Clinical trial NCT02942407
Conditions: Atrial Fibrillation End Stage Renal Disease
Keywords: Renal dialysis
Sponsor: Christopher Granger, MD
Start date: 2016-12-01; Completion date: 2019-08-12
Enrollment: 154 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, randomized, open-label, blinded end-point evaluation trial. The patient population consists of patients on hemodialysis who have atrial fibrillation (AF) and end-stage renal disease (ESRD) .

Detailed description:
This is a multicenter study in adult patients with AF and ESRD who are on hemodialysis and who have stroke risk factors making them candidates for oral anticoagulation. Patients will be randomized to apixaban versus warfarin, and will be treated for up to 15 months.

Arms: arm 1: apixaban 5 mg twice daily (apixaban 2.5 mg twice daily for selected patients) arm 2: warfarin daily dose adjusted to target International Normalized Ration(INR) of 2-3
Interventions: intervention 1: apixaban intervention 2: warfarin
Intervention descriptions: intervention 1: oral anticoagulant intervention 2: oral anticoagulant

Protocol documents:
Prot_000.pdf: 
Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
1 
RENal hemodialysis patients ALlocated apixaban versus warfarin in Atrial 
Fibrillation (RENAL-AF)  
Randomized Clinical Trial 
PROTOCOL NUMBER: CV185-450 
IND Number: 128055 
NCT02942407
Sponsor-Investigator: 
Christopher B. Granger, MD 
Professor of Medicine 
Duke University Medical Center 
DUMC Box 3850 
Durham, NC  27715 
Phone: 919-668-8900 
Fax: 919-668-7056 
E-mail:
christopher.granger@duke.edu
Co-Principal Investigator: 
Glenn M. Chertow, MD 
Professor of Medicine 
Stanford University School of Medicine 
1070 Arastradero Road, Suite 313 
Palo Alto, CA 94034 
Phone:  650-725-4738 
Fax:  650-721-1443 
E-mail: gchertow@stanford.edu
Protocol Version/Date: Version 14, 12 September 2018 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
2 
1 
PROTOCOL SYNOPSIS 
Protocol Title: 
RENal hemodialysis patients Allocated apixaban versus warfarin 
in Atrial Fibrillation (RENAL-AF) Randomized Clinical Trial 
Study Sponsor: 
Christopher B. Granger, MD 
Number of Sites: 
Approximately 65 sites 
Research Hypothesis: 
Treatment with apixaban causes less major or clinically 
relevant non-major bleeding than warfarin in patients with end-
stage renal disease (ESRD) on hemodialysis with non-valvular 
atrial fibrillation (NVAF), meaning atrial fibrillation without 
moderate or severe mitral stenosis. 
Study Schema: 
Drugs / Doses / 
Length of Treatment) 
Open label apixaban 5mg BID (or apixaban 2.5mg BID 
in patients ≥ 80 years of age and/or ≤ 60 kg) vs. adjusted dose 
warfarin.  Duration of treatment will be a maximum of 15 months, 
and the target is a mean follow-up of approximately 12 months 
with the last patient enrolled into the trial having a minimum of 6 
months of follow-up. 
Study Objectives: 
 
Primary objective:  
Assess the safety of apixaban versus warfarin with 
respect to major bleeding or clinically relevant non-major 
bleeding in patients with ESRD on hemodialysis and NVAF 
 
 
 
 
  
 
Secondary objectives: 
Evaluate stroke and systemic embolism event rates with 
warfarin and apixaban in patients with NVAF and ESRD on 
hemodialysis. 
Evaluate mortality rates with warfarin and apixaban in 
patients with NVAF and ESRD on hemodialysis. 
Evaluate persistence (meaning the duration of time from 
initiation to discontinuation of therapy) of and adherence 
(meaning the extent to which a patient acts in accordance with the 
prescribed interval and dose of a dosing regimen) to warfarin and 
apixaban in patients with NVAF and ESRD on hemodialysis. 
