 
0.3415 
Change from Baseline 
to 24 Weeks 
18.75 (82.49) 104    
15.5 (-316, 225) 
3.88 (80.19) 91      
4 (-375, 255) 
0.1976 

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Mean (SD) N 
Med (Min, Max) 
P-value1 
Study 
Visit 
OPTIMIZER 
Control 
 
Pooled 
Baseline 
322.34 (85.74) 191   
320 (75, 525) 
324.31 (90.57) 197   
323 (120, 600) 
0.9300 
24 Weeks 
351.73 (99.81) 173   
342 (90, 602) 
332.96 (92.53) 163   
336 (89, 644) 
0.0808 
Change from Baseline 
to 24 Weeks 
28.44 (82.43) 173    
30 (-316, 350) 
6.29 (83.25) 163     
11 (-375, 255) 
0.0120 
                                Program: Additional Exploratory.sas  
1Two-sample Wilcoxon (two-sided) for difference between treatment groups. 
 
There is a statistically significant effect of treatment on the change in 6-minute 
walk distance at 24 weeks in the FIX-HF-C data (p=0.0234) and the combined 
pooled analysis (p=0.0120).   
1.4.6.19.6 Comparison of Mean Changes from Baseline in the VE/VCO2 
The unadjusted means and changes from baseline at 24 weeks in VE/VCO2 are 
presented in the table below. 
Table 77: Means and Mean Changes from Baseline VE/VCO2 at 24 Weeks (complete case 
analysis) 
 
 
Mean (SD) N 
Med (Min, Max) 
P-value1 
Study 
Visit 
OPTIMIZER 
Control 
 
FIX-HF-
C 
Baseline 
32.95 (5.43) 74     
33 (22.5, 44) 
34.15 (6.01) 86    
33.5 (23.5, 56) 
0.3190 
24 Weeks 
33.87 (6.79) 68     
33 (22.5, 54.5) 
33.86 (6.32) 72    
32 (25.5, 52) 
0.9235 
Change from Baseline to 
24 Weeks 
1.07 (5.17) 68      
0.75 (-11, 20) 
0.39 (4.27) 72     
-0.25 (-7.5, 17) 
0.2595 
FIX-HF 
Baseline 
34.3 (5.96) 117     
33 (24, 59) 
33.19 (6.31) 112   
33 (19, 60) 
0.1241 
24 Weeks 
32.86 (6.48) 102    
32 (-2, 56) 
32.76 (6.44) 91    
31 (21, 59) 
0.4197 
Change from Baseline to 
24 Weeks 
-1.21 (5.94) 102     
0 (-36, 10) 
0.08 (4.35) 91     
0 (-10, 13) 
0.3369 
Pooled 
Baseline 
33.78 (5.78) 191    
33 (22.5, 59) 
33.6 (6.18) 198    
33 (19, 60) 
0.6109 
24 Weeks 
33.26 (6.6) 170     
32.75 (-2, 56) 
33.25 (6.39) 163   
32 (21, 59) 
0.5695 
Change from Baseline to 
24 Weeks 
-0.3 (5.74) 170      
0 (-36, 20) 
0.21 (4.3) 163     
0 (-10, 17) 
0.9001 
                      Program: Additional Exploratory.sas  
1Two-sample Wilcoxon (two-sided) for difference between treatment groups. 

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There were no significant effects of treatment on the change in VE/VCO2 at 24 
weeks in the FIX-HF-C data (p=0.2595), the FIX-HF-5 data (p=0.3369) or the 
combined pooled analysis (p=0.9001).   
1.4.6.19.7 Comparison of Peak VO2 and Primary Safety Endpoint by Gender 
 
There were 7 primary safety endpoint complications that occurred in 4 males and 3 
females. The following 2x2 contingency table, constructed for the 68 treated 
OPTIMIZER subjects, shows that the association between gender and the primary 
safety endpoint was not statistically significant: 
 
          Table 78: Comparison by Gender 
 
Males 
Females 
Total 
Primary Safety Event 
4 (8.2%) 
3 (15.8%) 
7 
Event Free 
45 (91.8%) 
16 (84.2%) 
61 
Total 
49 
19 
68 
Fisher’s Exact P-value = 0.39 (2-sided) 
                                       Program: Safety Primary by Gender.sas 
 
The Forest plot below is for the primary efficacy endpoint (peak VO2) with no 
imputation of data, with the differences at 24 weeks from the mixed model using 
all available data (complete case). P(int)=Interaction p-value for gender with 
treatment at 24 weeks. 
 
