Clinical trial NCT02836652
Conditions: Heart Failure
Keywords: HeartMate II (HMII) Left Ventricular Assist Device (LVAD)
Sponsor: Abbott Medical Devices
Start date: 2016-11-01; Completion date: 2019-07-18
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a prospective, multi-center, randomized, double-blind placebo-controlled study of subjects receiving the HM II LVAD as per the current FDA approved indications for use.

Detailed description:
This is a post-market clinical study of HM II patient management practices to be conducted in the United States.

Subjects will be randomized in a 1:1 fashion to the following research drug groups:

1. Treatment Arm: Warfarin (INR target: 2.0-2.5, median: 2.25) + Placebo (1 pill/day)
2. Control Arm: Warfarin (INR target: 2.0-2.5, median: 2.25) + ASA Therapy (81mg/day)

The study will investigate if subjects in the Treatment Arm experience a reduced incidence of non-surgical bleeding, without an increased risk of thromboembolic events.

Arms: arm 1: Warfarin (INR Target 2.0-2.5, median 2.25, per standard of patient care) + placebo (1 pill/day) post HeartMate II implant arm 2: Warfarin (INR Target 2.0-2.5, median 2.25, per standard of patient care) + acetylsalicylic acid (ASA) therapy (81mg/day) post HeartMate II implant
Interventions: intervention 1: HeartMate II (HMII) intervention 2: Warfarin intervention 3: acetylsalicylic acid (ASA) therapy
Intervention descriptions: intervention 1: Left Ventricular Assist Device intervention 2: (INR Target 2.0-2.5, median 2.25, per standard of patient care) intervention 3: (81mg/day)

Protocol documents:
Prot_SAP_000.pdf: 
 
Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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Page 1 of 60 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed 
or used without the express written consent of Abbott 
 
 
PREVENT II 
PREVENTion of Non-Surgical Bleeding by Management of  
HeartMate II Patients without Antiplatelet Therapy 
Clinical Investigation Plan (CIP) 
 
 
 
Sponsor: 
Abbott (formerly St. Jude Medical, Inc.) 
 
23 Fourth Avenue 
 
Burlington, MA 01803 
 
Tel: (781) 272-0139 
 
Fax: (781) 852-8320 
 
Document Date 
July 16 2020 
ClinicalTrials.gov ID:  
 
NCT02836652 


 
Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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or used without the express written consent of Abbott 
 
 
Principal Investigator Signature Page 
 
 
 
PREVENTion of Non-Surgical Bleeding by Management of HeartMate II  
Patients without Antiplatelet Therapy (PREVENT II) 
 
 
Version A 
 
 
Reference #: ABT-CIP-10353 
 
 
 
 
I have read and agree to adhere to the clinical investigational plan and all regulatory requirements 
applicable in conducting this clinical study. 
 
 
Principal Investigator 
 
Printed Name: 
 
Signature: 
 
Date: 
 
 
 


 
Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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TABLE OF CONTENTS 
Table of Appendices ............................................................................................................... 6 
List of Figures ......................................................................................................................... 6 
List of Tables ........................................................................................................................... 6 
1 
Synopsis ...................................................................................................................... 7 
2 
Background and Justification for Clinical Study .......................................................... 11 
2.1 
Bleeding in HM II Patients .............................................................................. 11 
2.2 
Thrombosis in HM II Patients ......................................................................... 12 
2.3 
Clinical Equipoise on the Use of ASA in HM II Patients .................................. 12 
2.4 
Study Justification .......................................................................................... 13 
3 
Risks and Benefits of the Clinical Study ..................................................................... 13 
3.1 
Anticipated Clinical Benefits ........................................................................... 13 
3.2 
Anticipated Adverse Events and Adverse Device Effects ............................... 13 
3.3 
Possible Interactions with Concomitant Medical Treatments and/or Concurrent 
Medical Interventions ..................................................................................... 13 
3.4 
Mitigation of Risks .......................................................................................... 13 
4 
Study Design ............................................................................................................. 14 
4.1 
Purpose ......................................................................................................... 14 
4.2 
Study Design and Scope ................................................................................ 14 
4.3 
Study Blinding ................................................................................................ 14 
4.3.1 
Description of Subject Population .................................................... 15 
4.3.2 
PREVENT Recommendations to Reduce Pump Thrombus ............. 15 
4.3.3 
Number of Subjects Required to be Included in the Study ............... 15 
4.3.4 
Estimated Time Needed to Enroll Subject Population ...................... 15 
4.4 
Objective ........................................................................................................ 15 
4.5 
Endpoints ....................................................................................................... 15 
4.5.1 
Primary Endpoints ........................................................................... 15 
4.5.2 
Descriptive Endpoints ...................................................................... 16 
4.6 
Inclusion and Exclusion Criteria ..................................................................... 16 
4.6.1 
Inclusion Criteria .............................................................................. 16 
4.6.2 
Exclusion Criteria ............................................................................. 16 
4.7 
Subject Population ......................................................................................... 16 
4.8 
Subject Screening .......................................................................................... 17 
4.9 
Informed Consent Process ............................................................................. 17 
4.10 
Point of Enrollment ......................................................................................... 17 
5 
Device Used and Research Drug Treatment.............................................................. 17 
5.1 
Device Description ......................................................................................... 17 
5.2 
Device Accountability ..................................................................................... 19 
5.3 
Research Drug ............................................................................................... 19 
5.3.1 
Project Management........................................................................ 19 
5.3.2 
Research Drug Blinding ................................................................... 20 
5.3.3 
Research Drug Dispensing .............................................................. 20 
5.3.4 
Research Drug Dosing .................................................................... 20 
5.3.5 
Research Drug Accountability .......................................................... 21 
6 
Procedures ................................................................................................................ 22 


 
Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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TABLE OF CONTENTS 
6.1 
Study Flow Chart............................................................................................ 22 
6.2 
Study Activities and Procedures ..................................................................... 23 
6.2.1 
Antiplatelet Testing and Platelet Function Testing ........................... 24 
6.2.2 
Avoidance of Additional Antiplatelet Medications ............................. 24 
6.3 
Screening and Enrollment .............................................................................. 24 
6.4 
Baseline Visit ................................................................................................. 25 
6.5 
Implant Procedure .......................................................................................... 26 
6.6 
Scheduled Follow-Up Visits ............................................................................ 26 
6.7 
Unscheduled Visits......................................................................................... 28 
6.7.1 
Operative Procedures ...................................................................... 28 
6.7.2 
Rehospitalizations ........................................................................... 28 
6.7.3 
Outcomes ........................................................................................ 28 
6.8 
Subject Study Completion .............................................................................. 28 
6.9 
Criteria and Procedures for Subject Withdrawal ............................................. 28 
7 
Adverse Event and Complaint Reporting ................................................................... 30 
7.1 
Definitions ...................................................................................................... 30 
7.1.1 
Adverse Event ................................................................................. 30 
7.1.2 
Serious Adverse Event .................................................................... 30 
7.1.3 
Procedure for Assessing, Recording, and Reporting Adverse Events 
and Serious Adverse Events ............................................................ 30 
7.1.4 
Subject Death .................................................................................. 31 
7.2 
Complaints ..................................................................................................... 31 
8 
Compliance to CIP ..................................................................................................... 32 
8.1 
Statements of Compliance ............................................................................. 32 
8.2 
Adherence to the Clinical Investigation Plan................................................... 32 
8.2.1 
Repeated and Serious Non-Compliance .......................................... 32 
9 
Data Management ..................................................................................................... 32 
9.1 
Data Management Plan.................................................................................. 33 
9.2 
Document and Data Control ........................................................................... 33 
9.2.1 
Traceability of Documents and Data ................................................ 33 
9.2.2 
Recording Data ................................................................................ 33 
10 
Monitoring .................................................................................................................. 33 
11 
Regulatory Inspections .............................................................................................. 34 
12 
Statistical Considerations .......................................................................................... 34 
12.1 
Statistical Design, Hypotheses, Method and Analytical Procedures ............... 35 
12.1.1 
Primary Efficacy Endpoint ................................................................ 35 
12.1.2 
Primary Safety Endpoint .................................................................. 35 
12.1.3 
Sample Size .................................................................................... 35 
12.1.4 
Primary Efficacy Endpoint ................................................................ 36 
12.1.5 
Primary Safety Endpoint .................................................................. 36 
12.2 
Addressing Clinical Scenarios in which Changes to Antiplatelet Therapy may 
be Required ................................................................................................... 36 
12.2.1 
Persistent Changes to Antiplatelet Therapy ..................................... 41 
12.3 
Safety Assessment ........................................................................................ 41 


 
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Clinical Investigational Plan  
 
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TABLE OF CONTENTS 
12.4 
Randomization Approach ............................................................................... 41 
13 
Document Management and Retention...................................................................... 41 
13.1 
Regulatory Documentation ............................................................................. 41 
13.2 
Retention of Records ..................................................................................... 42 
14 
Study Committees ..................................................................................................... 42 
15 
Outsourcing of Duties and Functions ......................................................................... 43 
16 
Investigation Suspension or Termination ................................................................... 43 
16.1 
Premature Termination of the Whole Study or the Study at One or More 
Investigational Sites ....................................................................................... 43 
16.2 
Study Conclusion ........................................................................................... 44 
17 
Publication Policy ...................................................................................................... 44 
18 
Bibliography ............................................................................................................... 44 
 


 
Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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TABLE OF APPENDICES 
Appendix A: Abbreviations .................................................................................................... 48 
Appendix B: CIP Revision History ......................................................................................... 51 
Appendix C: PREVENT Recommended Practices to Reduce the Risk of Pump Thrombosis 52 
Appendix D: Adverse Event Definitions ................................................................................. 55 
Appendix E: Case Report Forms ........................................................................................... 59 
Appendix F: Sample Informed Consent ................................................................................. 60 
 
 
 
 
LIST OF FIGURES 
Figure 1 – The HeartMate II Left Ventricular Device ..................................................................19 
Figure 2 – Study Overview ........................................................................................................22 
Figure 3 – Treatment of Non-Surgical Bleeding Events .............................................................37 
Figure 4 – Treatment of Thromboembolic Events ......................................................................38 
Figure 5 – Treatment of Hemolysis Events ................................................................................39 
Figure 6 – Treatment of Transient Ischemic Attack Events........................................................40 
 
 
 
LIST OF TABLES 
Table 1 – Schedule of Assessments .........................................................................................23 
Table 2 – Baseline Data Collection ...........................................................................................25 
Table 3 – Implant Procedure Data Collection ............................................................................26 
Table 4 – Follow-Up Visit Windows ...........................................................................................26 
Table 5 – Scheduled Follow-Up Visit Data Collection ................................................................27 
 
 
 


 
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Study Name: PREVENT II 
Clinical Investigational Plan  
 
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1 
SYNOPSIS  
Study Synopsis 
Title 
PREVENTion of Non-Surgical Bleeding by Management of HeartMate II 
Patients without Antiplatelet Therapy 
Acronym 
PREVENT II 
Objectives 
Reduce the incidence of non-surgical bleeding in HeartMate II (HM II) 
patients without increasing the risk of thromboembolic (TE) events 
Primary 
Hypothesis 
HM II patients managed with warfarin alone (Treatment Arm) have a lower 
rate of non-surgical bleeding and an equivalent rate of stroke and TE events 
compared to patients managed with warfarin + acetylsalicylic acid (aspirin, 
ASA) together (Control Arm) 
Primary 
Endpoints 
A comparison between the Treatment and Control Arms of: 
Primary Efficacy Endpoint (Superiority): Composite incidence of non-surgical 
bleeding at 6 months post initial implantation, including but not limited to 
gastrointestinal (GI), genitourinary (GU), epistaxis, subdural hematoma, and 
primary hemorrhagic stroke (not due to ischemic conversion, or to treatment 
of a hemolysis/suspected thrombosis event) 
Primary Safety Endpoint (Non-Inferiority): Composite incidence of pump 
thrombosis and TE stroke at 6 months post initial implantation, including 
ischemic 
stroke, 
or 
hemorrhagic 
stroke 
due 
to 
an 
ischemic 
conversion/treatment of an hemolysis/pump thrombosis event 
Descriptive 
Endpoints 
Comparison between the Treatment and Control Arms in the rates of:  
• 
Overall bleeding  
• 
GI bleeding  
• 
Suspected and confirmed pump thrombosis 
• 
Stroke (ischemic and hemorrhagic) 
• 
Hemolysis (major and minor)  
• 
As treated analysis of anticoagulation and antiplatelet medications 
• 
Survival  
• 
Assessment of adherence to the PREVENT study recommended 
practices 


 
Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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Study Synopsis 
Design 
PREVENT II is a prospective, multi-center, randomized, double-blind 
placebo controlled study.  
The randomization scheme will be 1:1, with a total sample size of 350 
subjects, with 175 subjects in the Treatment Arm and 175 subjects in the 
Control Arm defined as:  
• 
Treatment Arm: Warfarin (INR Target 2.0-2.5, median 2.25, per 
standard of patient care) + placebo (1 pill/day) 
• 
Control Arm: Warfarin (INR Target 2.0-2.5, median 2.25, per standard 
of patient care) + acetylsalicylic acid (ASA) therapy (81mg/day)  
Maximum follow-up duration per subject will be 12 months. Primary 
endpoints will be evaluated at 6 months. Individual components of the 
primary endpoints along with the descriptive endpoints will be evaluated at 
12 months. 


