Conditions: Heart Failure
Keywords: heart failure ventricular assist device LVAD aspirin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 628
Healthy volunteers: no

Brief summary:
Prospective, randomized, double-blinded, placebo-controlled clinical investigation of advanced heart failure patients treated with the HM3 with two different antithrombotic regimens: vitamin K antagonist with aspirin versus vitamin K antagonist with placebo

Detailed description:
This clinical investigation is a prospective, randomized, double-blinded, placebo-controlled study of advanced heart failure patients treated with the HM3 with two different antithrombotic regimens: vitamin K antagonist with aspirin versus vitamin K antagonist with placebo.

Arms:
arm 1: LVAD Patients on the placebo arm will be given placebo medication arm 2: LVAD Patients on the active arm will be given 100mg Aspirin

Interventions: intervention 1: LVAD Implant intervention 2: Aspirin 100mg intervention 3: Placebo oral tablet
Intervention descriptions: intervention 1: Subjects will undergo Heartmate 3 LVAD implant prior to randomization intervention 2: Subjects will be randomized to either Placebo or Aspirin post implant. intervention 3: Subjects will be randomized to either Placebo or Aspirin post implant

Protocol document:
Prot_000.pdf: 
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Clinical Investigation Plan 
 
 
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CRD_971 
ARIES HM3 
Antiplatelet Removal and HemocompatIbility EventS with the HeartMate 3 Pump 
 
Version  
C 
Date 
MAR 13, 2020 
Steering Committee 
Mandeep Mehra MD, MSc, FRCP (Lon) - Chair  
Nir Uriel MD, MSc  
Francis Pagani MD, PhD  
Ulrich Jorde MD 
Jason Katz MD, MHS 
Finn Gustafsson MD, PhD 
Ivan Netuka MD, PhD 
Planned Number of Sites  
Up to 50 sites 
Geographies 
International 
Clinical Investigation Type 
Prospective, randomized, double-blinded, placebo-controlled 
clinical investigation of advanced heart failure patients treated 
with the HM3 with two different antithrombotic regimens: vitamin 
K antagonist with aspirin versus vitamin K antagonist with 
placebo 
Sponsor 
Abbott 
168 Middlesex Turnpike 
Burlington, MA 01803 
USA 
Randomization and Treatment 
Arm Medication Logistics 
WebEZ (ALMAC Clinical Services) 
Electronic Data Capture Software 
Oracle Clinical 
CIP Author (Current Version) 
Daniel Crandall, PhD 
Abbott Medical Expert 
Robert Kormos, MD, FACS, FRCS (C), FAHA 
 
 


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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical investigation. 
 
 
Site Principal Investigator 
 
Printed name: 
Signature: 
Date: 
 
 
 


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TABLE OF CONTENTS 
 
 
1.0
INTRODUCTION .............................................................................................................................. 9
1.1
Background and Rationale ........................................................................................................... 9

Background ........................................................................................................................... 9

Rationale for Conducting this Clinical Investigation ............................................................. 10
2.0
CLINICAL INVESTIGATION OVERVIEW ...................................................................................... 11
2.1
Clinical Investigation Objective ................................................................................................... 11
2.2
Hypothesis .................................................................................................................................. 11
2.3
Device(s) To Be Used in the Clinical Investigation ..................................................................... 11

Indication for Use ................................................................................................................ 12

Description of the Device(s) Under Investigation ................................................................ 13

Device Accountability .......................................................................................................... 13
2.4
Treatment Arm Medication ......................................................................................................... 13

Project Management ........................................................................................................... 13

Treatment Arm Blinding ....................................................................................................... 14

Treatment Arm Bottle Dispensing........................................................................................ 14

Antithrombotic Therapy ....................................................................................................... 14

Treatment Arm Medication Accountability ........................................................................... 15

Aspirin Response Testing.................................................................................................... 15
3.0
CLINICAL INVESTIGATION DESIGN ............................................................................................ 15
3.1
Clinical Investigation Procedures and Follow-up Schedule ........................................................ 16
3.2
Measures Taken to Avoid and Minimize Bias ............................................................................. 18
3.3
Suspension or Early Termination of the Clinical Investigation .................................................... 18
4.0
ENDPOINTS .................................................................................................................................. 19
4.1
Primary Endpoint and Rationale ................................................................................................. 19
4.2
Secondary Endpoint ................................................................................................................... 19
4.3
Descriptive Endpoints ................................................................................................................. 20
5.0
SUBJECT SELECTION AND WITHDRAWAL ............................................................................... 20
5.1
Subject Population ...................................................................................................................... 20
5.2
Subject Screening and Informed Consent .................................................................................. 20

Subject Screening ............................................................................................................... 20

Informed Consent ................................................................................................................ 20


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5.3
Eligibility Criteria ......................................................................................................................... 21
Inclusion Criteria..................................................................................................................22

Exclusion Criteria................................................................................................................. 22
5.4
Subject Enrollment ..................................................................................................................... 22

Enrollment of Medicare Beneficiaries .................................................................................. 22

Historically Under-Represented Demographic Subgroups .................................................. 23
5.5
Subject Withdrawal ..................................................................................................................... 24

Incidental Use of Aspirin Containing Products .................................................................... 25
5.6
Transition to Open Label ............................................................................................................ 25
5.7
Number of Subjects .................................................................................................................... 26
5.8
Total Expected Duration of the Clinical Investigation ................................................................. 26
6.0
TREATMENT AND EVALUATION OF ENDPOINTS ..................................................................... 26
6.1
Avoidance of Additional Antiplatelet Medications ....................................................................... 26
6.2
Avoidance of Platelet Function Testing ...................................................................................... 26
6.3
Study Activities and Procedures ................................................................................................. 26
6.4
Baseline ...................................................................................................................................... 28
6.5
Implant Procedure ...................................................................................................................... 29
6.6
Randomization ............................................................................................................................ 30
6.7
Initial Discharge Data.................................................................................................................. 30
6.8
Scheduled Follow-up for All Subjects ......................................................................................... 30

Continued follow up beyond 12-months post implant .......................................................... 32
6.9
Unscheduled Visits .....................................................................................................................32

Adverse Events ................................................................................................................... 32
6.9.1.1
Neurologic Adverse Events .......................................................................................... 32

Operative Procedures.......................................................................................................... 32

Hospitalizations ................................................................................................................... 32

Outcomes ............................................................................................................................ 33
6.10
Blinding ....................................................................................................................................... 33
6.11
Patient Reported Outcome (PRO) Measure ............................................................................... 33
7.0
ADVERSE EVENTS ....................................................................................................................... 34
7.1
Definition ..................................................................................................................................... 34

Adverse Event ..................................................................................................................... 34

Serious Adverse Event ........................................................................................................ 34

Device Deficiency ................................................................................................................ 34


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7.2
Device Relationship .................................................................................................................... 34
Unanticipated Serious Adverse Device Effect (USADE) .....................................................35
7.3
Adverse Event and Device Deficiency/Device Malfunction Reporting ........................................ 35

Adverse Event Reporting..................................................................................................... 35

Unanticipated Serious Adverse Device Effect Reporting to Sponsor and IRB/EC .............. 36

Device Deficiency Reporting ............................................................................................... 36

Adverse Event Reporting to Country Regulatory Authorities by the Sponsor ..................... 36
8.0
STATISTICAL CONSIDERATIONS ............................................................................................... 37
8.1
Analysis Populations .................................................................................................................. 37

Modified Intention to Treat Population (mITT) ..................................................................... 37

Intent-To-Treat (ITT) Population .......................................................................................... 37
8.2
Statistical Analyses ..................................................................................................................... 37

Primary Endpoint Hypothesis .............................................................................................. 37

Primary Endpoint Analyses Methodology ............................................................................ 38

Secondary Endpoint Analyses............................................................................................. 38

Descriptive Endpoints .......................................................................................................... 38
8.3
Sample Size Calculation and Assumptions ................................................................................ 38
8.4
Timing of Analysis....................................................................................................................... 39
8.5
Subgroup Analysis ...................................................................................................................... 39
8.6
Multiplicity ................................................................................................................................... 39
8.7
Pooling Strategy ......................................................................................................................... 39
8.8
Procedures for Accounting for Missing Data ..............................................................................39
8.9
Planned Interim Analysis ............................................................................................................ 39
8.10
Statistical Criteria for Termination............................................................................................... 39
8.11
Success Criteria ......................................................................................................................... 40
8.12
Deviations from Statistical Plan .................................................................................................. 40
9.0
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................................................................. 40
10.0
QUALITY CONTROL AND QUALITY ASSURANCE ..................................................................... 40
10.1
Selection of Clinical Sites and Investigators ............................................................................... 40
10.2
Clinical Investigation Finances and Agreements ........................................................................ 40
10.3
CIP Amendments........................................................................................................................ 40
10.4
Training ....................................................................................................................................... 41

Site Training ........................................................................................................................ 41
10.5
Monitoring ................................................................................................................................... 41


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10.6
Deviations from the CIP .............................................................................................................. 41
10.7
Quality Assurance Audit .............................................................................................................42
10.8
Committees ................................................................................................................................ 43

Steering Committee ............................................................................................................. 43

Data Safety Monitoring Board (DSMB) ................................................................................ 43

Clinical Events Committee (CEC) ........................................................................................ 43
11.0
DATA HANDLING AND RECORD KEEPING ................................................................................ 44
11.1
Protection of Personally Identifiable Information ........................................................................ 44
11.2
Data Management Plan .............................................................................................................. 45
11.3
Source Documentation ............................................................................................................... 45
11.4
Case Report Form Completion ................................................................................................... 45
11.5
Record Retention ........................................................................................................................ 46
12.0
ETHICAL CONSIDERATION ......................................................................................................... 46
12.1
Institutional Review Board/Medical Ethics Committee Review and Approval ............................. 46
13.0
CLINICAL INVESTIGATION CONCLUSION ................................................................................. 46
14.0
REPORTS AND PUBLICATIONS .................................................................................................. 47
14.1
Sponsor Reports ......................................................................................................................... 47
14.2
Publication Policy ....................................................................................................................... 47
14.3
Trial Registration ........................................................................................................................ 47
15.0
RISK ANALYSIS ............................................................................................................................ 47
15.1
Anticipated Clinical Benefits ....................................................................................................... 47
15.2
Foreseeable Adverse Events and Anticipated Adverse Device Effects......................................47
15.3
Residual Risks Associated with the Clinical Investigation, as Identified in the Risk Analysis 
Report ......................................................................................................................................... 48
15.4
Risks Associated with Participation in this Clinical Investigation ................................................ 48
15.5
Possible Interactions with Protocol-Required Concomitant Medications .................................... 48
15.6
Steps Taken to Control or Mitigate Risks ................................................................................... 49
15.7
Risk to Benefit Rationale ............................................................................................................ 49
APPENDIX I: ABBREVIATIONS AND ACRONYMS ................................................................................. 51
APPENDIX II: DEFINITIONS .................................................................................................................... 54
APPENDIX III: STUDY CONTACT INFORMATION ................................................................................. 63
APPENDIX IV: INFORMED CONSENT FORM ........................................................................................ 64
APPENDIX V: MONITORING PLAN ......................................................................................................... 65
APPENDIX VI: DEVICE POSITION SUBSTUDY PROTOCOL ................................................................ 66


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APPENDIX VII: REVISION HISTORY ...................................................................................................... 74 
APPENDIX VIII: CIP SUMMARY .............................................................................................................. 76 
APPENDIX IX: REFERENCES ................................................................................................................. 80 
 
 


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COMPLIANCE STATEMENT:  
This clinical investigation will be conducted in accordance with this Clinical Investigation Plan, the 
Declaration of Helsinki, applicable Good Clinical Practices and regulations (e.g., US 21 CFR Part 50, 21 
CFR Part 56, 21 CFR Part 812, and OUS ISO14155:2011) and the appropriate local legislation(s). The 
most stringent requirements, guidelines or regulations must always be followed. The conduct of the 
clinical investigation will be approved by the appropriate Institutional Review Board (IRB)/Ethics 
Committee (EC) of the respective investigational site and by the applicable regulatory authorities. 
 
 


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1.0 
INTRODUCTION 
Heart failure (HF) is a growing epidemic, with 915,000 new cases diagnosed each year, resulting in over 
1 million hospitalizations and costs the United States (US) healthcare system over $30 billion annually1. 
Left ventricular assist devices (LVAD) are increasingly being used for treating patients with advanced 
heart failure as they have demonstrated improved survival over optimal medical management2. 
Progressively improving outcomes with newer LVAD technology has led to LVAD therapy becoming a 
mainstay in the treatment of advanced heart failure3, however, LVAD therapy has been beleaguered by 
hemocompatibility related adverse events – namely thrombosis, stroke and bleeding4. Within the 
prospective randomized multicenter MOMENTUM 3 clinical trial, the HeartMate 3 (HM3) Left Ventricular 
Assist System (LVAS; Abbott, Chicago, IL, Study Sponsor) showed a decrease in hemocompatibility 
related adverse events relative to the HeartMate II (HMII) LVAS (Abbott, Chicago, IL)5. This included 
decreases in pump thrombosis6, stroke7-9, and bleeding9 event rates. Despite these noted improvements 
a high residual risk of bleeding persists in patients treated with the HM3 LVAD9. Patients implanted with 
the HM3 pump are treated with a combination of antiplatelet and anticoagulation therapy but the role and 
implications of this regimen in determining the burden of hemocompatibility related adverse events have 
not been adequately investigated9,10. Whether antiplatelet therapy is essential in concert with 
anticoagulation in treating such patients remains unknown. 
 
This clinical investigation is a prospective, randomized, double-blinded, placebo-controlled study of 
advanced heart failure patients treated with the HM3 with two different antithrombotic regimens: vitamin 
K antagonist with aspirin versus vitamin K antagonist with placebo. The objective of this investigation is 
to study the safety and efficacy of an anti-platelet-free antithrombotic regimen in patients with advanced 
heart failure treated with the HM3 LVAS.  
 
This clinical investigation will be conducted in accordance with this clinical investigation plan (CIP). All 
investigators involved in the conduct of the clinical investigation will be qualified by education, training, or 
experience to perform their tasks and this training will be documented appropriately. 
1.1
Background and Rationale
 Background 
The CE Mark trial (clinicaltrials.gov identifier: NCT02170363) for the HM3 LVAD was a prospective, 
multicenter, single arm trial that enrolled 50 subjects at 10 sites. Six-month outcomes from this trial 
demonstrated 92% (confidence interval 83-97%) survival and led to the CE Mark approval of the HM3. 
Analysis of longer term data demonstrated a 2-year survival of 74 ± 6%11. No instances of device 
thrombosis were observed in this cohort at 2 years11. Subjects will be followed through 5 years as a 
condition of CE Mark approval.  
 
After approval, the ELEVATE (Evaluating the HeartMate 3 with Full MagLev Technology in a Post-Market 
Approval Setting; clinicaltrials.gov identifier: NCT02497950) registry was initiated to collect real-world data 
(i.e. there were no enrollment criteria) on consecutive HM3 patients at 26 total centers in Europe, Israel, 
Singapore, and Kazakhstan. The study enrolled 463 primary implant patients, 19 pump exchange patients, 
and collected only outcome data on an additional 58 patients who were unable to provide consent due to 
a study outcome (n=57 death, n=1 explant). The ELEVATE trial reported, for the primary implant cohort at 
2-years, actuarial survival of 83.4%, and adverse events of stroke in 10%, suspected pump thrombosis in 
1.5%, and bleeding in 34%12. 


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The MOMENTUM 3 study (clinicaltrials.gov identifier: NCT02224755) was a prospective, randomized, 
multicenter, non-blinded, clinical trial that enrolled 1,028 patients at 69 sites in the US. The study 
randomized patients to receive either the HM3 or HMII LVAD. The study design incorporated an initial 
safety phase that evaluated 30 subjects at 5 sites prior to study expansion13. The primary objective of the 
trial was to evaluate the safety and efficacy of using the HM3 LVAD in indicated patients at two timepoints: 
6 months (short-term n=294) and 2 years (long-term n=366)13. The primary endpoint was a composite of 
survival free of disabling stroke or survival free of reoperation to replace or remove the device (for reasons 
other than recovery)14. The secondary endpoint, which the study was powered to assess, was freedom 
from pump exchange through 2-years of follow-up in the full cohort of 1028 patients. All study endpoints 
were successfully met6,8,9. The MOMENTUM 3 trial reported the full cohort HM3 actuarial survival at 2-
years as 79.0% and stroke rates of 9.9%, suspected pump thrombosis rates of 1.4%, and bleeding rates 
of 43.7%9. An analysis of the burden of hemocompatibility related adverse events showed improved 
survival free of hemocompatibility related adverse events with the HM3 over the HMII at 6 months5 and 2 
years15. Within the full cohort HM3 arm of MOMENTUM 3, at all time points, a cohort of patients were 
noted without aspirin as a part of their anti-thrombotic regimen, specifically at 6-months n=72/446 (16%), 
at 1-year n=78/371 (21%), at 18-months n=73/314 (23%), and at 2-years n=64/286 (22%)9. The 
MOMENTUM 3 study will continue to follow patients through 5-years post-implant as a condition of 
approval. After full enrollment in the MOMENTUM 3 study, a single arm (HM3 only) continued access 
protocol (CAP) was initiated while the MOMENTUM 3 IDE patients were being followed. This CAP study 
enrolled 1685 patients who will be followed for 2 years post implant.   
 
A single center in Europe has investigated the use of the HM3 with low intensity anticoagulation (INR 1.5-
1.9) in select patients, and reported positive outcomes10. These outcomes lead to the full removal of 
anticoagulation therapy in a subset of the low intensity anticoagulation patients, with favorable outcomes16. 
Additionally two reports from Europe have emerged on their initial experience with warfarin monotherapy 
with the HM317,18. Both studies conclude it may be safe to remove aspirin therapy from HM3 patients and 
called for further evaluation of the effects of discontinuation of aspirin in HM3 patients. Specifically, in a 
multicenter, retrospective, observational study performed at the San Raffaele Scientific Institute in Milan 
and A.O. Brotzu in Cagliari, Italy, patients were stratified based on bleeding risk; patients with a HAS-BLED 
score ≥ 4 or who experienced a post-operative bleeding event were considered high risk17. Patients at high 
bleeding risk were discharged on warfarin monotherapy with INR targeted to 2.0-2.5 whereas the 
remaining patients were discharged with warfarin (INR 2.0-2.5) and aspirin (100mg/day) antithrombotic 
therapy17. In the other study at the University Hospital Birmingham, United Kingdom, a retrospective 
analysis of a prospective audit of a change in their institutional standard of care was conducted18. The 
center implemented as standard of care the discontinuation of aspirin therapy after >3 months or following 
a bleeding complication.  
 Rationale for Conducting this Clinical Investigation 
Patients implanted with LVADs are typically treated with a combination of antiplatelet and anticoagulant 
therapy but the role and implications of this regimen in determining the burden of hemocompatibility related 
adverse events in patients implanted with the HM3 LVAS have not been adequately investigated9,10. 
Furthermore, a recent study showed that aspirin, in older, healthy adults without an LVAD, was associated 
with increased risk of major bleeding, including upper gastrointestinal bleeding, without a reduction in 
thromboembolic events including ischemic stroke19. Whether antiplatelet therapy is essential in concert 
with anticoagulation in treating LVAD patients remains unknown. 
 


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Hemocompatibility related adverse events, both thrombotic and hemorrhagic, are highly interrelated. 
Frequently changes to a patient’s antithrombotic therapy that occur in the setting of hemocompatibility 
related adverse events increase the propensity toward opposing events. Specifically, treatment of a 
thrombotic event with additional antithrombotic intensity may result in a hemorrhagic event or vise-versa. 
While these events may be commonly discussed discretely, decoupling them in the setting of a patient 
population predisposed to both events is not possible, which can lead to difficulty interpreting the results 
of clinical studies or, in the worst-case scenario, studies with little or no interpretive value. As such, this 
study focuses on de novo LVAD implants and the first events, prior to such modifications to the treatment 
arm antithrombotic regimen while encouraging investigators to maintain the randomized treatment arm 
therapy as long as clinically permissible, in an effort to avoid such confounding factors. 
 
Bleeding events with the HM3, while decreased in comparison to a predicate device, remain burdensome9. 
All major prospective clinical trials conducted with the HM3 (MOMENTUM 3, CE Mark) have been in the 
context of a prescribed antithrombotic regimen of aspirin in concert with vitamin K antagonist. Within clinical 
studies9,10,16, as institutional changes to their standard of care18, or in response to increased bleeding risk17, 
modifications to the HM3 anticoagulation regimen have been explored. Prior to the introduction of the HM3, 
which has a decreased thrombotic profile relative to the HMII, studies investigating the need for aspirin 
within the HMII antithrombotic regimen were conducted20-23. The experience with the HMII, the improved 
outcomes with the HM3 and the early experience of single centers exploring modification to the 
antithrombotic regimen in HM3 patients provide evidence for the clinical equipoise in HM3 antithrombotic 
therapy and forms the basis for randomization of patients to aspirin (100mg) vs placebo arms within this 
trial.   
2.0 
CLINICAL INVESTIGATION OVERVIEW 
2.1 
Clinical Investigation Objective 
To study the safety and efficacy of an anti-platelet-free antithrombotic regimen in patients with advanced 
heart failure treated with the HM3 LVAS. 
2.2 
Hypothesis 
Withdrawal of antiplatelet therapy from the antithrombotic regimen of HM3 pump patients will not 
adversely affect safety or efficacy of the HM3 and may reduce non-surgical bleeding. 
2.3 
Device(s) To Be Used in the Clinical Investigation 
This Clinical Trial investigates the treatment of advanced heart failure with the HM3 and if the use of 
antiplatelet therapy is required as part of the antithrombotic regimen. Refer to the HM3 Instruction for 
Use (IFU) in your country for additional details.  
 


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Table 1 – Device Details 
Device name 
Model/Type 
Serial/Lot 
Controlled 
Manufacturer 
Investigational or 
Market Released 
HeartMate 3 
(HM3) Left 
Ventricular 
Assist System 
(LVAS) 
106523 
Standard 
Commercial 
Controls 
Abbott 
The HM3 will be 
Market Released in 
all geographies 
included in this 
international study 
 
 
 
Figure 1 – HeartMate 3 LVAD (A) and System during Battery-powered Operation (B): The HM3 LVAS 
consists of an LVAD with an outflow graft and modular driveline cable, a pump controller and a power 
source (i.e. portable Batteries, Power Module, or Mobile Power Unit). 
 
 Indication for Use 
The HM3 is market released in all geographies participating in this study, therefore refer to the local IFU 
for the local indication. In the US, the HM3 LVAS is indicated for providing mechanical circulatory support 
in patients with advanced refractory left ventricular heart failure (e.g. pending cardiac transplantation or 
myocardial recovery, or for permanent support). In Europe, the HM3 LVAS is intended to provide long 
term hemodynamic support in patients with advanced, refractory left ventricular heart failure. It is 
intended either for temporary support, such as a bridge to cardiac transplantation (BTT), or as permanent 


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destination therapy (DT) and it is intended for use inside or outside the hospital. In Canada, The HM3 
LVAS is indicated for providing mechanical circulatory support in patients with advanced refractory left 
ventricular heart failure (e.g., pending cardiac transplantation or myocardial recovery, or for permanent 
support). 
 Description of the Device(s) Under Investigation 
The HM3 LVAS consists of a centrifugal LVAD with an outflow graft and modular driveline cable, a pump 
controller and a power source (i.e. portable Batteries, Power Module, or Mobile Power Unit). The HM3 
LVAD is comprised of an Inflow Cannula, a Pump Cover, a Lower Housing, a Screw Ring to attach the 
Pump Cover to the Lower Housing, a Motor, the Outflow Graft, the Outflow Graft Clip (if required), and a 
Pump Cable.  
 