                             Table 79: FIX-HF-5C Study Only 
Group 
Diff (95% Cl) 
P-Value 
(2-sided) 
Male (N=121) 
0.52 (-0.28, 1.32) 
0.2046 
Female (N=38) 
0.36 (-0.97,1.69) 
  0.5927 
                                           Program: Primary Efficacy MalevFemale.sas 
 
Program: F-Forest_Subgroup.sas 
P-value: 2-sided 
                Figure 27: FIX-HF-5C Study Only 
 

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                              Table 80: FIX-HF-5 (subgroup) Study Only 
Group 
Diff (95% Cl) 
P-Value 
(2-sided) 
Male (N=165) 
1.04 (0.24, 1.83) 
0.0109 
Female (N=63) 
1.30 (-0.06,2.66) 
0.0605 
                                           Program: Primary Efficacy MalevFemale.sas 
 
Program: F-Forest_Subgroup.sas 
P-value: 2-sided 
      Figure 28: FIX-HF-5 (subgroup) Study Only 
 
                             Table 81: FIX-HF-5 (subgroup) + FIX-HF-5C Pooled 
Group 
Diff (95% Cl) 
P-Value 
(2-sided) 
Male (N=286) 
0.80 (0.23, 1.37) 
0.0059 
Female (N=101) 
0.97 (-0.02, 1.96) 
0.0539 
                                        Program: Primary Efficacy MalevFemale.sas 
 
Program: F-Forest_Subgroup.sas 
P-value: 2-sided 
Figure 29: FIX-HF-5 (subgroup) + FIX-HF-5C Pooled 
 

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1.4.6.19.8 Comparison of Peak VO2 in OPTIMIZER Subjects Implanted 
with Different Leads (FIX-HF-5C only) 
There were 3 manufacturer’s leads used in this study, St. Jude Medical (SJM), 
Biotronik, and BSC/Guidant.  All but one subject had the same leads implanted in 
both locations.  This subject had one SJM lead and one Biotronik lead. For the 
purposes of this analysis, this subject is analyzed in the Biotronik group. The 
analysis is repeated without this subject.  
The unadjusted mean change from baseline at 24 weeks is presented in the table 
below for the three different leads. 
 
Table 82: Unadjusted Mean Changes from Baseline in Peak VO2 Scores at 24 Weeks 
(complete case analysis)  
SJM (N=37) 
Mean (SD) N  
Med (Min, Max) 
Biotronik (N=20) 
Mean (SD) N  
Med (Min, Max) 
BSC/Guidant (N=11) 
Mean (SD) N 
Med (Min, Max) 
P-value1 
(2-sided) 
0.43 (2.23) 34       
0.35 (-4.55, 5.90) 
-1.04 (3.42) 19      
 -1.60 (-7.30, 5.50) 
0.17 (2.90) 11       
0.15 (-5.70, 3.650) 
0.2344 
Program: Additional Exploratory.sas 
1 K-sample Kruskal-Wallis Test. 
Table 83: Unadjusted Mean Changes from Baseline in Peak VO2 Scores at 24 Weeks 
removing the subject with two different leads (complete case analysis)  
SJM (N=37) 
Mean (SD) N  
Med (Min, Max) 
Biotronik (N=19) 
Mean (SD) N  
Med (Min, Max) 
BSC/Guidant (N=11) 
Mean (SD) N 
Med (Min, Max) 
P-value1 
(2-sided) 
0.43 (2.23) 34       
0.35 (-4.55, 5.90) 
-1.01 (3.51) 18      
 -1.65 (-7.30, 5.50) 
0.17 (2.90) 11       
0.15 (-5.70, 3.650) 
0.3046 
Program: Additional Exploratory.sas 
1 K-sample Kruskal-Wallis Test. 
The primary model on the complete case data was refit separately by lead type. 
All control subjects are used in each analysis, but the OPTIMIZER group is 
reduced to those in each lead category.  
 