 
Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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Study Synopsis 
Statistical 
Considerations 
Primary Efficacy Endpoint Analysis – Reduction of Bleeding: The rate of non-
surgical bleeding at 6 months will be compared between the Treatment and 
Control Arms utilizing the Fisher’s Exact Test. The primary endpoint for 
efficacy will be assumed to be met if the p-value < 0.05. The assumption is 
that there will be a 15% rate reduction at 6 months. 
A sample size of 330 subjects (165 in each arm) with an alpha of 0.05 will 
provide 80% power to demonstrate a significant difference between the 
Treatment and Control Arms.  
Primary Safety Endpoint Analysis – Non-Inferiority of Stroke and Thrombus: 
The difference in the rates of the composite endpoint of stroke and pump 
thrombosis between Treatment and Control Arms and the 95% confidence 
limit of the difference will be evaluated. If the upper confidence limit of the 
difference is < 10% then the non-inferiority criterion will be considered to 
have been met.  
A sample size of 338 subjects (169 in each arm) will provide 80% power, 
with a target alpha of 0.025 (because this will be a one-sided test on the 
upper confidence limit) to demonstrate non-inferiority of the Treatment Arm 
to the Control Arm.  
A total study sample size of 350 subjects will provide enough statistical 
power to demonstrate both efficacy and safety of the warfarin only 
anticoagulation regimen in these patients.  
Both primary endpoints must be met for the study to be successful. 
Intermediate Safety Assessment: A safety assessment will be performed 
after 60 subjects have completed 3 months of follow-up. Both incidence of 
stroke and pump thrombosis will be analyzed and results will be presented 
to the Steering Committee. Additionally, after the initial 3-month safety 
review, an analysis of AEs associated with primary endpoints will be 
presented to the Steering Committee for continued safety assessment in 
regular 6-month intervals. The Steering Committee will review the findings 
and make a decision to proceed or stop the study due to safety concerns.  
Devices Used 
HM II Left Ventricular Assist Device (LVAD) 
Research Drug 
Aspirin (81mg – active ingredient: Acetylsalicylic acid (ASA); Enteric-Coated 
Low Dose Aspirin, Bayer Corporation, Whippany, NJ) will be blinded to a 
matching placebo (ALMAC Clinical Services, Souderton, PA) 
Study 
Population 
All patients undergoing HM II implantation per approved indications who 
meet inclusion/exclusion criteria may be considered for this study.   


 
Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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Study Synopsis 
Inclusion & 
Exclusion 
Criteria  
Inclusion Criteria 
• 
Subject is receiving the HM II per standard of care (SOC) in accordance 
with the approved indications for use 
• 
Subject is ≥ 50 years of age 
• 
Subject is receiving the HM II as their first LVAD  
• 
Subject or legally authorized representative (LAR) has signed an 
informed consent form (ICF). 
Exclusion Criteria 
• 
Existence of ongoing mechanical circulatory support (MCS) other than 
intra-aortic balloon pump or Abiomed Impella® devices 
• 
Participation in any other clinical investigation(s) involving an MCS 
device, or an investigation(s) that is likely to confound study results or 
affect study outcome 
• 
Antiplatelet therapy is mandated for other conditions, in particular: a) 
recent coronary artery stenting (≤ 6 months), b) carotid artery disease, 
and c) other conditions where the investigator is not comfortable 
leaving subjects off-ASA or starting ASA post LVAD implantation. In 
situations where the investigator is uncertain, the Steering Committee 
can provide a recommendation to the investigator as needed.  
• 
Subjects in whom heart transplantation is expected in ≤ 6 months 
• 
Subjects with a known ASA allergy 
Data Collection 
Data will be collected on all subjects at the following time points:  
• 
Baseline 
• 
Implant  
• 
Week 1 post-implant (± 3 days) 
• 
Month 1 post-implant (± 7 days) 
• 
Month 3 post-implant (± 20 days) 
• 
Month 6 post-implant (± 20 days) 
• 
Month 9 post-implant (± 20 days) 
• 
Month 12 post-implant (± 20 days) 
Data will be collected for as occurs events, including initial discharge, 
adverse events, re-hospitalizations, operative events and outcomes. All 
changes to anticoagulant and antiplatelet therapies and all available values 
for INR and LDH will be collected during the follow-up period. 
 
 
 
 


 
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Study Name: PREVENT II 
Clinical Investigational Plan  
 
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2 
BACKGROUND AND JUSTIFICATION FOR CLINICAL STUDY 
Over the last decade, mechanical circulatory support (MCS) with continuous-flow (CF) left 
ventricular assist devices (LVADs) has become the standard of care (SOC) treatment for 
patients with advanced stage heart failure. The HeartMate® II (HM II) LVAD is a 
commercially available, U.S. Food and Drug Administration (FDA) and Health Canada 
approved device. The HM II was approved for New York Heart Association Class (NYHA) 
IIIB/IV patients as a bridge to cardiac transplantation (BTT) by the FDA in April 2008 and 
Health Canada in May 2009. The HMII was approved for permanent destination therapy 
(DT) by the FDA in January 2010 and Health Canada in October 2010. Numerous 
publications have documented the success of the HM II in extending and improving the 
quality of life in patients with advanced heart failure (1-10). Over 22,000 patients have 
been implanted and treated with the HM II LVAD, and over 8,000 patients are currently 
supported by the HM II (data on file).  
Patients with LVADs require adjunctive antithrombotic therapy, typically with warfarin +/- 
acetylsalicylic acid (aspirin, ASA). While ASA therapy, the research topic of this study, is 
suggested in the HM II IFU, the usage of ASA as SOC is variable. Some centers routinely 
utilize ASA while others do not (11, 12). Additionally, ASA therapy is usually discontinued 
when patients experience a serious bleeding event (13). 
2.1 
BLEEDING IN HM II PATIENTS 
While overall outcomes with the HM II have steadily improved, bleeding and 
thromboembolic (TE) complications continue to persist (5, 8). In practice, clinicians must 
balance the risk of bleeding against that of thrombosis by managing patients on chronic 
antithrombotic therapy, which includes warfarin as well as ASA therapy (14). In HM II 
patients, the prevalence and incidence of bleeding, particularly gastro-intestinal (GI) 
bleeding, is elevated and is usually the leading cause of hospital readmissions post-LVAD 
implant (15, 16).  
Antithrombotic therapy in CF-LVAD patients is complicated by the presence of acquired 
Von Willebrand Syndrome (AVWS) (17-19). In AVWS, patients present with a degradation 
of high molecular weight (HMW) multimers of Von Willebrand Factor (VWF) protein, which 
are necessary for platelet binding and normal hemostatic function of the coagulation 
system. The loss of HMW VWF reduces the ability of platelets to bind to each other, and 
predisposes patients to bleeding diatheses, including increased rates of GI bleeding (20).  
Some investigators have hypothesized that ASA therapy in the presence of AVWS 
increases the risk of non-surgical bleeding in HM II patients (11). In a single center 
experience from France, the risk of TE events was not elevated when patients were 
managed on single antithrombotic therapy (Vitamin K antagonist – Fluindione only, target 
INR: 2.0-3.0)(11).  
These observations led to the design of the TRACE study (Study of Reduced 
Anticoagulation/Antiplatelet Therapy in Patients with the HeartMate II Left Ventricular 
Assist System) (Clinical Trials.Gov: NCT01477528), a prospective, multi-center safety 
study of reduced antithrombotic therapy in HM II patients. TRACE enrolled 200 subjects 
across the United States and Europe, and demonstrated that HM II patients who were 
managed without ASA therapy did not experience an increased risk of TE events (12, 13). 


 
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The rate of bleeding in the TRACE EU cohort, in particular, appeared to be lower 
compared to published clinical experience (12, 21).  
2.2 
THROMBOSIS IN HM II PATIENTS 
Despite bleeding being the more common adverse event, consequences of thrombosis 
can be far more serious. Early HM II clinical experience demonstrated a low rate of pump 
thrombosis and stroke (1, 2, 7, 14), but over time changes in management practices to 
address bleeding events have partially contributed to an increasing risk of pump 
thrombosis in HM II patients (22). Starling et al. reported an alarming increasing incidence 
of HM II pump thrombosis from 2.2% before 2011 to 8.4% after 2011 (23). Despite the 
alarming trend, there was significant disparity and center-to-center variability in the 
reported rates of pump thrombosis. For example, an analysis of clinical experience from 
7 centers (24) showed that the risk of early pump thrombosis was found to be much lower 
(3.9%) compared to the published clinical experience (23, 25). In addition, subsequently 
published letters to the editor suggested that the increases in pump thrombosis rates 
observed in some centers were not evident at all HM II centers (26, 27).  
Due to the variability in pump thrombosis rates and patient management practices, the 
PREVENT study (PREVENtion of HeartMate II Thrombosis through Clinical Management; 
ClinicalTrials.gov identifier: NCT02158403) was developed to investigate a set of 
recommended practices (Appendix C) based on the HM II instructions for use (IFU) with 
modifications derived from clinical practice (28). PREVENT evaluated the rate of pump 
thrombosis in HM II patients when the recommended practices were adopted across 
centers to minimize center-to-center variability and standardize clinical management. 
Primary endpoint results from the PREVENT study were recently presented at the 
International Society of Heart and Lung Transplantation (ISHLT) 2016 annual meeting, 
where the rate of early (≤ 3 month) pump thrombosis was demonstrated to be 2.9% 
(significantly lower than the published rate of 8.4% at 3 months) (29). The reduction in the 
early risk of pump thrombosis associated with the adoption of consistent patient 
management techniques, has been confirmed by other studies (30, 31). Furthermore, an 
analysis of PREVENT data revealed that a sub-group of patients (~20% of the enrolled 
patient population) were not on ASA or any antiplatelet therapy; these patients did not 
experience any of the pump thrombosis events captured as part of the primary endpoint. 
2.3 
CLINICAL EQUIPOISE ON THE USE OF ASA IN HM II PATIENTS 
The growing body of scientific evidence seems to suggest that ASA therapy in HM II 
patients may not have an impact on TE events, but may increase the risk of bleeding 
events in the presence of AVWS. This effect may be particularly accentuated in older 
patient populations who have higher risk of bleeding (21). The PREVENT 
recommendations, as well as the HM II IFU, recommend initiation of ASA therapy within 
2-5 days post implant, with maintenance of ASA therapy throughout support. Despite 
these recommendations, clinical experiences from the US and EU cohorts of the TRACE 
study, as well as single-center experiences in Europe have indicated that ASA therapy 
may not be required in HM II LVAD patients. Furthermore, in a recent study, the use of 
high dose ASA therapy (325 mg) was associated with a significantly higher incidence of 
hemorrhagic events compared to low dose (81 mg) ASA therapy [54% vs. 22%, p<0.004] 
(32). These results suggest a clinical equipoise for the use of ASA therapy for 


 
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antithrombotic management of HM II patients, especially in older patients who are at 
higher risk of bleeding.  
2.4 
STUDY JUSTIFICATION 
The high rates of bleeding in HM II patients, presence of AVWS, uncertainty behind the 
clinical benefit of ASA therapy, and results from both PREVENT and TRACE studies form 
the basis of the design for the PREVENT II study. PREVENT II will be the first prospective, 
randomized, multi-center, double-blind, placebo-controlled clinical study conducted in the 
field of MCS therapy, comparing patients managed with warfarin alone to patients 
managed with warfarin + ASA therapy together. PREVENT II will set the precedent for 
future studies focused on developing evidence-driven best practices for improving 
outcomes in LVAD patients. Results of the study may not only impact the thousands of 
patients who will receive the HM II LVAD over the next few years, but also the thousands 
of patients who are currently supported by the HM II. 
3 
RISKS AND BENEFITS OF THE CLINICAL STUDY 
The risks associated with the use of the HM II LVAD are anticipated to be comparable to 
those associated with the use of other currently available LVADs. Subjects participating in 
this study are indicated for an LVAD system as part of their standard medical management 
and are subject to the risks associated with the use of these devices. The study seeks to 
evaluate the safety and efficacy of eliminating ASA therapy in HM II patients. Subjects in 
the Treatment Arm of the study may have an increased risk for TE events due to the 
removal of ASA therapy. 
3.1 
ANTICIPATED CLINICAL BENEFITS 
Commercially available MCS devices have been previously shown to provide safe and 
effective hemodynamic support in advanced heart failure subjects with clinically 
meaningful improvement in survival, quality of life and functional capacity when compared 
to optimal medical management (1-10, 33).  
This study may or may not benefit the subjects involved, but it may help future subjects 
by increasing what we know about ways to care for subjects who are supported on LVADs. 
3.2 
ANTICIPATED ADVERSE EVENTS AND ADVERSE DEVICE EFFECTS 
Adverse events potentially associated with LVAD therapy are documented in the HM II 
IFU.  
3.3 
POSSIBLE INTERACTIONS WITH CONCOMITANT MEDICAL TREATMENTS AND/OR CONCURRENT 
MEDICAL INTERVENTIONS 
There are no known interactions of the HM II LVAD with concomitant medical treatment. 
Subjects experiencing an adverse event will be treated by their physician per SOC at the 
investigation site. 
3.4 
MITIGATION OF RISKS 
Actions to control or mitigate risks will include the selection of qualified and experienced 
investigators and site personnel, and strict adherence to the clinical investigational plan 
(CIP). Investigators will be actively involved in the follow-up of all study subjects. Risks 