The HM3 LVAD has a displacement volume of 80 milliliters and weighs 200 grams. All blood contacting 
surfaces are composed of titanium (LVAD body and centrifugal rotor) or gelatin-impregnated woven 
polyester (outflow graft). The HM3 LVAD is designed to reduce adverse events associated with LVAD 
thrombosis. Primary design features include full magnetic levitation and large flow gaps, which minimize 
the shear stress imparted onto the blood elements. 
 
The HM3 Controller is an extracorporeal interface device that receives power from the Power Module, 
Mobile Power Unit, or portable Batteries, and appropriately delivers that power to the HM3 LVAD. It is the 
primary user interface and has several important functions including: 
• 
operating condition display, 
• 
source of audible and visible alarms, 
• 
communication link for transferring event/period log and alarm information, and 
• 
battery backup in the case of full power disconnection. 
 
The HM3 LVAD and Controller are sterilized using 100% ethylene oxide. Please refer to the local IFU for 
additional information regarding the device used in this clinical investigation. 
 Device Accountability  
All devices used in this study will be commercial stock at each investigative site. The HM3 is commercially 
available and approved for the patient population enrolled in this study; therefore, study specific device 
accountability is not required. The standard commercial practices for device tracking, return and reporting 
to the Sponsor’s Product Performance Group should be followed in accordance with local practices.  
2.4 
Treatment Arm Medication 
 Project Management
ALMAC Clinical Services will manufacture the blinded treatment arm medication at their facility at 25 Fretz 
Road, Souderton, PA 18964. The medication shall consist of 100mg aspirin blinded against a matching 
placebo. Distribution logistics, site inventory management, patient randomization and treatment arm 
medication bottle requisition will be coordinated by ALMAC Clinical Services’ WebEZ system. Treatment 
arm medication will be stored in Souderton PA and may be stored in international depot sites administered 
by ALMAC including Craigavon, Northern Ireland and Singapore, prior to dispatch to sites. Medication 
accountability will be performed at their facility in Durham, NC or may be performed at depot sites in 
Craigavon, Northern Ireland or Singapore. Treatment arm medication accountability will include pill counts 


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of any bottle requisitioned to a patient and opened, as well as reconciliation of unused bottles that were 
not requisitioned to a patient or otherwise remain sealed, prior to destruction. All bottles should be returned 
to ALMAC or reported as lost within the Abbott electronic data capture system (EDC).  
 
ALMAC Clinical Services is a part of ALMAC Group Limited headquartered at ALMAC House, 20 Seagoe 
Industrial Estate, Craigavon, BT63 5QD, Northern Ireland (Registration Number: NI 41905). 
 
ALMAC Clinical Services responsibilities will be, but not limited to, the following: 
• 
Treatment arm medication manufacture (blinded aspirin with placebo-to-match), including 
packaging and labelling (due to country-specific requirements treatment arm medication bottle 
labeling may vary) 
• 
Patient randomization via the ALMAC WebEZ system 
• 
Supplying treatment arm medication to sites including maintaining adequate site supply 
• 
Providing support dispensing to study subjects via the ALMAC WebEZ system  
• 
Treatment arm medication accountability, including both used and unused drug bottle returns 
 Treatment Arm Blinding 
This study shall use 100mg aspirin, blinded against a placebo-to-match. Sites should reach out to the 
sponsor immediately regarding unblinding questions.  
 Treatment Arm Bottle Dispensing 
Initial dispensing of the treatment arm bottle will occur upon randomization. Subjects will begin taking the 
treatment arm medication within 24 hours of randomization. Subjects will be resupplied 1 bottle at Month 
3, Month 6, and Month 9 follow-up visits and 2 bottles at month 12 and every 6 months thereafter until 
study closure. Dispensing will be controlled at the sites with the use of ALMAC Clinical Services’ WebEZ 
system. At each dispensing time point, the designated site personnel will log on to the WebEZ system, 
enter information required for randomization or resupply, and requisition a bottle to dispense to the subject 
from the on-site stock.  
 
Each bottle will be tracked by individual bottle number. The WebEZ system will provide sites with the bottle 
number to be dispensed to a given subject. Bottle details should be tracked per patient by sites. Site supply 
and resupply shipments will be automatically controlled by ALMAC Clinical Services.  
 
If a subject reports a lost or empty bottle of treatment arm medication or is unable to attend a resupply 
visit, the designated site personnel will log onto the WebEZ system to requisition a replacement bottle from 
the onsite supply. The replacement bottle may be shipped overnight to the subject, or the subject may 
choose to retrieve the replacement bottle from the site in person.  
 
Subjects should always be sufficiently supplied with treatment arm medication until their next resupply visit. 
Each bottle will contain 120 capsules of the treatment arm medication, which is a sufficient supply for the 
period leading up to the subject’s next visit, including the acceptable visit windows. Sites should carefully 
schedule follow up visits to ensure subjects are always sufficiently supplied.  
 Antithrombotic Therapy 
Antithrombotic therapy throughout the study should consist of a vitamin K antagonist (e.g. warfarin, 
fluindione, phenprocoumon, etc.) and the treatment arm medication. No additional anti-platelet agents 


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will be added while patients are on the treatment arm medication. The treatment arm medication will be 
taken once daily by mouth. Vitamin K antagonist therapy will be per standard of care (SOC) with a target 
INR of 2.0-3.0. The use of aspirin and a vitamin K antagonist is normal clinical practice at many centers 
and is part of the HM3 IFU.  
 Treatment Arm Medication Accountability 
To ensure treatment arm medication accountability, all bottles including (if applicable) all unused doses 
will be returned to ALMAC Clinical Services by the site. Subjects will be instructed to return the bottle and 
any unused doses of the treatment arm medication at each resupply visit.  
 
The bottles and unused doses will be shipped (at the Sponsor’s expense) per country- or region-specific 
Treatment Arm Medication Accountability Return Instructions. 
 
In the event that a site has several bottles or unused portions to return to ALMAC Clinical Services, return 
shipments may be combined into a batch shipment. Empty research bottles and unused doses should not 
be stored on site and should be shipped to ALMAC Clinical Services within 14 days of receipt from the 
subject. Treatment Arm Medication Accountability Return Instructions will be provided during training. 
 Aspirin Response Testing 
US-based patients receiving the treatment arm medication will have their response to aspirin assessed by 
serum thromboxane B2 testing. Testing will be performed by a core lab (Corgenix, Broomfield, Colorado). 
To retain the study blind, sites will not receive the results of the test. Samples will be collected and 
processed by the sites at baseline, 3, 6, and 12 months post-implant. Samples will be stored frozen at the 
sites until they are shipped (within 15 days of collection; overnight shipment Monday-Thursday with 
sufficient dry ice to retain frozen state) to Corgenix at: 
 
Corgenix Clinical Laboratory 
ATTN: General Supervisor 
11575 Main Street  
Suite 400 
Broomfield CO 80020  
 
Additional sample processing, storage, and shipment details will be provided in the ARIES HM3 Aspirin 
Response Instructions.  
 
NOTE: Additional antiplatelet testing or platelet function testing, beyond the core lab test, should not be 
performed while patients are on the treatment arm medication, as it may result in un-blinding of the subject 
or the investigator. 
3.0 
CLINICAL INVESTIGATION DESIGN 
This is a prospective, randomized, double-blinded, placebo-controlled clinical investigation of advanced 
heart failure patients treated with the HM3 with two different antithrombotic regimens: vitamin K 
antagonist with aspirin versus vitamin K antagonist with placebo. Subjects will be randomized in a 1:1 
ratio.  
 


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The clinical investigation has been designed to involve as little pain, discomfort, fear, and any other 
foreseeable risk as possible for subjects. Refer to the Risks Analysis section of the clinical investigation 
plan for details.  
 
The clinical investigation will be conducted at up to 50 centers worldwide. Greater than 50% of the 
patients enrolled in this study will be from centers based in the United States. The primary and 
secondary endpoints will be evaluated according to the statistical section (Section 8 and in the study 
statistical analysis plan; SAP). Outcomes for this study include death, transplant, withdrawal or pump 
exchange. All subjects, site, Clinical Events Committee (CEC), and sponsor personnel will remain 
blinded to the randomization scheme until the last ongoing study subject completes follow-up 
(specifically, experiences an outcome or has final study visit) and all data have been collected and 
adjudicated. Exceptions will be justified in the study blinding plan (e.g. DSMB). After a patient reaches 
12-months of follow up, they will continue to be followed every 6-months, as long as they remain on the 
treatment arm medication, until the last ongoing patient reaches 12-months of follow up. Beginning at the 
12-month follow-up visit, patients should be requisitioned two bottles of the treatment arm medication to 
cover the 6 months until the next follow up visit.  
3.1 
Clinical Investigation Procedures and Follow-up Schedule 
The study flow chart (Figure 2) and the follow-up schedule of this clinical investigation are described 
below. 


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Figure 2 – Clinical Investigation Flow Chart 


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3.2 
Measures Taken to Avoid and Minimize Bias 
This study is designed to minimize bias by blinding all subjects, site personnel, sponsor personnel, and 
the CEC to the randomly assigned treatment regimen. Furthermore, screening logs will be captured 
including details on patients who are excluded from the study only because of investigator mandated 
antiplatelet therapy (presence or absence) prior to or after consent to understand any effect of selection 
bias on the generalizability of the study. 
3.3 
Suspension or Early Termination of the Clinical Investigation 
While no formal statistical rule for early termination of the clinical investigation for insufficient 
effectiveness of the device under investigation is defined by the Sponsor or Steering Committee, the 
Sponsor reserves the right to discontinue the clinical investigation at any stage or reduce the follow-up 
period with suitable written notice to the investigator. Possible reason(s) may include, but are not limited 
to: 
• 
Unanticipated adverse device effect (e.g., UADE) occurs and it presents an unreasonable risk to 
the participating subjects 
• 
An oversight committee (e.g., Steering Committee, DSMB) makes a recommendation to stop or 
terminate the clinical investigation (such as in the event of higher frequency of anticipated 
adverse device effects) 
o The Data Safety Monitoring Board will create independent rules for study oversight 
including prespecified rules for recommending cessation of the study, which will be 
captured in the DSMB charter. In the event these rules are met, the sponsor will meet with 
the Steering Committee. The Sponsor will notify sites and, if agreed with the Steering 
Committee, enrollment in the study will be paused.  
• 
Further study progress is cancelled. 
 
Should the clinical investigation be discontinued by the Sponsor, subjects will be followed per routine 
hospital practice with device-related AEs reported to the Sponsor as per vigilance/commercial reporting 
requirements. The investigator shall return all clinical investigation materials (including both partially used 
and unused treatment arm medication bottles) to ALMAC or the Sponsor, as appropriate, and provide a 
written statement to the IRB/EC (if applicable). All applicable clinical investigation documents shall be 
subject to the same retention policy as detailed in Section 11.5 of the CIP.  
 
A Principal Investigator, IRB/EC or regulatory authority may suspend or prematurely terminate 
participation in the clinical investigation at the investigational site(s) for which they are responsible. The 
investigators will follow the requirements specified in the Clinical Trial Agreement.  
 
If the Sponsor suspends or prematurely terminates the clinical investigation at an individual site in the 
interest of safety, the Sponsor will inform all other Principal Investigators. 
 
If suspension or premature termination occurs, the Sponsor will remain responsible for providing 
resources to fulfill the obligations from the CIP and existing agreements for following the subjects 
enrolled in the clinical investigation, and the Principal Investigator or authorized designee will promptly 
inform the enrolled subjects at his/her site, and return patients to their standard medical treatment. 


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4.0 
ENDPOINTS 
4.1 
Primary Endpoint and Rationale 
The primary endpoint for this study will be met if the placebo arm is non-inferior to the aspirin arm in the 
composite of survival free of any non-surgical1 major hemocompatibility related adverse event2 at 1-year 
post implant. 
 
1 - Non-surgical is defined as any event occurring > 14-days post implant. 
2 - Major Hemocompatibility Related Adverse Events include: 
• 
Stroke 
• 
Pump Thrombosis (suspected or confirmed) 
• 
Bleeding (including intracranial bleeds that do not meet the stroke definition) 
• 
Arterial Peripheral Thromboembolism. 
 
This study assesses the overall change in the overall incidence of major hemocompatibility related 
adverse events between the two groups. Additional secondary endpoints will also be evaluated to 
monitor effects on other safety and efficacy measures.  
 
This composite primary endpoint reflects the interrelatedness of hemocompatibility related adverse 
events, providing an endpoint that will result in a clear answer to the study’s primary question of whether 
or not anti-platelets are required to maintain the safety and efficacy profile of the HM3. Because the post-
implant clinical course can be widely variable due to clinical responses to adverse events, this composite 
endpoint focuses on the first major hemocompatibility related adverse event to ensure the effect of the 
treatment arm is reflected in the primary endpoint measure. Non-composite endpoints or endpoints that 
do not focus on the first event have the possibility of being rendered futile or distorted by treatment 
responses to prior adverse events. Refer to section 8 of this CIP and the SAP for details. 
4.2 
Secondary Endpoint 
As secondary endpoints: 
• 
Non-surgical Major Hemorrhagic Events 
• 
Non-surgical Major Thrombotic Events 
• 
Survival 
• 
Stroke Rates,  
• 
Pump Thrombosis Rates 
• 
Bleeding Rates, including: 
o Non-surgical Bleeding 
o Moderate Bleeding 
o Severe Bleeding 
o Fatal Bleeding 
o GI Bleeding 
 
will be compared between the two arms of the study as detailed in section 8 of this CIP and the SAP. 


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4.3 
Descriptive Endpoints 
This study will also assess changes in the Hemocompatibility Score, Rehospitalization, and Economic 
Cost Implications as a result of removal of antiplatelet therapy from the antithrombotic regimen. Refer to 
section 8 of this CIP and the SAP for details. 
5.0 
SUBJECT SELECTION AND WITHDRAWAL  
5.1 
Subject Population 
This clinical investigation will enroll male and female subjects from the advanced heart failure population 
who, as part of their standard course of treatment, will receive a HM3 LVAD. Subjects are considered 
enrolled when they provide written informed consent. Subjects must meet all applicable eligibility criteria 
and provide written informed consent prior to the conduct of any investigation-specific procedures not 
considered standard of care. Furthermore, patients must meet all randomization eligibility requirements 
at randomization. Only randomized subjects will continue to be followed in this study. Subjects not 
meeting randomization eligibility requirements will be considered screen failures and withdrawn from the 
study. Reason(s) for not meeting randomization eligibility requirements will be captured in the study 
EDC. Randomized subjects ongoing without a surgical adverse event, defined as ≤14 days post-implant, 
requiring investigator mandated antiplatelet therapy will form the analysis population for study endpoints. 
Details are available in section 8 of this CIP and the SAP. 
5.2 
Subject Screening and Informed Consent 
 Subject Screening 
Patients receiving an LVAD at study sites should be considered for enrollment. All patients evaluated for 
inclusion in the clinical study, including those who provide informed consent and are enrolled, will be 
recorded on the site screening log. Rationale for exclusion from the trial will be recorded. Specifically, 
reasons may include refusal to consent, did not meet eligibility criteria or other specified reasons. To 
monitor for selection bias in enrollment, any patient excluded exclusively due to an investigator 
mandated antiplatelet therapy (either mandated antiplatelet presence or mandated absence of 
antiplatelets) will require specific clinical reasons recorded on the screening log.  
 
Potential subjects presenting at the clinical sites will be fully informed about the clinical investigation, 
following the established informed consent process (described in Section 5.2.2). Once informed consent 
is obtained, subjects are considered enrolled. Thereafter, all subjects will have required baseline data 
beyond site standard of care captured and US-based patients will have blood drawn for baseline aspirin 
responsiveness testing (per section 2.4.6). Subjects who do not meet enrollment or randomization 
criteria will be considered screen failures. 
 Informed Consent 
The Investigator or his/her authorized designee will conduct the informed consent process, as required 
by applicable regulations and the center’s IRB/EC. This process will include a verbal discussion with the 
subject on all aspects of the clinical investigation that are relevant to the subject’s decision to participate, 
such as details of clinical investigation procedures, anticipated benefits, and potential risks of clinical 
investigation participation. Subjects must be informed about their right to withdraw from the clinical 


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investigation at any time and for any reason without sanction, penalty or loss of benefits to which the 
subject is otherwise entitled. Withdrawal from the clinical investigation will not jeopardize their future 
medical care or relationship with the investigator.  
 
During the discussion, the Principal Investigator or his/her authorized designee will avoid any improper 
influence on the subject and will respect the subject’s legal rights. Financial incentives will not be given to 
the subject. The subject shall be provided with the informed consent form written in a language that is 
understandable to the subject and has been approved by the center’s IRB/EC. The subject shall have 
adequate time to review, ask questions, and consider participation. The Principal Investigator or his/her 
authorized designee will make efforts to ensure that the subject understands the information provided. If 
the subject agrees to participate, the informed consent form must be signed and dated by the subject 
and thereafter by the person obtaining the consent prior to any clinical investigation-specific procedures 
beyond SOC. The signed original will be filed in the subject’s hospital or research charts, and a copy will 
be provided to the subject. 
 
Failure to obtain informed consent from a subject prior to clinical investigation enrollment should be 
reported to Sponsor within 5 working days and to the reviewing center’s IRB/EC according to the IRB’s/ 
EC’s reporting requirements. 
 
If, during the clinical investigation, new information becomes available that can significantly affect a 
subject's future health and medical care, the Principal Investigator or his/her authorized designee will 
provide this information to the subject. If relevant, the subject will be asked to confirm their continuing 
informed consent in writing. 
 
In addition, an authorization for use and disclosure of the subject’s protected health information, in 
accordance with the Health Insurance Portability and Accountability Act (HIPAA) or local equivalent, as 
applicable, must be obtained from the subject. This may be incorporated into the main ICF or captured 
as a standalone document.   
 
This study will not permit informed consent via legally authorized representatives. Therefore, 
incapacitated individuals, including the mentally handicapped or individuals without legal authority or 
individuals under the age of 18 or local age of legal consent, are excluded from the study population. 
Furthermore, individuals unable to read or write are excluded from the study population. 
5.3 
Eligibility Criteria 
Assessment for general eligibility criteria is based on the medical records of the site and an interview with 
a candidate patient. If some of the clinical and laboratory tests are not included in site standard tests, 
they must be done but after written informed consent is obtained. Patients must meet ALL of the 
inclusion criteria to be considered for the clinical investigation. If ANY of the exclusion criteria are met, 
the patient is excluded from the clinical investigation and cannot be enrolled. If the subject is found after 
the time of informed consent but prior to randomization to no longer meet any of the inclusion criteria, or 
to meet any of the exclusion criteria (randomization eligibility), the subject will not be randomized and will 
be considered a screen failure and withdrawn from the study. 


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 Inclusion Criteria 
1. Subject will receive the HeartMate 3 per standard of care (SOC) in accordance with the approved 
indications for use in the country of implant. 
2. Subject will receive the HeartMate 3 as their first durable VAD.  
3. Subject must provide written informed consent prior to any clinical investigation related 
procedure. 
4. In patients of child bearing capability, subject will not be currently pregnant or breastfeeding and 
on appropriate contraception.  
 Exclusion Criteria 
1. Post-implant additional temporary or permanent mechanical circulatory support (MCS).  
2. Post-implant Investigator mandated antiplatelet therapy for other conditions (including mandated 
presence or absence of antiplatelet agent). 
3. Patients who are nil per os (NPO) post-implant through day 7. 
4. Subjects with a known allergy to acetylsalicylic acid (aspirin). 
5. Participation in any other clinical investigation(s) involving an MCS device, or interventional 
investigation(s) likely to confound study results or affect study outcome. 
6. Presence of other anatomic or comorbid conditions, or other medical, social, or psychological 
conditions that, in the investigator’s opinion, could limit the subject’s ability to participate in the 
clinical investigation or to comply with follow-up requirements, or impact the scientific soundness 
of the clinical investigation results. 
5.4 
Subject Enrollment 
Once informed consent is obtained, subjects are considered enrolled. Subject data entry into the EDC 
will begin following enrollment into the clinical investigation. Subject data will be collected following 
enrollment to the clinical investigation until the subject is withdrawn, experiences an outcome (transplant, 
explant, exchange, or death), or completes study follow-up. 
 
Subjects who provide informed consent and are subsequently found to not meet inclusion/exclusion 
criteria prior to randomization or otherwise do not proceed to randomization will be withdrawn in 
accordance with section 5.5 of this CIP. Subjects who experience a surgical adverse event prior to day 
14 that requires investigator mandated antiplatelet therapy (either presence or absence) will be 
withdrawn and not included in the analysis population. Subjects who expire prior to day 14 will not be 
included in the analysis population. All patients considered for this study, including enrolled subjects not 
included in the analysis population, will be reported in the study consort diagram.   
 Enrollment of Medicare Beneficiaries 
This clinical investigation will enroll both Medicare beneficiaries and private payors in the US. Because 
this study enrolls Medicare beneficiaries, it conforms to all standards of Medicare coverage 
requirements. The Risks and Benefits in section 15 of this CIP describe how all enrolled subjects, 
including Medicare beneficiaries, may be affected by the hypothesis under investigation. The 
demographics representative of LVAD therapy reflect primarily a CMS population. Common 
complications associated with LVADs are frequently associated with hemocompatibility-related adverse 
events such as pump thrombosis, stroke and bleeding events. Improvements in contemporary LVAD 
technology with the HeartMate 3 LVAD have shown significant improvement in reduction of pump 


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thrombosis, stroke and bleeding, but bleeding events persist at a high incidence. If bleeding events could 
be reduced with the withdrawal of antiplatelet therapy from the antithrombotic regiment with HM3, this 
could improve clinical outcomes for Medicare beneficiaries and have added relevancy to their treatment 
plan. For this purpose, it is important that Medicare beneficiaries are studied in this trial so that relevant 
outcomes may be translated more broadly. 
 