 

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Table 84: Least Squares Means from Repeated Measures Analysis of Variance for Peak 
VO2 over Study Visits by Lead Type (complete case analysis) 
 
SJM 
Biotronik 
BSC/Guidant 
Visit 
Treatment 
Difference  
(LCL, UCL) 
P-
value1 
Treatment 
Difference 
(LCL, UCL) 
P-
value1 
Treatment 
Difference  
(LCL, UCL) 
P-
value1 
12 Weeks 
0.426  
(-0.363, 1.214) 
0.1452 
0.097  
(-0.923, 1.116) 
0.4248 
0.947  
(-0.319, 2.213) 
0.0704 
24 Weeks 
0.930  
(0.141, 1.719) 
0.0107 
-0.446  
(-1.482, 0.591) 
0.8018 
0.546  
(-0.72, 1.812) 
0.1983 
Program: Additional Exploratory.sas 
1 One sided P-value for difference in least squares means from mixed model by Lead type. 
 
Table 85: Least Squares Means from Repeated Measures Analysis of Variance for Peak 
VO2 over Study Visits by Lead Type removing the subject with two different leads 
(complete case analysis) 
 
SJM 
Biotronik 
BSC/Guidant 
Visit 
Treatment 
Difference  
(LCL, UCL) 
P-
value1 
Treatment 
Difference 
(LCL, UCL) 
P-
value1 
Treatment 
Difference  
(LCL, UCL) 
P-
value1 
12 Weeks 
0.426  
(-0.363, 1.214) 
0.1452 
0.004  
(-1.039, 1.047) 
0.4960 
0.947  
(-0.319, 2.213) 
0.0704 
24 Weeks 
0.930  
(0.141, 1.719) 
0.0107 
-0.427  
(-1.488, 0.635) 
0.7847 
0.546  
(-0.72, 1.812) 
0.1983 
Program: Additional Exploratory.sas 
1 One sided P-value for difference in least squares means from mixed model by Lead type. 
 
While there are some observed differences in treatment effects by Lead type, 
there is not a significant difference between the lead types in terms of change in 
Peak VO2 at 24 weeks.   
1.4.6.19.9 Comparison of Hospitalizations in patients with EF<35% versus 
EF≥35% 
 
As detailed in the Primary Analysis & Key Secondary Analysis Report 
(Attachment 07), the impact of CCM™ on exercise tolerance and quality of life 
indices was significantly greater in patients with EF≥35%, though still clinically 
and statistically significant in patients with EF<35%. It was also shown that 
compared to Controls, patients treated with CCM™ had better survival free of 
heart failure hospitalizations and greater total number of days alive out of hospital 
during the study period.  It was also explored whether the impact of CCM™ on 
heart failure hospitalizations differed by LVEF.  Results are summarized in 
Tables 86, 87 and 88 for patients in the FIX-HF-5C population, the FIX-HF-5 
populations and in the pooled populations. 

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In the FIX-HF-5C study alone (Table 86), the rate of survival and survival free 
of the composite of death and hospitalizations was very high in patients with 
EF≥35% and did not differ between Treatment and Control.  In patients with 
EF<35%, survival free of the composite of cardiovascular death and heart failure 
hospitalizations trended for CCM™ between (0.97 vs 0.87, p=0.077) as were 
survival free of cardiac death (1.0 vs 0.95, p=0.14) and survival free of heart 
failure hospitalizations (0.97 vs 0.90, p=0.18).  Similar trends were observed in 
the FIX-HF-5 study as well (Table 87).  Thus, in the FIX-HF-5C and FIX-HF-5 
pooled population (Table 88), survival free of cardiovascular death and heart 
failure hospitalizations was significantly improved by CCM™ (0.97 vs 0.88, 
p=0.009), an effect that was driven primarily by improved survival free of heart 
failure hospitalizations (0.97 vs 90.0, p= 0.032).  CV deaths were also trending 
in favor of reduced events in the treatment group.  Even though event rates were 
low in the EF≥35% group, there was no indications of any adverse effects.