Evaluate the pharmacokinetics and pharmacodynamics of 
apixaban in ESRD NVAF patients on hemodialysis. 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
3 
Study Design: 
Prospective, randomized, open-label, blinded end-point 
evaluation trial (PROBE).  Patients with NVAF, ESRD, and a 
CHA2DS2-VASc score of 2 or greater will be randomized in a 
1:1 fashion to apixaban or warfarin.  The primary outcome is 
International Society of Thrombosis and Haemostasis (ISTH) 
major or clinically relevant non-major bleeding, as defined by a 
central blinded-clinical events adjudication process.  A total of 
approximately 230 patients (randomized 1:1 in the apixaban and 
warfarin arms) will be enrolled at approximately 65 sites across 
the Unites States.  Duration of treatment will be a maximum of 15 
months, and the target is a mean follow-up of approximately 12 
months with the last patient enrolled into the trial having a 
minimum of 6 months of follow-up. 
Accrual Goal: 
(Total number of patients) 
Approximately 230 patients 
Pharmacokinetics/ 
Pharmacodynamics 
(PK/PD)  
For patients enrolled using versions 13 or earlier of the 
protocol, at Day 1 visit, blood samples were collected for PK on 
all patients randomized to apixaban.  A subset of no more than 50 
patients randomized to apixaban had additional PK/PD samples 
collected at Day 3 visit and at Month 1 visit. Samples were drawn 
at the start of the hemodialysis session and at the end of the 
hemodialysis session.  For patients enrolled under version 14 of 
the protocol, no PK/PD samples will be collected. 
Inclusion Criteria: 
1. Males and Females, age at least 18 years, or the local age 
of consent, whichever is greater.  
2. Patients will be defined as having qualifying AF, if they 
meet any of the following criteria: 
a. AF on ECG at enrollment or 
b. two or more reports of AF from separate 
monitoring events at least 2 weeks apart (report 
of ECG, single lead rhythm strip such as 
AliveCor, inpatient telemetry, Holter monitor, 
event monitor, implantable loop recorder, 
pacemaker, 
or 
implantable 
cardioverter-
defibrillator), or 
c. 1 report of AF (report of ECG, single lead rhythm 
strip such as AliveCor, inpatient telemetry, 
Holter monitor, event monitor, implantable loop 
recorder, 
pacemaker, 
or 
implantable 
cardioverter-defibrillator) and being treated with 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
4 
oral anticoagulation for stroke prevention for 
atrial fibrillation at enrollment, or 
d. 1 report of AF (report of ECG, single lead rhythm 
strip such as AliveCor, inpatient telemetry, 
Holter monitor, event monitor, implantable loop 
recorder, 
pacemaker, 
or 
implantable 
cardioverter-defibrillator) and any mention in the 
medical record of a second episode of AF, or 
e. history of cardioversion for AF and any mention 
in the medical record of a second episode of AF 
or being treated with oral anticoagulation for 
stroke prevention for atrial fibrillation at 
enrollment. 
3. CHA2DS2-VASc score ≥ 2. 
4. End-stage renal disease treated with hemodialysis for ≥ 3 
months.  
5. Considered by the treating physician(s) to be candidates 
for oral anticoagulation (for example the patient does not 
have a reversible cause for AF) 
6. If of childbearing potential, be willing to avoid pregnancy 
during the study.  
Exclusion Criteria: 
1. Not considered by the treating physician(s) to be 
candidates for oral anticoagulation (for example, 
hemoglobin 
< 8.5g/dL, 
history 
of 
intracranial 
hemorrhage, active bleeding, recent gastrointestinal bleed 
or retroperitoneal bleed, severe hepatic impairment, or 
anaphylactic reaction to apixaban) 
2. Moderate or severe mitral stenosis 
3. Conditions other than NVAF that require anticoagulation 
such as mechanical prosthetic valve, deep venous 
thrombosis, or pulmonary embolism 
4. Need for aspirin at a dose > 100 mg a day or need for 
aspirin in combination with P2Y12 antagonist therapy (for 
example clopidogrel, prasugrel, or ticagrelor) 
5. Life expectancy < 3 months  
6. Anticipated kidney transplant within the next 3 months 
7. Prisoners or others who are involuntarily incarcerated or 
detained 
8. Pregnant, breastfeeding, or considering pregnancy.  
9. Participation in a clinical trial of an unapproved, 
experimental treatment within the past 30 days 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
5 
Criteria for Evaluation:  
(Efficacy, safety,  
stopping rules, etc.) 