To further characterize the portion of the subjects enrolled in the clinical investigation that display 
characteristics consistent with the Medicare population based on age, the clinical investigation results will 
be analyzed by age (< 65 years and ≥ 65 years) to ensure that the outcomes are similar between the 
Medicare and non-Medicare populations. Additional subgroup analyses are detailed in section 8.5. 
 Historically Under-Represented Demographic Subgroups 
The Sponsor intends to implement the FDA's guidance on sex-specific data in medical device clinical 
investigations to ensure adequate representation of women and other traditionally under-represented 
demographic subgroups in this clinical investigation. As noted in the guidance, some barriers to 
participation of women and ethnic minorities in clinical investigations have traditionally been: 
• Lack of understanding about main obstacles to participation of such subgroups in clinical 
research  
• Inclusion/exclusion criteria potentially not needed to define the clinical investigation population 
may unintentionally exclude specific subgroups  
• Under diagnosis of disease etiologies and pathophysiology leading to under referral of 
demographic subgroups 
• Sex differences in disease etiology, which predispose one sex to LVAD therapy 
• Avoidance of specific subgroups by investigators and Sponsors due to the perception that it takes 
more time and resources to recruit them  
• Family responsibilities limiting women's ability to commit time for follow-up requirements 
 
The Sponsor will take the following steps to ensure adequate representation of women and racial or 
ethnic minorities in this clinical investigation:  
• 
All patients receiving an LVAD at enrolling sites will be considered for this study and this data will 
be reviewed regularly
• 
The Sponsor will provide training to investigational site personnel to ensure adequate 
representation of these demographic subgroups  
• 
As appropriate and necessary, the Sponsor will retrain sites on the importance of recruiting and 
retaining subjects in the clinical investigation if trends in withdrawal or selection bias are noted 
• 
The Sponsor will approach sites without bias or consideration for specific demographic subgroups  
• 
The Sponsor will have informed consent materials in alternative languages and will work with 
sites and IRBs/ECs on recruitment materials  


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5.5 
Subject Withdrawal 
If a subject does not meet all inclusion criteria, or meets at least one exclusion criteria after the subject is 
enrolled (consented), but prior to randomization, the subject will be considered a screen failure and 
withdrawn and will not be included in the analysis populations.  
 
Those enrolled (consented) subjects that meet all inclusion criteria and no exclusion criteria post implant 
will be randomized within 2-7 days post-implant (the day of implant is day 0). However, if these subjects 
do not meet the randomization eligibility criteria, are not randomized, never start the treatment arm 
regimen, experience a surgical event (≤ 14 days post implant) that requires investigator mandated anti-
platelet therapy or experience an outcome ≤ 14 days post implant then they will be withdrawn.  
 
Each randomized subject shall remain in the clinical investigation until completion of the required follow-
up period; however, a subject’s participation in any clinical investigation is voluntary and the subject has 
the right to withdraw at any time without penalty or loss of benefit. Conceivable reasons for 
discontinuation may include, but not be limited to, the following: 
• 
Subject outcome including death, transplant, or device explant or exchange 
• 
Physician or subject voluntary withdrawal 
• 
Subject lost-to follow-up as described below.  
 
The Sponsor must be notified of the reason(s) for subject discontinuation. The site will provide this 
information to the Sponsor. Investigators must also report this to their respective IRB/EC as defined by 
their institution’s procedure(s).  
 
No additional follow–up will be required or data recorded from subjects once withdrawn from the clinical 
investigation, except for the reason and status at the time of withdrawal (deceased/alive). Subjects 
withdrawn from the study will cease treatment arm medication and be transitioned to an anticoagulation 
regiment in accordance with site standard of care by the investigator.  
 
In case of subject withdrawal of consent, the site should make attempts to schedule the subject for a final 
clinical investigation visit. At this final follow-up visit, the following will be recorded, with the subject’s 
permission: 
• 
Subject status (deceased/alive) 
• 
Any adverse event details prior to withdrawal of consent 
 
Lost-to-Follow-up 
 
If all attempts at contacting the subject have been exhausted, then the subject is considered lost-to-
follow-up Site personnel shall make all reasonable efforts to locate and communicate with the subject 
(and document these efforts in the source documents), including the following, at each contact time 
point: 
• 
A minimum of two telephone calls on different days over the specified follow-up windows to 
contact the subject should be recorded in the source documentation, including date, time and 
initials of site personnel trying to make contact. 
• 
If these attempts are unsuccessful, a letter (certified, if applicable) should be sent to the subject. 


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• 
If a subject misses one or more non-consecutive follow-up contact time points, it will be 
considered a missed visit. The subject may then return for subsequent visits.  
 
Note: Telephone contact with General Practitioner, non-clinical investigation cardiologist or relative 
without the presence of the subject or indirect documentation obtained via discharge letters will not be 
considered as subject contact. 
 
Sites should attempt to retrieve unused portions of the treatment arm medication in subjects lost-to-
follow, which should be returned to ALMAC Clinical Services per section 2.4.5. 
 Incidental Use of Aspirin Containing Products 
At baseline and at each scheduled visit, subjects should be provided with the Sponsor provided list of 
aspirin containing products. At each visit post-implant, subjects should be asked if they have taken or 
been prescribed (by non-study physicians) any of the medications containing aspirin or aspirin-like 
compounds and, if so for what duration. Responses will be captured in the EDC. If a subject reports or 
other evidence of incidental aspirin use is obtained (i.e. a prescription which the patient confirms from a 
non-investigator healthcare provider) lasting for a duration of > 7 days, the subject will be withdrawn from 
the study.  
5.6 
Transition to Open Label 
During a subject’s clinical course, post-randomization events may result in the investigator mandating 
antiplatelet therapy. The mandate may consist of the presence of an antiplatelet or the absence of all 
antiplatelets from the patient’s antithrombotic regimen in response to clinical events. These subjects 
should remain in the study for the full 12-month study follow up whenever possible. Investigators may 
cease administration of the treatment arm medication for up to 72 hours without transitioning the subject 
to open label. In these instances, the treatment arm medication is no-longer administered, and 
investigator initiates their mandated therapy. If the cessation extends beyond 72 hours, these subjects 
are considered to have transitioned to open label and may not resume the treatment arm medication 
after transition.  
 
Transition to open label does not constitute unblinding. Investigators will not know which randomized 
treatment arm patients who transition to open label were initially allocated. Study blinding will continue in 
patients transitioned to open label.
 
Clinical events which resulted in the transition to open label will be documented in the EDC. Subjects 
who transition to open label after 12 months will be considered to have completed the study required 
follow up at12 months post implant. Subjects who transition to open label after 12-months of study follow 
up will be considered to have completed study follow up at that time except if a subject has experienced 
a stroke or potential stroke neurologic adverse event prior to transitioning to open label, then they will be 
followed for an additional 60-days post event for MRS score evaluation. In this case, the subject is 
considered to have reached end of study follow up upon completion of the MRS evaluation. 


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5.7 
Number of Subjects  
This study will enroll enough subjects to randomize 628 subjects in the clinical investigation. No site may 
randomize more than 15% of the total number of randomized subjects without Sponsor authorization. 
5.8 
Total Expected Duration of the Clinical Investigation 
The expected duration of each subject’s participation is at least 12 months and up to 36 months post-
implant. Scheduled visits and data collection for this clinical investigation will occur at Baseline, Implant, 
Randomization, Week 1 ± 3 days, Discharge, Month 1 ± 7 days, Month 3 ± 30, Month 6 ± 30 days, Month 
9 ± 30 days, Month 12 ± 30 days and, in patients still on the treatment arm medication, follow up will 
continue every 6 months ± 60 days until the final ongoing patient completes their month 12 follow up 
visit. Subjects not on the treatment arm medication will be exited from the trial at the conclusion of their 
month 12 follow-up visit. The expected duration of enrollment is 24 months. Therefore, the total duration 
of the clinical investigation is expected to be 36 months. 
6.0 
TREATMENT AND EVALUATION OF ENDPOINTS 
6.1 
Avoidance of Additional Antiplatelet Medications 
Subjects on the treatment arm medication will not be prescribed or administered additional antiplatelet 
medications. 
6.2 
Avoidance of Platelet Function Testing 
Antiplatelet testing or platelet function testing should not be performed while patients are on the 
treatment arm medication, except for Aspirin Response Testing per Section 2.4.6. The results of protocol 
specified Aspirin Response Testing will not be provided the physician or patient through the follow up 
period. Performing additional antiplatelet testing or platelet function testing may result in un-blinding of 
the subject or the investigator. Un-blinding of a subject or investigator will be considered a protocol 
deviation. Sites should address any questions related to potential unblinding to the Sponsor.  
6.3 
Study Activities and Procedures 
The assessments in table 2 will occur throughout the study. 
Table 2 – Schedule of Assessments 
 Assessment 
Baseline 
Implant 
Randomization 
Discharge 
Week 1 
(± 3 days) 
Month 11 
(± 7 days) 
Month 31 
(± 30 days) 
Month 61 
(± 30 days) 
Month 91 
(± 30 Days) 
Month 121 
(± 30 days) 
Every 6 months ± 
60 days thereafter 
As Occurs/ 
Unscheduled 
Inclusion/ Exclusion 
X 
 
X 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 


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 Assessment 
Baseline 
Implant 
Randomization 
Discharge 
Week 1 
(± 3 days) 
Month 11 
(± 7 days) 
Month 31 
(± 30 days) 
Month 61 
(± 30 days) 
Month 91 
(± 30 Days) 
Month 121 
(± 30 days) 
Every 6 months ± 
60 days thereafter 
As Occurs/ 
Unscheduled 
General and Cardiac Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Assessment 
 X4 
 
 
 
 
 
 
 
 
 
 
 
Right Heart Catheterization 
 X2 
 
 
 
 
 
 
 
 
 
 
 X4 
Modified Rankin Score (MRS) 
X 
 
 
 
 
 
 
 
 
 
 
X 
Incidental Use of Aspirin Containing Products 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Laboratory Assessments 
 X3 
 
 
 
X 
X 
X 
X 
X 
X 
 
 X4 
Anticoagulation/Antiplatelet Medications Log 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 X9 
X 
Echocardiogram 
 X2 
 
 
 
 X4 
 X4 
 X4 
 X4 
 X4 
 X4 
 
 X5 
Other Medications 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
Sample for Core Lab (ASA response, US only) 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
QOL and Functional Capacity 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
Implant Data 
 
X 
 
 
 
 
 
 
 
 
 
 X6 
Enrollment 
 X7 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Pump Parameters 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 X5 
Bottle Requisition via WebEZ 
 
 
X 
 
 
 
X 
X 
X 
X 
X8 
X 
Bottle Dispensing/Return Log 
 
 
X 
 
 
 
X 
X 
X 
X 
X8 
X 
Return Used Bottle to ALMAC for Accountability 
 
 
 
 
 
 
X 
X 
X 
X 
X8 
X 
Initial Discharge Data 
 
 
 
X 
 
 
 
 
 
 
 
 
Cardiac Arrhythmias Assessment (e.g. EGM, EKG) X 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Subject Status 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X8 
 
INR & LDH Log 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Death 
 
 
 
 
 
 
 
 
 
 
 
X 
Withdrawal (early termination) 
 
 
 
 
 
 
 
 
 
 
 
X 
Transition to Open Label 
 
 
 
 
 
 
 
 
 
 
 
X 
Hospitalizations 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
X 
Device Deficiencies 
 
 
 
 
 
 
 
 
 
 
 
X 
Operative Procedures (excluding primary implant) 
 
 
 
 
 
 
 
 
 
 
 
X 
1 For follow-up visit scheduling, one month = 30 days. 
2 Most recent results within 30 days prior to implant, if collected as SOC. 
3 Most recent results obtained within 30 days prior to implant will be permitted as baseline data.  
4 If performed as SOC. 
5 At time of suspected thrombotic adverse event or pump exchange, if performed as SOC. 
6 Pump exchange data collection includes all required implant data for HM3 to HM3 exchanges and all relevant data for 
HM3 to other LVAD exchanges. 
7 Subject is considered enrolled upon signing of the informed consent form. 
8 Subjects on the treatment arm medication will be followed every six months after the 12-month visit. Safety monitoring 
including adverse events, outcomes and device deficiencies and other associated “as occurs” procedures will be collected 
9 Only Treatment Arm Medication use will be logged after the completion of the 12 month visit.  
 
The clinical study will be conducted in accordance with the CIP. All parties participating in the 
implementation of the study will be qualified to perform their designated tasks by education, training, and 
experience. Applicable documentation will be maintained. 


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No study activities may begin until the site has received written Sponsor approval. Copies of written 
approval from the IRB and/or the relevant regulatory authorities, as well as all required regulatory 
documents must be received by the Sponsor before approval will be given. 
6.4 
Baseline 
The baseline assessments in table 3 will be performed.  
 
Table 3 – Baseline Data Collection 
Study Activity 
Data Collection 
Informed Consent 
Informed consent details 
Inclusion/Exclusion 
Subject’s eligibility details 
Demographics 
Age, height, gender, ethnicity (except where prohibited by regulation), race (except 
where prohibited by regulation), blood type, INTERMACS profile, and NYHA class 
General and Cardiac 
Medical History 
Etiology of HF, duration of HF, therapeutic intent (BTT/BTC/DT), arrhythmias, 
prosthetic valve(s), history of stroke, diabetes, smoking, history of bleeding (diverticular 
disease, diagnosed arteriovenous malformations (AVMs), GI ulcer(s), anemia and/or 
erythropoietin treatment), aortic stenosis, hypertension, history of MI, peripheral 
thromboembolism, coronary stents, CABG, substance abuse (drug/alcohol), 
drug/radiation toxicity, peripheral vascular disease, carotid artery disease, cardiac 
rhythm management device, intra-aortic balloon pump, other pre-implant circulatory 
support, CardioMEMS, and HIV status 
Modified Rankin Score 
Modified Rankin Score (MRS) 
Vital Signs 
Weight, blood pressure, and heart rate 
Anticoagulation/Antiplatelet 
Medications 
Vitamin K antagonist (e.g. warfarin, fluindione, phenprocoumon, etc.), clopidogrel, 
dipyridamole, other anticoagulation agents, other vitamin K antagonists, direct 
thrombin inhibitors, etc. (including treatment arm medication) 
All new medications started, or current medications stopped during the follow-up period 
must be recorded. All dose changes (including IV titrations as total daily dose) during 
the follow-up period must be recorded with the exclusion of vitamin K antagonist. Only 
the type, start and stop dates, and target INR will be collected for vitamin K antagonist. 
Other Medications 
ACE inhibitors, inotropes, ARBs, beta blockers, antiarrhythmics, statins, nitrates, 
allopurinol, aldosterone blockers, antibiotics, diuretics, insulin and antidiabetic 
medications, and other cardiovascular medications 


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Study Activity 
Data Collection 
Laboratory Assessments1 
Hemoglobin (Hgb), Hematocrit (Hct), White Blood Cell Count (WBC), Platelets (PLT), 
Creatinine (Cr), Estimated Glomerular Filtration Rate (eGFR), LDH and INR, liver 
function tests (AST, ALT, total bilirubin, albumin, pre-albumin), blood urea nitrogen 
(BUN) 
Collected only if SOC: Activated Partial Thromboplastin Time (aPTT), Partial 
Thromboplastin Time (PTT), Plasma free Hgb (PHgb), D-Dimers, P Selectin, and 
fibrinogen. For diabetic patients: HbA1c, brain natriuretic peptide (BNP) or N-terminal 
pro-BNP (NT-pro-BNP) and fasting glucose 
Coagulation Assessment2 
Collected only if prior testing performed or SOC: Tests may include but are not limited 
to HIT, protein C deficiency, protein S deficiency, antithrombin deficiency, plasminogen 
deficiency, lupus anticoagulant, factor V Leiden, prothrombin G20210A mutation, and 
primary antiphospholipid syndrome 
Right Heart Catheterization2 
Central venous pressure (CVP) or right atrial pressure (RAP), systolic, diastolic and 
mean pulmonary artery pressure (PAS, PAD, PAM), pulmonary capillary wedge 
pressure (PCWP), cardiac output (CO), and cardiac index (CI) 
Echocardiogram2 
Type of assessment, LVEF, LVEDD, LVESD, AI, MR, TR, PR, including severity and/or 
grade, and presence of LV or LA thrombus, and aortic valve opening ratio 
QOL and Functional 
Capacity 
EQ-5D-5L, 6-minute Walk Test (if subject is able, reason must be provided if not 
performed), NYHA Class, INTERMACS Profile 
1 Most recent results obtained within 30 days prior to implant will be permitted as baseline data. 
2 If collected per standard of care, most recent results within 30 days prior to implant. 
6.5 
Implant Procedure 
The data in table 4 will be collected for each subject’s HM3 implant procedure. 
Table 4 – Implant Procedure Data Collection 
Study Activity 
Data Collection 
HM3 System Information 
VAD serial number, reference number and date of implant of entire implanted 
system 
Implant Data 
Presence of intracardiac (LA or LV) thrombus, concurrent procedures, Factor VII 
administration, vitamin K administration, anti-fibrinolytic administration, pump 
position, transfusions (whole blood, packed red blood cells [PRBC], fresh frozen 
plasma [FFP], platelets, cryoprecipitate, Cell Saver), cardiopulmonary bypass 
(CPB) time, and total implant time, procedure initiation/completion time, 
additional post-implant MCS 
Pump Parameters 
Pump Speed, Pump Flow, Pulsatility Index, and Pump Power 


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6.6 
Randomization  
Only subjects who have provided informed consent, been enrolled, been implanted with the HM3 and 
subsequently met all inclusion and no exclusion criteria (randomization eligibility) will be randomized in 
the study. Randomization will be performed through ALMAC Clinical’s WebEZ system. Subjects will be 
randomized 1:1, by site, and in permuted blocks of 4. Prior to randomizing a patient in WebEZ, patients 
will have been initialized in the Sponsor’s EDC portal upon enrollment and obtained a subject ID number, 
which will also be used as the patient identifier in the WebEZ system. Subjects should begin taking the 
treatment arm medication within 24 hours of randomization. 
6.7 
Initial Discharge Data 
Upon discharge from the initial hospitalization for the implant procedure, the days hospitalized, including 
the days in the Intensive Care Unit, will be collected. Vital signs and subject status will be recorded along 
with anticoagulation/antiplatelet medications, LDH, and INR logs. 
6.8 
Scheduled Follow-up for All Subjects 
The required assessments (detailed in tables 2 and 6), follow-up schedule, and associated visit windows 
(table 5) are generally aligned with SOC LVAD patient follow up and MCS registry data collection. All 
follow-up visits are based on the initial implant date. The windows for each follow-up visit are as follows:  
Table 5 – Follow-up Visit Windows 
Randomization 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7+ 
2-7 days 
Week 1 
± 3 days 
Month 1 
± 7 days 
Month 3 
± 30 days 
Month 6 
± 30 days 
Month 9 
± 30 days 
Month 12 
± 30 days 
Every 6 Months 
± 60 days 
 
The follow-up visit must occur within the designated window. Follow-up assessments for a single visit do 
not have to occur on the same date, but must occur within the designated window, or will be considered 
a protocol deviation. The Sponsor understands that some lab results may be received several days after 
the visit has occurred, in these instances the date the lab occurred is considered as the date the blood 
draw occurred. All subjects should be asked, at each follow up visit after discharge, if they were seen at 
an outside facility. If so, medical records from any facility that has seen the patient must, with the 
subject’s consent, be requested and reviewed for potential adverse events.  
 
For subjects not on the treatment arm medication, the completion of the Month 12 visit will signify 
completion of the study, with the exception of some lab results that may be received after the visit has 
occurred, no other assessments or study related activities may be performed after the final visit has 
occurred, even if later assessments are performed within the acceptable window. Month 12 assessments 
(including required laboratory assessments blood draws) not collected by the date of the final visit will be 
considered protocol deviations.  
 
Subjects on the treatment arm medication will continue to be followed every 6 months after their month 
12 visit until the final ongoing patient completes their month 12 visit or experiences a study outcome. 
Upon close of enrollment, the sponsor will notify sites of the anticipated date of study conclusion which 
will be 12 months after the last patient enrolls. All required visit data must be collected by the final visit, 
as outlined above.  


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Table 6 – Scheduled Follow-Up Visit Data Collection through 12-months 
Study Activity 
Definition 
Subject Status 
Whether the subject is ongoing on HM3 LVAD support, if not, what was the 
outcome the patient experienced 
Vital Signs 
Weight, blood pressure and method of blood pressure measurement 
Pump Parameters 
Pump Speed, Pump Flow, Pulsatility Index, and Pump Power 
Cardiac Arrhythmias 
Atrial (fibrillation/flutter), ventricular (fibrillation/VT), and treatment  
Anticoagulation / Antiplatelet 
Medications 
All changes made during the follow-up period 
 
All new medications started, or current medications stopped during the follow-up 
period must be recorded. All dose changes (including IV titrations) during the 
follow-up period must be recorded with the exclusion of vitamin K antagonist. Only 
the type, start and stop dates, and target INR will be collected for vitamin K 
antagonist. 
Other Medications 
ACE inhibitors, inotropes, ARBs, beta blockers, antiarrhythmics, statins, nitrates, 
allopurinol, aldosterone blockers, antibiotics, diuretics, insulin and antidiabetic 
medications, and other cardiovascular medications 
Treatment Arm Bottle 
Dispensing/Return Log 
All bottles dispensed during the follow-up period (Month 3, 6 and 9 follow-up visits 
only), including replacement bottles that are dispensed outside of the follow-up 
schedule, bottle status (lost by patient, returned to ALMAC) and shipping 
information. 
All bottles and unused doses must be returned to ALMAC Clinical within 14 days of 
receipt from subject. 
Laboratory Assessments 
 
Hemoglobin (Hgb), Hematocrit (Hct), White Blood Cell Count (WBC), Platelets 
(PLT), Creatinine (Cr), Estimated Glomerular Filtration Rate (eGFR), liver function 
tests (AST, ALT, total bilirubin, albumin, pre-albumin), blood urea nitrogen (BUN) 
 
Log Data (all measurements during the follow up period will be collected with, at a 
minimum, 1 reading within each follow up window): LDH and INR. 
 
Collected only if SOC: Activated Partial Thromboplastin Time (aPTT), Partial 
Thromboplastin Time (PTT), Plasma free Hgb (PHgb), D-Dimers, P Selectin, and 
fibrinogen. For diabetic patients: HbA1c, brain natriuretic peptide (BNP) or N-
terminal pro-BNP (NT-pro-BNP) and fasting glucose 
Note: To protect blinding of the study, platelet function testing (including ASA 
resistance testing) will not be performed while patient is on the treatment arm 
medication, except as outlined in section 2.4.6.  
1 Echocardiogram  
LVEF, LVEDD, LVESD, AI, MR, TR, PR, including severity and/or grade, and 
presence of LV or LA thrombus, and aortic valve opening ratio 
QOL and Functional Capacity EQ-5D-5L, 6-minute Walk Test, NYHA Class, INTERMACS Profile 
1 If collected per SOC. 
 