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Table 86: FIX-HF-5C only 
 
Program: Safety Survival Analyses.sas 
P-value:  2-sided
Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 
95% 
CI 
Upper 
95% CI 
Log-
Rank 
P 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 
95% CI 
Upper 
95% CI 
Log-
Rank 
P 
 
 
EF < 35 
 
EF ≥ 35 
 
Cardiac Death and HF Hospitalizations 
Active 
0 Weeks 
39 
0 
1 
. 
. 
0.0774 
29 
0 
1 
. 
. 
0.5908 
12 Weeks 
38 
1 
0.9744 
0.8316 
0.9963 
. 
28 
1 
0.9655 
0.7795 
0.9951 
. 
24 Weeks 
31 
1 
0.9744 
0.8316 
0.9963 
. 
19 
1 
0.9655 
0.7795 
0.9951 
. 
Controls 
0 Weeks 
54 
0 
1 
. 
. 
. 
30 
0 
1 
. 
. 
. 
12 Weeks 
47 
6 
0.8889 
0.7693 
0.9485 
. 
29 
1 
0.9667 
0.7861 
0.9952 
. 
24 Weeks 
26 
7 
0.8687 
0.744 
0.9352 
. 
17 
2 
0.9333 
0.7589 
0.9829 
. 
Cardiac Death 
Active 
0 Weeks 
39 
0 
1 
. 
. 
0.1422 
29 
0 
1 
. 
. 
. 
12 Weeks 
39 
0 
1 
. 
. 
. 
29 
0 
1 
. 
. 
. 
24 Weeks 
34 
0 
1 
. 
. 
. 
20 
0 
1 
. 
. 
. 
Controls 
0 Weeks 
56 
0 
1 
. 
. 
. 
30 
0 
1 
. 
. 
. 
12 Weeks 
51 
3 
0.9458 
0.8412 
0.9822 
. 
30 
0 
1 
. 
. 
. 
24 Weeks 
39 
3 
0.9458 
0.8412 
0.9822 
. 
23 
0 
1 
. 
. 
. 
HF Hospitalizations 
Active 
0 Weeks 
39 
0 
1 
. 
. 
0.1824 
29 
0 
1 
. 
. 
0.5908 
12 Weeks 
38 
1 
0.9744 
0.8316 
0.9963 
. 
28 
1 
0.9655 
0.7795 
0.9951 
. 
24 Weeks 
31 
1 
0.9744 
0.8316 
0.9963 
. 
19 
1 
0.9655 
0.7795 
0.9951 
. 
Controls 
0 Weeks 
54 
0 
1 
. 
. 
. 
30 
0 
1 
. 
. 
. 
12 Weeks 
47 
4 
0.9245 
0.8113 
0.971 
. 
29 
1 
0.9667 
0.7861 
0.9952 
. 
24 Weeks 
26 
5 
0.9035 
0.7833 
0.9587 
. 
17 
2 
0.9333 
0.7589 
0.9829 
. 

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Table 87: FIX-HF-5 only 
 
Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 
95% 
CI 
Upper 
95% CI 
Log-
Rank 
P 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 
95% CI 
Upper 
95% CI 
Log-
Rank 
P 
 