The primary safety outcome is ISTH major bleeding or 
clinically relevant non-major bleeding 
Statistics: 
The analytic plan will be exploratory, and based on 
the observed point estimate (hazard ratio) and its 95% CIs  
for the  comparison of the primary endpoint for the apixaban 
arm versus the warfarin arm.   In addition, Kaplan-Meier 
cumulative risk curves will be constructed and a log-rank 
test will be used.  
 
 
 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
6 
2 
TABLE OF CONTENTS 
1 
PROTOCOL SYNOPSIS ......................................................................................2 
2 
TABLE OF CONTENTS ......................................................................................6 
2.1 
List of Tables .................................................................................................9 
2.2 
List of Figures ................................................................................................9 
3 
INTRODUCTION................................................................................................10 
3.1 
Overall Risk/Benefit Assessment ...............................................................11 
3.2 
Research Hypothesis ...................................................................................11 
3.3 
Study Rationale ...........................................................................................11 
4 
STUDY OBJECTIVES ........................................................................................12 
4.1 
Primary Objective .......................................................................................12 
4.2 
Secondary Objectives..................................................................................12 
4.3 
Other Objectives .........................................................................................13 
5 
ETHICAL CONSIDERATIONS ........................................................................13 
5.1 
Good Research Practice .............................................................................13 
5.2 
Institutional Review Board/Independent Ethics Committee ..................13 
5.3 
Informed Consent .......................................................................................13 
6 
INVESTIGATIONAL PLAN .............................................................................14 
6.1 
Study Design and Duration ........................................................................14 
6.2 
Study Population & Eligibility Criteria ....................................................15 
6.2.1 Inclusion Criteria ........................................................................................15 
6.2.2 Exclusion Criteria .......................................................................................16 
6.2.3 Women of Childbearing Potential & Breastfeeding Women ..................16 
6.2.4 Discontinuation of Patients from Treatment ............................................18 
6.2.5 Transition to Standard of Care Anticoagulation Therapy at End of 
Trial 
19 
7 
TREATMENTS....................................................................................................19 
7.1 
Study Treatment: Apixaban ......................................................................19 
7.1.1 Identification ...............................................................................................19 
7.1.2 Handling and Dispensing ...........................................................................20 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
7 
7.1.3 Drug Destruction .........................................................................................20 
7.2 
Drug Ordering and Accountability ...........................................................20 
7.2.1 Initial Orders ...............................................................................................20 
7.2.2 Re-Supply.....................................................................................................20 
7.2.3 Accountability .............................................................................................20 
7.3 
Method of Assigning Patients to a Treatment ..........................................20 
7.4 
Selection and Timing of Dose for Each Patient ........................................21 
7.4.1 Apixaban Dose Modifications ....................................................................21 
7.4.2 Temporary Discontinuation of Apixaban .................................................22 
7.4.3 Warfarin Dose Modifications.....................................................................22 
7.5 
Blinding/Unblinding ...................................................................................23 
7.6 
Concomitant Treatments............................................................................23 
7.6.1 Prohibited and/or Restricted Treatments .................................................23 
7.6.2 Other Restrictions and Precautions ..........................................................24 
7.7 
Treatment Adherence and Persistence .....................................................24 
8 
STUDY ASSESSMENTS AND PROCEDURES ..............................................25 
8.1 
Screening & Randomization ......................................................................25 
8.2 
Day 1 Visit (Enrollment) ............................................................................26 
8.3 
Day 3 Visit (Day 3, 4, 5, or 6 depending on hemodialysis session 
schedule) [Appendix 3] ...............................................................................27 
8.4 
Month 1 Visit (± 4 days) .............................................................................27 
8.5 
Month 2 (± 4 days) ......................................................................................28 
8.6 
Month 3, Month 6, Month 9, and Month 12 (± 4 days) ...........................28 
8.7 
Month 15 or Final Visit (+ 4 days) .............................................................29 
8.8 
Discontinuation of Patient from Study .....................................................29 
9 
ADVERSE EVENTS ...........................................................................................30 
9.1 
Safety Management ....................................................................................30 
9.2 
Suspected Adverse Reaction ......................................................................30 
9.3 
Serious Criteria ...........................................................................................30 
9.3.1 Events of Special Interest ...........................................................................31 
9.3.2 Protocol Specific Exceptions to SAE Reporting .......................................31 
9.4 
Assessment of Adverse Event Severity ......................................................32 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
8 
9.5 
Assessment of Causal Relationship ...........................................................32 
9.6 