 
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or used without the express written consent of Abbott 
will be minimized by careful assessment of each subject prior to, during, and at regular 
intervals throughout the study. 
To address the risk of TE events in the Treatment Arm, the study design includes a safety 
assessment to be performed by the Steering Committee after 60 subjects reach 3 months 
of follow-up. If the Steering Committee determines that there are safety concerns, the 
study will be terminated. Furthermore, for continued safety assessment, after the initial 
safety assessment, an analysis of AEs associated with the primary endpoints will be 
performed at regular 6-month intervals by the Steering Committee. 
4 
STUDY DESIGN 
4.1 
PURPOSE 
The purpose of this clinical study is to evaluate the safety and efficacy of managing HM II 
patients ≥50 years of age on warfarin (target INR 2.0-2.5, median: 2.25) alone, compared 
to HM II patients managed on warfarin (target INR 2.0-2.5, median: 2.25) and ASA (81 
mg/day) together (11, 12)(13). 
4.2 
STUDY DESIGN AND SCOPE 
This study is a prospective, multi-center, randomized, double-blind placebo-controlled 
study of subjects receiving the HM II LVAD as per currently approved indications for use. 
This is a post-market clinical study of HM II patient management practices to be conducted 
in the United States and Canada.  
Subjects will be randomized in a 1:1 fashion to the following research drug groups: 
1) Treatment Arm: Warfarin (INR target: 2.0-2.5, median: 2.25) + Placebo (1 pill/day) 
2) Control Arm: Warfarin (INR target: 2.0-2.5, median: 2.25) + ASA Therapy (81mg/day) 
The study will investigate if subjects in the Treatment Arm experience a reduced incidence 
of non-surgical bleeding, without an increased risk of TE events.  
Once randomized, subjects will be placed on the research drug (ASA therapy or placebo) 
no later than post-operative day (POD) 5, provided bleeding has subsided and the subject 
is hemodynamically stable.  
If the subject is experiencing bleeding or is not hemodynamically stable by POD 5, the 
subject must start the study drug as soon as bleeding has subsided and hemodynamic 
stability has been achieved, but no later than POD 15. If administration of the research 
drug has not begun by POD 15, the subject will be withdrawn from the study. 
Withdrawn subjects will not be replaced. 
4.3 
STUDY BLINDING 
The subjects and the investigators will be blinded to the subject’s research drug 
assignment. Un-blinding will not be performed unless the subject is experiencing a major 
allergic reaction potentially attributable to the research drug. If a major allergic reaction 
occurs, the subject should be medically managed per standard of care. Un-blinding will 
occur only with approval from the Steering Committee and will be documented. Requests 
for unblinding will be answered within three business days of the request. If un-blinding 
occurs, the subject will be withdrawn from the study.   


 
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4.3.1 
DESCRIPTION OF SUBJECT POPULATION 
All subjects receiving a HM II implant in accordance with the approved 
indications for use (BTT or DT) will be considered for this study, regardless of 
gender, race, or ethnicity.  
4.3.2 
PREVENT RECOMMENDATIONS TO REDUCE PUMP THROMBUS 
All subjects enrolled into this study will be implanted and managed in accordance 
with the PREVENT study recommended practices to reduce pump thrombosis 
with the exception of the use of antiplatelet therapy, which is the research topic 
of this study. Refer to Appendix C for full details of the PREVENT study 
recommended practices.  
4.3.3 
NUMBER OF SUBJECTS REQUIRED TO BE INCLUDED IN THE STUDY 
A total sample size of up to 350 subjects will be enrolled. Subjects enrolled into 
the study will be randomized in a 1:1 fashion and randomization will be stratified 
by study site and blocked to maintain a 1:1 ratio over time.  
Subjects will be followed up to 12 months with the primary endpoints evaluated 
at 6 months. The study will be conducted at up to 45 sites, and up to 45 subjects 
may be enrolled at any site. An enrollment increase may be requested by 
individual sites, and approval will be granted at the discretion of the Sponsor.  
4.3.4 
ESTIMATED TIME NEEDED TO ENROLL SUBJECT POPULATION 
Based on the anticipated enrollment rate, the estimated time needed to enroll 
this subject population is approximately 2.75 years. 
4.4 
OBJECTIVE 
The primary objective of the study is to reduce the incidence of non-surgical bleeding in 
HM II patients, without increasing the risk of TE events, by eliminating ASA therapy from 
the antithrombotic management regimen for HM II patients. The primary objective will be 
accomplished by a comparison of non-surgical bleeding and TE events at 6 months post 
initial implantation between the Treatment and Control Arms.  
4.5 
ENDPOINTS 
4.5.1 
PRIMARY ENDPOINTS 
There are two primary endpoints of this study: 
Efficacy Endpoint (Superiority): Composite incidence of non-surgical bleeding at 
6 months post initial implantation, including but not limited to GI, GU, epistaxis, 
subdural hematoma, and primary hemorrhagic stroke (not due to ischemic 
conversion, or due to the treatment of a hemolysis/suspected thrombosis event). 
Safety Endpoint (Non-Inferiority): Composite incidence of pump thrombosis and 
TE stroke at 6 months post initial implantation, including ischemic stroke, or 
hemorrhagic stroke due to an ischemic conversion/treatment of hemolysis/pump 
thrombosis event.  


 
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4.5.2 
DESCRIPTIVE ENDPOINTS 
The descriptive endpoints will involve a comparison between the Treatment and 
Control Arms in the rates of: 
• 
Overall bleeding  
• 
GI bleeding 
• 
Suspected and confirmed pump thrombosis 
• 
Stroke (both ischemic and hemorrhagic) 
• 
Hemolysis (major and minor)  
• 
As treated analysis of anticoagulation and antiplatelet medications 
• 
Survival  
• 
Assessment of adherence to the PREVENT study recommended practices. 
4.6 
INCLUSION AND EXCLUSION CRITERIA 
To qualify for inclusion in the study, subjects must meet all eligibility criteria listed below.  
4.6.1 
INCLUSION CRITERIA 
• 
Subject is receiving the HM II per SOC in accordance with the approved 
indications for use 
• 
Subject is ≥ 50 years of age 
• 
Subject is receiving the HM II as their first LVAD  
• 
Subject or legally authorized representative (LAR) has signed an informed 
consent form (ICF). 
4.6.2 
EXCLUSION CRITERIA 
• 
Existence of ongoing mechanical circulatory support (MCS) other than intra-
aortic balloon pump or Abiomed Impella® devices. 
• 
Participation in any other clinical investigation(s) involving an MCS device, 
or an investigation(s) that is likely to confound study results or affect study 
outcome. 
• 
Antiplatelet therapy is mandated by treating physician for other conditions, in 
particular: a) recent coronary artery stenting (≤ 6 months), b) carotid artery 
disease, and c) other conditions where the investigator is not comfortable 
leaving subjects off ASA or starting ASA post LVAD implantation. In 
situations where the investigator is uncertain, the Steering Committee can 
provide a recommendation to the investigator as needed.  
• 
Subjects in whom heart transplantation is expected in ≤ 6 months. 
• 
Subjects with a known ASA allergy. 
4.7 
SUBJECT POPULATION 
All patients undergoing HM II implantation  approved indications for use who meet 
inclusion/exclusion criteria may be considered for this study.  


 
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4.8 
SUBJECT SCREENING 
The Principal Investigator (PI) or designated site personnel will screen all subjects 
receiving a HM II LVAD per SOC. Subjects who do not meet inclusion/exclusion criteria 
will not qualify to participate in this study. The reason for ineligibility will be documented. 
Refer to Section 6.3 for a description of the screening process. 
4.9 
INFORMED CONSENT PROCESS 
Prior to participation in the study or any study-specific procedures, all subjects will be 
consented as required by applicable regulations and the applicable institutional review 
board (IRB). The subject will be provided with the informed consent form written in a 
language that is understandable to the subject. The informed consent form must be 
approved by the Sponsor and applicable IRB prior to use.  
The PI or an authorized designee will conduct the Informed Consent Process. This 
process will include a verbal discussion with the subject (or designated LAR) on all aspects 
of the study relevant to the subject’s decision to participate in the study. Written consent 
must be signed and dated by the subject (or designated LAR), and by the designated site 
personnel obtaining the consent.  
A copy of the fully executed informed consent form must be given to the subject at the 
time of signature, and the original signed confirmed form will be filed in the site research 
files. A consent note, which documents the complete Informed Consent Process, will be 
entered into the subject’s hospital record with a copy of the fully executed consent form.  
Failure to obtain informed consent from a subject prior to study enrollment should be 
reported to the Sponsor within 5 working days, and to the applicable IRB consistent with 
the applicable reporting requirements.  
4.10 
POINT OF ENROLLMENT 
Subjects are considered enrolled in the study when subject consent has been provided, 
the HM II LVAD implant has been successfully completed, and the subject has been 
randomized to a research drug arm. Enrollment reporting and randomization must occur 
immediately when the subject leaves the operating room or no later than 48 hours 
following implant. An enrollment is reported to the Sponsor upon submission of the Implant 
and Randomization CRFs in the EDC. The follow-up assessment schedule is based on 
Day 1 being the date that the implant was completed.  
5 
DEVICE USED AND RESEARCH DRUG TREATMENT 
5.1 
DEVICE DESCRIPTION 
The HM II Left Ventricular Assist System (LVAS) utilizes a rotary axial-flow pump that 
weighs 290 grams and has a displacement volume of 63 milliliters. A microprocessor-
based system controller provides power, control and monitoring of the implanted pump. 
Control and power to pump are through a percutaneous lead connected to the external 
controller and power supply. External system components include batteries, battery 
charger, power supply, and system monitor. Batteries are used in pairs to power the pump 
during ambulatory operation. A power module provides AC electrical power to the system 
during tethered operation. The battery charger charges, tests, and calibrates the14 volt Li-


 
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Clinical Investigational Plan  
 
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Ion or 12-volt NiMH batteries. The system monitor displays pump operating parameters 
and provides an interface for the operator.  
The HM II pump contains a single moving component, the rotor. Vanes on the rotor move 
the blood through the pump in the range of 3 to 10 liters per minute. The pump does not 
have valves and venting is not required. The inflow conduit and outflow elbow are textured 
with titanium microspheres to promote cellular adhesion and the development of a 
thromboresistant tissue lining. The remaining internal blood-contacting components have 
smooth, polished titanium surfaces. The rotor is suspended between the inlet and outlet 
stators with ball-and-cup bearings.  
The pump is implanted just below the left hemidiaphragm with the inflow attached to the 
apex of the left ventricle and the outflow graft anastomosed to the ascending aorta. Blood 
is pumped continuously throughout the cardiac cycle from the left ventricle to the aorta. 
The percutaneous lead is tunneled subcutaneously across the abdomen and exits the 
abdominal wall in the right or left upper quadrant.  
 
 
 
 
 


 
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Figure 1 – The HeartMate II Left Ventricular Device 
 
The HM II Left Ventricular Assist Device is implanted below the heart 
and is connected by a percutaneous lead to a controller and 
batteries worn by the patient. Blood is pumped continuously 
throughout systole and diastole from a cannula inserted into the left 
ventricular apex with flow redirected to the ascending aorta. 
 
5.2 
DEVICE ACCOUNTABILITY 
Because the HM II is commercially available and approved, device accountability is not 
required for this study; however, the standard commercial practices for device 
accountability and reporting to the Sponsor should be followed. Refer to Section 7.2 for 
complaints reporting. 
5.3 
RESEARCH DRUG 
5.3.1 
PROJECT MANAGEMENT 
ALMAC Clinical Services will manage manufacturing and distribution logistics of 
the research drug at their facility at 25 Fretz Road, Souderton, PA 18964.   


 
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ALMAC Clinical Services will manage the WebEZ system and drug 
accountability at their facility at 4228 Technology Drive, Durham, NC 27704.   
ALMAC Clinical Services is a part of ALMAC Group Limited headquartered at 
ALMAC House, 20 Seagoe Industrial Estate, Craigavon, BT63 5QD, Northern 
Ireland (Reg. No: NI 41905). 
ALMAC Clinical Services responsibilities will be, but not limited to, the following: 
• Research drug blinding and matching placebo manufacture, including packaging and 
labelling (due to country-specific requirements research drug labels may vary) 
• Dispensing research drug to sites 
• Providing support dispensing to study subjects via the ALMAC WebEZ system  
• Research drug accountability 
5.3.2 
RESEARCH DRUG BLINDING 
ALMAC Clinical Services will blind the Control Arm research drug (81mg ASA; 
Enteric-Coated Low Dose Aspirin, Bayer Corporation, Whippany, NJ) to a 
matching placebo, the Treatment Arm research drug.  
5.3.3 
RESEARCH DRUG DISPENSING 
Initial dispensing of the research drug will occur after randomization, which will 
be performed immediately after the patient has been successfully implanted with 
the HM II. Resupply dispensing will occur at Month 3, Month 6, and Month 9 
follow-up visits. 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 of research drug will be tracked by bottle number. The WebEZ 
system will provide sites with the bottle number to be dispensed to a given 
subject. Site supply and resupply shipments will be automatically controlled by 
ALMAC Clinical Services.  
If a subject reports a lost or empty bottle of research drug 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 research drug until their next 
resupply visit. Each bottle will contain 110 days of research drug, which is a 
sufficient supply for the period leading up to the subject’s next visit, including the 
acceptable visit windows. 
5.3.4 
RESEARCH DRUG DOSING 
The research drug will be taken once daily by mouth. Warfarin therapy will be 
per SOC with a target INR of 2.0-2.5.  


 
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5.3.5 
RESEARCH DRUG ACCOUNTABILITY 
To ensure research drug accountability, all empty research drug bottles and (if 
applicable) all unused doses will be returned to ALMAC Clinical Services by the 
site. Subjects will be instructed to return the research drug bottle and any unused 
portion of the research drug at each resupply visit.  
The research drug bottles and unused portions will be shipped (at the Sponsor’s 
expense) per country-specific Drug Return Instructions (DRI). 
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. Drug return instructions (DRI) will be provided during training. 