 
EF < 35 
 
EF ≥ 35 
 
Cardiac Death and HF Hospitalizations 
Active 
0 Weeks 
91 
0 
1 
. 
. 
0.0625 
18 
0 
1 
. 
. 
0.2774 
12 Weeks 
89 
2 
0.978 
0.915 
0.9945 
. 
17 
1 
0.9444 
0.6664 
0.992 
. 
24 Weeks 
88 
3 
0.967 
0.9013 
0.9892 
. 
15 
3 
0.8333 
0.5677 
0.943 
. 
Controls 
0 Weeks 
88 
0 
1 
. 
. 
. 
19 
0 
1 
. 
. 
. 
12 Weeks 
84 
2 
0.977 
0.9112 
0.9942 
. 
19 
0 
1 
. 
. 
. 
24 Weeks 
76 
9 
0.8946 
0.8072 
0.9437 
. 
18 
1 
0.9474 
0.6812 
0.9924 
. 
Cardiac Death 
Active 
0 Weeks 
91 
0 
1 
. 
. 
0.9778 
18 
0 
1 
. 
. 
0.1405 
12 Weeks 
90 
1 
0.989 
0.9246 
0.9984 
. 
17 
1 
0.9444 
0.6664 
0.992 
. 
24 Weeks 
90 
1 
0.989 
0.9246 
0.9984 
. 
16 
2 
0.8889 
0.6242 
0.971 
. 
Controls 
0 Weeks 
88 
0 
1 
. 
. 
. 
19 
0 
1 
. 
. 
. 
12 Weeks 
85 
1 
0.9885 
0.9212 
0.9984 
. 
19 
0 
1 
. 
. 
. 
24 Weeks 
84 
1 
0.9885 
0.9212 
0.9984 
. 
19 
0 
1 
. 
. 
. 
HF Hospitalizations 
Active 
0 Weeks 
91 
0 
1 
. 
. 
0.1012 
18 
0 
1 
. 
. 
0.9354 
12 Weeks 
89 
2 
0.978 
0.915 
0.9945 
. 
17 
0 
1 
. 
. 
. 
24 Weeks 
88 
3 
0.967 
0.9013 
0.9892 
. 
15 
1 
0.9375 
0.6323 
0.991 
. 
Controls 
0 Weeks 
88 
0 
1 
. 
. 
. 
19 
0 
1 
. 
. 
. 
12 Weeks 
84 
1 
0.9885 
0.9212 
0.9984 
. 
19 
0 
1 
. 
. 
. 
24 Weeks 
76 
8 
0.9051 
0.8192 
0.9514 
. 
18 
1 
0.9474 
0.6812 
0.9924 
. 
 
Program: Safety Survival Analyses.sas 
P-value:  2-sided

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Table 88: FIX-HF-5 and FIX-HF-5C Pooled 
 
Treatment 
Group 
Time 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 
95% 
CI 
Upper 
95% CI 
Log-
Rank 
P 
Number 
at Risk 
Total 
Number 
Failed 
Proportion 
Surviving 
Lower 
95% CI 
Upper 
95% CI 
Log-
Rank 
P 
 
 
EF < 35 
 
EF ≥ 35 
 
Cardiac Death and HF Hospitalizations 
Active 
0 Weeks 
130 
0 
1 
. 
. 
0.0087 
47 
0 
1 
. 
. 
0.6549 
12 Weeks 
127 
3 
0.9769 
0.9302 
0.9925 
. 
45 
2 
0.9574 
0.8404 
0.9892 
. 
24 Weeks 
119 
4 
0.9692 
0.9201 
0.9883 
. 
34 
4 
0.9149 
0.7889 
0.9672 
. 
Controls 
0 Weeks 
142 
0 
1 
. 
. 
. 
49 
0 
1 
. 
. 
. 
12 Weeks 
131 
8 
0.9434 
0.8899 
0.9713 
. 
48 
1 
0.9796 
0.8638 
0.9971 
. 
24 Weeks 
102 
16 
0.8836 
0.817 
0.9271 
. 
35 
3 
0.9388 
0.8221 
0.9798 
. 
Cardiac Death 
Active 
0 Weeks 
130 
0 
1 
. 
. 
0.2115 
47 
0 
1 
. 
. 
0.1466 
12 Weeks 
129 
1 
0.9923 
0.9467 
0.9989 
. 
46 
1 
0.9787 
0.8584 
0.997 
. 
24 Weeks 
124 
1 
0.9923 
0.9467 
0.9989 
. 
36 
2 
0.9574 
0.8404 
0.9892 
. 
Controls 
0 Weeks 
144 
0 
1 
. 
. 
. 
49 
0 
1 
. 
. 
. 
12 Weeks 
136 
4 
0.9719 
0.9269 
0.9894 
. 
49 
0 
1 
. 
. 
. 
24 Weeks 
123 
4 
0.9719 
0.9269 
0.9894 
. 
42 
0 
1 
. 
. 
. 
HF Hospitalizations 
Active 
0 Weeks 
130 
0 
1 
. 
. 
0.032 
47 
0 
1 
. 
. 
0.7038 
12 Weeks 
127 
3 
0.9769 
0.9302 
0.9925 
. 
45 
1 
0.9783 
0.8555 
0.9969 
. 
24 Weeks 
119 
4 
0.9692 
0.9201 
0.9883 
. 
34 
2 
0.956 
0.8354 
0.9888 
. 
Controls 
0 Weeks 
142 
0 
1 
. 
. 
. 
49 
0 
1 
. 
. 
. 
12 Weeks 
131 
5 
0.9643 
0.9163 
0.985 
. 
48 
1 
0.9796 
0.8638 
0.9971 
. 
24 Weeks 
102 
13 
0.9032 
0.8391 
0.9427 
. 
35 
3 
0.9388 
0.8221 
0.9798 
 