Expectedness ................................................................................................33 
9.7 
Adverse Event Collecting and Reporting .................................................33 
9.7.1 SAE Reconciliation performed by DCRI ..................................................34 
9.7.2 Follow-up .....................................................................................................35 
9.8 
Health Authority Reporting (US FDA IND) ............................................35 
9.8.1 Expedited events..........................................................................................35 
9.8.2 Non-Serious Adverse Events (NSAEs) Collecting and Reporting ..........35 
9.9 
Laboratory Test Abnormalities .................................................................36 
9.10 
Pregnancy ....................................................................................................36 
9.11 
Overdose ......................................................................................................36 
10 
DATA MONITORING COMMITTEE .............................................................37 
11 
CLINICAL EVENTS CLASSIFICATION .......................................................37 
12 
STATISTICAL CONSIDERATIONS ...............................................................37 
12.1 
Sample Size Determination ........................................................................37 
12.2 
Populations for Analyses ............................................................................38 
12.3 
Outcome Definitions ...................................................................................38 
12.4 
Analyses .......................................................................................................39 
12.4.1 Demographics and Baseline Characteristics ............................................39 
12.4.2 Analysis for Primary Safety Endpoint ......................................................40 
12.4.3 Efficacy Analyses ........................................................................................40 
12.4.4 Persistence and Adherence Analyses ........................................................41 
12.4.5 Pharmacokinetic and Pharmacodynamic Analyses .................................41 
12.4.6 Biomarker Analyses ....................................................................................42 
13 
STUDY MANAGEMENT ...................................................................................42 
13.1 
Compliance with the Protocol ....................................................................42 
13.2 
Records Retention .......................................................................................42 
13.2.1 Study and Source Document Records Retention .....................................42 
13.2.2 Study Drug Records ....................................................................................42 
13.3 
Destruction of Investigational Product .....................................................43 
14 
GLOSSARY OF TERMS ....................................................................................44 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
9 
15 
LIST OF ABBREVIATIONS .............................................................................45 
16 
REFERENCES .....................................................................................................47 
17 
APPENDICES ......................................................................................................50 
Appendix 1: CHA2DS2-VASc Score .....................................................................50 
Appendix 2: Schedule of Procedures ....................................................................51 
Appendix 3: Timing of First Dose, Day 1, and Day 3 ..........................................54 
Appendix 4: Expected Events in Patients on Hemodialysis ................................55 
 
List of Tables 
Table 7-1 
Study Drugs for RENAL-AF .........................................................19 
Table 7-2 
Warfarin Dosing Algorithm from the ARISTOTLE Trial as 
Optional Guidance for Warfarin Management ..............................23 
List of Figures 
Figure 6-1 
Study Schematic.............................................................................15 
Figure 12-1 
Log-Rank Test for Two Survival CurvesError! Bookmark not defined. 
 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
10 
3 
INTRODUCTION 
Impaired kidney function and atrial fibrillation (AF) commonly occur together with 
approximately 13% of patients on hemodialysis in the United States having AF.1  Impaired kidney 
function is common in the elderly, who are also at the highest risk for AF.  Impaired kidney 
function is an independent predictor both of stroke and of bleeding in patients with AF.  There is 
a 1.5-fold increased risk of stroke and 2-fold increased risk of bleeding in patients with end-stage 
renal disease (ESRD) compared to patients without ESRD.2 Among patients on hemodialysis, the 
risks of gastrointestinal and other serious bleeding events, ESRD-related dietary restrictions, frailty 
and a high risk of falls, polypharmacy, and the need for repeated cannulation of arteriovenous 
fistulas and grafts vascular access type may influence decisions regarding the use of  
anticoagulation.  In addition to the usual risks associated with anticoagulation in general, the use 
of warfarin in particular is associated with additional risks unrelated to bleeding, related to 
inhibition of other vitamin K dependent pathways, including those related to dystrophic 
calcification.  Warfarin has consistently been identified as a risk factor in the development of 
calcific uremic arteriolopathy (“calciphylaxis”), a rare, but life-threatening complication, 
emblematic of accelerated medial vascular calcification.3, 4 
There is uncertainty as to the risk-benefit balance of warfarin for patients on hemodialysis 
with AF. 2, 5-7  Patients receiving hemodialysis may have different relative benefits given different 
pro- and anti-thrombotic factors related to ESRD and different risks related to hemostasis defects, 
gastrointestinal and vascular access bleeding.  In any case, it is clear that patients with advance 
kidney disease are at high risk for stroke.  A Danish registry study showed that warfarin use was 
associated with lower risk of stroke in ESRD and that aspirin was not associated with lower risk 
of stroke in this population.2  These findings are consistent with a benefit from warfarin and lack 
of substantial benefit from aspirin.  There is striking geographic variability in the treatment of AF 
in patients with ESRD, with only about fewer than half of patients being treated with warfarin in 
the United States.5  Many experts have suggested that therapy should be individualized, such that 
patients at high risk for stroke and without high bleeding risk should be treated with oral 
anticoagulation.  In reality, this may be difficult to do, since many of the same factors predict risk 
of bleeding and thrombosis. 