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 Continued follow up beyond 12-months post implant 
Subjects on the treatment arm medication will be followed every six months after the 12-month follow up 
visit until the final ongoing subject reaches the 12 month visit or experiences a study outcome. Only 
treatment arm medication details, subject status (including death, withdrawal, or transplant) along with 
adverse events and device deficiencies will be collected along with additional supportive data should 
adverse events or device deficiencies occur. If a patient’s clinical course after 12 months of follow up 
requires transition to open-label, the patient will be considered to have reached the end of study follow 
up unless the transition to open label is due to a stroke, in which case the patient should be followed for 
an additional 60-days to capture the MRS score. The clinical reason for transition to open-label will be 
captured. Subjects transitioned to open label prior to 12 months of follow up should be followed to their 
12-month follow up.  
6.9 
Unscheduled Visits 
 Adverse Events 
For additional details regarding adverse events, refer to section 7. Data related to adverse events will be 
collected as they occur. Depending on the type of adverse event, relevant data will be collected.  
6.9.1.1 Neurologic Adverse Events 
Modified Rankin Scores (MRS) scores will be captured at: 
• 
Baseline, 
• 
The time of any stroke or potential stroke events, and  
• 
60-days after any stroke or potential stroke events to adjudicate the severity of the event.  
MRS will be determined by an independent assessor, defined as an independent, trained, and certified 
clinician. Event severity will be determined based on MRS, specifically MRS > 3 as disabling versus 
MRS ≤ 3 as nondisabling. Strokes will be characterized as ischemic or hemorrhagic in etiology with 
ischemic-hemorrhagic conversion considered an ischemic stroke. 
 Operative Procedures 
Data related to any cardiac or non-cardiac operative procedures, excluding the primary HM3 LVAD 
implant, occurring after enrollment will be collected. Operative procedures must be reported to the 
Sponsor through the EDC system within three days of awareness of the event or, at the latest, if the 
operation is unknown to the implanting site (i.e. occurring at another facility), during the next follow-up 
visit. For pump exchanges, additional implant data will be collected, including exchange status and pump 
exchange type.  
 Hospitalizations 
All hospitalizations, excluding the primary implant hospitalization, with associated reasons will be 
captured during the follow-up period for all subjects. While hospitalized, the follow-up visit assessments 
will continue to be performed according to the follow-up schedule. Hospitalizations must be reported to 
the Sponsor through the EDC system within three days of awareness or discovery of the event or, at the 
latest, if the hospitalization is unknown to the implanting site (i.e. occurring at another facility), during the 
next follow-up visit.  


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 Outcomes 
Subjects will be followed for at least 12 months and until the final ongoing subject reaches their 12 month 
visit or an outcome is reached, whichever occurs first. Outcomes include death, heart transplantation, 
device explant, and withdrawal from the study. Outcomes must be reported to the Sponsor through the 
EDC system immediately upon discovery of the event. Subjects should continue follow up through 12-
months whenever possible, even in the instance the subject has transitioned to open-label (e.g. due to 
pump thrombosis the investigator believes the patient should remain on open-label aspirin therapy).  
 
If a subject receives a pump exchange during the follow-up period, this event will be considered a device 
explant outcome and data will be collected on the pump exchange procedure but not after. If a subject 
has a device explanted for suspected or confirmed pump thrombosis, the pump will be returned to the 
Sponsor for analysis. Standard commercial processes will be used for pump return. 
6.10 Blinding 
This is a double-blind study, neither patient nor investigator will know the subject’s randomization 
throughout the study follow up. Additionally, sponsor personnel, and the CEC will not have access to 
patient or population blinding information. The blind of the study will only be broken once the study 
follow-up is completed, and all adverse events have been adjudicated. Questions related to unblinding 
should be directed to the Sponsor.
6.11 Patient Reported Outcome (PRO) Measure 
The Coordinator or designee will administer patient-reported outcome questionnaires. It is important the 
subject understands the meaning of all words and instructions in the questionnaires. The subject should 
be instructed to ask any questions about the questionnaires if further explanation is needed. Once the 
questionnaires are completed, the Coordinator or designee will review for completeness to verify that all 
questions have been answered according to the directions provided. 
 
The following PRO measures will be collected according to the requirements of the questionnaire and 
this CIP. 
• 
EQ-5D-5L - EuroQOL 
 
The EQ-5D-5L is a standardized measure of health status developed by the EuroQOL Group in order to 
provide a simple, generic measure of health for clinical and economic appraisal. Applicable to a wide 
range of health conditions and treatments, it provides a simple descriptive profile and a single index 
value for health status that can be used in the clinical and economic evaluation of healthcare as well as 
in population health surveys. The questionnaire will take approximately two minutes to complete.  
 
The EQ-5D-5L consists of two components – the EQ-5D-5L descriptive system and the EQ Visual 
Analogue scale (VAS). For the descriptive system, five dimensions are measured (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression). Each dimension has five levels: 1=none, 
2=slight, 3=moderate, 4=severe, and 5=extreme. The respondent indicates his or her health state by 
ticking in the box against the most appropriate statement in each of the five dimensions. The VAS is 
scored from 0 (worst health) to 100 (best health).  


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7.0 
ADVERSE EVENTS 
To comply with worldwide standards and guidelines on clinical investigation adverse event reporting, the 
Sponsor has adopted uniform and worldwide applicable standard definitions and reporting timelines to be 
used and adhered to by the investigators.  
7.1 
Definition 
 Adverse Event 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects. 
 Serious Adverse Event 
If the AE meets any of the criteria below, it is regarded as a serious adverse event (SAE).  
a) Led to a death, 
b) Led to a serious deterioration in health of the subject, that either resulted in  
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient hospitalization or prolongation of existing hospitalization, or 
4. medical or surgical intervention to prevent life threatening illness or injury or permanent 
impairment to a body structure or a body function. 
5. chronic disease  
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
Note: A planned hospitalization for pre-existing condition, or a procedure required by the CIP, without a 
serious deterioration in health, is not considered to be an SAE.
 Device Deficiency 
Device deficiency is defined as an inadequacy of a medical device related to its identity, quality, 
durability, reliability, safety or performance, such as malfunction, misuse or use error and inadequate 
labeling. This includes the failure of the device to meet its performance specifications or otherwise 
perform as intended. Note: Performance specifications include all claims made in the labeling of the 
device. 
7.2 
Device Relationship 
Determination of whether there is a reasonable possibility that the HM3 LVAS caused or contributed to 
an AE is to be determined by the Investigator and recorded on the appropriate CRF form. Determination 
should be based on assessment of temporal relationships, evidence of alternative etiology, 
medical/biologic plausibility, and patient condition (pre-existing condition). 


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 Unanticipated Serious Adverse Device Effect (USADE) 
Unanticipated Serious adverse device effect (USADE) refers to any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
7.3 
Adverse Event and Device Deficiency/Device Malfunction Reporting 
 Adverse Event Reporting 
Safety surveillance and reporting starts as soon as the patient is enrolled in the clinical investigation. 
Adverse events occurring prior to randomization which disqualify a patient for randomization, but occur 
after consent, will be captured in the EDC and, if necessary, should be reported to the sponsor through 
standard commercial practices. Safety surveillance and reporting will continue until the last follow-up visit 
has been performed, the subject is deceased, the subject concludes participation in the clinical 
investigation or the subject withdraws from the clinical investigation. All adverse event, deaths, and 
device deficiency data will be collected throughout the time period defined above and will be reported to 
the Sponsor on a CRF. Additional information about an adverse event should be updated within the 
appropriate CRF. An offline form will be made available to allow the investigator to report SAEs in the 
event the entry cannot be made in the EDC. This offline form can be submitted by email to 
AdverseEvent@abbott.com. This does not replace the EDC reporting system. All information must still 
be entered in the EDC system as soon as feasible. 
 
Unchanged, chronic, non-worsening or pre-existing conditions are not AEs and should not be reported.  
 
Abnormal laboratory values will not be considered AEs unless:  
• 
the investigator determined that the value is clinically significant,  
• 
the abnormal lab value required intervention, or  
• 
the abnormal lab value required subject withdrawal from the clinical investigation, or 
• 
the abnormal lab value meets the definition of an adverse event. 
 
All adverse events will be collected on each subject throughout the follow up period – until the subject 
reaches an outcome or withdraws or until the study ends. Causes of death will be captured for all 
subjects who expire during follow up. 
 
SAE Reporting 
The investigator should report all SAEs to the Sponsor as soon as possible but no later than outlined 
below.  
 


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Clinical Site 
Reporting timelines 
All Sites 
SAEs must be reported to the Sponsor no later than 3 calendar days from the 
day the site personnel became aware of the event or as per the investigative 
site’s local requirements, if the requirement is more stringent than those outlined. 
 
The date the site staff became aware the event met the criteria of an SAE must be recorded in the 
source document. The Investigator will further report the SAE to the local IRB/EC according to the 
institution’s IRB/EC reporting requirements. 
 Unanticipated Serious Adverse Device Effect Reporting to Sponsor and IRB/EC 
The Sponsor requires the Investigator to report any USADE to the Sponsor within 3 calendar days of the 
investigator’s knowledge of the event, unless local requirements are more stringent, and to the IRB/EC 
per IRB/EC requirements.  
 Device Deficiency Reporting 
All device deficiencies/malfunctions should be reported on the appropriate CRF form.  
 
The investigator should report all device deficiencies/malfunctions to the Sponsor as soon as possible 
but no later than outlined below.  
 
Clinical Sites 
Reporting timelines 
All Sites 
Device deficiencies/malfunctions must be reported to the Sponsor no later 
than 3 calendar days from the day the site personnel became aware of the 
event or as per the investigative site’s local requirements, if the requirement 
is more stringent than those outlined. 
 
Device deficiencies/malfunctions should be reported to the IRB/EC per the investigative site’s local 
requirements. 
 
An offline form will be made available to allow the investigator to report device deficiencies/malfunctions 
in the event that the entry cannot be made in the EDC system. This offline form can be submitted by 
email to AdverseEvent@abbott.com. This does not replace the EDC reporting system. All information 
must still be entered in the EDC system as soon as feasible.  
 Adverse Event Reporting to Country Regulatory Authorities by the Sponsor  
The Sponsor will report SAEs and reportable device deficiencies/malfunctions to the country regulatory 
authority, per local requirements.  
 


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Note: Reportable device deficiencies/malfunctions include device deficiencies/malfunctions that might 
have led to an SAE if a) suitable action had not been taken or b) intervention had not been made or c) if 
circumstances had been less fortunate. These are handled under the SAE reporting system. 
 
Clinical investigation SAEs and device deficiencies/malfunctions reportable per MedDEV 2.7/3 
regulations will be submitted to European Competent Authorities by the Sponsor’s Clinical Safety Group. 
The Sponsor’s Clinical Safety Group’s contact details can be found in Appendix III.  
8.0 
STATISTICAL CONSIDERATIONS 
The following section describes the statistical methods for the clinical investigation. Additional details on 
statistical analyses, including justification of clinical investigation design, sensitivity analyses, poolability 
analyses, subgroup analyses and analysis of descriptive endpoints, will be maintained in a separate 
Statistical Analysis Plan (SAP). 
8.1 
Analysis Populations 
 Modified Intention to Treat Population (mITT) 
The Modified Intention to Treat Population (mITT) will include all randomized subjects with the following 
exception: 
 
1. Subjects who experience a surgical adverse event, defined as ≤14 days post-implant, 
requiring investigator mandated antiplatelet therapy 
2. Subjects who expire, are transplanted, or withdrawn within 14 days of implant 
 
Non-surgically related major hemocompatibility related adverse events will only be analyzed up to the 
transition to open label.  Subjects will be analyzed according to the treatment arm assigned at 
randomization. The mITT population will be used for all analyses unless noted differently in one 
sensitivity analysis. 
 Intent-To-Treat (ITT) Population 
The ITT population will consist of all subjects randomized. Subjects will be analyzed according to the 
treatment arm assigned at randomization. The ITT population will only be used for one sensitivity 
analysis of the primary endpoint. 
8.2 
Statistical Analyses  
 Primary Endpoint Hypothesis 
The primary endpoint hypothesis is formally expressed as: 
H0: πplacebo  ≤ πaspirin - ∆ 
Ha: πplacebo  > πaspirin - ∆ 
 
where πplacebo and πaspirin are the percentage of subjects who successfully achieve the composite endpoint 
in the placebo and aspirin groups and where ∆ is the non-inferiority margin fixed at 10%. Justification of 
the non-inferiority margin is included in the SAP.  


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 Primary Endpoint Analyses Methodology 
The primary endpoint composite success rate will be calculated for each treatment arm based on the 
number of subjects who successfully meet the primary endpoint divided by the total number of subjects 
in the mITT population. The placebo arm will be considered non-inferior to the aspirin arm if the lower 
boundary of the one-sided 97.5% confidence limit of the risk difference in the composite success 
between treatment arms (Placebo-arm minus Aspirin-arm) is greater than the non-inferiority margin (-
10%).  
 Secondary Endpoint Analyses 
The secondary endpoints will be analyzed using the mITT Populations. Details of the secondary endpoint 
analyses are provided in the SAP. The secondary endpoints are: 
• 
Non-surgical Major Hemorrhagic Events
• 
Non-surgical Major Thrombotic Events 
• 
Survival 
• 
Stroke Rates,  
• 
Pump Thrombosis Rates 
• 
Bleeding Rates, including: 
o Non-surgical Bleeding
o Moderate Bleeding 
o Severe Bleeding 
o Fatal Bleeding 
o GI Bleeding 
 Descriptive Endpoints 
Hemocompatibility Score: The Hemocompatibility Score (HCS) is a tiered hierarchal score that weighs 
each hemocompatibility related adverse event by its escalating clinical relevance4. The HCS will be 
calculated for each subject in mITT Population and summarized for the treatment group as a median 
score and range.  
 
Rehospitalizations: The rehospitalization rate will be calculated based on the number of subjects who 
require a rehospitalization, for any cause, after randomization and initiation of the study treatment, 
divided by the number of subjects in the mITT. The number of rehospitalizations per treatment arm will 
also be presented as rehospitalizations per patient year of support. Details of the analysis are presented 
in the SAP.  
 
Economic Cost: Health resource utilization will be assessed by comparing days hospitalized (categorized 
by intensive care vs general ward) between groups in the mITT Population with cost implications 
compared based on cost of hospitalization, per day hospitalized. 
8.3 
Sample Size Calculation and Assumptions 
Results from the MOMENTUM 3 trial were used to derive a point estimate of 71% survival to 1 year free 
of any major hemocompatibility related adverse events in the aspirin treated arm. It is assumed that in 
the absence of aspirin a 2% improvement in the composite endpoint will be noted, mainly due to the 
reduction of bleeding complications without a change in thromboembolic complications. Based on these 
assumptions 220 patients will need to be randomized in each arm (440 total) to achieve 80% power to 


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prove that the placebo group is non-inferior to the aspirin group using a non-inferiority margin of 10% 
with the Farrington-Manning risk difference approach to non-inferiority at a one-sided alpha = 0.025. To 
account for an expected 30% dropout rate associated with events occurring 2-14 days post implant, up to 
628 patients will be randomized in the trial. Sample size calculations were performed using PASS 15 
software.  
8.4 
Timing of Analysis 
The primary endpoint analysis will be performed, and the clinical report prepared when all randomized 
subjects have reached a primary endpoint and the study has been unblinded.   
8.5 
Subgroup Analysis 
A subgroup analysis will be performed to examine the consistency of results for the primary endpoint 
across specific populations. Analysis will be performed using Fisher’s exact test. No subgroup specific 
labeling claims are intended for the primary endpoint and no adjustment will be made for multiplicity. 
Subgroups to be examined include, but are not limited to, gender, age (stratified by median age), age 
(less than 65 vs 65 and greater), race, INTERMACS profile (INTERMACS 1-2 vs INTERMACS 3+), TTR 
and surgical implant method. If home monitoring of anticoagulation is used in some sites but not others, 
a subgroup analysis based on home monitoring will be conducted. 
8.6 
Multiplicity 
This study includes a single primary endpoint and no Type 1 error adjustment is required.  
8.7 
Pooling Strategy  
An analysis will be performed to assess if data can be pooled among study sites and geographic regions. 
A detailed description of the pooling analysis is included in the SAP.  
8.8 
Procedures for Accounting for Missing Data 
Primary endpoint data is unambiguous. Missing primary endpoint data is not expected due to monitoring 
activities. No imputation is planned for primary endpoint data. 
8.9 
Planned Interim Analysis 
No interim analyses to stop the trial early for futility or success are planned for this study. 
8.10 Statistical Criteria for Termination 
There are no statistical criteria for termination of this clinical investigation. 


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8.11 Success Criteria 
The trial will be considered successful if null hypothesis of the primary endpoint is rejected (i.e. the 
placebo group is non-inferior to the aspirin group). 
8.12 Deviations from Statistical Plan 
Any major changes to the statistical plan will be documented in an amendment to the statistical plan. 
Less significant changes to the planned analyses will be documented in the final report.   
9.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/institution will permit direct access to source data/documents for the purpose of 
performing clinical investigation-related monitoring, audits, IRB/EC review and regulatory inspections. 
 
Subjects providing informed consent are agreeing to allow clinical investigation monitors or regulatory 
authorities including foreign countries to review, in confidence, any records identifying the subjects in this 
clinical investigation. This information may be shared with regulatory agencies; however the Sponsor 
undertakes not to release the subject's personal and private information otherwise. 
10.0 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Selection of Clinical Sites and Investigators 
The Sponsor will select investigators qualified by training and experience to participate in the clinical 
investigation. Sites will be selected based upon review of a recent site assessment, if applicable, and the 
qualifications of the investigators who will participate in the clinical investigation. 
10.2 Clinical Investigation Finances and Agreements 
The clinical investigation will be financed by Abbott. Investigational sites will be compensated by Abbott 
for participation in the clinical investigation per the conditions of agreement between the Sponsor and the 
Investigational site. 
10.3 CIP Amendments  
Approved CIP amendments will be provided to the Investigators by the Sponsor prior to implementing the 
amendment. The Principal Investigator is responsible for notifying the IRB/EC or equivalent committee of 
the CIP amendment (administrative changes) or obtaining IRB’s/EC’s approval of the CIP amendment 
(changes in subject care or safety), according to the instructions provided by the Sponsor with the CIP 
amendment.   
 
Acknowledgement/approval by the IRB/EC of the CIP amendment must be documented in writing prior to 
implementation of the CIP amendment. Copies of this documentation must also be provided to the 
Sponsor. 


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10.4 Training 
Site Training 
All Investigators and clinical investigation personnel are required to attend Sponsor training sessions, 
which may be conducted at an Investigator's meeting, a site initiation visit, or other appropriate training 
sessions. Over-the-phone or self-training may take place as required. Training of Investigators and 
clinical investigation personnel will include, but is not limited to, the CIP requirements, electronic case 
report form completion, WebEZ functionality, and clinical investigation personnel responsibilities. All 
Investigators and clinical investigation personnel that are trained must sign a training log (or an 
equivalent) upon completion of the training. Prior to signing the training log, Investigators and clinical 
investigation personnel must not perform any CIP-related activities that are not considered standard of 
care at the site.  
10.5 Monitoring  
Sponsor and/or designee will monitor the clinical investigation over its duration according to the CIP-
specific monitoring plan which will include the planned extent of source data verification.  
 
Prior to initiating any procedure, the Sponsor monitor (or delegate) will ensure that the following criteria 
are met:  
 
• 
The investigator understands and accepts the obligation to conduct the clinical investigation 
according to the CIP and applicable regulations and has signed the Investigator Agreement or the 
Clinical Trial Agreement, as applicable.  
• 
The Investigator and his/her staff should have sufficient time and facilities to conduct the clinical 
investigation and should have access to an adequate number of appropriate subjects to conduct 
the clinical investigation.  
• 
Source documentation (including original medical records) must be available to substantiate 
proper informed consent procedures, adherence to CIP procedures, adequate reporting and 
follow-up of adverse events, accuracy of data collected on case report forms, and device 
information.  
• 
The Investigator/site will permit access to such records. A monitoring visit sign-in log will be 
maintained at the site. The Investigator will agree to dedicate an adequate amount of time to the 
monitoring process. The Investigator and/or research coordinator will be available for monitoring 
visits. It is expected that the Investigator will provide the monitor with a suitable working 
environment for review of clinical investigation-related documents. 
10.6 Deviations from the CIP 
The Investigator should not deviate from the CIP for any reason except in cases of medical emergencies 
when the deviation is necessary to protect the rights, safety and well-being of the subject or eliminate an 
apparent immediate hazard to the subject. In that event, the Investigator will notify Sponsor immediately 
by phone or in writing and will also file required protocol deviation documentation.  
 


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No waivers for CIP deviations will be granted by the Sponsor. All deviations must be reported to the 
Sponsor using the Deviation CRF. The occurrence of protocol deviations will be monitored by the 
Sponsor for evaluation of investigator compliance to the CIP and regulatory requirements and dealt with 
according to written procedures. Investigators will inform their IRB/EC or equivalent committee of all CIP 
deviations in accordance with their specific IRB/EC or equivalent committee reporting policies and 
procedures.  
 
In the event of repeated non-compliance, as determined by the Sponsor, a Sponsor’s monitor or 
company representative will attempt to secure compliance by one or more of the following (and not 
limited to):  
• Visiting the investigator and/or delegate 
• Telephoning the investigator and/or delegate 
• Corresponding with the investigator and/or delegate 
 
Repeated non-compliance with the signed agreement, the CIP or any other conditions of the clinical 
investigation may result in further escalation in accordance with the Sponsor’s written procedures, 
including securing compliance or, at its sole discretion, Sponsor may terminate the investigator's 
participation in the clinical investigation.  
 
Deviations from the protocol include, but are not limited to:  
• 
withdrawal of the treatment arm antithrombotic regimen without clinical reasons  
• 
additional antiplatelet medications added to the treatment arm antithrombotic regimen  
• 
enrollment or randomization of patients who do not meet eligibility requirements 
• 
informed consent deviations, except inadvertent incorrect dating.  
10.7 Quality Assurance Audit 
A Sponsor representative or designee may request access to all clinical investigation records, including 
source documentation, for inspection during a Quality Assurance audit.  
1. The Sponsor shall prepare an audit plan as well as the operating procedures for the related duties, 
and conduct audits in accordance with the audit plan and the operating procedures. 
2. Individual engaged in auditing (hereinafter referred to as "auditor") shall be different than those in 
charge of medical device development or monitoring. 
3. The auditor shall prepare an audit report documenting the matters confirmed in the audit to certify 
and verify that the audit has been conducted, and submit them to the Sponsor. 
 
In the event that an investigator is contacted by a Regulatory Agency in relation to this clinical 
investigation, the Investigator will notify Sponsor immediately. The Investigator and Research 
Coordinator must be available to respond to reasonable requests and audit queries made during the 
audit process. The Investigator must provide Sponsor with copies of all correspondence that may affect 
the review of the current clinical investigation (e.g., Form FDA 483, Inspectional Observations, Warning 
Letters, Inspection Reports, etc.). Sponsor may provide any needed assistance in responding to 
regulatory audits. 


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10.8 Committees 
Steering Committee  
The Steering Committee is assigned by the Sponsor and consists of investigators. The Steering 
Committee will remain blinded to the treatment group assignments throughout the study. The Sponsor 
will also be represented on the committee. The Steering Committee is responsible for overseeing the 
scientific and operational aspects of the clinical investigation. This committee will meet regularly to 
monitor subject enrollment, general data collection and non-compliance with the CIP at individual 
centers, to review and act upon recommendations of the Data Safety Monitoring Board (DSMB), to 
review operational issues that may arise and warrant a CIP amendment or other corrective action and to 
determine policy regarding any publications arising from data generated from the performance of the 
clinical investigation. The Steering Committee or designee will determine policy and strategies regarding 
individual presentations and/or publications arising from clinical investigation generated data. The 
committee will also review all external requests for accessing clinical investigation-related data and 
strategies aligning with the Sponsor’s presentation and publication team expectations. The Sponsor will 
align with the committee to ensure the Sponsor’s applicable policies and Standard Operating Procedures 
are followed. 
Data Safety Monitoring Board (DSMB) 
The Data Safety Monitoring Board (DSMB) is an independent multidisciplinary group restricted to 
individuals free of apparent significant conflicts of interest. The source of these conflicts may be financial, 
scientific, or regulatory in nature. The DSMB is typically composed of at least two physicians with 
experience relevant to the clinical investigation and a biostatistician. The DSMB will meet within 3 
months of study initiation for protocol/study training and to discuss oversight rules including first data 
review point, recurring data review points, and formal rules for recommending study cessation. Formal 
rules for recommending study cessation will be determined by the DSMB prior to review of safety data. 
The DSMB will have access to unblinded datasets, so they may properly assess any safety signal that 
may arise during the conduct of the study. 
 