 
Program: Safety Survival Analyses.sas 
P-value:  2-side

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1.4.6.20 CCM™ Therapy Delivery During FIX-HF-5C Study 
 
1.4.6.20.1 Dosage 
Impulse Dynamics conducted multiple clinical trials which explored several 
therapy dosage timing configurations that were proven to provide a desirable 
clinical benefit.  For example, the FIX-HF-3 study delivered CCM™ at a “dose” 
of 3 hours/day administered continuously for 3 hours once a day.  In the FIX-3-
ext and FIX-CHF-4 studies, CCM™ was delivered in 1 hour intervals for a total 
of 7 hours/day, while in the FIX-HF-5 study, the CCM™ “dose” was reduced to 
5 hours/day, also in 1-hour intervals equally spaced throughout the day.  Of note, 
a single center study (FIX-CHF-13) did a preliminary evaluation of 5 vs. 12 
hours/day therapy dosage which did not indicate a clinical difference between the 
two times.18 
 
1.4.6.20.2 Number of Hours/Day 
As the difference in clinical performance of 5 versus 12 hours/day was not found 
to be significant, the schedule recommended by Impulse Dynamics is 5 hours per 
day in equally-spaced 1-hour intervals. Dosage of CCM™ therapy, as delivered 
in the FIX-HF-5C trial, was pre-set at 5 hours duration in a given 24 hour period. 
The therapy delivery duration was non-programmable.  
 
This “therapy delivery period” started each day at 00:00 hours and was delivered 
in increments lasting 1 hour in duration. After each one hour period, CCM signal 
delivery is halted for 3.8 hours. This cycle continued until 23:59 hours at which 
time the cycle repeats. This cycle continues unless interrupted by certain 
preprogrammed safety features, such as high PVC count, atrial arrhythmia, etc.  
 
 
 
                     Table 89: CCM™ Therapy delivery cycle 
CCM 
Duration 
Start Time 
End Time 
On 
1 hour 
00:00 HRS 
01:00 HRS 
Off 
3 hours 48 minutes 
01:01 HRS 
04:48 HRS 
On 
1 hour 
04:49 HRS 
05:48 HRS 
Off 
3 hours 48 minutes 
05:49 HRS 
09:36 HRS 
On 
1 hour 
09:37 HRS 
10:36 HRS 
Off 
3 hours 48 minutes 
10:37 HRS 
14:24 HRS 
On 
1 hour 
14:25 HRS 
15:24 HRS 
Off 
3 hours 48 minutes 
15:25 HRS 
19:12 HRS 
On 
1 hour 
19:13 HRS 
20:12 HRS 

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CCM 
Duration 
Start Time 
End Time 
Off 
3 hours 48 minutes 
20:13 HRS 
23:59 HRS 
 
 
1.4.6.20.3 CCM™ Percentage per Day 
 
Subjects have their Optimizer device interrogated at every study visit, during 
which CCM delivery percentage and other diagnostic data is gathered. Despite 
the 5 hours of scheduled CCM therapy, the programmed cycle may be interrupted 
when there is a high PVC count, atrial fibrillation, or any other type of 
tachyarrhythmia. The total amount of time CCM therapy is delivered can be 
estimated based on the number of CCM beats delivered (recorded as total trains). 
Assuming the average heart rate is 72bpm, approximately 21,600 CCM trains 
would equate to 5 hours (100%) of CCM effectively provided. During the FIX-
HF-5C study, over 80% of the subjects received the full 5 hours and 
approximately 94% of the subjects received more than 80% of the CCM therapy. 
The remaining 6% of the subjects received less than 4 hours of therapy due 
primarily to a high number of PVCs or new onset atrial fibrillation. 
 