Apixaban is an oral factor Xa inhibitor that is an anticoagulant with superior efficacy for 
reducing stroke or systemic embolism in NVAF (non-valvular AF, meaning atrial fibrillation 
without moderate or severe mitral stenosis) compared to warfarin and with significantly less major 
bleeding than warfarin when used in the general AF population.  It is also significantly more 
efficacious than aspirin, with a non-statistical slightly higher rate of major bleeding and similar 
risk of intracranial hemorrhage.8, 9  Apixaban has been labeled by the FDA as suitable for use in 
patients with impaired kidney function (including those receiving dialysis), although this 
designation was based on pharmacokinetic and pharmacodynamics data without clinical outcomes 
data.10  Dabigatran or rivaroxaban, which are not labeled as suitable for use in ESRD, are being 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
11 
used in nearly 6% of ESRD patients receiving anticoagulation, and dabigatran and rivaroxaban 
relative to warfarin are associated with higher rates of hospitalization or death due to bleeding in 
this population.11  Patients with advanced kidney disease may obtain similar or greater benefit 
from optimally dosed non-vitamin K antagonist oral anticoagulants (NOAC), as warfarin.12  There 
is a need for randomized clinical trials of novel oral anticoagulants in the population of patients 
with AF and ESRD on hemodialysis.7, 13, 14  
3.1 
Overall Risk/Benefit Assessment 
Patients with AF and ESRD are at high risk of stroke, and warfarin has been proven to be 
very effective at stroke prevention in the general population.15  Warfarin is currently a standard 
treatment for stroke prevention in patients with ESRD.  However, warfarin has not been studied in 
a randomized manner in AF patients with ESRD, and warfarin may have limitations in population 
with ESRD that are different from the population without ESRD.  Warfarin is associated with 
calciphylaxis, which carries a high mortality.3, 4  Patients with ESRD are at high risk of bleeding, 
and when treated with warfarin, ESRD may be at higher risk of serious bleeding such as 
intracranial hemorrhage relative to non-ESRD patients.16   
All currently marketed NOACs have some component of renal clearance, and there has 
been concern with using these medications in patients with ESRD.  However, there is an unmet 
need for alternatives to warfarin for reducing the risk of stroke or systemic embolism in NVAF 
patients with ESRD.  Based on pharmacokinetics and pharmacodynamics, apixaban may be safe 
in the ESRD population.10  In the ARISTOLE trial, patients with impaired kidney function  
(estimated creatinine clearance 25 to 50 ml/min, roughly corresponding to stage 3b/4a CKD) had 
a more pronounced relative reduction in major bleeding versus warfarin than patients with higher 
creatinine clearance (HR 0.50, 95% CI 0.38-0.66, interaction p = 0.005.17  Apixaban may result in 
less intracranial hemorrhage than warfarin in the ESRD patient population, similar to the general 
population.9  There is also evidence that warfarin may become less effective at preventing ischemic 
stroke, compared to NOACs, as kidney function decreases.26   
3.2 
Research Hypothesis 
Treatment with apixaban causes less major or clinically relevant non-major bleeding than 
warfarin in patients with end-stage renal disease (ESRD) on hemodialysis with non-valvular atrial 
fibrillation (NVAF), meaning atrial fibrillation without moderate or severe mitral stenosis. 