 
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6 
PROCEDURES 
6.1 
STUDY FLOW CHART  
 
Figure 2 – Study Overview 
 


 
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6.2 
STUDY ACTIVITIES AND PROCEDURES 
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. 
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. 
Table 1 – Schedule of Assessments 
 
 
 
 
 Assessment 
Baseline 
Implant 
Week 1 
(± 3 days) 
Month 11 
(± 7 days) 
Month 31 
(± 20 days) 
Month 61 
(± 20 days) 
Month 91 
(± 20 Days) 
Month 121 
(± 20 days) 
As Occurs/ 
Unscheduled 
Inclusion/ Exclusion 
X 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
General and Cardiac Medical History 
X 
 
 
 
 
 
 
 
 
Coagulation Assessment 
 X2 
 
 
 
 
 
 
 
 
Right Heart Catheterization 
 X2 
 
 
 
 
 
 
 
X4 
Vital Signs 
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 
Echocardiogram 
 X2 
 
 X4 
 X4 
 X4 
 X4 
 X4 
 X4 
 X5 
Other Medications 
X 
 
 
X 
X 
X 
X 
X 
 
ASA Resistance Testing 
X 
 
 
 
 
 
 
 
 
Implant Data 
 
X 
 
 
 
 
 
 
X6 
Enrollment 
 
 X7 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Adherence to Recommended Practices 
 
X 
X 
X 
X 
X 
X 
X 
 
Pump Parameters 
 
X 
X 
X 
X 
X 
X 
X 
 X5 
Bottle Assignment via WebEZ 
 
X 
 
 
X 
X 
X 
 
 
Research Drug Bottle Dispensing and Dispensing Log 
 
X 
 
 
X 
X 
X 
 
X 
Bridging Therapy Log 
 
X 
X 
 
 
 
 
 
 X8 
Anti-Factor Xa Assay Log 
 
X 
X 
 
 
 
 
 
 X8 
Initial Discharge Data 
 
 
 
 
 
 
 
 
X 
Subject Status 
 
 
X 
X 
X 
X 
X 
X 
 
Cardiac Arrhythmias 
 
 
X 
X 
X 
X 
X 
X 
 
INR & LDH Log 
 
 
X 
X 
X 
X 
X 
X 
X 
Chest/Abdominal X-Ray  
 
 
 
X9 
 
 
 
 
 X5 
Return Bottle with Remaining Test Drug to ALMAC Clinical for 
Accountability 
 
 
 
 
X 
X 
X 
X 
 
Death 
 
 
 
 
 
 
 
 
X 
Withdrawal (early termination) 
 
 
 
 
 
 
 
 
X 
Rehospitalizations 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
Operative Procedures 
 
 
X 
X 
X 
X 
X 
X 
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: Implant Data and Recommended Practices. 
7 Subject is considered enrolled when inclusion/exclusion criteria are met; has been successfully implanted with a HM II LVAD; and has 
been randomized to a research drug arm (Treatment or Control). 
8 Within the first 21 days post implant. 
9    Best view available between Implant and Month 1 visit. 
 


 
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6.2.1 
ANTIPLATELET TESTING AND PLATELET FUNCTION TESTING  
Subjects in both the Treatment and Control Arms will receive ASA resistance 
testing (e.g. TEG® PlateletMapping®, VerifyNow®, etc.) at the baseline visit. 
After obtaining informed consent, testing will be performed prior to implantation, 
and may require a brief administration of ASA (recommended 3-5 days) to 
subjects who are not currently on ASA therapy. Testing should be timed 
adequately prior to surgery so as not to effect subjects’ ability to reach post-
operative hemodynamic stability.  
To retain investigator and patient blinding to the test results, all site labs should 
be directed to return de-identified (patient screening ID only) ASA resistance test 
results at the Sponsor’s expense to the Sponsor. Results will not be entered into 
the subject’s hospital record to protect blinding. 
While the subject is on the research drug, antiplatelet testing or platelet function 
testing should not be performed, as it may result in un-blinding of the subject or 
the investigator. Un-blinding of the subject or investigator will be considered a 
CIP deviation and the subject will be withdrawn from the study. 
6.2.2 
AVOIDANCE OF ADDITIONAL ANTIPLATELET MEDICATIONS 
Investigators should not prescribe or administer additional antiplatelet 
medications to subjects, except in the instance in which the subject has met the 
primary study endpoints. 
6.3 
SCREENING AND ENROLLMENT 
All patients who are screened for eligibility will be documented in the PREVENT II 
Screening Log and assigned a Screening ID number. To protect patient privacy, no 
identifying information will be recorded.  
The Sponsor may request copies of the Screening Log throughout the study, but the 
ongoing log will be maintained on site.  
Patients who qualify to participate in the study will be approached to discuss the study, 
consider voluntary participation, and, if applicable, provide informed consent. For patients 
who do not qualify to participate in this study, the reason for ineligibility will be entered in 
the screening log. For enrolled subjects, the assigned Subject ID number will be entered 
in the screening log. Patients with an Impella® device must have the device removed 
during HMII implant to be enrolled into the study. 
Qualified subjects who have provided consent will be entered in the appropriate EDC CRF, 
which must be submitted to the Sponsor after the patient has been screened and prior to 
enrollment, or no later than 48 hours post implantation. Notification of enrollment to the 
Sponsor will only take place when the consented subject has been entered in the EDC. 
Enrollment information (name of the study, date of consent, and inclusion/exclusion 
criteria) will be recorded in the subject’s hospital records. 
If a consented subject does not meet all eligibility criteria at the time of implant; does not 
receive a HM II LVAD; experiences a serious adverse event in the perioperative period 
that the investigator feels would compromise the patient’s participation in the trial (e.g., 
debilitating stroke); or expires during the implant procedure, then the subject will not be 
enrolled or contribute to the study endpoints. The reason for ineligibility at the time of 


 
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implant will be recorded in the screening log. The subject is enrolled upon successful 
implantation of the HM II and randomization per Section 4.10. 
6.4 
BASELINE VISIT 
The following baseline assessments will be performed:  
Table 2 – Baseline Data Collection 
 
Study Activity 
Data Collection 
Informed Consent 
Informed consent details 
Inclusion/Exclusion 
Subject’s eligibility details 
Demographics 
Age, gender, ethnicity, race, blood type, INTERMACS profile, and NYHA class 
General and Cardiac Medical 
History 
Etiology of HF, duration of HF, indication (BTT/DT), arrhythmias, prosthetic valve(s), 
stroke, diabetes, smoking, history of bleeding (diverticular disease, diagnosed 
arteriovenous malformations (AVMs), GI ulcer(s), anemia, and/orerythropoietin 
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, CardioMEMS, and HIV 
Vital Signs 
Height, weight, blood pressure, and heart rate 
Anticoagulation/Antiplatelet 
Medications 
Warfarin, clopidogrel, dipyridamole, other anticoagulation agents, other vitamin K 
antagonists, direct thrombin inhibitors, etc (including research drug). 
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 Warfarin/Coumadin. Only the start 
and stop dates will be collected for Warfarin/Coumadin 
Other Medications 
ACE inhibitors, inotropes, ARBs, beta blockers, antiarrhythmics, statins, nitrates, 
allopurinol, aldosterone blockers, antibiotics, diuretics, insulin and antidiabetic 
medications, and other cardiovascular medications 
1 Laboratory Assessments 
 
Hemoglobin (Hgb), Hematocrit (Hct), White Blood Cell Count (WBC), Platelets (PLT), 
Creatinine (Cr), Estimated Glomerular Filtration Rate (eGFR), LDH and INR. 
For diabetic patients: HbA1c, and fasting glucose 
Collected only if SOC: Activated Partial Thromboplastin Time (aPTT), Partial 
Thromboplastin Time (PTT), Plasma free Hgb (PHgb), liver function tests (AST, ALT, 
total bilirubin, albumin, pre-albumin), blood urea nitrogen (BUN), D-Dimers, P 
Selectin, and fibrinogen  
ASA Resistance Testing 
ASA resistance testing (e.g. TEG® PlateletMapping®, VerifyNow®, etc.) 
Note: To protect blinding of the study, platelet function testing (including ASA 
resistance testing) should be avoided during the course of the study except where 
indicated by the CIP.  
2 Coagulation Assessment 
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 
2 Right Heart Catheterization  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) 
2 Echocardiogram  
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, 
including percent AV area opening, and AV opening time 
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. 


 
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6.5 
IMPLANT PROCEDURE 
The following data will be collected for each subject’s HM II implant procedure. 
Table 3 – Implant Procedure Data Collection 
Study Activity 
Data Collection 
HM II System Information 
VAD serial number, reference number and date of implant of entire implanted 
system 
Implant Data 
Signs of infection prior to implant, location of outflow anastomosis, apical cuff 
attachment method, driveline location and positioning, percutaneous driveline 
exit type, initial pump parameters, presence of LV or LA 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 
completion time 
Adherence to PREVENT 
Recommended Practices 
Pump pocket size, pump pocket location (inferiorly deep and lateral), inflow 
cannula position, outflow graft position, pump position, pump fixation, pump 
speed management, post-operative anticoagulation/antiplatelet management 
(including Heparin bridging) and blood pressure management 
Pump Parameters 
Pump Speed, Pump Flow, Pulsatility Index, and Pump Power 
Randomization 
Confirmation of randomization, date of randomization, and date that research 
drug was started following implant 
Research Drug Bottle 
Dispensing 
Bottle number of the research drug dispensed and date dispensed. 
6.6 
SCHEDULED FOLLOW-UP VISITS 
The required assessments, follow-up schedule, and associated visit windows are 
generally aligned with INTERMACS, a national MCS registry. All follow-up visits are based 
on the initial implant date, even if a pump exchange occurs while the subject is being 
followed on the study. The windows for each follow-up visit are as follows:  
Table 4 – Follow-Up Visit Windows 
Baseline 
Implant 
Visit 1 
Visit 2 
1 Visit 3 
1 Visit 4 
1 Visit 5 
1 Visit 6 
- 
- 
Week 1  
± 3 days 
Month 1  
± 7 days 
Month 3 
± 20 days 
Month 6 
± 20 days 
Month 9 
± 20 days 
Month 12 
± 20 days 
1 Note that the window for these visits have been shortened to ± 20 days from the original INTERMACS ± 30 days window. 
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 CIP deviation. The Sponsor understands that some lab 
results may be received several days after the visit has occurred. 
At the completion of the Month 12 visit, the subject has completed 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 not collected by the date of the final visit will be considered a protocol 
deviation. 


 
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Table 5 – Scheduled Follow-Up Visit Data Collection 
Study Activity 
Definition 
Subject Status 
Initial discharge status, and visit completion 
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 Warfarin/Coumadin. Only 
the start and stop dates will be collected for Warfarin/Coumadin 
Other Medications 
ACE inhibitors, inotropes, ARBs, beta blockers, antiarrhythmics, statins, nitrates, 
allopurinol, aldosterone blockers, antibiotics, diuretics, insulin and antidiabetic 
medications, and other cardiovascular medications 
Bottle Dispensing  
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 and Unused Research 
Drug Return 
Bottle status and shipping information. 
All bottles and unused doses must be returned to ALMAC Clinical upon receipt 
from subject.  
Laboratory Assessments 
 
Hemoglobin (Hgb), Hematocrit (Hct), White Blood Cell Count (WBC), Platelets 
(PLT), Creatinine (Cr), Estimated Glomerular Filtration Rate (eGFR), LDH and INR. 
For diabetic patients: HbA1c, and fasting glucose 
Collected only if SOC: Activated Partial Thromboplastin Time (aPTT), Partial 
Thromboplastin Time (PTT), Plasma free Hgb (PHgb), liver function tests (AST, 
ALT, total bilirubin, albumin, pre-albumin), blood urea nitrogen (BUN), D-Dimers, P 
Selectin, fibrinogen, and Anti Factor Xa Assay (Heparin Assay). 
Note: To protect blinding of the study, platelet function testing (including ASA 
resistance testing) should be avoided during the course of the study except where 
indicated by the CIP.  
Adherence to PREVENT 
Recommended Practices 
Blood pressure management, INR goals, and pump speed management 
Chest/Abdominal X-Ray  
PA and lateral chest/abdominal X-rays (that show the entire pump relative to major 
cardiac/anatomical structures) will be submitted to Sponsor for independent 
analysis of pump position  
Note: Collected between Implant and Month 1 visits, or at pump thrombosis or 
pump exchange events 
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, including percent 
AV area opening, and AV opening time 
1 If collected per SOC. 