Table 90: CCM™ Therapy Delivery Summary 
Hours/day 
% CCM 
% of Subjects 
Reasons for <5hr delivery 
4.0 - 5.0 
80-100% 
94% 
4 
subjects 
with 
atrial 
fibrillation, 6 with a high 
PVC count, 2 with therapy 
delivery timing changes, all 
others with no explanation 
provided 
0.00 – 3.9 
0-79% 
6% 
6 subjects with high PVC 
count, 
1 
with 
atrial 
fibrillation, all others no 
explanation provided 
 
  
 
1.4.6.20.4 CCM Delivery Programming 
 
Impulse Dynamics discovered that electrical currents delivered during Phase 2 of 
the ventricular action potential lead to an increase in ventricular contractility.  The 
actual CCM™ signal parameters were developed based on animal experiments, 
engineering considerations, and clinical experience.19  
 
As described by Prutchi and Norris in “Design and Development of Medical 
Electronic Instrumentation,”20 CCM™ signals consist of charge-balanced 
biphasic pulse bursts of 5 to 10 ms in duration per phase; one to three pulses per 

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burst delivered 30 to 60 ms into ventricular absolute refractory period. 
 
CCM™ delivery must occur within the absolute refractory period.  
Programmability allows the physician to deliver the CCM™ signal at a time when 
it produces maximal effect on contractility. As shown in Figure 30, the delay and 
duration of the CCM™ pulse train were selected to place the CCM™ signal fully 
within the ventricular action potential’s plateau (Phase 2), leaving sufficient 
margin of safety to stay clear of ventricular repolarization (T-wave).  Biphasic 
pulses and a 40 ms balancing phase were chosen to ensure net-zero current flow 
to prevent electrochemical damage to the tissue.  Lastly, CCM™ pulse phase 
durations in the 5-7 ms range were shown in animal experiments to yield the 
desired contractility-enhancement effects. 
 
 
                    Figure 30: Delay and Duration of CCM™ Pulse Train 
 
The start of the timing cycle for CCM™ signal delivery is triggered by the “Local 
Sense” event. The delay parameter (coupling interval) is the time interval between 
the leading edge of the Local Sense triggering event and the start of CCM™ pulse 
train delivery. With the OMNI II Programmer, the delay parameter can be set to 
values between 3 ms and 140 ms. To determine the proper programmed setting, 
the following criteria are applied:  
 
• Programmed value is initiated by LS event 
• Appropriate programmed value is 35ms after second sensed ventricular event, 
either the RV or LS event, whichever occurs last 

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• If LS event is after RV event, programmed value should be 35ms 
• If RV event is after LS event, programmed value should be 35ms plus the 
measured RV-LS interval 
 
Further descriptions of the CCM signal are provided in the following sections. 
 
a. 
CCM Train Delay 
The Train Delay is a programmable value between 3 and 140 ms in increments 
of 1 ms. The “Standard” or nominal setting is 35 ms. The purpose of this Train 
Delay is to ensure the entire ventricular mass (right and left) is depolarized. There 
is no specific value that would always be correct, since each patient’s conduction 
system serves as their own norm. 
 
b. 
Phase duration 
The phase duration limits the amount of energy delivered to the patient in one 
event. The phase duration of the pulses comprising the CCM™ signal can be 
programmed with the OMNI II Programmer to one of 4 possible values between 
5.14 ms and 6.60 ms. The duration of both phases is automatically set to identical 
values. At no time can they be programmed to different values. The nominal 
setting for this Phase Duration is 5.14 ms. 
 
As described by Prutchi and Norris in “Design and Development of Medical 
Electronic Instrumentation,”20 CCM™ signals consist of charge-balanced 
biphasic pulse burst of 5 to 10 ms in duration per phase; one to three pulses per 
burst delivered 30 to 60 ms into the ventricular absolute refractory period. 
 
Biphasic pulses with phase duration of 5.14 to 6.60 ms delivered during the 
absolute refractory period of the heart have been shown to be therapeutic when 
treating patients with CHF. The effectiveness of these signals has been reported 
by Morita et al.21 
 
Programmability of the Phase Duration allows the physician to modulate the 
intensity of the therapy: Patients with discomfort felt at the time of therapy 
delivery could be treated by increasing the phase duration. If no discomfort is felt 
at the initiation of therapy, the Phase Duration is left at the nominal setting.  
 