The DSMB will serve in an advisory role to the Sponsor to ensure safety by reviewing cumulative data 
from the clinical investigation at prescribed intervals for the purpose of safeguarding the interests of 
enrolled subjects and those patients yet to be enrolled, as well as the continuing validity and scientific 
merit of the clinical investigation. The composition, frequency of the meetings and the statistical 
monitoring guidelines will be described in detail in the DSMB charter. 
 
The DSMB may consider a recommendation for modifications or termination of the clinical investigation 
based on any perceived safety concerns regardless of statistical significance. The recommendations of 
the DSMB are not binding, and all final decisions related to clinical investigations modifications rest with 
the Sponsor in consultation with the study Steering Committee.  
Clinical Events Committee (CEC) 
The Clinical Events Committee (CEC) is an independent adjudication body comprised of qualified 
physicians who are not participants in the clinical investigation. The CEC will remain blinded to the 
subjects’ treatment arm assignments. The CEC will review and adjudicate pre-specified events reported 
by investigators or identified by Safety personnel for the clinical investigation as defined in the CEC 
charter and according to definitions provided in this CIP. The CEC will adjudicate all deaths, neurologic 


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dysfunction, pump thrombosis events, bleeding events, and arterial peripheral thromboembolism events 
including events that could be adjudicated to one of these categories.   
11.0 DATA HANDLING AND RECORD KEEPING  
Sponsor and/or its affiliates will maintain documentation of the systems and procedures used in data 
collection for the duration of the clinical investigation.  
 
CRF data collection will be performed through a secure web portal and only authorized personnel will 
access the Electronic Data Capture (EDC) system using a unique username and password to enter, 
review or correct data. Passwords and electronic signatures will be strictly confidential.   
 
The data will be subjected to consistency and validation checks within the EDC system and 
supplemental review by the Sponsor.  
 
At the conclusion of the clinical investigation, completed CRF images with the date-and-time stamped 
electronic audit trail indicating the user, the data entered, and any reason for change (if applicable) will 
be provided to the investigational sites, if requested.  
 
For the duration of the clinical investigation, the Investigator will maintain complete and accurate 
documentation including, but not limited to, medical records, clinical investigation progress records, 
laboratory reports, CRFs, signed ICFs, correspondence with the IRB/EC and clinical investigation 
monitor/Sponsor, adverse event reports, and information regarding subject discontinuation or completion 
of the clinical investigation. 
11.1 Protection of Personally Identifiable Information 
The Sponsor respects and protects personally identifiable information collected or maintained for this 
clinical investigation.  
 
The Sponsor implements technical and physical access controls to ensure that Personal Information is 
accessible only to and processed only on a ‘need to know’ basis, including periodic review of access 
rights, and revocation of access when an individual’s employment is terminated or the individual 
transitions to a role that does not require access to Personal Information, and appropriate restrictions on 
physical access to premises, facilities, equipment, and records containing Personal Information. 
 
The Sponsor requires the investigational sites to transfer into Sponsor’s data management systems only 
pseudonymous Personal Information (key-coded) necessary to conduct the Clinical Investigation, such 
as the patient’s medical condition, treatment, dates of treatment, etc. The Sponsor discloses as part of 
the clinical investigation informed consent process that some Sponsor representatives still may see 
Personal Information at the participating sites for technical support of the participating physicians on the 
device implant or procedures, monitoring and quality control purposes. Confidentiality of Personal 
Information will be observed by all parties involved at all times throughout the clinical investigation. The 
privacy of each subject and confidentiality of his/her information will be preserved in reports and when 
publishing any data. 
 


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The Sponsor data management systems and processes were designed, developed, and tested 
according to industry standards to appropriately safeguard Confidential Information (including any 
Personal Information) against unauthorized access and/or interference by third parties, intrusion, theft, 
destruction, loss or alteration. Clinical Investigation data are encrypted in transit and at rest.  
 
The Sponsor maintains a Privacy Incident procedure that complies in all respects with Applicable Law 
and industry best practices. 
11.2 Data Management Plan 
A Data Management Plan (DMP) will describe procedures used for data review, data cleaning, and 
issuing and resolving data discrepancies. If appropriate, the DMP may be updated throughout the 
duration of the clinical investigation. All revisions will be tracked and document-controlled. 
11.3 Source Documentation  
Regulations and GCP require the Investigator to maintain information in the subject’s original medical 
records that corroborates data collected on the CRFs. In order to comply with these regulatory 
requirements/GCP, the following information should be included in the subject record at a minimum and 
if applicable to the clinical investigation: 
• 
Medical history/physical condition of the subject before involvement in the clinical investigation 
sufficient to verify CIP entry criteria 
• 
Dated and signed notes on the day of entry into the clinical investigation referencing the Sponsor, 
CIP number, subject ID number and a statement that informed consent was obtained 
• 
Dated and signed notes from each subject visit (for specific results of procedures and exams) 
• 
Adverse events reported and their resolution, including supporting documents, such as discharge 
summaries, catheterization laboratory reports, ECGs, and lab results including documentation of 
site awareness of SAEs and of investigator assessment of device relationship for SAEs. 
• 
CIP-required laboratory reports and other tests, reviewed and annotated for clinical significance 
of out of range results (if applicable).  
• 
Notes regarding CIP-required and prescription medications taken during the clinical investigation 
(including start and stop dates) 
• 
Subject’s condition upon completion of or withdrawal from the clinical investigation 
• 
Any other data required to substantiate data entered into the CRF 
• 
Patient reported outcome measures may be completed using CRF worksheets. These serve as 
the source documentation. 
11.4 Case Report Form Completion  
Primary data collection based on source-documented hospital and/or clinic chart reviews will be 
performed clearly and accurately by site personnel trained on the CIP and CRF completion. The 
investigator will ensure accuracy, completeness, legibility and timeliness of the data reported to the 
Sponsor on the CRFs and in all required reports. 


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Data on CRFs will be collected for all subjects that are enrolled into the clinical investigation.   
 
Only authorized site personnel will be permitted to enter the CRF data through the EDC system deployed 
by the Sponsor. An electronic audit trail will be used to track any subsequent changes of the entered 
data. 
11.5 Record Retention 
The Sponsor and Investigator/Site will archive and retain all documents pertaining to the clinical 
investigation as per the applicable regulatory record retention requirements. The Investigator must obtain 
permission from Sponsor in writing before destroying or transferring control of any clinical investigation 
records. 
12.0 ETHICAL CONSIDERATION 
 
12.1 Institutional Review Board/Medical Ethics Committee Review and Approval 
Institutional Review Board (IRB)/ Ethics Committee (EC) approval for the CIP and ICF/other written 
information provided to the patient will be obtained by the Principal Investigator at each investigational 
site prior to consenting and enrolling patients in this clinical investigation. The approval letter must be 
received prior to the start of this clinical investigation and a copy must be provided to the Sponsor.  
 
Any amendments to the CIP as well as associated ICF changes will be submitted to the IRB/EC and 
written approval obtained prior to implementation, according to each institution’s IRB/EC requirements.  
 
No changes will be made to the CIP or ICF or other written information provided to the patient without 
appropriate approvals, including IRB/EC, the Sponsor, and the regulatory agencies (if applicable).  
 
Until the clinical investigation is completed, the Investigator will advise his/her IRB/EC of the progress of 
this clinical investigation, per IRB/EC requirements. Written approval must be obtained from the IRB/EC 
yearly to continue the clinical investigation, or according to each institution’s IRB/EC requirements.  
 
No investigative procedures other than those defined in this CIP will be undertaken on the enrolled 
subjects without the written agreement of the IRB/EC and the Sponsor. 
13.0 CLINICAL INVESTIGATION CONCLUSION 
The clinical investigation will be concluded when: 
• 
All sites are closed AND 
• 
The final report has been provided to investigators (within one year of the end of the 
investigation) or the Sponsor has provided formal documentation of clinical investigation closure. 
Upon conclusion of the study (when the last subject completes their 12 month follow up), investigators 
will return patients to their standard of care aspirin use. Study blinding will be maintained, even after 


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patients transition to their standard of care aspirin use, at the conclusion of the investigation. Refer to 
section 6.10 for additional details on study blinding.  
14.0 REPORTS AND PUBLICATIONS 
14.1 Sponsor Reports 
The Sponsor will submit study progress reports to all principle investigators for submission to reviewing 
IRBs/ECs at least yearly. The sponsor will submit a final report to appropriate regulatory bodies and to all 
principle investigators for submission to all reviewing IRBs/ECs and participating investigators within one 
year after completion or termination. The Sponsor will comply with all other reporting requirements. 
14.2 Publication Policy 
The data and results from the clinical investigation are the sole property of the Sponsor. The Sponsor 
shall have the right to access and use all data and results generated during the clinical investigation. The 
Investigators will not use clinical investigation-related data without the written consent of the Sponsor for 
any purpose other than for clinical investigation completion or for generation of publication materials, as 
referenced in the Clinical Trial Agreement. Single-center results are not allowed to be published or 
presented before the multi-center results. Any proposals for publications or presentations by the 
investigators must be reviewed and approved by the Sponsor in a timely manner to enable Sponsor 
review in compliance with the Sponsor’s publication policy set forth in the Clinical Trial Agreement. 
14.3 Trial Registration 
The Sponsor will register the clinical trial on www.clinicaltrials.gov, in accordance with the International 
Committee of Medical Journal Editors guidelines, or any other applicable guidelines. The Sponsor shall 
be responsible for any such registration and results posting as required by ClinicalTrials.gov. 
Investigational sites shall not take any action to register the trial. A full report of the pre-specified 
outcomes, including any negative outcomes, will be made public through the ClinicalTrials.gov website 
according to the requirements of Section 801 of the FDA Amendments Act. If this clinical investigation is 
terminated early, the Sponsor will make every effort to hasten the release of the pre-specified outcomes 
through ClinicalTrials.gov website. 
15.0 RISK ANALYSIS 
 
15.1 Anticipated Clinical Benefits 
Withdrawal of aspirin from the antithrombotic regimen of HM3 pump patients will not adversely affect 
safety and efficacy and may reduce non-surgical bleeding. 
15.2 Foreseeable Adverse Events and Anticipated Adverse Device Effects 
Risks associated with the specified device and aspirin treatment arm are available in the local IFU and 
expected to be similar to those reported in the Short-Term (6 months post-implant)6 and Full Cohort (24 


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months post-implant)9 cohort of the MOMENTUM 3 Clinical Trial, which are described in Table 7. There 
may be risks related to the device that are unknown at present. Likewise, the exact frequency of the risk 
associated with the placebo treatment arm are not known, but are hypothesized to be similar to the 
aspirin arm. 
 
Table 7 – Expected Incidence Rate of Adverse Events 
Adverse Event 
Short-Term (6-month) 
MOMENTUM 3 
Results6 n=151:  
Full Cohort (24-month) 
MOMENTUM 3 Results9 
n=515 
Death 
11% 
19% 
Bleeding 
33% 
44% 
Cardiac Arrhythmia 
31% 
36% 
Hepatic Dysfunction 
5% 
5% 
Driveline Infection 
12% 
23% 
Blood Infection 
9% 
15% 
Localized Infection (not 
associated with LVAS) 
31% 
41% 
Stroke 
8% 
10% 
Other Neurological Dysfunction 
6% 
12% 
Renal Dysfunction 
11% 
14% 
Respiratory Failure 
22% 
22% 
Moderate or Severe Right Heart 
Failure 
30% 
34% 
Suspected Device Thrombosis 
0% 
1.4% 
 
15.3 Residual Risks Associated with the Clinical Investigation, as Identified in the Risk 
Analysis Report 
No additional Residual Risks associated exclusively with the withdrawal of aspirin from the antithrombotic 
regimen have been identified at this time. Refer to the local IFU for warning and caution statements 
associated with the HM3.  
15.4 Risks Associated with Participation in this Clinical Investigation 
There are no known additional risks for the clinical population and hypothesis under investigation.   
15.5 Possible Interactions with Protocol-Required Concomitant Medications 
Anti-platelet medications, which in this study are replaced by the treatment arm medication which may be 
active aspirin or a placebo, are typically required as standard of care for LVAD patients along with 
vitamin K antagonists and as such no new possible interactions are expected. No new medications are 
introduced in this study. For further detail, refer to the prescribing information for the anticoagulants in 
use – specifically vitamin K antagonists (e.g. warfarin, fluindione, phenprocoumon, etc.) or aspirin. 


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15.6 Steps Taken to Control or Mitigate Risks 
Mitigations and treatment for all adverse events should be per the current practice standards/standards 
of care as determined by the investigator, except for the antithrombotic therapy for mitigation of 
thrombotic risk in enrolled patients, which is the subject of this study. 
Subject risk from study participation will be mitigated by ensuring that only experienced LVAD personnel 
will be involved in the care of research subjects. In addition to providing local product specific IFU, study 
staff will have undergone product, implant and study training prior to initiating study activities, and all 
subjects will be closely monitored throughout the study duration at pre-specified time points to assess 
their clinical status. 
Specific information applicable to this study are listed below. 
• 
Inclusion/Exclusion criteria avoid patients who are at an inordinately elevated risk for 
complications including, but not limited to, women who are or may become pregnant, patients 
with a known allergy to aspirin, and patients who require aspirin therapy or lack of aspirin therapy 
post-implant in the opinion of the investigator.  
• 
It is suggested that patients possess a minimum 5th grade educational level and shall be versed 
in basic computer literacy (i.e., Microsoft Windows® and Office software). 
• 
All users, including clinicians, patients, and caregivers, must be trained on system operation and 
safety before use. 
• 
All implanting surgeons must be trained on HeartMate 3 surgical implant technique.  
• 
Clinical procedures (including LVAS settings) should be conducted under the direction of the 
prescribing physician (Authorized Personnel) only. 
• 
A data safety monitoring board (DSMB) will be monitoring adverse event data at regular intervals 
independently specified to assure safety is maintained throughout the study. In the event of an 
unacceptable safety profile, the DSMB will make a recommendation to pause or stop study 
enrollment while the DSMB, Sponsor, and steering committee determine if additional actions are 
necessary. Formal rules for making a recommendation to stop the study will be independently 
determined by the DSMB prior to data review. Rules will be contained within the DSMB Charter.  
15.7 Risk to Benefit Rationale 
The HM3 is a safe and effective treatment for advanced, refractory heart failure, and the medical benefits 
outweigh the risks of harm to the patient. MCS therapy is proven to be an effective treatment for 
advanced, refractory heart failure. The HM3 is an advancement in MCS technology and complies with all 
relevant international standards.  
There have been no additional risks identified with the HM3 beyond what has been established with 
other VAD devices in clinical trials that have not been effectively mitigated within this trial; the risks are 
comparable or superior to the HMII. 
All identified risks were managed through the risk management process and reduced as much as 
possible. The overall residual risks have been deemed acceptable, per the risk management process, 
and in consideration of the benefits provided by the therapy. The risk benefit analysis “basis for 
acceptance” for each of the residual risks are documented in the HeartMate 3 Risk Management Report. 
Removal of antiplatelet agents from the antithrombotic therapy of HM3 patients may reduce bleeding 
This study hypothesizes that there will be no additional thrombotic risk based on the growing body of 


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scientific evidence that shows the HM3 has a low thromboembolic profile5,9,11. However, bleeding events, 
while decreased in comparison to a predicate device, remain burdensome9. All major prospective clinical 
trials conducted with the HM3 (MOMENTUM 3, CE Mark) have been in the context of a prescribed 
antithrombotic regimen of aspirin in concert with vitamin K antagonist. Within clinical studies9,10,16, as 
institutional changes to their standard of care18, or in response to increased bleeding risk17, modifications 
to the HM3 anticoagulation regimen have been explored. Prior to the introduction of the HM3, which has 
a decreased thrombotic profile relative to the HMII, studies investigating the need for aspirin within the 
HMII antithrombotic regimen were conducted20-23.  
In conclusion, for the intended patient population, the probable medical benefits of the HM3 outweigh the 
overall residual risk and may be improved in the absence of antiplatelet agents as part of the 
antithrombotic regimen. This study aims to conclusively determine if antiplatelet agents are required as 
part of the HM3 antithrombotic regimen. 


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APPENDIX I: ABBREVIATIONS AND ACRONYMS 
Abbreviation 
Term 
ACE 
Angiotensin Converting Enzyme 
AE 
Adverse Event 
AI 
Aortic Insufficiency 
ALT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
ARB 
Angiotensin II Receptor Blockers 
AST 
Aspartate Aminotransferase 
AVM 
Arterio-venous malformation 
BTC 
Bridge-to-Candidacy 
BTT 
Bridge-to-Transplant 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary Artery Bypass Graft 
CEC 
Clinical Events Committee 
CI 
Cardiac Index 
CIP 
Clinical Investigation Plan 
CK 
Creatinine Kinase 
CK-MB 
Creatinine Kinase Muscle/Brain 
CMS 
Centers for Medicare and Medicaid SERVICES 
CNS 
Central Nervous System 
CO 
Cardiac Output 
CPB 
Cardiopulmonary Bypass 
Cr 
Creatinine 
CRF 
Case Report Form 
CT 
Computed Tomography 
CVP 
Central Venous Pressure 
DMP 
Data Management Plan 
DSMB 
Data Safety Monitoring Board 
DT 
Destination Therapy 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EGM 
Intracardiac electrogram 
EKG 
Electrocardiogram 
ELEVATE 
Evaluating the HeartMate 3 with Full MagLev Technology in a Post-
Market Approval Setting 
EQ-5D-5L 
EuroQOL 5 Dimension 5 Level questionnaire 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GI 
Gastrointestinal 
HAS-BLED 
Hypertension, Abnormal renal and liver function, Stroke, Bleeding, 
Labile INR, Elderly, Drugs or Alcohol 


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Abbreviation 
Term 
HbA1c 
Glycated Hemoglobin 
HCS 
Hemocompatibility Score 
Hct 
Hematocrit 
HF 
Heart Failure 
Hgb 
Hemoglobin 
HIE 
Hypoxic-ischemic injury 
HIPAA 
Health Insurance Portability and Accountability Act 
HIT 
Heparin Induced Thrombocytopenia 
HM3 
HeartMate 3 
HMII 
HeartMate II 
ICF 
Informed Consent Form 
ICH 
Intracranial Hemorrhage 
IFU 
Instructions for Use 
INR 
International Normalized Ratio 
INTERMACS 
Interagency Registry for Mechanically Assisted Circulatory Support 
ITT 
Intention to Treat 
IRB 
Institutional Review Board 
LA 
Left Atrium 
LAAO 
Left Atrial Appendage Occlusion 
LDH 
Lactate dehydrogenase 
LV 
Left Ventricle 
LVAD 
Left Ventricular Assist Device 
LVAS 
Left Ventricular Assist System 
LVEDD 
Left Ventricular End Diastolic Diameter 
LVEF 
Left Ventricular Ejection Fraction 
LVESD 
Left Ventricular End Systolic Diameter 
MCS 
Mechanical Circulatory Support 
MedDEV 
Medical Device Directives 
MI 
Myocardial Infarction 
mITT 
Modified Intention to Treat 
MOMENTUM3 Multi-center Study of MagLev Technology in Patients Undergoing 
MCS Therapy With HeartMate 3™ IDE Study 
MR 
Mitral Regurgitation 
MRI 
Magnetic Resonance Imaging 
MRS 
Modified Rankin Score 
NPO 
Nil per os. Latin for “Nothing through the Mouth”. 
NYHA 
New York Heart Association 
OUS 
Outside the United States 
PAD 
Diastolic Pulmonary Artery Pressure 
PAM 
Mean Pulmonary Artery Pressure 
PAS 
Systolic Pulmonary Artery Pressure 
PCWP 
Pulmonary Capillary Wedge Pressure 
PHgb 
Plasma Free Hemoglobin 


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Abbreviation 
Term 
PLT 
Platelets 
PR 
Pulmonary Regurgitation 
PRBC 
Packed Red Blood Cells 
PRO 
Patient Reported Outcome 
PTFE 
Polytetrafluoroethylene 
PTT 
Partial Thromboplastin Time 
QOL 
Quality of Life 
RAP 
Right Atrial Pressure 
RHF 
Right Heart Failure 
RVAD 
Right Ventricular Assist Device 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
Standard of Care 
tPA 
Tissue Plasminogen Activator 
TR 
Tricuspid Regurgitation 
UADE 
Unanticipated Adverse Device Effect 
UNOS 
United Network for Organ Sharing 
UADE 
Unanticipated Serious Adverse Device Effect 
VAS 
Visual Analogue Scale 
VT 
Ventricular Tachycardia 
WBC 
White Blood Cells 
 
 
 


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APPENDIX II: DEFINITIONS 
ADVERSE EVENT DEFINITIONS: 
 
1. 
Bleeding 
 
VAD-IMPLANT-RELATED BLEEDING: 
VAD-implantation-related bleeding (includes concomitant cardiac or non-cardiac surgical 
procedures) that requires: 
• Reoperation after closure of incision or incisions used to implant the VAD for the 
purpose of controlling bleeding 
• If ≥ 50 kg, ≥ 4U packed red blood cells (PRBC) within any 48-hour period during 
first 7 days post implant. 
• If < 50 kg, ≥ 20 cc/kg packed red blood cells (PRBC) within any 24-hour period 
during first 7 days post implant. 
• Or any transfusion from 8-14 days 
or exhibits: 
• Chest tube output > 2L within a 24-h period 
 
MODERATE: 
Any overt, actionable sign of hemorrhage (e.g., more bleeding than would be expected 
for a clinical circumstance, including bleeding found by imaging alone) that does not fit 
the criteria for a Severe or Surgical Bleeding Definitions but meets the following criteria:  
• requiring nonsurgical, medical intervention by a healthcare professional;  
and 
• leading to hospitalization or increased level of care (unscheduled clinical visit or 
use of emergency services). 
 
SEVERE: 
o Type A: (Meets any of the below) 
• Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL (provided hemoglobin drop is 
related to bleed) 
• Any transfusion with overt bleeding 
o Type B: (Meets any of the below) 
• Overt bleeding plus hemoglobin drop 5 g/dL or greater (provided hemoglobin drop 
is related to bleed) 
• Cardiac tamponade 
• Bleeding requiring surgical intervention for control (excluding dental, nasal, skin, or 
hemorrhoid) 
• Hypotension attributable to bleeding and requiring intravenous vasoactive agents 
for hemodynamic support 
• Intracranial Hemorrhage that does not meet the definition of hemorrhagic stroke 
o Type C1: Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious 


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o Type C2: Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
 
2. 
Cardiac Arrhythmias 
Any documented arrhythmia that results in clinical compromise (e.g., diminished VAD 
flow, oliguria, pre-syncope or syncope) that requires hospitalization or occurs during a 
hospital stay.  Cardiac arrhythmias are classified as 1 of 2 types: 
• Sustained ventricular arrhythmia requiring defibrillation or cardioversion. 
• Sustained supraventricular arrhythmia requiring drug treatment or cardioversion. 
 