 
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Clinical Investigational Plan  
 
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6.7 
UNSCHEDULED VISITS 
6.7.1 
OPERATIVE PROCEDURES 
Data related to any cardiac or non-cardiac operative procedures occurring after 
enrollment will be collected. Operative procedures must be reported to the 
Sponsor through the EDC system immediately upon discovery of the event or, 
at the latest, if the operation is unknown to the implanting site (i.e. at another 
facility), during the next follow-up visit.  
For pump exchanges (HM II to HM II only), additional Pump Exchange data will 
be collected, including exchange status, implant data, PREVENT recommended 
practices and Chest/Abdominal X-ray. In the event of a pump exchange, the 
follow-up visit schedule will continue to be based on the initial implant date. 
6.7.2 
REHOSPITALIZATIONS 
All hospitalizations extending over 24 hours 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. Rehospitalizations must be reported to the Sponsor through the 
EDC system immediately upon discovery of the event or, at the latest, if the 
rehospitalization is unknown to the implanting site (i.e. at another facility), during 
the next follow-up visit.  
6.7.3 
OUTCOMES 
Subjects will be followed for 12 months or until an outcome is reached, whichever 
occurs first. Outcomes include death, heart transplantation, explant (except in 
cases of HM II to HM II pump exchange), and withdrawal from the study. 
Outcomes must be reported to the Sponsor through the EDC system 
immediately upon discovery of the event.  
If a subject receives a pump exchange (HM II to non-HM II) during the follow-up 
period, this event will be considered an explant outcome. If a subject receives a 
pump exchange (HM II to HM II) during the follow-up period, the subject will 
remain in the study on the original follow-up schedule.  
If a subject has a device explanted for confirmed or suspected pump thrombosis, 
the pump will be returned to the Sponsor for analysis. Standard commercial 
processes should be used for pump return. 
6.8 
SUBJECT STUDY COMPLETION 
When the subject has completed the study, the physician will resume management per 
SOC. To preserve blinding for investigators and remaining enrolled subjects, the research 
drug arm assignments of individual subjects will not be disclosed until all subjects at the 
respective site have completed the study.  
6.9 
CRITERIA AND PROCEDURES FOR SUBJECT WITHDRAWAL  
Subjects will be informed about their right to withdraw from the study at any time and for 
any reason without sanction, penalty, or loss of benefits to which the subject is otherwise 
entitled. Withdrawal from the study will not jeopardize their future medical care or 


 
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relationship with the investigator. Subjects will be asked to specify the reason for the 
termination, but have the right not to answer.  
The investigator may decide to withdraw a subject from the study at any time with 
reasonable rationale. The subject’s future care will not be influenced by a withdrawal, 
voluntary or otherwise, from the study. All reasonable efforts should be made to retain the 
subject in the clinical study until completion of the study. 
Reasons for subject’s withdrawal may include, but are not limited to: 
• 
Subject refuses to continue participating in the study 
• 
Research drug is not initiated by post-operative day 15 
• 
Subject non-compliance 
• 
Subject participation is terminated by the investigator, as participation is no longer 
medically appropriate, even though the subject has provided consent 
• 
Subject is lost to follow-up, or can no longer be tracked for data collection at a 
participating center. This does not apply to missed visits. Site personnel should at all 
times make all reasonable efforts to locate and communicate with the subject in order to 
achieve subject compliance to the scheduled follow-up visits: 
o The subject will be considered lost to follow-up after missing two consecutive 
visits; however, the PI or designated site personnel must document a minimum of 
two phone calls over a period of two consecutive weeks to demonstrate efforts to 
communicate with the subject. These phone calls will be documented in the 
subject’s hospital records. 
o If these attempts are unsuccessful, a letter will be sent to the subject’s last known 
address or general practitioner (GP) and a copy of the letter will be maintained in 
the subject’s hospital records. 
Note: If a subject does not attend a scheduled follow-up visit within the visit window, this 
will be considered a missed visit. The subject should attend the next scheduled visit and 
will not be excluded from the study. 
If a subject withdraws from the study, the reason for withdrawal will be documented if 
available. 
If subject withdrawal is due to an adverse event, the subject will be followed until resolution 
of the event or a determination has been made that the subject’s condition is stable. The 
status of the subject’s condition will be documented at the time of withdrawal.  
When a subject is withdrawn for any reason, there are no withdrawal procedures to be 
performed, but all follow-up visits, study assessments, and research drug will be 
immediately stopped. The physician will resume management according to SOC. 
Withdrawn subjects should return all remaining research drug to the site. Refer to Section 
5.3.5 for the return of unused study drug. 


 
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7 
ADVERSE EVENT AND COMPLAINT REPORTING 
7.1 
DEFINITIONS 
7.1.1 
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, users or other persons, whether or not related to the investigational 
medical device. 
This definition includes AEs related to the medical device, the research drug, 
and study procedures. 
For this study, data for specified AEs will be collected as follows: 
• 
Neurological Dysfunction, including hemorrhagic stroke, ischemic stroke, and/or TIA 
• 
Pump Thrombosis  
• 
Major Bleeding  
• 
Hemolysis 
• 
Major Infection  
• Right Heart Failure  
Refer to Appendix D for a detailed description of each type of AE. 
7.1.2 
SERIOUS ADVERSE EVENT  
A serious adverse event (SAE) is an adverse event that: 
• 
Led to death 
• 
Led to serious deterioration in the health of the subject, that either resulted in: 
o A life-threatening illness or injury, or 
o A permanent impairment of a body structure or a body function, or 
o In-patient or prolonged hospitalization, or 
o Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
• 
Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
Note: Planned hospitalization for a pre-existing condition, or a procedure 
required by the CIP, without serious deterioration in health, is not considered an 
SAE. 
7.1.3 
PROCEDURE FOR ASSESSING, RECORDING, AND REPORTING ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS  
Investigators are responsible for the safety surveillance and reporting for the 
study. Safety surveillance begins at implant and after-the-fact reporting for all 
enrolled subjects will occur at the time enrollment and will continue until the 
subject has been withdrawn, experienced an outcome, or completed the study. 


 
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Investigators are responsible for reporting AEs to the Sponsor in a timely manner 
through the EDC, as well as for reporting applicable AEs to their IRB in 
accordance with their institutional requirements, national and local laws and 
regulations. 
AEs will be followed until they are adequately resolved. Records relating to the 
subject’s subsequent medical course must be maintained until the event has 
subsided, or until the event stabilizes and the overall clinical outcome is 
determined. The Sponsor may request de-identified source documentation as 
applicable. 
There are known and anticipated AEs associated with LVAD therapy. These AEs 
along with detailed definitions can be found in the HM II IFU.  
All suspected and confirmed pump thrombosis events will be adjudicated by an 
independent committee. 
The Sponsor will ensure that all events are reported to the relevant authorities in 
accordance with applicable regulations.  
7.1.4 
SUBJECT DEATH 
All subject deaths will be documented and reported to the Sponsor in a timely 
manner after the investigator becomes aware of the event. 
The Sponsor may request de-identified source documentation as applicable. 
Additional information may be requested, when required, by the Sponsor in order 
to support the reporting of deaths to regulatory authorities. 
The PI or designated site personnel must notify the IRB, if appropriate, of the 
deaths reported to the Sponsor in accordance with national and local laws and 
regulations. 
7.2 
COMPLAINTS  
During the study, the investigator will be responsible for reporting all complaints.  A 
complaint means any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance 
of a device after it is released for distribution. 
If the complaint does not involve an AE, the investigator must notify the Abbott Post-market 
Surveillance Department by entering complaints information into the Thoratec® 
Connect™ System or by calling the HeartLine™ at 1-800-456-1477 as soon as possible 
after becoming aware of the complaint. Please contact the local Abbott representative to 
coordinate product returns as applicable. This information will not be collected on a CRF 
for the study. 
If the complaint involves an AE, the investigator must complete an AE Case Report Form 
(CRF) including the information on the complaint and report to Abbott as soon as possible.  
Should a subject death be caused by the Abbott device or the device contributed to the 
death, the investigator should complete a Form 3500A (MedWatch) and submit to Abbott 
and the FDA within 10 days after becoming aware of the event. 


 
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8 
COMPLIANCE TO CIP 
8.1 
STATEMENTS OF COMPLIANCE 
The investigator will not begin subject enrollment or request informed consent from any 
subject prior to obtaining IRB approval and authorization from the Sponsor in writing for 
the study. 
In case additional requirements are imposed by the IRB, those requirements will be 
followed, if appropriate. If any action is taken by the IRB, and regulatory requirements with 
respect to the study, that information will be forwarded to the Sponsor. 
8.2 
ADHERENCE TO THE CLINICAL INVESTIGATION PLAN  
A deviation is defined as an event in which the investigator, site personnel, Sponsor or 
Sponsor representative did not conduct the study in accordance with the CIP, IRB 
requirements, or the Investigator Agreement. The investigator is not allowed to deviate 
from the CIP, which includes inclusion/exclusion criteria and protection of subject safety, 
except as specified under emergency circumstances. Investigators and sites agreeing to 
participate in the study must believe that there is equipoise for randomization, and must 
be willing to be blinded for the duration of the study at their site. Un-blinding will not be 
performed unless subject is experiencing a major allergic reaction potentially attributable 
to the research drug, and will require Steering Committee approval. If the study drug is 
un-blinded, then the subject will be withdrawn from the study.  
8.2.1 
REPEATED AND SERIOUS NON-COMPLIANCE 
In the event of repeated non-compliance or one-time serious non-compliance (as 
determined by the Sponsor), a Clinical Research Associate or clinical 
representative will attempt to secure compliance by one or more of the following 
actions: 
• 
Visiting the investigator 
• 
Contacting the investigator by telephone 
• 
Contacting the investigator in writing 
• 
Retraining of the investigator and/or site personnel 
• 
Corrective and Preventive Action (CAPA) 
If an investigator is found to be repeatedly non-compliant with the CIP, research 
contract, or any other conditions of the study, the Sponsor will either secure 
compliance or, at its sole discretion, suspend or terminate the investigator’s 
participation in the clinical study. 
9 
DATA MANAGEMENT 
Overall, the Sponsor will be responsible for the data handling. The Sponsor and/or its 
affiliates will be responsible for compiling and submitting all required reports to 
governmental agencies. 
Data will be analyzed by the Sponsor and may be transferred to the Sponsor’s locations 
or regulatory authorities worldwide in support of a market-approval application. 


 
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The PI or institution will provide direct access to source data during and after the clinical 
study for monitoring, audits, IRB review and regulatory authority inspections. As required, 
the PI or institution will obtain permission for direct access to source documents from the 
subject, hospital administration, and national regulatory authorities before starting the 
clinical study. 
9.1 
DATA MANAGEMENT PLAN 
A detailed Data Management Plan (DMP) will be established to ensure consistency of the 
data. This document will include procedures used for data review, database cleaning, and 
the issuance and resolution of data queries. If appropriate, the DMP may be updated 
throughout the study. All revisions will be tracked and document controlled. 
CRF data will be captured in a validated electronic database management system hosted 
by the Sponsor. Only specially trained designated site personnel will be permitted to enter 
the CRF data through the EDC system. An electronic audit trail will be used to track any 
subsequent changes of the entered data. 
9.2 
DOCUMENT AND DATA CONTROL 
9.2.1 
TRACEABILITY OF DOCUMENTS AND DATA 
The PI will ensure accuracy, completeness, legibility, and timeliness of the data 
reported to the Sponsor on the CRFs and in all required reports.  
9.2.2 
RECORDING DATA 
Original documentation supporting the data recorded in the CRFs must be 
maintained, including clinical charts, medical records, laboratory reports, 
physician referral or consultation letters, X-ray reports, etc. AEs, which are 
managed at a health care facility other than the study site, must be reported to 
the Sponsor and every attempt must be made to obtain source documentation 
from that facility.  
The EDC CRFs will be electronically validated by the designated site personnel. 
Any change or correction to data will be recorded in the EDC system’s audit trail.  
10 
MONITORING  
It is the responsibility of the Sponsor to ensure that the study is conducted, recorded, and 
reported in accordance with the approved CIP, subsequent amendment(s), applicable 
regulations, and guidance documents.  
Prior to beginning the study, the Sponsor will contact the PI and designated site personnel 
to discuss the study and data requirements.  
Centralized monitoring will occur through routine internal data review. This monitoring is 
designed to identify missing and inconsistent data, data outliers, and potential CIP 
deviations that may be indicative of site non-compliance. Remote monitoring will be 
performed. On-site monitoring may occur in lieu of remote monitoring at the discretion of 
the sponsor. A Sponsor monitor may periodically review the subject records and 
associated source documents. The PI will make subject and study records available to the 
clinical monitor for monitoring. 


 
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11 
REGULATORY INSPECTIONS 
The PI or designated site personnel should contact the Sponsor immediately upon 
notification of a governmental agency inspection at the site. A clinical monitor or designee 
will assist the site in preparing for the audit. 
An investigator who has authority to grant access, will permit authorized governmental 
agency employees, at reasonable times and in reasonable manner, to enter and inspect 
any establishment where devices are held (including any establishment where devices 
are used or where records or results are kept). 
An investigator, or designated site personnel, will permit authorized governmental agency 
employees, at reasonable times and in reasonable manner, to inspect and copy all records 
relating to the study. 
An investigator will permit authorized governmental agency employees to inspect and 
copy records that identify subjects, upon notice that governmental agency has reason to 
suspect that adequate informed consent was not obtained, or that reports required to be 
submitted by the investigator, to the Sponsor or IRB have not been submitted or are 
incomplete, inaccurate, false, or misleading. 
12 
STATISTICAL CONSIDERATIONS 
PREVENT II is a prospective, multi-center, randomized, double-blinded, placebo-
controlled study evaluating the risk of subjects over 50 years of age being managed on 
warfarin therapy alone compared to warfarin and ASA therapy together. The two groups 
in the study are as follows: 
1) Treatment Arm: Warfarin (INR target: 2.0-2.5, median: 2.25) + Placebo (1 pill/day) 
2) Control Arm: Warfarin (INR target: 2.0-2.5, median: 2.25) + ASA therapy (81mg/day) 
In general, continuous data will be presented as the number of subjects, mean with 
standard deviation, median, minimum, and maximum values. Categorical data will be 
reported as frequencies and percentages. Adverse events will additionally be reported as 
events per subject year, with only those events that start after implantation of the HM II 
analyzed. The adverse events will be compared between the two arms of the study using 
risk ratios (Poisson’s regression). Survival data will be presented and analyzed using the 
Kaplan-Meier method.  
The primary endpoints will be analyzed per protocol method as defined in Section 12.1. 
Every effort will be made to avoid crossovers, but in such instances, analysis will be 
performed in accordance with Section 12.1. The study will be conducted in a double-
blinded fashion with neither the investigator, nor the subject having the knowledge of 
whether the subject is in the Treatment or the Control Arm. Only the primary statistician 
from the Sponsor will have knowledge of the specific groups, and all other parties will be 
blinded.  
Every effort will be made to collect all required data. A one-sided 0.025 level of significance 
or two-sided 0.05 level of significance will be used to declare statistical significance as 
outlined below. Multiplicity adjustments will not be made unless specified below. A 
sensitivity analysis will be performed to account for any bias that may have been 
introduced by subjects withdrawing from the study or being removed from the study. 