 
 

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1.5 Discussion 
 
The results of this investigation confirm that CCM™ is safe and significantly improves 
exercise tolerance (peak VO2), quality of life (MLWHFQ score), and functional status (NYHA 
class) in patients with heart failure and EF ranging from 25% to 45%, QRS duration <130 ms, 
normal sinus rhythm and persistent functional class NYHA III or ambulatory IV symptoms 
despite guideline directed medical therapies.  These observations are further supported by a 
between-group difference (improvement) in 6MHW distance in excess of 30 meters favoring 
CCM™ Treatment over Control.  Additional sensitivity analyses further confirmed the 
robustness of the findings, independent of other assumptions concerning the methods of 
Bayesian borrowing and imputation for deaths and missing data.  Finally, a significant 
reduction in the composite of cardiac deaths and heart failure hospitalizations was observed. 
 
An analysis of a small subset of the FIX-HF-5 study population (n=38) (further discussed in 
section 6.3 below) suggested that CCM™ treatment effects were particularly large in patients 
with EF ≥35%.  That finding was also further corroborated when data from an additional 59 
patients from the FIX-HF-5C study were included in the analysis.  This cohort is of interest 
since these patients do not have an indication for an ICD, so that a standalone CCM™ device 
could be applicable.     
 
In addition to the data of the present study, the safety of CCM™ has been consistently 
demonstrated in prior studies.22,23,3  In particular, the FIX-HF-5 study demonstrated that 1-year 
event-free survival was noninferior in the CCM™ group compared to the Control group22 
Consistent across studies has been the finding that the rate and severity of overall adverse 
events is not significantly different than in the respective control group, despite the fact that 
the Control group does not receive a device implant.   
 
The magnitude of the treatment effect of CCM™ on peak VO2 is comparable to those identified 
in patients studied in prior studies of Cardiac resynchronization therapy (CRT).  These include 
MIRACLE (0.9 ml/kg/min)Error! Bookmark not defined., MIRACLE-ICD (1.0 ml/kg/min)Error! 
Bookmark not defined., CONTAC-CD (0.8 ml/kg/min)Error! Bookmark not defined..  Although these studies 
have different entry criteria, they do provide a basis for comparing effects of CCM™ to CRT. 
The current study also identified a significant reduction of the composite of cardiovascular 
death and heart failure hospitalizations which are important therapeutic targets for this therapy.   
 
While the current study was too short in duration and included too few patients to fully address 
survival benefit, prior studies have provided evidence of beneficial effects on survival and 
hospitalizations. The European registry (CCM-REG, fully discussed in section 5 below) 
provides further evidence of the impact and magnitude of CCM™ in reducing cardiac 
hospitalization. 
 
CRT has long been available for patients with EF ≤35%, normal sinus rhythm, QRS duration 
≥130 ms and persistent NYHA class III or ambulatory class IV symptoms despite guideline-
directed medical therapies.  However, HF patients not qualifying for CRT represent a large 
group suffering from poor quality of life and poor exercise tolerance despite optimal medical 
therapies.  While ICDs are applicable to the broad population of patients with EF ≤35%, they 

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do not deliver a therapy for improving exercise tolerance or quality of life.  It is noteworthy 
that for patients with EF <35%, a device that combines CCM and ICD functions is under 
development.  Similarly, indwelling pulmonary artery pressure sensors are also applicable and 
help optimize medical therapies but do not, on their own, provide a heart failure therapy.  Thus, 
there is a relatively large cohort of heart failure patients failing medical therapy that do not 
have the benefit of a simply implanted device-based therapy.  It is such patients that CCM™ 
is currently designed to serve.   
 
Conclusions 
In summary, the results of the present study supplement and confirm results of prior studies in 
showing that CCM™ is safe and improves exercise tolerance and quality of life in patients 
with EF ranging from 25% to 45%, QRS duration <130 ms, normal sinus rhythm and persistent 
NYHA class III or ambulatory class IV symptoms despite guideline directed therapies 
including medications and ICDs when indicated.  The composite of cardiovascular deaths and 
heart failure hospitalizations was reduced.  The clinical effects were observed across the range 
of EFs studied, and clinical effectiveness was even greater in patients with EFs between 35 
and 45% consistent with the FIX-HF-5 study.  
 
 
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