3. 
Device Thrombosis 
Device thrombosis is an event in which the pump or its conduits contain a thrombus that 
results in or could potentially induce circulatory failure. Suspected device thrombus is an 
event in which clinical or pump parameters suggest thrombus on the blood contacting 
components of the pump, cannula, or grafts. Signs and symptoms should include at least 
2 of the 3 following criteria: 
• Presence of hemolysis 
• Worsening heart failure or inability to decompress the left ventricle 
• Abnormal pump parameters 
 
Suspected pump thrombus should be accompanied by 1 or more of the following events 
or interventions: 
• Treatment with intravenous anticoagulation (e.g., heparin), intravenous 
thrombolytics (e.g., tPA), or intravenous antiplatelet therapy (e.g., eptifibatide, 
tirofiban) 
• Pump replacement 
• Pump explantation 
• Urgent transplantation (UNOS status 1A) 
• Stroke 
• Arterial non-CNS thromboembolism 
• Death 
 
Confirmed device thrombus is an event in which thrombus is confirmed by the Sponsor’s 
returned product analysis to be found within the blood contacting surfaces of device 
inflow cannula or outflow conduit or grafts. This can also be reported via direct visual 
inspection or by incontrovertible contrast radiographic evidence or by the absence of an 
appropriate Doppler flow signal that results in or could potentially induce circulatory 
failure or result in thromboembolism. 
 
4. 
Hemolysis* 
A plasma-free hemoglobin value that is greater than 40 mg/dl, concomitant with a rise in 
serum LDH above three times the upper limit of normal, in association with clinical signs 


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associated with hemolysis (e.g., anemia, low hematocrit, hyperbilirubinemia) occurring 
after the first 72 hours post-implant.  
*Hemolysis in the presence of worsening heart failure or inability to decompress the left 
ventricle or abnormal pump parameters should be reported as suspected device 
thrombosis, not as hemolysis  
 
5. 
Hepatic Dysfunction 
An increase in any two of the following hepatic laboratory values (total bilirubin, aspartate 
aminotransferase/AST and alanine aminotransferase/ALT) to a level greater than three 
times the upper limit of normal for the hospital, beyond 14 days post-implant (or if hepatic 
dysfunction is the primary cause of death).   
 
6. 
Hypertension 
Blood pressure elevation of a mean arterial pressure greater than 110 mm Hg, despite 
anti-hypertensive therapy.    
 
7. 
Major Infection 
A clinical infection accompanied by pain, fever, drainage and/or leukocytosis that is 
treated by anti-microbial agents (non-prophylactic).  A positive culture from the infected 
site or organ should be present unless strong clinical evidence indicates the need for 
treatment despite negative cultures.  The general categories of infection are listed below: 
Localized Non-Device Infection 
Infection localized to any organ system or region (e.g. mediastinitis) without evidence of 
systemic involvement (see sepsis definition), ascertained by standard clinical methods 
and either associated with evidence of bacterial, viral, fungal or protozoal infection, 
and/or requiring empirical treatment.  
Percutaneous Site and/or Pump Infection 
A positive culture from the skin and/or tissue surrounding the drive line or from the tissue 
surrounding the external housing of a pump implanted within the body, coupled with the 
need to treat with antimicrobial therapy, when there is clinical evidence of infection such 
as pain, fever, drainage, or leukocytosis. 
Internal Pump Component, Inflow or Outflow Tract Infection 
Infection of blood-contacting surfaces of the LVAD documented by positive site culture. 
Sepsis 
Evidence of systemic involvement by infection, manifested by positive blood cultures 
and/or hypotension. 
 
8. 
Myocardial Infarction 
Two categories of myocardial infarction will be identified: 
 
Peri-Operative Myocardial Infarction 
The clinical suspicion of myocardial infarction together with CK-MB or Troponin > 10 
times the local hospital upper limits of normal, found within 7 days following VAD implant 


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together with ECG findings consistent with acute myocardial infarction.  (This definition 
uses the higher suggested limit for serum markers due to apical coring at the time of VAD 
placement and does not use wall motion changes because the apical sewing ring 
inherently creates new wall motion abnormalities.)  
 
Non-Perioperative Myocardial Infarction 
The presence at > 7 days post-implant of two of the following three criteria:   
 
• Chest pain which is characteristic of myocardial ischemia,  
• ECG with a pattern or changes consistent with a myocardial infarction, and  
• Troponin or CK (measured by standard clinical pathology/laboratory medicine 
methods) greater than the normal range for the local hospital with positive MB 
fraction (≥ 3% total CK).  This should be accompanied by a new regional LV or RV 
wall motion abnormality on a myocardial imaging study. 
 
9. 
Neurologic Dysfunction 
Any new, temporary or permanent, focal or global neurological deficit, ascertained by a 
standard neurological history and examination administered by a neurologist or other 
qualified physician and documented with appropriate diagnostic tests and consultation 
note; or an abnormality identified by surveillance neuroimaging. The examining physician 
will classify the event as defined below:  
 
• Transient ischemic attack*, defined as an acute transient neurological deficit 
conforming anatomically to arterial distribution cerebral ischemia, which resolves 
in < 24 hours and is associated with no infarction on brain imaging (head CT 
performed >24 hours after symptom onset; or MRI) 
• Ischemic Stroke*: a new acute neurologic deficit of any duration associated with 
acute infarction on imaging corresponding anatomically to the clinical deficit, or a 
clinically covert ischemic stroke seen by surveillance imaging, without clinical 
findings of stroke or at the time of event recognition. 
• Hemorrhagic Stroke*: a new acute neurologic deficit attributable to intracranial 
hemorrhage (ICH), or a clinically covert ICH seen by surveillance imaging, without 
clinical findings of ICH at the time of event recognition. 
• Encephalopathy: Acute new encephalopathy** due to hypoxic-ischemic injury 
(HIE), or other causes, manifest as clinically evident signs or symptoms, or 
subclinical electrographic seizures found by complete neurological diagnostic 
evaluation to be attributable to acute global or focal hypoxic, or ischemic brain 
injury not meeting one of ischemic stroke or ICH events as defined above. 
• Seizure of any kind 
•  Other neurological event (non-CNS event): examples include neuro muscular 
dysfunction or critical care neuropathy 
 


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*Modified Rankin Score (MRS) will be used to classify the severity of all strokes. MRS will 
be captured at baseline, the time of stroke, and at 60 days post-stroke. MRS will be 
determined by an independent assessor, defined as an independent, trained, and 
certified clinician. Severity will be defined as disabling (MRS > 3) or nondisabling (MRS ≤ 
3). MRS is defined below.  
**Acute encephalopathy is a sign or symptom of some underlying cerebral disorder, and 
is manifest as depressed consciousness with or without any associated new global or 
multifocal neurologic deficits in cranial nerve, motor, sensory, reflexes and cerebellar 
function. 
 
10. Renal Dysfunction 
Two categories of renal dysfunction will be identified: 
 
Acute Renal Dysfunction 
Abnormal kidney function requiring dialysis (including hemofiltration) in Subjects who did 
not require this procedure prior to implant, or a rise in serum creatinine of greater than 3 
times baseline or greater than 5 mg/dL sustained for over 48 hours. 
 
Chronic Renal Dysfunction 
An increase in serum creatinine of 2 mg/dl or greater above baseline, or requirement for 
hemodialysis sustained for at least 90 days. 
 
11. Respiratory Failure 
Impairment of respiratory function requiring reintubation, tracheostomy or the inability to 
discontinue ventilatory support within six days (144 hours) post-VAD implant.  This 
excludes intubation for reoperation or temporary intubation for diagnostic or therapeutic 
procedures. 
 
12. Right Heart Failure 
Symptoms and signs of persistent right ventricular dysfunction requiring RVAD 
implantation, or requiring inhaled nitric oxide or inotropic therapy for a duration of more 
than 14 days at any time after LVAD implantation. To compare to prior studies, this study 
will begin collecting details of events involving nitric oxide or inotropic therapy for a 
duration of more than 7 days, whereas reportable right heart failure will begin at 14 days 
of therapy. 
 
To further stratify right heart failure (RHF) events, the following criteria will be used to 
identify a sub-category of persistent, clinically significant RHF events: 
• Death due to right heart failure or 
• RVAD or 
• Hospitalization with primary diagnosis of decompensated heart failure with 
evidence of right heart support or 
• Post-discharge inotropes or 


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• > 30 consecutive days on inotropes. 
 
13. Arterial Peripheral Thromboembolism  
An acute systemic arterial perfusion deficit in any non-cerebrovascular organ system due 
to thromboembolism confirmed by one or more of the following:  
 
1) 
Standard clinical and laboratory testing 
2) 
Operative findings 
3) 
Autopsy findings 
 
This definition excludes neurological events. 
 
14. Venous Thromboembolism Event 
Evidence of venous thromboembolic event (e.g. deep vein thrombosis, pulmonary 
embolism) by standard clinical and laboratory testing.  
 
15. Other 
An event that causes clinically relevant adverse changes in the Subject’s health (e.g. 
cancer) not otherwise categorized above. 
 
 
 


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NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION 
 
NYHA Classification 
Definition 
I 
Cardiac disease without resulting limitations of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitations, dyspnea or 
anginal pain. 
II 
Cardiac disease resulting in slight limitation of physical activity. Subjects are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea or anginal pain. 
IIIA 
Cardiac disease resulting in marked limitations of physical activity. Subjects 
are comfortable at rest. Less than ordinary physical activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
IIIB 
Cardiac disease resulting in marked limitations of physical activity. Subjects 
are comfortable at rest. Mild physical activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
IV* 
Cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort 
is increased. 
 
 
 


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INTERMACS PROFILE 
 
INTERMACS 
Profile* 
Definition 
1 
Critical cardiogenic shock describes a patient who is “crashing and burning”, in which 
a patient has life-threatening hypotension and rapidly escalating inotropic pressor 
support, with critical organ hypoperfusion often confirmed by worsening acidosis and 
lactate levels.  
2 
Progressive decline describes a patient who has been demonstrated “dependent” on 
inotropic support but nonetheless shows signs of continuing deterioration in nutrition, 
renal function, fluid retention, or other major status indicator. Patient profile 2 can also 
describe a patient with refractory volume overload, perhaps with evidence of impaired 
perfusion, in whom inotropic infusions cannot be maintained due to tachyarrhythmias, 
clinical ischemia, or other intolerance.  
3 
Stable but inotrope dependent describes a patient who is clinically stable on mild-
moderate doses of intravenous inotropes (or has a temporary circulatory support 
device) after repeated documentation of failure to wean without symptomatic 
hypotension, worsening symptoms, or progressive organ dysfunction (usually renal). 
It is critical to monitor nutrition, renal function, fluid balance, and overall status 
carefully in order to distinguish between a patient who is truly stable at Patient Profile 
3 and a patient who has unappreciated decline rendering this person a Patient Profile 
2. This patient may be either at home or in the hospital.  
4 
Resting symptoms describes a patient who is at home on oral therapy but frequently 
has symptoms of congestion at rest or with ADL. He or she may have orthopnea, 
shortness of breath during ADL such as dressing or bathing, gastrointestinal 
symptoms (abdominal discomfort, nausea, poor appetite), disabling ascites or severe 
lower extremity edema. This patient should be carefully considered for more intensive 
management and surveillance programs, by which some may be recognized to have 
poor compliance that would compromise outcomes with any therapy.  
5 
Exertion Intolerant describes a patient who is comfortable at rest but unable to 
engage in any activity, living predominantly within the house or housebound. This 
patient has no congestive symptoms, but may have chronically elevated volume 
status, frequently with renal dysfunction, and may be characterized as exercise 
intolerant.  
6 
Exertion Limited also describes a patient who is comfortable at rest without evidence 
of fluid overload, but who is able to do some mild activity. Activities of daily living are 
comfortable and minor activities outside the home such as visiting friends or going to 
a restaurant can be performed, but fatigue results within a few minutes of any 
meaningful physical exertion. This patient has occasional episodes of worsening 
symptoms and is likely to have had a hospitalization for heart failure within the past 
year.  
7 
Advanced NYHA Class 3 describes a patient who is clinically stable with a reasonable 
level of comfortable activity, despite history of previous decompensation that is not 
recent. This patient is usually able to walk more than a block. Any decompensation 
requiring intravenous diuretics or hospitalization within the previous month should 
make this person a Patient Profile 6 or lower.   


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MODIFIED RANKIN SCORE (MRS) 
 
MRS  
Definition1  
0 
No observed neurological symptoms 
1 
No significant neurological disability despite symptoms; able to 
carry out all usual duties and activities 
2 
Slight neurological disability; unable to carry out all previous 
activities, but able to look after own affairs without assistance 
3 
Moderate neurological disability; requiring some help, but able to 
walk without assistance 
4 
Moderate severe neurological disability; unable to walk without 
assistance and unable to attend to own bodily needs without 
assistance 
5 
Severe neurological disability; bedridden, incontinent and 
requiring constant nursing care and attention as a result of a 
neurological deficit 
6 
Dead 
 
 
NON-SURGICAL 
Greater than 14 days post implant.   
 
 
 
 
1 van Swieten J, Koudstaal P, Visser M, Schouten H, et al (1988). “Interobserver agreement for the assessment of 
handicap in stroke Subjects”. Stroke 19 (5): 604-607 


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APPENDIX III: STUDY CONTACT INFORMATION 
Contact information for each participating clinical site is available under separate cover by 
contacting the Project Management. 
 
Project Management Contact 
 
Nina Sinanovic 
Abbott 
3200 Lakeside Drive 
Santa Clara, CA, 95054  
USA 
Phone: +1 408 845 0655 
E-mail: nina.sinanovic@abbott.com 
 
 
Clinical Safety Contact  
 
Venu Parimi 
Medical Safety Monitor 
168 Middlesex Turnpike 
Burlington, MA, 01803 
USA 
E-mail: AdverseEvent@abbott.com 
 
Requests for further clarifications on submitted reports can be sent to 
clinicalsafety@abbott.com. 
 
 


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APPENDIX IV: INFORMED CONSENT FORM 
The study template informed consent form is available under a separate cover. 
 
 
 
 


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APPENDIX V: MONITORING PLAN 
A copy of the Monitoring Plan can be obtained upon request from the Sponsor Clinical Project Manager. 
 
 


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APPENDIX VI: DEVICE POSITION SUBSTUDY PROTOCOL 
Study Title 
Assessment of HeartMate 3 Device Position using a Radiopaque Marker 
Positioned on the Aortic Root 
 
Study Phase 
Substudy within the ARIES Clinical Study 
 
Rationale 
     Implantation of a durable left ventricular assist device (LVAD) is now the most 
frequently utilized surgical therapy for treatment of patients with advanced heart 
failure (HF) refractory to medical management.  Previous studies have 
demonstrated that inflow cannula malposition, which occurs 1) due to incorrect 
surgical placement, or 2) as a consequence of device migration, is associated with 
significant adverse events including pump thrombosis, stroke and persistent heart 
failure due to the inability to provide adequate left ventricular unloading and device 
flow.(1) 
    Specific surgical configurations have not been studied in depth, and its influence 
on hemocompatatibility-related events associated with LVAD therapy remains 
poorly understood.(2) Thrombogenesis in patients with an LVAD is at least, in part, 
attributable to nonphysiological blood flow characteristics: shear environments, as 
well as high spatial gradients and high-frequency temporal fluctuations, which lead 
to platelet activation. This adverse hemodynamic environment may be 
exacerbated by malposition of the LVAD inflow cannula. Anecdotal evidence 
suggests that surgical implantation of the inflow cannula at different angles with 
respect to the apical ventricular axis influences LVAD thrombosis.(3-5) 
     Prior studies investigating inflow cannula malposition have utilized various 
reference lines to determine optimal inflow cannula position.  Typically, these 
reference lines utilize the spine as a vertical reference line and a horizontal line 
drawn perpendicular to the vertical line usually positioned at the apex of the right 
diaphragm serves as a horizontal reference point.(3-5)  However, this approach 
does not take into consideration differences in anatomy of the heart in relation to 
the spine and diaphragms.  Optimal inflow position in oriented to the orifice of the 
mitral valve.  Thus, the utility of these reference lines to identify the orifice of the 
mitral valve is brought into question.  
     This substudy utilizes a simple technique to identify a more anatomical 
reference point to assess HeartMate 3 inflow cannula position.  A radiopaque 
surgical marker (i.e., surgical clip) will be placed on the anterior surface of the 
aortic root below the sino-tubular ridge of the aorta just above the ostia of the right 
coronary artery.   
     The surgical clips used in this study are generally standard to use in cardiac 
surgery for both hemostasis and as radiopaque markers. They have been used for 
the development of this substudy in 4 LVAD implants with a cumulative follow up 
of 245-days post-implant at a single center without safety concerns (data not 
published). The location of the clip reduces the likelihood of interference with the 
coronary artery. Placement of the clips will be under direct visualization and will 
not prolong the implant procedure. Participation in this substudy is not expected 
to present appreciable additional risk. This substudy will not affect the main 
objectives of the ARIES HM3 clinical trial. 


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    The hypothesis of this sub-study is to develop and validate a surgical marker 
to serve as a consistent anatomical landmark to allow for accurate evaluation of 
the HeartMate 3 inflow canula position at the time of implant and subsequently, 
over time.  We further hypothesize that differences in inflow canula positions and 
their changes over time may correlate with clinical outcomes.  
 
Primary Objectives To develop and validate the use of a radiopaque surgical marker placed on the 
anterior surface of the aortic root below the sino-tubular ridge of the aorta just 
above the ostia of the right coronary artery to be used as a surrogate anatomical 
reference or landmark to more optimally assess HeartMate 3 inflow cannula 
position. Validation will be performed by assessing: 
1. The safety and feasibility of placing and visualizing the radiopaque 
marker; 
2. The variation in cannula angulation relative to the radiopaque marker and 
cannula positional changes over time; 
3. The relationship between the initial cannula angulation or its change over 
time with adverse clinical outcomes and functional capacity, as an 
exploratory analysis.  
 
Study Populations 
Subjects enrolled in the ARIES HM3 study who also meet eligibility requirements 
for this substudy at participating centers.  
Study Design 
Multi-center, prospective, non-controlled, non-randomized, observational sub-
study within ARIES 
 
Number of 
Subjects 
Per ARIES HM3 study 
Number of Centers 
 
Up to 10 Centers 
Duration of 
Subject 
Participation 
 
Per ARIES HM3 study 
Inclusion Criteria 
1. Subjects enrolled within the ARIES HM3 study. 
Exclusion Criteria 
1. In the judgement of the implanting surgeon, that placement of the radiopaque 
surgical marker would have unacceptable risk based upon technical reasons 
or patient anatomy. 
2. Subjects undergoing placement of the HeartMate 3 device through a 
minimally-invasive approach where sternotomy or upper sternotomy will not be 
performed and access to the anterior surface of the aorta below the sino-
tubular ridge is not feasible. 


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Intervention 
A radiopaque surgical marker (i.e., surgical clip) will be placed on the anterior 
surface of the aortic root midway between the sino-tubular ridge of the aorta and 
the ostia of the right coronary artery.  The radiopaque marker will include 
placement of 2 standard surgical clips (manufacturer, size, picture; see Figures 1, 
2A and B, 3 and 4) attached to the adventitia of the aorta and positioned as 
described above. 
 
Assessments 
Anteroposterior (AP) and lateral radiographs will be captured prior to discharge 
(but within 30 days of implant) and at the 3-month follow up visit. Radiographs 
will be obtained by a fixed radiography (fixed x-ray) and sent to the study 
sponsor in DICOM format. If standard of care (SOC), chest x-ray computed 
tomography (CT) scans will be obtained in addition to the radiographs.  
References 
1. Chivukula VK, Beckman JA, Prisco AR, et al.  Left ventricular assist device 
inflow cannular angle and thrombosis risk.  Circulation: Heart Failure.  
2018;11:e004325. 
2. Mancini D, Colombo PC. Left ventricular assist devices: a rapidly evolving 
alternative to transplant. J Am Coll Cardiol. 2015;65:2542–2555.  
3. Taghavi S, Ward C, Jayarajan SN, Gaughan J, Wilson LM, Mangi 
AA. Surgical technique influences HeartMate II left ventricular assist device 
thrombosis.Ann Thorac Surg. 2013; 96:1259–1265.  
4. Atkins BZ, Hashmi ZA, Ganapathi AM, Harrison JK, Hughes GC, Rogers 
JG, Milano CA. Surgical correction of aortic valve insufficiency after left 
ventricular 
assist 
device 
implantation.J 
Thorac 
Cardiovasc 
Surg. 2013; 146:1247–1252.  
5. Bhama J, Eckert C, Lockard K, Shiose A, Bermudez C, Teuteberg J, 
Ramani R, Simon M, Badhwar V, Kormos R. Does LVAD inflow cannula 
position contribute to the development of pump thrombosis requiring 
device exchange?J Am Coll Cardiol. 2013; 61:E719.  
 
 
 
 


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Figure 1:  Acceptable Anteroposterior  and Lateral Chest Radiograph Demonstrating Placement of a 
Radiopaque marker (two standard surgical clips). Clips are placed on the anterior surface of the aorta 
positioned halfway between the sino-tubular ridge of the aorta and the right coronary artery. Note: the full 
body of the HM3 is visible within the radiograph. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2A:  Measurement Method on Anteroposterior and Lateral Chest Radiograph. Radiopaque 
marker (two standard surgical clips) on the anterior surface of the aorta is positioned halfway between 
the sino-tubular ridge of the aorta and the right coronary artery (Red Arrow).  Black line indicates center 
line of the HeartMate 3 inflow canula.  The dotted red line indicates the degree of deviation from the 
reference point (surgical radiopaque marker). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2B:  Measurement Method on Anteroposterior and Lateral Chest Radiograph. Radiopaque 
marker (two standard surgical clips) on the anterior surface of the aorta is positioned halfway between 
the sino-tubular ridge of the aorta and the right coronary artery (Red Circle).  Black line indicates center 
line of the HeartMate 3 inflow canula.  The dotted red line indicates the degree of deviation from the 
reference point (surgical radiopaque marker). 
 
 


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Figure 3:  Radiopaque Surgical Marker  
 
 
 
 
 


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Figure 4:  Radiopaque Surgical Marker 
 
 


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APPENDIX VII: REVISION HISTORY 
This CIP may be amended as appropriate by the Sponsor. Rationale will be included with each amended 
version in the revision history table below. The version number and date of amendments will be 
documented. 
 
IRB/EC and relevant Regulatory Authorities, if applicable, will be notified of amendments to the CIP. 
 
Amendment 
Number 
Version Date 
Details 
Rationale 
Not 
Applicable 
A 
22AUG2019 
First release of CIP 
NA 
1 
B 
15JAN2020 
DSMB is unblinded; 
Sponsor is fully blinded. 
 
 
Update Statistics Section to 
reflect updated analysis 
plan including removal of 
superiority analysis, 
combining secondary and 
safety endpoints, adding 
secondary endpoints.  
 