 
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12.1 
STATISTICAL DESIGN, HYPOTHESES, METHOD AND ANALYTICAL PROCEDURES 
Subjects will be block randomized per site on a 1:1 ratio into the Treatment and Control 
Arms. The study is designed to satisfy two primary endpoints. Both primary endpoints 
must be met for the study to be successful. 
12.1.1 
PRIMARY EFFICACY ENDPOINT 
The primary efficacy endpoint is the incidence of non-surgical bleeding within the 
first 6 months of support. If a subject experiences any non-surgical bleeding 
including GI bleeding, epistaxis, subdural hematoma, or a primary hemorrhagic 
stroke (not due to an ischemic conversion or due to a treatment of a 
hemolysis/suspected thrombosis event), then the subject will be counted as 
having reached the primary efficacy endpoint. The determination of whether a 
hemorrhagic stroke is due to ischemic conversion or due to treatment of a 
hemolysis/suspected thrombosis event or is a primary hemorrhagic stroke will 
be made by the Clinical Events Committee (CEC). 
The incidence of non-surgical bleeding will be compared between the Treatment 
and Control Arms using the following null and alternative hypotheses as follows: 
Ho: πTREATMENT ≥ πCONTROL  
HA: πTREATMENT < πCONTROL  
where πTREATMENT and πCONTROL are the incidence rates of non-surgical bleeding 
in the Treatment and Control Arms, respectively.  
12.1.2 
PRIMARY SAFETY ENDPOINT 
The primary safety endpoint is the composite incidence of TE events within the 
first 6 months of HM II support. If a subject experiences any TE event, including 
pump thrombosis, ischemic stroke, or hemorrhagic stroke as a result of treatment 
of a suspected thrombosis/hemolysis event, then the subject will be counted as 
having reached the primary safety endpoint. The determination of whether a 
hemorrhagic stroke is due to ischemic conversion or due to treatment of a 
hemolysis/suspected thrombosis event or is a primary hemorrhagic stroke will 
be made by the Clinical Events Committee (CEC). 
The incidence of TE events in the Treatment Arm will be compared to the Control 
Arm in a non-inferiority manner. The null and alternative hypotheses are as 
follows: 
Ho: πTREATMENT ≤ πCONTROL + Δ 
HA: πTREATMENT > πCONTROL + Δ 
where πTREATMENT and πCONTROL are the incidence rates of TE events in the 
Treatment and Control Arms respectively, and where Δ is the non-inferiority 
margin.  
12.1.3 
SAMPLE SIZE 
A total sample size of up to 350 subjects will provide adequate power to satisfy 
both the primary efficacy and the safety endpoints respectively. The assumptions 
and rationale are provided in the sections below.  


 
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12.1.4 
PRIMARY EFFICACY ENDPOINT 
Assumptions: Based on the analysis of the first 100 subjects enrolled in the 
PREVENT study (Data on file), the anticipated incidence of non-surgical 
bleeding in the Control Arm at 6 months is 40%. The assumption for PREVENT 
II is that there will at least be a 15% reduction in the incidence of non-surgical 
bleeding in the Treatment Arm compared to the Control Arm.  
The comparison of Treatment and Control Arms will be made using the Fishers 
Exact Test. The primary endpoint for efficacy will be considered to be met if the 
p-value ≤ 0.05. A sample size of 330 subjects (165 in each of the Treatment and 
Control Arms) with an alpha of 0.05 will provide 80% power to demonstrate a 
significant difference between the Treatment and Control Arms. 
12.1.5 
PRIMARY SAFETY ENDPOINT 
Assumptions: Based on the analysis of the first 100 subjects enrolled in the 
PREVENT study (Data on file), the anticipated composite incidence of TE events 
in the Control Arm at 6 months is expected to be 8%. The assumption for 
PREVENT II is that the Treatment Arm will experience an incidence of TE events 
of no more than 9% at 6 months. The Treatment Arm will be considered non-
inferior to the Control Arm if the upper one-sided 95% confidence limit of the risk 
difference in the 6 month TE rate between research drug arms (Treatment - 
Control) is less than +10% (“positive 10%”, where 10% is the non-inferiority Δ in 
the above null and alternative hypotheses).  
A sample size of 338 subjects (169 each in the Treatment and Control Arms) will 
achieve 80% power to prove the Treatment Arm is non-inferior to HM II when the 
margin of non-inferiority is 10% (=Δ in the above null and alternative hypotheses) 
using the Farrington-Manning risk difference approach to non-inferiority at a one-
sided alpha = 0.025. 
12.2 
ADDRESSING CLINICAL SCENARIOS IN WHICH CHANGES TO ANTIPLATELET THERAPY MAY BE 
REQUIRED 
Subjects should be maintained on both Warfarin (with a target INR: 2.0-2.5) and the 
research drug (ASA or placebo) for the entire duration of the study. Changes in therapies 
are only accepted under the following scenarios: 


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Figure 3 – Treatment of Non-Surgical Bleeding Events 
 
 
 


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Clinical Investigational Plan  
 
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Figure 4 – Treatment of Thromboembolic Events 
 
 
 


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Clinical Investigational Plan  
 
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Figure 5 – Treatment of Hemolysis Events
 
 
 


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Figure 6 – Treatment of Transient Ischemic Attack Events 
 
 


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12.2.1 
PERSISTENT CHANGES TO ANTIPLATELET THERAPY 
If the investigator persistently deviates from the CIP by deliberately changing 
antiplatelet therapy outside of the scenarios outlined above, the subject will be 
censored from that point onwards. Follow-up will continue, but the data will not 
contribute to the primary endpoints. This will be considered a CIP deviation and 
may result in site disqualification. The deviation and details about therapy 
changes will be recorded on the appropriate CRF.  
12.3 
SAFETY ASSESSMENT 
A safety assessment will be performed after 60 subjects have completed 3 months of 
follow-up. Both incidence of stroke and pump thrombosis will be analyzed. Results will be 
presented to the Steering Committee, which will review the findings and make a decision 
to proceed or stop the study due to safety concerns. Enrollment will continue during this 
review process. Additionally, after the initial 3-month safety review, an analysis of AEs 
associated with the primary endpoints will be presented to the Steering Committee for 
continued safety assessment at regular 6-month intervals. The Steering Committee will 
review the findings and make a recommendation to proceed or stop the study due to safety 
concerns. 
12.4 
RANDOMIZATION APPROACH 
Subjects will be randomized in a 1:1 fashion (one Treatment Arm subject to one Control 
Arm subject). The randomization will be stratified by study site and blocked to maintain 
the 1:1 ratio over time. The Sponsor will implement randomization through ALMAC 
Clinical’s WebEZ system. Randomization will occur after the subject is successfully 
implanted with the HM II, and must be completed within 48 hours of implant.  
13 
DOCUMENT MANAGEMENT AND RETENTION 
13.1 
REGULATORY DOCUMENTATION 
The following study documents will be maintained by the study site and copies of site-
specific documents sent to Sponsor (including but not limited to): 
• Research Agreement and 
amendments 
• Approved Protocol and 
amendments 
• Protocol signature page 
• IRB approved ICF templates  
• IRB Submissions and Approval(s) 
• IRB Membership Roster(s) or 
Federal wide Assurance (FWA) 
number  
• Pertinent IRB Correspondence 
• Delegation of Authority Log 
• Training Log  
• Financial Disclosure(s) 
• Curriculum Vitae(s) 
• Medical License(s) 
• Laboratory Certifications and Normals  
• Screening Log  
• Aspirin Resistance Testing Instructions 
• WebEZ Instructions 
• Drug Return Instructions (DRI) 
• Research Drug Shipping/Receiving 
Receipts 
• Submission of Media Instructions 
• Media Shipping/Receiving Receipts 
• Monitoring Log 
• Sponsor Correspondence 


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• Source documentation (such as 
subject clinic charts, medical 
records, laboratory records) 
 
• Notes to File 
13.2 
RETENTION OF RECORDS 
The PI will maintain all study documents from prior, during, and (as specified) after the 
clinical study on file at the site for a minimum of 15 years after the termination of this study, 
or longer as per local laws, or when it is no longer needed to support a marketing 
application, whichever is later.  
The PI must contact the Sponsor prior to destroying or archiving off-site any records and 
reports pertaining to this study to ensure that they no longer need to be retained on site. 
All original subject files must be stored for the longest possible time permitted by the 
regulations at the hospital, research institute, or practice in question. If archiving can no 
longer be maintained at the site, or if the responsibility of retention transfers to a different 
individual, the investigator will notify the Sponsor.  
All data and documents will be made available on request of the relevant authorities in 
case of an audit. In the event of an audit by the FDA or other regulatory authority, the PI 
must notify the Sponsor. 
The Sponsor will archive and retain all essential clinical study documents from prior, during 
and (as specified) after the clinical study as per requirements.  
14 
STUDY COMMITTEES  
At least two committees will be established as part of this study: the Steering Committee 
and the Clinical Events Committee (CEC).  
The Steering Committee will oversee the conduct and execution of the study. The Steering 
Committee, already established, is comprised of three cardiologists and two 
cardiovascular surgeons, who are each leaders in the field of MCS therapy for advanced 
heart failure. The Steering Committee will meet regularly to discuss study progress and 
proceedings of the meetings will be documented. See Section 12.3 for additional 
information on the Steering Committee’s safety assessment of trial progress. The 
responsibilities of the Steering Committee may include, but are not limited to:  
• 
Reviewing and providing input to the study design, and the study protocol 
• 
Providing assessment of perceived evidence gaps and opinions of the medical 
community regarding study design and execution 
• 
Providing guidance on study execution including study eligibility questions, data 
analysis, presentation/publication of study results, patient safety, and address 
any study-related issues (e.g. recruitment and compliance to study protocol) 
• 
Provide recommendations for the selection of other committee members, 
including the Publication Committee, the CEC, and other sub-committees 
The CEC will be responsible for the adjudication process for adverse events that are 
related to bleeding and thromboembolic events. The CEC will be established prior to study 


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initiation, and will meet regularly to ensure that adverse events reported as part of the 
study are adequately adjudicated.  
15 
OUTSOURCING OF DUTIES AND FUNCTIONS  
The Sponsor may transfer any or all of the duties and functions related to the clinical study, 
including monitoring, to an external organization (such as a CRO or individual contractor), 
but the ultimate responsibility for the quality and integrity of the clinical study will reside 
with the Sponsor. All requirements applying to the Sponsor will also apply to the external 
organization inasmuch as this organization assumes the clinical study related duties and 
functions of the Sponsor. 
16 
INVESTIGATION SUSPENSION OR TERMINATION 
16.1 
PREMATURE TERMINATION OF THE WHOLE STUDY OR THE STUDY AT ONE OR MORE 
INVESTIGATIONAL SITES 
The Sponsor reserves the right to stop the study at any stage, with appropriate written 
notice to the PI. Possible reasons for early termination of the study by the Sponsor, either 
at a local or national level, may include, but are not limited to: 
• 
The device / therapy fails to perform as intended 
• 
Sponsor’s decision 
• 
Recommendation from Steering committee to Sponsor 
• 
Request of IRB(s) 
• 
Concern for subject safety and welfare 
• 
Failure to secure subject Informed Consent prior to any investigational activity 
• 
Failure to report unanticipated adverse device effects within 72 hours to Abbott 
• 
Repeated non-compliance with the CIP or the Clinical Trial Agreement 
• 
Inability to successfully implement the CIP 
• Violation of applicable national or local laws and regulations 
• Falsification of data, or any other breach of ethics or scientific principles. 
The investigator may discontinue participation in the study with appropriate written notice 
to the Sponsor. 
If the investigator or Sponsor terminates site participation, the investigator will return all 
documents to the Sponsor, provide a written statement as to why the premature 
termination has taken place, and notify the IRB and/or regulatory authority (if applicable). 
Follow-up for all enrolled subjects will be as per CIP requirements. 
A PI, IRB, or regulatory authority may suspend or prematurely terminate participation in a 
clinical study at the investigational sites for which they are responsible.  
If suspicion of an unacceptable risk to subjects arises during the study or when so 
instructed by the IRB or regulatory authority, the Sponsor may suspend the clinical study 


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as appropriate while the risk is assessed. The Sponsor will terminate the clinical study if 
an unacceptable risk is confirmed.  
If suspension or premature termination occurs, the terminating party will justify its decision 
in writing and promptly inform the other parties with whom they are in direct 
communication. The PI and the Sponsor will keep each other informed of any 
communication received from IRB or regulatory authority.  
If for any reason the Sponsor suspends or prematurely terminates the study at an 
individual investigational site, the Sponsor will inform the responsible regulatory authority, 
as appropriate, and ensure that the IRB is notified, either by the PI or by the Sponsor. If 
the suspension or premature termination was in the interest of subject safety, the Sponsor 
will inform all other PIs.  
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 up the subjects enrolled in the clinical study, and the PI or authorized designee 
will promptly inform the enrolled subjects at his/her investigational site, if appropriate.   
16.2 
STUDY CONCLUSION 
The study will be concluded when: 
• 
All sites are closed, AND 
• 
The Final Report generated by the Sponsor has been provided all participating to sites 
or the Sponsor has provided formal documentation of study closure. 
17 
PUBLICATION POLICY 
The results of the clinical study, whether positive or negative, will be submitted for 
publication. The Steering Committee will oversee the development of a Publication 
Committee, as well as the development of study publication policy in close collaboration 
with the Sponsor. Publication Committee membership may consist of Steering Committee 
members, site PIs who have provided significant contributions (e.g. enrollment, scientific 
contribution), and three representatives from the Sponsor. The Publication Committee will 
be responsible for identifying, selecting, and approving publication proposals and 
determining authorship according to the publication policy. 
For more information on publication guidelines, please refer to the International Committee 
of Medical Journal Editors (ICMJE) on www.icmje.org. 
This study will be posted on ClinicalTrials.gov and results will be posted on 
ClinicalTrials.gov as required.  
18 
BIBLIOGRAPHY 
1. 
Miller LW, Pagani FD, Russell SD, et al.: Use of a continuous-flow device in patients 
awaiting heart transplantation. N Engl J Med 2007;357:885-96. 
2. 
Pagani FD, Miller LW, Russell SD, et al.: Extended mechanical circulatory support 
with a continuous-flow rotary left ventricular assist device. J Am Coll Cardiol 
2009;54:312-21. 


Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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or used without the express written consent of Abbott 
3. 
Slaughter MS, Rogers JG, Milano CA, et al.: Advanced heart failure treated with 
continuous-flow left ventricular assist device. N Engl J Med 2009;361:2241-51. 
4. 
Rogers JG, Aaronson KD, Boyle AJ, et al.: Continuous flow left ventricular assist 
device improves functional capacity and quality of life of advanced heart failure 
patients. J Am Coll Cardiol 2010;55:1826-34. 
5. 
John R, Naka Y, Smedira NG, et al.: Continuous flow left ventricular assist device 
outcomes in commercial use compared with the prior clinical trial. Ann Thorac Surg 
2011;92:1406-13; discussion 13. 
6. 
Starling RC, Naka Y, Boyle AJ, et al.: Results of the post-U.S. Food and Drug 
Administration-approval study with a continuous flow left ventricular assist device as 
a bridge to heart transplantation: a prospective study using the INTERMACS 
(Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll 
Cardiol 2011;57:1890-8. 
7. 
Park SJ, Milano CA, Tatooles AJ, et al.: Outcomes in advanced heart failure patients 
with left ventricular assist devices for destination therapy. Circ Heart Fail 2012;5:241-
8. 
8. 
Jorde UP, Kushwaha SS, Tatooles AJ, et al.: Results of the Destination Therapy Post-
Food and Drug Administration Approval Study With a Continuous Flow Left 
Ventricular Assist Device: A Prospective Study Using the INTERMACS Registry 
(Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll 
Cardiol 2014;63:1751-7. 
9. 
Grady KL, Naftel DC, Myers S, et al.: Change in health-related quality of life from 
before to after destination therapy mechanical circulatory support is similar for older 
and younger patients: analyses from INTERMACS. J Heart Lung Transplant 
2015;34:213-21. 
10. Kirklin JK, Naftel DC, Pagani FD, et al.: Seventh INTERMACS annual report: 15,000 
patients and counting. J Heart Lung Transplant 2015;34:1495-504. 
11. Litzler PY, Smail H, Barbay V, et al.: Is anti-platelet therapy needed in continuous flow 
left ventricular assist device patients? A single-centre experience. Eur J Cardiothorac 
Surg 2013. 
12. Netuka I, Litzler PY, Berchtold-Herz M, et al.: Minimal Adverse Events in HeartMate 
II Patients with No Antiplatelet Therapy: Preliminary Results from the TRACE Study. 
International Society of Heart and Lung Transplantation. San Diego, CA; 2014. 
13. Katz JN, Adamson RM, John R, et al.: Safety of reduced anti-thrombotic strategies in 
HeartMate II patients: A one-year analysis of the US-TRACE Study. J Heart Lung 
Transplant 2015. 
14. Slaughter MS, Pagani FD, Rogers JG, et al.: Clinical management of continuous-flow 
left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 
2010;29:S1-39. 
15. Estep JD, Starling RC, Horstmanshof DA, et al.: Risk Assessment and Comparative 
Effectiveness of Left Ventricular Assist Device and Medical Management in 
Ambulatory Heart Failure Patients: Results From the ROADMAP Study. J Am Coll 
Cardiol 2015;66:1747-61. 


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Study Name: PREVENT II 
Clinical Investigational Plan  
 
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or used without the express written consent of Abbott 
16. Hasin T, Marmor Y, Kremers W, et al.: Readmissions after implantation of axial flow 
left ventricular assist device. J Am Coll Cardiol 2013;61:153-63. 
17. Crow S, John R, Boyle A, et al.: Gastrointestinal bleeding rates in recipients of 
nonpulsatile and pulsatile left ventricular assist devices. J Thorac Cardiovasc Surg 
2009;137:208-15. 
18. Crow S, Chen D, Milano C, et al.: Acquired von Willebrand syndrome in continuous-
flow ventricular assist device recipients. Ann Thorac Surg 2010;90:1263-9; discussion 
9. 
19. Demirozu ZT, Radovancevic R, Hochman LF, et al.: Arteriovenous malformation and 
gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device. 
J Heart Lung Transplant 2011;30:849-53. 
20. Uriel N, Pak SW, Jorde UP, et al.: Acquired von Willebrand syndrome after 
continuous-flow mechanical device support contributes to a high prevalence of 
bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol 
2010;56:1207-13. 
21. Boyle AJ, Jorde UP, Sun B, et al.: Pre-operative risk factors of bleeding and stroke 
during left ventricular assist device support: an analysis of more than 900 HeartMate 
II outpatients. J Am Coll Cardiol 2014;63:880-8. 
22. Mehra MR, Stewart GC, Uber PA: The vexing problem of thrombosis in long-term 
mechanical circulatory support. J Heart Lung Transplant 2014;33:1-11. 
23. Starling RC, Moazami N, Silvestry SC, et al.: Unexpected abrupt increase in left 
ventricular assist device thrombosis. N Engl J Med 2014;370:33-40. 
24. Klodell CT, Massey HT, Adamson RM, et al.: Factors Related to Pump Thrombosis 
With the Heartmate II Left Ventricular Assist Device. J Card Surg 2015;30:775-80. 
25. Kirkin JK, Naftel DC, Kormos RL, et al.: Intermacs Analysis of Pump Thrombosis in 
the HeartMate II Left Ventricular Assist Device. J Heart Lung Transplant 2013. 
26. Hoefer D, Velik-Salchner C, Antretter H: Increase in left ventricular assist device 
thrombosis. N Engl J Med 2014;370:1464. 
27. Schmitto JD, Avsar M, Haverich A: Increase in left ventricular assist device 
thrombosis. N Engl J Med 2014;370:1463-4. 
28. Klodell CT, Massey HT, Adamson R, et al.: Factors Related to Pump Thrombosis at 
Select Medium to High Volume Centers. International Society of Heart and Lung 
Transplantation. San Diego, CA; 2014. 
29. Maltais S, Kilic A, Nathan S, et al.: Prevention of HeartMate II Pump Thrombosis 
Through Clinical Management. International Society of Heart and Lung 
Transplantation. Washington D.C.; 2016. 
30. Kirklin JK, Naftel DC, Pagani FD, et al.: Pump thrombosis in the Thoratec HeartMate 
II device: An update analysis of the INTERMACS Registry. J Heart Lung Transplant 
2015;34:1515-26. 
31. Stulak JM, Maltais S: A different perspective on thrombosis and the HeartMate II. N 
Engl J Med 2014;370:1467-8. 


Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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or used without the express written consent of Abbott 
32. Saeed O, Maybaum S, Alessandro DD, Goldstein DJ, Patel SR: Aortic valve opening 
and thrombotic events with continuous-flow left ventricular assist devices. J Heart 
Lung Transplant 2014;33:109-12. 
33. Rose EA, Gelijns AC, Moskowitz AJ, et al.: Long-Term Use of a Left Ventricular Assist 
Device for End-Stage Heart Failure. New England Journal of Medicine 
2001;345:1435-43. 
34. 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;96:1259-65. 
35. Uriel N, Han J, Morrison KA, et al.: Device thrombosis in HeartMate II continuous-
flow left ventricular assist devices: a multifactorial phenomenon. J Heart Lung 
Transplant 2014;33:51-9. 
36. Slaughter MS, Naka Y, John R, et al.: Post-operative heparin may not be required for 
transitioning patients with a HeartMate II left ventricular assist system to long-term 
warfarin therapy. J Heart Lung Transplant 2010;29:616-24. 
37. Boyle AJ, Russell SD, Teuteberg JJ, et al.: Low thromboembolism and pump 
thrombosis with the HeartMate II left ventricular assist device: analysis of outpatient 
anti-coagulation. J Heart Lung Transplant 2009;28:881-7.  


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or used without the express written consent of Abbott 
Appendix A: Abbreviations 
 
Abbreviation 
Term 
ACE 
Angiotensin-converting Enzyme 
AC 
Alternating Current 
AE 
Adverse Event 
AI 
Aortic Insufficiency 
ALT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
ARBs 
Angiotensin II Receptor Blockers 
ASA 
Acetylsalicylic Acid (aspirin) 
AST 
Aspartate Aminotransferase  
AVMs 
Arteriovenous Malformations 
AVWS 
Acquired von Willebrand Syndrome 
BTT 
Bridge-to-Transplantation 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary Artery Bypass Graft 
CAPA 
Corrective and Preventative Action  
CEC 
Clinical Events Committee 
CF-LVAD 
Continuous Flow Left Ventricular Assist Device 
CI 
Cardiac Index 
CIP 
Clinical Investigational Plan 
CNS 
Central Nervous System 
CO 
Cardiac Output 
CPB 
Cardiopulmonary Bypass 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CVP 
Central Venous Pressure 
DMP 
Data Management Plan 
DRI 
Drug Return Instructions 
DT 
Destination Therapy  
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EU 
European Union 
FDA 
Food and Drug Administration 
FFP 
Fresh Frozen Plasma 
GI 
Gastrointestinal 
GP 
General Practitioner 
GU 
Genitourinary 
HbA1c 
Hemoglobin A1c 
Hct 
Hematocrit 
HF 
Heart Failure 
Hgb 
Hemoglobin 
HIT 
Heparin Induced Thrombocytopenia 


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Abbreviation 
Term 
HIV 
Human Immunodeficiency Virus 
HM II 
HeartMate II 
HMW 
High Molecular Weight 
ICF 
Informed Consent Form 
ICH 
Intracranial Hemorrhage  
ICMJE 
International Committee of Medical Journal Editors 
ID 
Identification 
IFU 
Instructions for Use 
INR 
International Normalized Ratio 
INTERMACS 
Interagency Registry for Mechanically Assisted Circulatory Support 
IRB 
Institutional Review Board 
ISHLT 
International Society for Heart & Lung Transplantation  
LA 
Left Atrium 
LAR 
Legally Authorized Representative 
LDH 
Lactate Dehydrogenase 
LMWH 
Low Molecular Weight Heparin 
LV 
Left Ventricle  
LVAD 
Left Ventricular Assist Device 
LVAS 
Left Ventricular Assist System 
LVEF 
Left Ventricular Ejection Fraction 
LVEDD 
Left Ventricular End Diastolic Diameter 
LVESD 
Left Ventricular End Systolic Diameter 
MAP 
Mean Arterial Pressure 
MCS 
Mechanical Circulatory Support 
MCSD 
Mechanical Circulatory Support Device 
MI 
Myocardial Infarction  
mmHg 
Millimeters of Mercury 
MO 
Month 
MR 
Mitral Regurgitation  
MRI 
Magnetic Resonance Imaging 
NA 
Not Applicable 
NC 
North Carolina 
NJ 
New Jersey 
NYHA 
New York Heart Association Class 
PA 
Pennsylvania  
PAD 
Diastolic Pulmonary Artery Pressure 
PAM 
Mean Pulmonary Artery Pressure 
PAS 
Systolic Pulmonary Artery Pressure 
PCPW 
Pulmonary Capillary Wedge Pressure 
PHgb 
Plasma Free Hemoglobin 
PI 
Principal Investigator 
PLT 
Platelet Count 
POD 
Post-Operative Day 
PR 
Pulmonary Regurgitation 


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Abbreviation 
Term 
PRBC 
Packed Red Blood Cells 
PT 
Pump Thrombosis 
PTT 
Partial Thromboplastin Time 
PVAD 
Paracorporeal Ventricular Assist Device 
RAP 
Right Atrial Pressure 
REV 
Revision 
RPM 
Revolutions Per Minute 
SAE 
Serious Adverse Event 
SOC 
Standard of Care 
TE 
Thromboembolic  
TEG 
Thromboelastography  
TIA 
Transient Ischemic Attack 
tPA 
Tissue Plaminogen Activator 
TR 
Tricuspid Regurgitation 
UNOS 
United Network for Organ Sharing 
US 
United States 
VAD 
Ventricular Assist Device 
VER 
Version 
VT 
Ventricular Tachycardia 
VWF 
Von Willebrand Factor 
WBC 
White Blood Cell Count 
 


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Appendix B: CIP Revision History 
 
Revision History 
Amendment 
Number 
Version 
Date 
Rationale 
Details 
N/A 
A 
13JUN2016 
First release of CIP 
N/A 
1.0 
B 
25JUL2016 
Clarification of multiple 
sections 
Additional detail/edits 
added to sections on 
blinding, assessments, 
screening and complaints  
2.0 
C 
17APR2017 
Addition of geographical 
region; increase in number 
of subjects; addition of 
patients with Impella® 
devices; rebranding, 
clarification of multiple 
sections 
Canada added as an 
additional geography; 
maximum number of 
subjects was increased 
from 40 to 45; patients 
with an Impella® device 
may now be considered; 
branding has changed 
from SJM to Abbott, and 
additional detail was 
added to Appendix C, 
treatment guidelines, 
safety assessment and on 
stroke determination. 
3.0 
D 
09OCT2017 
Updated language for 
consistency between 
sections, updated inclusion 
criteria; updated study 
contacts 
Updated language in 
section 3.4 to be 
consistent with other 
sections regarding safety 
assessment; updated 
inclusion criteria and 
study description to 
include subjects 50 years 
or older; updated study 
contacts  
4.0 
ABT-CIP-
10353 Rev. A 
16JUL2020 
Redacted for 
clinicaltrials.gov posting 
• 
Contact information 
of study personnel was 
removed from page 13.  
• 
Since the document 
was redacted for 
submission to 
clinicaltrials.gov, a new 
document number (ABT-
CIP-10353 Rev. A) was 
issued by our QMS, but 
apart from the redacted 
information, the CIP is 
the same as SJM-CIP-
10134 Rev. D 
 


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Appendix C: PREVENT Recommended Practices to Reduce 
the Risk of Pump Thrombosis 
The PREVENT recommended practices outlined are aimed at maximizing flow through the LVAD, 
reducing risk of cannula malposition, and ensuring that the patient is adequately anticoagulated 
while on LVAD support. These recommendations are similar to what is published in the HM II IFU 
with modifications derived from clinical practice. Additional recommendations have also been 
provided regarding the HM II implantation technique itself, as recent publications have highlighted 
that pump migration and cannula obstruction can increase the risk of device thrombosis (34, 35). 
It is anticipated that adoption of these patient management practices will ultimately lower the risk 
of pump thrombosis, while maintaining an acceptable rate of bleeding; however, it is understood 
that deviation from these recommendations may be necessary in certain clinical scenarios. 
Summary of Recommended Practices 
Implantation Technique 
• 
Create an adequately sized pump pocket, located inferiorly deep and lateral.  
• 
Position the inflow cannula parallel to the septum, oriented to the central LV. 
• 
Position the outflow graft right of sternal midline to avoid compression of RV. 
• 
Position the pump below the diaphragm.  
• Fixate the pump (e.g., to the diaphragm or chest wall) to prevent migration. 
Anticoagulation/Antiplatelet Management 
• 
In patients without persistent bleeding, begin bridging with unfractionated heparin or 
LMWH within 48 hours of device implant with a goal PTT of 40-45 sec in the first 48 
hours, followed by titration up to PTT 50–60 by 96 hours. If heparin is contraindicated, 
consider other alternatives including argatroban, intravenous warfarin, and bivalirudin. 
• 
Initiate warfarin within 48 hours to obtain a goal INR of 2.0-2.5 by POD 5-7, at which 
time heparin therapy may be discontinued. 
• 
Once there is no evidence of bleeding, initiate research drug within 5 days post HM II 
implantation. 
• 
Maintain the patient throughout LVAD support on the research drug and Warfarin with a 
goal INR of 2.0-2.5. 
Pump Speed Management 
• 
Run pump speeds above 9000 rpm when possible. 
• 
Avoid pump speeds below 8600 rpm when possible. 
• 
Adjust pump speed to permit intermittent aortic valve opening only after the above goals 
are achieved. 
 


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Blood Pressure Management 
• 
Maintain a mean arterial pressure (MAP) < 90 mm Hg 
Implantation Technique 
Proper implantation of the HM II helps to maximize flow and reduce the incidence of adverse 
events. The goals are intuitive: unobstructed inflow cannula, unobstructed outflow graft with 
avoidance of right ventricular compression, and prevention of pump migration. The basic 
principles summarized above address these objectives and include recommendations for pocket 
size and location, pump position and anchoring.  
Anticoagulation Management 
The recommended anticoagulation strategy is divided into early anticoagulation therapy and long 
term anti-thrombotic therapy. 
Heparin Bridging (Early Anticoagulation Therapy) 
The HM II IFU calls for perioperative intravenous heparin as a bridge to warfarin therapy. 
However, over time, the use of heparin bridging in clinical practice has gone down in order to 
reduce the risk of post-operative bleeding (14, 36). Although bleeding rates have decreased since 
the clinical trial (5, 8), this may have contributed to an increased incidence of pump thrombosis. 
As such, the recommended practices outlined here include a return to heparin bridging as outlined 
originally in the HM II IFU.  
Warfarin Anticoagulation (Early and Long-Term Therapy) 
The recommendation regarding warfarin anticoagulation is to obtain a goal INR of 2.0-2.5 by post-
operative day 5-7 and to maintain this goal throughout the duration of LVAD support. This INR 
target is within the management guidance outlined in the HM II IFU. In the HM II DT trial, the 
median discharge INR was 2.1 (7). In general, the risk of thrombotic events increases with INR < 
1.5 and the risk of hemorrhagic stroke increases with INR > 2.5 (37).  
Administration of Research Drug 
Once bleeding has subsided and the patient is hemodynamically stable (typically PODs 2-5), 
begin administering a single pill of the research drug daily. Maintain the subject on the research 
drug and warfarin throughout the duration of support.  
Pump Speed Management  
Recent studies have indicated that a decreased frequency of aortic valve opening post LVAD 
implantation is associated with an increased risk of TE events (32). As such, there has been a 
gradual trend of reducing pump speeds in order to increase the frequency of aortic valve opening 
to reduce the risk of aortic insufficiency and increase flow pulsatility. However, low pump speeds 
may result in low flow through the pump, especially in situations when the patient is hypertensive. 
Pump speed optimization is critical to ensure that there is adequate flow through the pump.  
Pump speeds coming out of the operating room should be optimized. Pump speeds that are too 
high may adversely impact the right ventricle or septal position; those that are too low may result 
in low flow and increase risk of pump thrombosis or insufficient circulatory support. 
Recommendations for pump speed have been established based on observations from the HM II 


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Clinical Investigational Plan  
 
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clinical trial (14). Average speed in the HM II clinical was 9150 ± 495 rpm on day 1, and 9405 ± 
448 rpm on day 180 (data on file). Specifically, the recommendation is to run pump speeds greater 
than 9000 rpm for most patients and to avoid pump speeds less than 8600 rpm.  
Blood Pressure Management 
Post-implantation hypertension should be treated at the discretion of the attending physician. Per 
the HM II IFU, any therapy that consistently maintains mean arterial blood pressure (MAP) less 
than 90 mm Hg should be considered adequate. Manual auscultation with a Doppler is 
recommended. 
 


Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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Appendix D: Adverse Event Definitions 
The following definitions will be utilized for this study:  
Neurological Dysfunction (Modified INTERMACS Definition) 
Any new, temporary or permanent, focal or global neurologic dysfunction 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 a cerebrovascular event as defined below or as a non-vascular acute neurologic event. 
A neurologic event may be recognized by a clinically evident sign or symptom, or by clinically-
silent electrographic seizure activity, or as a clinically silent lesion detected by surveillance 
neuroimaging.  
Each neurologic event should be classified by the clinical provider following complete neurologic 
assessment as one of the following event types: 
• 
Transient Ischemic Attack (TIA): An acute transient neurologic 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. Ischemic stroke should 
be specified as due to arterial-distribution ischemia or venous thrombosis. 
• 
Acute Symptomatic Intracranial Hemorrhage: A new acute neurologic deficit attributable to 
intracranial hemorrhage (ICH). ICH subtype should be specified as one or a combination of 
the following types: subarachnoid, intraventricular, parenchymal, or subdural. 
• 
Other: Neurological dysfunction events that do not satisfy the criteria for a hemorrhagic or 
ischemic stroke such as hypoxic-ischemic encephalopathy (such as signs and symptoms of 
subclinical electrographic seizures), new encephalopathy due to other causes (such as 
meningitis, toxic-metabolic, or drug-related processes).  
Pump Thrombus (Modified INTERMACS Definition) 
Pump Thrombus represents a special case of major device malfunction and will be classified as 
either suspected or confirmed pump thrombus.  
Suspected Pump Thrombus: A pump-related malfunction in which clinical or MCSD parameters 
suggest thrombus on the blood contacting components of the pump, cannulae, or grafts.  
Signs and symptoms for suspected pump thrombus should include the following: 
1) Both of the following criteria: 
• 
Major Hemolysis:  A hemolysis event occurring after the first 72 hours post-implant and 
associated with clinical symptoms or findings of hemolysis such as hemoglobinuria, 
anemia, and/or hyperbilirubinemia, with one of the following: 
o Plasma-free hemoglobin value greater than 20 mg/dl 
o A serum lactate dehydrogenase (LDH) level greater than two and one-half times 
(2.5x) the upper limits of the normal range at the implanting center 


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Clinical Investigational Plan  
 
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o Hemoglobinuria  
• 
Presence of heart failure not explained by structural heart disease, an abnormal ramp test, 
or abnormal pump parameters  
AND 
2) An event or intervention, including one or more of the following: 
• 
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 Pump Thrombus: A major pump-related malfunction in which thrombus is confirmed 
within the blood contacting surfaces of device inflow cannula or outflow conduit or grafts. This can 
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. 
If a Suspected Pump Thrombus event is ultimately confirmed through visual inspection following 
pump replacement, urgent transplantation or upon autopsy following death, the event will be 
adjudicated by the CEC for reclassification to Confirmed Pump Thrombus. 
Major Bleeding (INTERMACS Definition) 
An episode of suspected internal or external bleeding that results in one or more of the following: 
• 
Death 
• 
Re-operation 
• 
Hospitalization 
• 
Transfusion of red blood cells as follows: 
o During first 7 days post implant 
 
≥ 50 kg:  ≥ 4U packed red blood cells (PRBC) within any 24-hour period 
during first 7 days post implant. 
 
< 50 kg:  ≥ 20 cc/kg packed red blood cells (PRBC) within any 24-hour 
period during first 7 days post implant. 
o After 7 days post implant 
 
A transfusion of packed red blood cells (PRBC) after 7 days following 
implant with the investigator recording the number of units given.  (Record 
number of units given per 24-hour period.)  
Note: Hemorrhagic stroke is considered a Neurological Dysfunction and not a separate bleeding 
event. 


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Clinical Investigational Plan  
 
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Hemolysis (Modified INTERMACS Definition) 
Minor Hemolysis:  A hemolysis event occurring after the first 72 hours post-implant in the absence 
of clinical symptoms or findings of hemolysis or abnormal pump function, with one of the following: 
• 
Plasma-free hemoglobin value greater than 20 mg/dl 
• 
A serum lactate dehydrogenase (LDH) level greater than two and one-half time (2.5x) the 
upper limits of the normal range at the implanting center. 
Major Hemolysis:  A hemolysis event occurring after the first 72 hours post-implant and associated 
with clinical symptoms or findings of hemolysis such as hemoglobinuria, anemia, and/or 
hyperbilirubinemia, with one of the following: 
• 
Plasma-free hemoglobin value greater than 20 mg/dl 
• 
A serum lactate dehydrogenase (LDH) level greater than two and one-half times (2.5x) the 
upper limits of the normal range at the implanting center.  
Major Infection (INTERMACs Definition) 
A clinical infection accompanied by pain, fever, drainage and/or leukocytosis that is treated by 
non-prophylactic anti-microbial agents.  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 Pocket Infection:  A positive culture from the skin and/or tissue 
surrounding the driveline or from the tissue surrounding the external housing of a pump implanted 
within the body, coupled with the need to treat with anti-microbial 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.  (There should be a separate data field 
for paracorporeal pump that describes infection at the percutaneous cannula site, e.g. Thoratec 
PVAD). 
Sepsis:  Evidence of systemic involvement by infection, manifested by positive blood cultures 
and/or hypotension. 
Right Heart Failure (INTERMACS Definition) 
Symptoms or findings of persistent right ventricular failure characterized by both of the following: 
1)  Elevated central venous pressure (CVP) documented by one or more of the following: 
• 
Direct measurement (e.g., right heart catheterization) with evidence of a central venous 
pressure (CVP) or right atrial pressure (RAP) > 16 mmHg 
• 
Findings of significantly dilated inferior vena cava with absence of inspiratory variation 
by echocardiography 


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Study Name: PREVENT II 
Clinical Investigational Plan  
 
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• 
Clinical findings of elevated jugular venous distension at least half way up the neck in 
an upright patient.  
AND 
2)  
Elevated central venous pressure manifestation characterized by one or more of the 
following: 
• 
Clinical findings of peripheral edema (>2+ either new or unresolved) 
• 
Presence of ascites or palpable hepatomegaly on physical examination (unmistakable 
abdominal contour) or by diagnostic imaging 
• 
Laboratory evidence of worsening hepatic (total bilirubin > 2.0) or renal dysfunction 
(creatinine > 2.0). 


Study Document No: ABT-CIP-10353 Ver. A 
Study Name: PREVENT II 
Clinical Investigational Plan  
 
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Appendix E: Case Report Forms 
Study-specific Case Report Forms (CRFs) will be provided separately. 
 
 
 
 
 
 


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Study Name: PREVENT II 
Clinical Investigational Plan  
 
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Appendix F: Sample Informed Consent 
A sample informed consent will be provided separately.