Add Device Position 
Substudy 
 
 
 
Clarify transition to open 
label and add 72-hour 
cessation window 
 
 
Add “Other” Adverse Event 
Definition and clarify 
Moderate Bleeding 
definition 
 
Remove 45 CFR part 46 
from Compliance Statement 
 
 
Minor corrections and 
clarifications throughout 
 
 
The DSMB has independently 
requested access to unblinded 
data to perform safety review.  
 
The statistical analysis plan of 
the study has been updated.  
 
 
 
 
 
 
Assess implant cannula 
position, changes over time 
and their potential impact on 
outcomes 
 
Allow 72-hour cessation of 
treatment arm medication prior 
to transition to open label for 
treatment of adverse events. 
 
All adverse events will be 
collected.  
 
 
 
Regulation not applicable to 
this study 
 
 
n/a 


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2 
C 
13MAR2020 Relabeled Primary 
Endpoint analysis 
population as mITT 
population and defined ITT 
Population  
 
Corrected 97.5% 
confidence limit in primary 
endpoint analysis method 
Using more unified definitions 
of populations as well as 
defining an ITT population for a 
sensitivity analysis 
 
 
Correction 
 
 
 


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APPENDIX VIII: CIP SUMMARY 
Clinical 
Investigation 
Name and 
Number 
ARIES HM3 
CRD_971 
Title 
Antiplatelet Removal and HemocompatIbility EventS with the 
HeartMate 3 Pump 
Background 
Heart failure (HF) is a growing epidemic, with 915,000 new cases diagnosed 
each year, resulting in over 1 million hospitalizations and costs the United 
States (US) healthcare system over $30 billion annually1. Left ventricular assist 
devices (LVAD) are increasingly being used for treating patients with advanced 
heart failure as they have demonstrated improved survival over optimal medical 
management2. Progressively improving outcomes with newer LVAD technology 
has led to LVAD therapy becoming a mainstay in the treatment of advanced 
heart failure3, however, LVAD therapy has been beleaguered by 
hemocompatibility related adverse events – namely thrombosis, stroke and 
bleeding4. Within the prospective randomized multicenter MOMENTUM 3 
clinical trial, the HeartMate 3 (HM3) Left Ventricular Assist System (LVAS; 
Abbott, Chicago, IL, Study Sponsor) showed a decrease in hemocompatibility 
related adverse events relative to the HeartMate II (HMII) LVAS (Abbott, 
Chicago, IL)5. This included decreases in pump thrombosis6, stroke7-9, and 
bleeding9 event rates. Despite these noted improvements a high residual risk of 
bleeding persists in patients treated with the HM3 LVAD9. Patients implanted 
with the HM3 pump are treated with a combination of antiplatelet and 
anticoagulation therapy but the role and implications of this regimen in 
determining the burden of hemocompatibility related adverse events have not 
been adequately investigated9,10. Whether antiplatelet therapy is essential in 
concert with anticoagulation in treating such patients remains unknown. 
 
Objective 
To study the safety and efficacy of an anti-platelet-free antithrombotic regimen 
in patients with advanced heart failure treated with the HM 3 LVAS 
Hypothesis 
Withdrawal of aspirin from the antithrombotic regimen of HM3 pump patients 
will not adversely affect safety and efficacy and may reduce non-surgical 
bleeding 
Clinical 
Investigation 
Design 
Prospective, randomized, double-blinded, placebo-controlled clinical 
investigation of advanced heart failure patients treated with the HM3 with two 
different antithrombotic regimens: vitamin K antagonist with aspirin versus 
vitamin K antagonist with placebo 


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Device Under 
Investigation and 
Indications 
HeartMate 3 Left Ventricular Assist System (LVAS)  
 
In the US, the HM3 LVAS is indicated for providing mechanical circulatory 
support in patients with advanced refractory left ventricular heart failure (e.g. 
pending cardiac transplantation or myocardial recovery, or for permanent 
support). In Europe, the HM3 LVAS is intended to provide long term 
hemodynamic support in patients with advanced, refractory left ventricular heart 
failure. It is intended either for temporary support, such as a bridge to cardiac 
transplantation (BTT), or as permanent destination therapy (DT) and it is 
intended for use inside or outside the hospital. In Canada, The HM3 LVAS is 
indicated for providing mechanical circulatory support in patients with advanced 
refractory left ventricular heart failure (e.g., pending cardiac transplantation or 
myocardial recovery, or for permanent support). 
Treatment Arm 
Medication  
Aspirin (100 mg– active ingredient: Acetylsalicylic acid)  
OR 
Placebo (ALMAC Group, Craigavon, UK) 
Study Sites 
Up to 50 US and international sites  
Patient Protection 
Procedures 
This study will employ an independent clinical events committee (CEC), which 
will remain blinded to subject randomization, to adjudicate primary endpoint 
related adverse events. Study monitoring will be performed by an independent 
data safety monitoring board (DSMB), which will be unblinded to population 
randomization and determine independent rules for safety oversight.   
Primary Endpoint 
Composite of Survival free of any non-surgical1 major hemocompatibility related 
adverse event2 at 1-year post implant. 
 
1Non-surgical – any event occurring > 14-days post implant 
 
2Major Hemocompatibility Related Adverse Event: 
• 
Stroke 
• 
Pump Thrombosis (suspected or confirmed) 
• 
Bleeding (including intracranial bleeds that do not meet the stroke 
definition) 
• 
Arterial Peripheral Thromboembolism 


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Primary Endpoint 
Evaluation 
 
The primary endpoint composite success rate will be calculated for each 
treatment arm based on the number of subjects who survive to 12 months with 
no primary endpoint events divided by the total number of subjects in the 
Modified Intention to Treat Population (mITT) population. The placebo arm will 
be considered non-inferior to the aspirin arm if the lower boundary of the one-
sided 97.5% confidence limit of the risk difference in the composite success 
between treatment arms (Placebo-arm minus Aspirin-arm) is greater than the 
non-inferiority margin (10%).   
Number of 
Subjects Required 
for Inclusion in 
Clinical 
Investigation 
Results from the MOMENTUM 3 trial were used to derive a point estimate of 
71% survival to 1 year free of any major hemocompatibility related adverse 
events in the aspirin treated arm. It is assumed that in the absence of aspirin a 
2% improvement in the composite endpoint will be noted, mainly due to the 
reduction of bleeding complications without a change in thromboembolic 
complications. Based on these assumptions 220 patients will need to be 
enrolled in each arm (440 total) to achieve 80% power to prove that the placebo 
group is non-inferior to the aspirin group using a non-inferiority margin of 10% 
with the Farrington-Manning risk difference approach to non-inferiority at a one-
sided alpha = 0.025. To account for an expected 30% dropout rate associated 
with events occurring 2-14 days post implant, up to 628 patients will be 
randomized in the trial. Sample size calculations were performed using PASS 
15 software. 
Secondary 
Endpoint 
• 
Non-surgical Major Hemorrhagic Events 
• 
Non-surgical Major Thrombotic Events 
• 
Survival 
• 
Stroke Rates,  
• 
Pump Thrombosis Rates 
• 
Bleeding Rates, including: 
o Non-surgical Bleeding 
o Moderate Bleeding 
o Severe Bleeding 
o Fatal Bleeding 
o GI Bleeding 
 
Descriptive 
Endpoints 
Hemocompatibility Score, Rehospitalizations, Economic Cost Implications  


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Subject Follow-up 
− 
Baseline 
− 
Implant 
− 
Randomization 
− 
Discharge 
− 
Week 1 ± 3 days 
− 
Month 1 ± 7 days  
− 
Month 3 ± 30 days 
− Month 6 ± 30 days 
− Month 9 ± 30 days 
− Month 12 ± 30 days 
− Every 6 month ± 60 days until last 
subject has completed the 12-
month follow-up. 
Inclusion Criteria 
• 
Subject will receive the HeartMate 3 per standard of care (SOC) in 
accordance with the approved indications for use in the country of implant. 
• 
Subject will receive the HeartMate 3 as their first durable VAD.  
• 
Subject must provide written informed consent prior to any clinical 
investigation related procedure. 
• 
In patients of child bearing capability, not currently pregnant and on 
appropriate contraception.  
Exclusion Criteria 
• 
Post-implant additional temporary or permanent mechanical circulatory 
support (MCS) post-implant (other than the HM3 LVAD). 
• 
Post-implant Investigator mandated antiplatelet therapy for other conditions 
(including mandated presence or absence of antiplatelet agent). 
• 
Patients who are nil per os (NPO) post-implant through day 7. 
• 
Subjects with a known allergy to acetylsalicylic acid. 
• 
Participation in any other clinical investigation(s) involving an MCS device, 
or interventional investigation(s) likely to confound study results or affect 
study outcome. 
• 
Presence of other anatomic or comorbid conditions, or other medical, social, 
or psychological conditions that, in the investigator’s opinion, could limit the 
subject’s ability to participate in the clinical investigation or to comply with 
follow-up requirements, or impact the scientific soundness of the clinical 
investigation results. 
 
 
 


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APPENDIX IX: REFERENCES 
1 
Mozaffarian, D. et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the 
American Heart Association. Circulation 133, e38-360, doi:10.1161/CIR.0000000000000350 
(2016). 
2 
Rose, E. A. et al. Long-term use of a left ventricular assist device for end-stage heart failure. N 
Engl J Med 345, 1435-1443, doi:10.1056/NEJMoa012175 (2001). 
3 
Cook, J. L. et al. Recommendations for the Use of Mechanical Circulatory Support: Ambulatory 
and Community Patient Care: A Scientific Statement From the American Heart Association. 
Circulation 135, e1145-e1158, doi:10.1161/CIR.0000000000000507 (2017). 
4 
Mehra, M. R. The burden of haemocompatibility with left ventricular assist systems: a complex 
weave. Eur Heart J 40, 673-677, doi:10.1093/eurheartj/ehx036 (2019). 
5 
Uriel, N. et al. Hemocompatibility-Related Outcomes in the MOMENTUM 3 Trial at 6 Months: A 
Randomized Controlled Study of a Fully Magnetically Levitated Pump in Advanced Heart Failure. 
Circulation 135, 2003-2012, doi:10.1161/CIRCULATIONAHA.117.028303 (2017). 
6 
Mehra, M. R. et al. A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure. N 
Engl J Med 376, 440-450, doi:10.1056/NEJMoa1610426 (2017). 
7 
Colombo Paolo, C. et al. Comprehensive Analysis of Stroke in the Long-Term Cohort of the 
MOMENTUM 3 Study. Circulation 139, 155-168, doi:10.1161/CIRCULATIONAHA.118.037231 
(2019). 
8 
Mehra, M. R. et al. Two-Year Outcomes with a Magnetically Levitated Cardiac Pump in Heart 
Failure. N Engl J Med 378, 1386-1395, doi:10.1056/NEJMoa1800866 (2018). 
9 
Mehra, M. R. et al. A Fully Magnetically Levitated Left Ventricular Assist Device - Final Report. N 
Engl J Med 0, null, doi:10.1056/NEJMoa1900486 (2019). 
10 
Netuka, I. et al. Evaluation of low-intensity anti-coagulation with a fully magnetically levitated 
centrifugal-flow circulatory pump-the MAGENTUM 1 study. J Heart Lung Transplant 37, 579-586, 
doi:10.1016/j.healun.2018.03.002 (2018). 
11 
Schmitto, J. D. et al. Long-term evaluation of a fully magnetically levitated circulatory support 
device for advanced heart failure—two-year results from the HeartMate 3 CE Mark Study. 
European journal of heart failure 21, 90-97, doi:10.1002/ejhf.1284 (2019). 
12 
Saeed, D. et al. Two-Year Outcomes in Real World Patients Treated with Heartmate 
3<sup>TM</sup> Left Ventricular Assist Device for Advanced Heart Failure: Data from the 
ELEVATE Registry. The Journal of Heart and Lung Transplantation 38, S67, 
doi:10.1016/j.healun.2019.01.153 (2019). 
13 
Heatley, G. et al. Clinical trial design and rationale of the Multicenter Study of MagLev 
Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 
(MOMENTUM 3) investigational device exemption clinical study protocol. J Heart Lung 
Transplant 35, 528-536, doi:10.1016/j.healun.2016.01.021 (2016). 
14 
Mehra, M. R. et al. A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure. N 
Engl J Med 376, 440-450, doi:10.1056/NEJMoa1610426 (2016). 
15 
Uriel, N. & Mehra, M. Long-Term Burden of Hemocompatibility Related Adverse Events in the 
MOMENTUM 3 Trial: Final Analysis of the 1028 Patient Cohort. The Journal of Heart and Lung 
Transplantation 38, S67, doi:10.1016/j.healun.2019.01.152 (2019). 
16 
Netuka, I. et al. A Trial of Complete Withdrawal of Anticoagulation Therapy in the Heartmate 3 
Pump. The Journal of Heart and Lung Transplantation 38, S113, 
doi:10.1016/j.healun.2019.01.264 (2019). 
17 
Consolo, F., Raimondi Lucchetti, M., Tramontin, C., Lapenna, E. & Pappalardo, F. Do we need 
aspirin in HeartMate 3 patients? European journal of heart failure, doi:10.1002/ejhf.1468 (2019). 


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18 
Lim, H. S., Ranasinghe, A., Mascaro, J. & Howell, N. Discontinuation of Aspirin in Heartmate 3 
Left Ventricular Assist Device. ASAIO Journal (American Society For Artificial Internal Organs: 
1992), doi:10.1097/MAT.0000000000000859 (2018). 
19 
McNeil, J. J. et al. Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly. 
New England Journal of Medicine 379, 1509-1518, doi:10.1056/NEJMoa1805819 (2018). 
20 
Katz, J. N. et al. Safety of reduced anti-thrombotic strategies in HeartMate II patients: A one-year 
analysis of the US-TRACE Study. Journal of Heart and Lung Transplantation 34, 1542-1548, 
doi:10.1016/j.healun.2015.06.018 (2015). 
21 
Netuka, I. et al. Outcomes in HeartMate II Patients With No Antiplatelet Therapy: 2-Year Results 
From the European TRACE Study. The Annals of thoracic surgery 103, 1262-1268, 
doi:10.1016/j.athoracsur.2016.07.072 (2017). 
22 
Van Tuyl, J. S. et al. Warfarin and Aspirin Versus Warfarin Alone for Prevention of Embolic 
Events in Patients with a HeartMate II Left Ventricular Assist Device. ASAIO journal 63, 731-735, 
doi:10.1097/mat.0000000000000561 (2017). 
23 
Litzler, P. Y. et al. Is anti-platelet therapy needed in continuous flow left ventricular assist device 
patients? A single-centre experience. European journal of cardio-thoracic surgery : official journal 
of the European Association for Cardio-thoracic Surgery 45, 55-59; discussion 59-60, 
doi:10.1093/ejcts/ezt228 (2014). 
 

SAP_001.pdf: 
 
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CRD_971 
 
ARIES HM3 
 
Antiplatelet Removal and HemocompatIbility EventS with the HeartMate 3 Pump 
 
 
Statistical Analysis Plan (SAP) 
 
 
Version F 
 
August 7, 2023 
 
 
 
 
 
 
John Henderson 
 
 
 
 
 


 
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TABLE OF CONTENTS  

SYNOPSIS OF STUDY DESIGN ..................................................................................................... 4

Purpose of the Statistical Analysis Plan ....................................................................................... 4

Clinical Investigation Objectives ................................................................................................... 4

Clinical Investigation Design ......................................................................................................... 4

Endpoints ...................................................................................................................................... 4

Primary Endpoint ................................................................................................................... 4
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Secondary Endpoint(s) .......................................................................................................... 5
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Descriptive Endpoint(s) ......................................................................................................... 5
Randomization..............................................................................................................................5
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Blinding ......................................................................................................................................... 5
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ANALYSIS CONSIDERATIONS ...................................................................................................... 6
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Analysis Populations .................................................................................................................... 6

Modified Intent to Treat Population (mITT) ............................................................................ 6
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Intent to Treat (ITT) Population ............................................................................................. 6
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Per Protocol (PP) Population................................................................................................. 6
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Statistical Methods........................................................................................................................ 7
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Descriptive Statistics for Continuous Variables ..................................................................... 7

Descriptive Statistics for Categorical Variables ..................................................................... 7
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Endpoint Analysis ......................................................................................................................... 7
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Primary Endpoint ................................................................................................................... 7
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Hypothesis ..................................................................................................................... 7
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Sample Size ................................................................................................................... 8
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Analysis Methods ........................................................................................................... 8
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Justification of the Non-Inferiority Margin ....................................................................... 8
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Poolability Analysis......................................................................................................... 8
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Sensitivity Analysis ......................................................................................................... 9
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Subgroup Analysis ....................................................................................................... 10
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Secondary Endpoints .......................................................................................................... 10
Descriptive Endpoints..........................................................................................................11
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Sensitivity Analyses to Evaluate Possible Impact of COVID-19 .......................................... 11
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Interim Analysis .......................................................................................................................... 12
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Timing of Analysis....................................................................................................................... 12
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Study/Trial Success .................................................................................................................... 12
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Handling of Missing Data ............................................................................................................ 12


 
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Multiplicity Issues ........................................................................................................................ 12
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Baseline and Demographic Characteristics ................................................................................ 12
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Adverse Events .......................................................................................................................... 13
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Operative Procedures ................................................................................................................. 13
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Quality of Life and Functional Status .......................................................................................... 13
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Stratification by Pre-implant Aspirin Use .................................................................................... 13
2.14
Subject Early Termination........................................................................................................... 13
2.15
Protocol Deviation ...................................................................................................................... 13
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DOCUMENTATION AND OTHER CONSIDERATIONS ................................................................ 14
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ACRONYMS AND ABBREVIATIONS ............................................................................................ 14
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REFERENCES ............................................................................................................................... 15
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APPENDICES ................................................................................................................................ 16
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SYNOPSIS OF STUDY DESIGN   
 
Purpose of the Statistical Analysis Plan
This statistical analysis plan (SAP) is intended to provide a detailed and comprehensive description of 
the planned methodology and analysis to be used for CIP 10305, the ARIES HM3 clinical investigation. 
Version F of the SAP is based on the Version C, March 13, 2020 Clinical Investigation Plan  
 
Clinical Investigation Objectives 
To study the safety and efficacy of an anti-platelet-free antithrombotic regimen in patients with advanced 
heart failure treated with the HM3 LVAS 
 
Clinical Investigation Design 
This is a prospective, randomized, double-blinded, placebo-controlled clinical investigation of advanced 
heart failure patients treated with the HM3 with two different antithrombotic regimens: vitamin K 
antagonist with aspirin vs vitamin K antagonist with placebo. Subjects will be randomized in a 1:1 ratio.  
 
The clinical investigation has been designed to involve as little pain, discomfort, fear, and any other 
foreseeable risk as possible for subjects.  
 
The clinical investigation will be conducted at up to 50 centers worldwide. The primary, and secondary 
endpoints will be evaluated as described in this SAP. Outcomes for this study include death, transplant, 
withdrawal or pump exchange. All subjects, site, Clinical Events Committee (CEC),  and sponsor 
personnel, will remain blinded to the randomization scheme until the last ongoing study subject 
completes follow-up (specifically, experiences an outcome or reaches 12-months of follow up) and all 
data have been collected and adjudicated, exceptions will be justified in the study blinding plan (eg. 
DSMB). After a patient reaches 12-months of follow up, they will continue to be followed every 6-months, 
as long as they remain on the treatment arm medication, until the last ongoing patient reaches 12-
months of follow up. Beginning at the 12-month follow-up visit, patients should be requisitioned two 
bottles of the treatment arm medication to cover the 6 months until the next follow up visit. 
 
Endpoints 
 Primary Endpoint 
The primary endpoint for this study will be met if the placebo arm is non-inferior to the aspirin arm in the 
composite of survival free of any non-surgical1 major hemocompatibility related adverse event2 at 1-year 
post implant. 
 
1 - Non-surgical – any event occurring > 14-days post implant. 
2 - Major Hemocompatibility Related Adverse Event: 
• 
Stroke 
• 
Pump Thrombosis (suspected or confirmed) 
• 
Bleeding (including intracranial bleeds that do not meet the stroke definition) 
• 
Arterial Peripheral Thromboembolism 
 


 
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This study assesses the overall change in the overall incidence of major hemocompatibility related 
adverse events. Additional secondary endpoints will also be evaluated to monitor effects on other study 
outcome measures.  
 
This composite primary endpoint reflects the interrelatedness of hemocompatibility related adverse 
events, providing an endpoint that will result in a clear answer to the study’s primary question of whether 
or not anti-platelets are required to maintain the safety and efficacy profile of the HM3. Because post-
implant clinical course can be widely variable due to clinical responses to adverse events, this composite 
endpoint focuses on the first major hemocompatibility related adverse event to ensure the effect of the 
treatment arm is reflected in the primary endpoint measure. Non-composite endpoints or endpoints that 
do not focus on the first event have the possibility of being rendered futile or distorted by treatment 
responses to prior adverse events. 
 Secondary Endpoint(s) 
To assess the safety of removal of antiplatelets from the antithrombotic regimen, non-surgical major 
hemorrhagic events, non-surgical major thrombotic events, bleeding, stroke, pump thrombosis and 
survival will be compared between the two arms of the study. 
 Descriptive Endpoint(s) 
This study will also assess changes in the Hemocompatibility Score, Rehospitalization, and Economic 
Cost Implications as a result of removal of antiplatelets from the antithrombotic regimen.  
 
Randomization 
Only subjects who have provided informed consent, been implanted with the HM3 and subsequently met 
all inclusion and no exclusion criteria will be randomized. Randomization will be performed through 
ALMAC Clinical’s WebEZ system. Subjects will be randomized in a 1:1 ratio between the placebo and 
aspirin group. Randomization will be stratified by study center and assigned using a block size of 4 
subjects.  Prior to randomizing a patient in WebEZ, patients will have been initialized in the Sponsor’s 
EDC portal upon enrollment and obtained a subject ID number, which will also be used as the patient 
identifier in the WebEZ system. Subjects should begin taking the treatment arm medication within 24 
hours of randomization. 
 
Blinding 
This is a double-blind study, neither patient nor investigator will know the subject’s randomization 
throughout the study follow up. Additionally, sponsor personnel and the CEC will not have access to 
patient or population blinding information. The blind of the study will only be broken once the study 
follow-up is completed, and adverse event adjudication is completed. Questions related to unblinding 
should be directed to the Sponsor.
 
 


 
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ANALYSIS CONSIDERATIONS 
 
Analysis Populations 
Subjects are considered enrolled at the time they sign informed consent. Subjects will be included in 
analysis populations when they have provided consent, have been implanted with the HeartMate 3 and 
have been randomized to a treatment arm. The reasons that enrolled subjects were not randomized will 
be summarized.   
 Modified Intent to Treat Population (mITT)  
The mITT population will include all randomized subjects with the following exception: 
 
1. Subjects who experience a surgical adverse event, defined as ≤14 days post-implant, requiring 
investigator mandated antiplatelet therapy 
2. Subjects who expire, are transplanted, or withdraw within 14 days of implant 
 
Non-surgically related major hemocompatibility related adverse events will only be analyzed up to the 
transition to open label. Subjects will be analyzed according to the treatment arm assigned at 
randomization. The mITT population will be used for all analyses unless noted differently in one 
sensitivity analysis. 
 Intent to Treat (ITT) Population 
The ITT population will consist of all subjects randomized. Subjects will be analyzed according to the 
treatment arm assigned at randomization. The ITT population will only be used for one sensitivity 
analysis of the primary endpoint. 
 
 Per Protocol (PP) Population 
The Per-Protocol (PP) population will consist of all randomized subjects within the mITT population 
excluding: 
 
• 
Subjects with protocol deviations for the following: 
o Randomized subjects who do not meet eligibility requirements 
o Unblinding of subject or investigator prior to completion of study including possible 
unblinding by platelet function testing 
o Withdrawal of the treatment arm antithrombotic regimen without clinical reason 
o Additional antiplatelet medications added to the treatment arm antithrombotic regimen 
• 
Subjects who transition to open label without experiencing any primary endpoint events  
• 
Subjects who terminate the study prematurely without experiencing any primary endpoint events 
prior to 12 month visit 
 
The PP population will only be used for one sensitivity analysis of the primary endpoint. 
 
 
 


 
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Statistical Methods 
 Descriptive Statistics for Continuous Variables 
Continuous variables will be summarized with the numbers of observations, means and standard 
deviations, with quartiles, minimum and maximum. 
 Descriptive Statistics for Categorical Variables 
Categorical variables will be summarized with subject counts and percentages/rates, and with exact 95% 
Clopper-Pearson confidence intervals. 
 
Endpoint Analysis 
 Primary Endpoint 
The primary endpoint is a composite of survival free of any non-surgical1 major hemocompatibility related 
adverse event2 at 1-year post implant. 
 
1 - Non-surgical – any event occurring > 14-days post implant. 
2 - Major Hemocompatibility Related Adverse Event: 
• 
Stroke 
• 
Pump Thrombosis (suspected or confirmed) 
• 
Bleeding (including intracranial bleeds that do not meet the stroke definition) 
• 
Arterial Peripheral Thromboembolism 
 
A subject will be considered a success if they survive to their 12 month visit and have not experienced a 
non-surgical hemocompatibility related adverse events. Subjects who have an outcome (e.g. 
transplanted or explanted due to recovery) prior to their 12 month visit that have not reported a non-
surgical hemocompatibility related adverse event prior to censoring will also be considered a success.  
 
A subject will be considered a failure if: 
 
• 
the subject expires prior to their 12 month visit 
• 
the subject experiences a non-surgical hemocompatibility related adverse event prior to their 12 
month visit. 
 
The primary analysis will be performed using the mITT population. 
 Hypothesis 
The primary endpoint hypothesis is formally expressed as: 
H0: πplacebo  ≤ πaspirin - ∆ 
Ha: πplacebo  > πaspirin - ∆ 
where πplacebo and πaspirin are the percentage of subjects who successfully achieve the composite endpoint 
in the placebo and aspirin groups and where ∆ is the non-inferiority margin (NIM) fixed at 10%. 
 
 


 
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 Sample Size 
Results from the MOMENTUM 3 trial were used to derive a point estimate of 71% survival to 1 year free 
of any major hemocompatibility related adverse events in the aspirin treated arm. It is assumed that in 
the absence of aspirin a 2% improvement in the composite endpoint will be noted, mainly due to the 
reduction of bleeding complications without a change in thromboembolic complications. Based on these 
assumptions 220 patients will need to be randomized in each arm (440 total) to achieve 80% power to 
prove that the placebo group is non-inferior to the aspirin group using a non-inferiority margin of 10% 
with the Farrington-Manning risk difference approach at a one-sided alpha = 0.025. To account for an 
expected 30% dropout rate associated with events occurring 2-14 days post implant, up to 628 patients 
will be randomized in the trial. Sample size calculations were performed using PASS 15 software and are 
included in Appendix 1.  
 Analysis Methods 
The primary endpoint composite success rate will be calculated for each treatment arm based on the 
number of subjects who successfully meet the primary endpoint divided by the total number of subjects 
in the mITT population (refer to section 2.1.1). Subjects who terminate the study prematurely (e.g. lost to 
follow-up or withdrawn) without experiencing any primary endpoint events prior to 12 month visit will be 
excluded in the denominator for the calculation of the composite success rate. The Farrington-Manning 
test for the difference of proportions will be performed at the 2.5% significance level. The null hypothesis 
will be rejected, and the placebo arm considered non-inferior to the aspirin arm, if the lower boundary of 
the one-sided 97.5% confidence limit of the difference in the composite success between treatment arms 
(Placebo-arm minus Aspirin-arm) is greater than the non-inferiority margin (10%) 
 Justification of the Non-Inferiority Margin 
Given the sample size of 220 subjects per group and a NIM of 10%, the null hypothesis would not be 
rejected if placebo group minus the aspirin group is less than -1%. If 71% of the aspirin group 
successfully achieves the primary composite endpoint, then 153 or more patients out of the 220 placebo 
subjects (70%) would need to be successful to demonstrate non-inferiority.  
 
The steering committee ruled that a small increase of 1% in the primary composite endpoint will not be a 
clinically meaningful difference and should be acceptable for non-inferiority, with no overriding safety 
concern noted within the individual safety endpoints. The individual components of the primary endpoint 
are evaluated independently as safety endpoints, therefore any deleterious effects of aspirin removal on 
individual outcomes will be reported separately. 
 Poolability Analysis 
2.3.1.5.1 
Multiple Geography Effect 
The trial will be conducted in up to 50 sites worldwide including, but not limited to, the United States, 
Europe and Canada following the same investigational plan and inclusion and exclusion criteria. The trial 
will be conducted following the same procedures, monitoring plan and training plan in all regions.  
Poolability of the primary endpoint across region (i.e., US vs. OUS) will be evaluated for subjects 
included in the mITT population.  
 
To evaluate the geography effect on the primary endpoint, Fisher’s exact test will be tested for 
geography effect against an alpha level of 0.15. If the p-value is less than 0.15, Abbott will examine 


 
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subject demographics, baseline clinical characteristics will be examined, and outlier or influential sites 
will be identified. 
2.3.1.5.2 
Multiple Center Effect 
Analysis will be performed by pooling data across study sites. The trial will have up to 50 sites globally. 
Subject randomization is capped at 94 per site (15% of the total number of randomized subjects 
assuming dropouts). This cap per site will prevent the scenario where the results from a few sites 
dominate the overall study result. For the analysis of center effect, data from smaller sites may be 
combined for the analysis. Smaller sites are defined as sites with fewer than 20 subjects per site. The 
pooling of the smaller sites will be based on the following rules: 
 
• 
Sort all smaller sites based on the number of subjects per site in an ascending order. If there are ties, 
sort further by site number. 
•
Starting from the smallest site in this list, combine sites by going up the list until the combined group 
size first reaches 20 or larger. At this point, a super site is identified. 
• 
Repeat the above grouping process from the next smallest site above the newly formed super site. 
• 
The grouping process ends when all smaller sites have been accounted for. 
 
The sizes of the super sites (which are a result of grouping smaller sites) will range between 20 and up to 
38 (19+19). This represents a reasonable range of sample sizes which will provide meaningful estimates 
of within-sites variations and will not alter between-sites variation. 
 
To evaluate the multiple center effect on the primary endpoint, Cochran-Mantel-Haenszel will be tested 
for center effect against an alpha level of 0.15.  If the p-value is less than 0.15, subject demographics, 
baseline clinical characteristics will be examined, and outlier or influential sites will be identified. 
 Sensitivity Analysis 
The following sensitivity analyses of the primary endpoint will be performed in the mITT population: 
 
1. To demonstrate robustness with respect to missing data, a tipping point analysis will be 
performed for the primary composite endpoint. This will involve imputing all possible combinations 
of outcomes for the primary endpoint among subjects who terminate the study prematurely 
without experiencing any primary endpoint events. 
 
2. In order to assess if the adequacy of anticoagulation or compliance with prescribed 
anticoagulation is confounding the primary endpoint result, the time in therapeutic (TTR) range 
will be assessed using the Rosendaal method. Time in therapeutic range will be compared 
between treatment groups using a Wilcoxon rank sum test. If it is determined there is a difference 
in TTR between treatment groups, a sensitivity analysis of the primary endpoint will be performed 
by stratifying the subjects by TTR. Poor anticoagulation control will be defined as a TTR less than 
65%. Stratification will include subjects with TTR < 65% vs subjects with TTR ≥ 65%.  
 
3. Sensitivity analysis of the primary endpoint will also be performed based on the time to the first 
primary endpoint event using the Kaplan-Meier product-limit method. Treatment arms will be 
tested for non-inferiority with a NIM = 10% using Com-Nougue method 3. 
 


 
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4. To assess the impact of transition to open label, a sensitivity analysis will be performed to include 
non-surgical major hemocompatibility related adverse events beyond the time of transition to 
open label. 
 
The following sensitivity analysis will be performed on the ITT and PP populations:  
 
5. The primary endpoint will be analyzed based on the time to the first primary endpoint event using 
the Kaplan-Meier product-limit method. Treatment arms will be tested for non-inferiority with a 
NIM = 10% using Com-Nougue method. 
 Subgroup Analysis 
Subgroup analyses will be performed to examine the consistency of results for the primary endpoint across 
specific populations. Subgroup analyses will be performed on mITT population, using Fisher’s exact test. 
No subgroup specific labeling claims are intended for the primary endpoint and no adjustment will be made 
for multiplicity. Subgroups to be examined include, but are not limited to, gender, race, age (stratified by 
median age), age (less than 65 years vs 65 and greater), INTERMACS Profile (INTERMACS 1-2 vs 
INTERMACS 3+), TTR and surgical implant method. If home monitoring of anticoagulation is used in some 
site but not others, a subgroup analysis based on home monitoring will be conducted. 
 Secondary Endpoints 
The secondary endpoints will be analyzed using the mITT population.
 
Non-surgical Major Hemorrhagic events: Hemorrhagic event rate per patient year will be calculated by 
dividing all non-surgical bleeding events and hemorrhagic stroke events by the cumulative years of study 
exposure. This rate will be compared between groups using Poisson regression. 
 
Non-surgical Major Thrombotic events: The thrombotic event rate per patient year will be calculated by 
dividing the number of non-surgical ischemic strokes, pump thrombosis and arterial peripheral 
thromboembolic events by the cumulative years of study exposure. This rate will be compared between 
groups using Poisson regression. 
 
Survival: The overall survival rate will be analyzed using a Kaplan-Meier analysis and the treatment 
groups compared using the log-rank test. Survival will be calculated starting at 14 days post implant.  
 
Stroke Rate: The stroke rate will be calculated based on the number of strokes experienced by subjects, 
14 days or more after device implant, and while on their treatment assignment, divided by the cumulative 
duration of study exposure (years of support). The treatment groups will be compared by using Poisson 
regression.  
 
 All strokes that occur 14 or more days after implant will be included, regardless of the treatment status of 
the subject (subjects who move off their randomized treatment will continue to be followed). Ischemic 
and hemorrhagic stroke rates and debilitating stroke rate (MRS > 3) will also be analyzed. The stroke 
rate and treatment comparison will be performed as described above.  
 
Time to first non-surgical stroke event will also be analyzed using a Kaplan-Meier analysis. The 
treatment groups will be compared using a log-rank test.  
 


 
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Pump Thrombosis: The pump thrombosis rate will be calculated based on the number of suspected or 
confirmed pump thrombosis events experienced by the subject, 14 or more days post device implant, 
while on their treatment assignment divided by the cumulative duration of study exposure (years of 
support). The treatment groups will be compared by using Poisson regression. 
 
 All suspected pump thrombosis that occurs 14 or more days post implant will be included, regardless of 
the treatment status of the subject (subjects who move off their randomized treatment will continue to be 
followed). The pump thrombosis rate and treatment comparison will be performed as described above.  
 
Bleeding: All bleeding events that occur will be captured. Subjects who terminate the study prematurely 
without experiencing any bleeding will have the time they were in the study counted in the analysis. For 
the mITT population, bleeding events will be included while the subject remains on their randomization 
assignment until the last randomized patient has been followed to one year. This will result in some 
subjects being followed for more than one year.  
 
Bleeding rates will be differentiated based on severity and will include moderate bleeding, severe 
bleeding and fatal bleeding. Gastrointestinal (GI) bleeding and non-surgical bleeding will also be
analyzed. The bleeding rate (events per patient year) will be calculated by dividing the number of 
bleeding events by the cumulative duration of study exposure (years of support).  Bleeding rates will be 
compared between treatment groups using Poisson regression. In addition, a subgroup analysis will be 
performed according to subject aspirin responsive testing. 
 
In addition, all secondary endpoints will be analyzed to include non-surgical major hemocompatibility 
related adverse events beyond the time of transition to open label in the mITT population. 
 Descriptive Endpoints 
Hemocompatibility Score: The Hemocompatibility Score (HCS) is a tiered hierarchal score that weighs 
each hemocompatibility related adverse event by its escalating clinical relevance (1, 2). The HCS will be 
calculated for each subject in the mITT population and summarized for the treatment group as a median 
score and range.  
 
Rehospitalizations: The rehospitalization rate will be calculated based on the number of subjects who 
require a rehospitalization (excluding the hospitalization for the implant), for any cause, after 
randomization and initiation of the study treatment (14 or more days post implant), divided by the number 
of subjects. Patient year of support will be the cumulative patient duration from 14 days post implant to 
outcome (transplant, explant, withdrawal or death) or until the last subject reaches their 12-month follow-
up, whichever occurs first. 
 
 Sensitivity Analyses to Evaluate Possible Impact of COVID-19 
 
In order to evaluate the possible impact of COVID-19 on the primary and secondary endpoints, sensitivity 
analyses will be implemented. A COVID-19 subject is defined as any subject obtaining a positive COVID-
19 test either prior to enrollment or during the 12-month follow-up or having an adjudicated COVID-19 
related or possibly related adverse event during the 12-month follow-up. The following analyses will be 
included: 
 


 
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1) The primary endpoint will be analyzed excluding COVID-19 subjects from the denominator for the 
calculation of the composite success rate.
 
2) The primary endpoint will be analyzed excluding primary endpoint adverse events adjudicated as 
related or possibly related to COVID-19. 
 
3) A subgroup analysis will be performed to examine the consistency of results for the primary 
endpoint between COVID-19 subjects and non-COVID-19 subjects. 
 
4) All secondary endpoints will be evaluated excluding adverse events adjudicated as related or 
possibly related to COVID-19.   
 
Other sensitivity analyses recommended based on available guidelines and modalities related to COVID-
19 may also be performed as appropriate.  
 
 
Interim Analysis 
No formal interim analysis is planned for this study to stop the trial early due to futility or success. 
 
Timing of Analysis 
The primary endpoint analysis will be performed, and the clinical report prepared when all randomized 
subjects have reached a primary endpoint and the study has been unblinded.  
 
Study/Trial Success 
The trial will be considered successful if null hypothesis of the primary endpoint is rejected (i.e. the 
placebo group is non-inferior to the aspirin group). 
 
Handling of Missing Data 
As described in Section 2.3.1.6, a tipping point analysis will be performed to evaluate the impact of 
missing data on the primary endpoint analysis result in mITT population. 
 
Any unused or spurious data will be noted as appropriate in the final report. 
 
Multiplicity Issues 
This study includes a single primary endpoint. Thus, no Type I error adjustment is necessary.  
 
Baseline and Demographic Characteristics 
The following baseline characteristics will be descriptively presented according to treatment assignment: 
demographics, medical history, INTERMACS profile, vital signs, medications, laboratory assessments, 
coagulation assessments, hemodynamic assessments, and echocardiogram results. Continuous 
variables will be reported as a mean with standard deviation, and by quartiles, minimum and maximum 
values. Categorical variables will be reported as the number and percentage of subjects in each 
category. 


 
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 Adverse Events 
Adverse events are described in Section 6.8.1 of the ARIES HM3 Clinical Investigational Plan and 
defined in Appendix II of that document.  Adverse events that occur within one year of implant will be 
reported per randomized treatment group. Adverse events in consented patients who are not reflected in 
the analysis populations (i.e. not randomized or who experience surgical events - ≤14 days post implant) 
will be summarized separately from the two treatment arms of the study. The data will be presented as 
the number and percentage of all subjects enrolled who experience the event and the total number of 
events.  
 
Adverse events in the analysis populations will be presented as number and percentage of all subjects 
enrolled who experience the event, the total number of events and the events rate (events per patient 
year). Adverse events will also be analyzed according to their severity.  
 
Operative Procedures 
All operative procedures, regardless of cause, will be reported per randomized treatment arm. The report 
will include the number and percentage of subjects who receive an operative procedure after implant and 
the total number of procedures that occur within one year of the initial device implant. The reason for the 
operation will also be summarized. 
 
Quality of Life and Functional Status 
Quality of life and functional status will be measured at baseline, 6 months and 12 months. Results will 
be reported per randomized treatment group: 
 
EQ-5D: The Visual Analog Score (VAS) will be summarized using descriptive statistics. A table will be 
created with the results of the EQ-5D questions 
 
NYHA Class: Results will be categorically presented by time interval and treatment arm 
 
6-Minute walk test (6MWT): Distance walked at each time interval will be descriptively presented. 
Subjects who are unable to walk due to heart failure will be imputed a score of 0. All other missing data 
will be ignored. 
 
Stratification by Pre-implant Aspirin Use 
The primary endpoint will be analyzed by stratifying subjects that are on aspirin pre-implant of the HM3 
versus subject who are not using aspirin pre-implant. 
2.14 
Subject Early Termination  
The reason for early termination will be summarized for each randomized treatment group. Causes of 
death will also be summarized by treatment group. 
2.15 
Protocol Deviation 
Protocol deviations will be summarized by major and minor categories for subjects in whom a protocol 
deviation was reported. Major protocol deviations will include: 
 


 
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• 
withdrawal of the treatment arm antithrombotic regimen without clinical reasons  
• 
additional antiplatelet medications added to the treatment arm antithrombotic regimen  
• 
enrollment or randomization of patients who do not meet eligibility requirements 
• 
informed consent deviations, except inadvertent incorrect dating.  
 
DOCUMENTATION AND OTHER CONSIDERATIONS 
All analyses will be performed using SAS for Windows, version 9.4 or higher.  
 
ACRONYMS AND ABBREVIATIONS  
Acronym or Abbreviation 
Complete Phrase or Definition 
CEC 
CIP 
CRF 
DSMB 
HCS 
HM3 
ITT 
LVAS 
MRS 
NIM 
SAE 
SAP 
TTR 
Clinical Events Committee 
Clinical Investigation Plan 
Case Report Form 
Data Safety Monitoring Board 
Hemocompatibility Score 
HeartMate 3 
Intent To Treat 
Left Ventricular Assist System 
Modified Rankin Score 
Non-Inferiority Margin 
Serious Adverse Event 
Statistical Analysis Plan 
Time in Therapeutic Range 
 
 


 
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REFERENCES 
1. Mehra, M. R. The burden of haemocompatibility with left ventricular assist systems: a complex weave. 
European Heart Journal. 2019, 40, 673-677. 
2.Uriel N. Colombo PC. Cleveland JC et al. Hemocompatibility-related outcomes in the MOMENTUM 3 
trial at 6 months. A randomized controlled study of a fully magnetically levitated pump in advanced heart 
failure. Circulation 2017; 135:2003-2012. 
3. Com-Nougue C, Rodary C, Patte C. How to establish equivalence when data are censored: a 
randomized trial of treatments for B non-Hodgkin lymphoma. Statist Med 1993; 12:1353-1364. 
 
 


 
Redacted - CL1007801 Ver. F 
Study Name:  ARIES HM3 
Statistical Analysis Plan  
 
Template: 86379 Rev. F                                                                                                                                     Page 16 of 17 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the 
express written consent of Abbott. 
 
 
APPENDICES 
 
APPENDIX A: POWER AND SAMPLE SIZE CALCULATIONS 
Non-Inferiority Tests for the Difference Between Two Proportions 
 
Numeric Results for Non-Inferiority Tests for the Difference Between Two Proportions 
Test Statistic: Farrington & Manning Likelihood Score Test 
H0: P1 - P2 ≤ D0 vs. H1: P1 - P2 = D1 > D0. 
 
Target
Actual 
 
Ref. 
P1|H0 
P1|H1 
NI Diff 
Diff 
 
 
Power Power* 
N1
N2 
N
P2 
P1.0 
P1.1 
D0 
D1 
Alpha 
 
0.80 
0.80013 
220
220 
440
0.7100 0.6100 
0.7300 -0.1000 0.0200 
0.025 
 
 
* Power was computed using the normal approximation method. 
 
 


 
Redacted - CL1007801 Ver. F 
Study Name:  ARIES HM3 
Statistical Analysis Plan  
 
Template: 86379 Rev. F                                                                                                                                     Page 17 of 17 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the 
express written consent of Abbott. 
 
APPENDIX B: Device Position Substudy 
 
A substudy is proposed to develop and validate the use of a radiopaque surgical marker placed on the 
anterior surface of the aortic root below the sino-tubular ridge of the aorta just above the ostia of the right 
coronary artery to be used as a surrogate anatomical reference or landmark to more optimally assess 
HeartMate 3 inflow cannula position. The substudy will include subjects enrolled in the ARIES HM3 study 
who also meet eligibility requirements for this substudy at participating centers. Validation will be 
performed by assessing: 
 
1. Safety and feasibility assessment of the radiopaque surgical marker will be made using 
anteroposterior (AP) and lateral radiographs captured prior to discharge (but within 30 days of 
implant) and at the 3-month follow up visit. The following assessments will be descriptively 
presented as the number and percentage of subjects for each category: successful placements, 
successful visualizations, and gross migrations. Adverse events related to the clip or placement 
procedure will be presented as the number and percentage of subjects enrolled in the substudy 
and total number of events. 
 
2. The angular position of the canula relative to the marker will be measured from the AP view, and 
the distance of the marker to the axial alignment of the canula will be measured from the lateral 
view. The cannula position relative to the radiopaque marker and cannula positional changes 
over time will be descriptively and graphically summarized from both the AP and lateral 
radiographs. These measurements will be summarized as mean with standard deviation, and by 
quartiles, minimum and maximum values. 
 
The radiographs recorded at both pre-discharge and 3 months will be reviewed by an 
independent evaluator and assessed visually for cannula position at both time points along with 
potential significant change in position from pre-discharge to 3 months. Visual assessments will 
be categorized and summarized as count and percentage of subjects enrolled in the substudy. 
 
3. Patients may also be grouped into clusters with each cluster representing different levels of 
change in cannula position.   Comparisons of adverse clinical outcomes and functional capacity 
including the following will be made between clusters: 
 
• 
Adverse Events: Mortality, Stroke, Pump Thrombosis, Bleeding, Major HRAE, HRAE, Right 
Heart Failure, Cardiac Arrhythmia  
• 
Major thrombotic and major hemorrhagic events 
• 
Hospitalizations 
• 
Index Hospitalization and ICU Length of Stay; All Cause readmission; Number of 
readmissions; Days out of the hospital vs in-hospital 
• 
RHF Caused Hospitalizations 
• 
6 Minute Walk Test Distance as a surrogate for LV unloading 
• 
Change over time, cumulative 6MWT distance (post implant only) 
• 
EQ-5D-5L  
• 
NYHA Classification 
• 
Effect of Treatment Arm designation on AEs as Sensitivity Analysis 
 
Clinical significance can then be interpreted with the results of comparison.