3.3 
Study Rationale 
There were 450,000 patients receiving maintenance dialysis in the US, as of 2012, which 
has increased by 57%, since the year 2000.18  The prevalence of NVAF is higher in the dialysis 
population than in the general population1 and the risk of stroke is also higher in the dialysis 
population.2  There is an important need to study and identify strategies to reduce stroke risk in 
patients on hemodialysis with NVAF.  Warfarin is highly effective in reducing the risk of stroke 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
12 
by 66% in the overall population of patients with NVAF.15  However, warfarin use has never been 
studied in patients on hemodialysis with NVAF.  Based on conflicting data from observational 
studies regarding the risks and benefits of warfarin for stroke prevention in patients on 
hemodialysis with NVAF,1, 2, 5, 16, 19 the 2011 statement from Kidney Disease: Improving Global 
Outcomes (KDIGO) did not advise warfarin for stroke prevention in patients on hemodialysis with 
NVAF, and these statements specifically highlighted the need for clinical trials addressing this 
issue.13  
The RENAL-AF (RENal hemodialysis patients ALlocated apixaban versus warfarin in 
Atrial Fibrillation) Trial is a prospective, randomized, open-label, blinded end-point evaluation 
(PROBE) study of apixaban versus warfarin for reduction of the composite of major bleeding or 
clinically relevant non-major bleeding in patients with NVAF and ESRD on hemodialysis.  The 
lower rates of bleeding with apixaban relative to warfarin, especially intracranial hemorrhage, may 
make apixaban safer than warfarin for the reduction of the risk of stroke or systemic embolism in 
patients with ESRD and NVAF.  This randomized clinical trial will also evaluate differences in 
stroke or systemic embolism among NVAF patients with ESRD on hemodialysis who are deemed 
candidates for anticoagulation by their treating physicians and will be randomly assigned to 
apixaban versus warfarin.  There have been no prospective, randomized clinical trials investigating 
reducing the risk of stroke or systemic embolism in patients with ESRD and NVAF.   
4 
STUDY OBJECTIVES 
4.1 
Primary Objective 
The primary objective is to assess the safety of apixaban versus warfarin regarding major 
bleeding or clinically relevant non-major bleeding events in patients with NVAF and ESRD on 
hemodialysis. 
4.2 
Secondary Objectives 
The secondary objectives are to: 
1. Evaluate stroke and systemic embolism event rates with warfarin and apixaban in patients 
with NVAF and ESRD on hemodialysis. 
2. Evaluate mortality rates with warfarin and apixaban in patients with NVAF and ESRD on 
hemodialysis. 
3. Evaluate persistence (meaning the duration of time from initiation to discontinuation of 
therapy) of and adherence (meaning the extent to which a patient acts in accordance with 
the prescribed interval and dose of a dosing regimen) to warfarin and apixaban in patients 
with NVAF and ESRD on hemodialysis. 
4. Evaluate the pharmacokinetics and pharmacodynamics of apixaban in ESRD NVAF 
patients on hemodialysis. 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
13 
4.3 
Other Objectives 
Other objectives will include analysis of outcomes and treatment effect according to levels 
of cardiovascular biomarkers at baseline. 
5 
ETHICAL CONSIDERATIONS 
5.1 
Good Research Practice 
This trial will be conducted in compliance with this protocol, Good Clinical Practice 
guidelines (e.g. ICH E6: Good Clinical Practice), and applicable regulatory requirements from the 
United States Code of Federal Regulations including 21 CFR parts 312 (Investigational New Drug 
[IND]), 50 (Protection of Human Subjects, 56 (institutional review board [IRB]), and 11 
(electronic records and signatures).  
All individuals responsible for the design and/or conduct of this study are to have 
completed and documented human subjects’ protection training prior to participation. 
The site principal investigator shall ensure that personnel involved in the conduct of this 
study are qualified by education, training, and experience to perform their respective tasks. The 
site principal investigator has ultimate responsibility for trial conduct at the site.  
5.2 
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, patient recruitment materials/process 
(e.g., advertisements), and any other written information to be provided to prospective patients. 
The investigator or sponsor should also provide the IRB/IEC with a copy of the product labeling 
information to be provided to prospective patients, and any updates.  
The investigator should provide the IRB/IEC with reports, updates, and other information 
(e.g., expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
5.3 
Informed Consent 
Investigators must ensure that patients are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
Before any study procedures are performed, potential patients will have the outline of the 
study described to them, and they will be given a written informed consent document to read. If 
they consent to participate in the study, they will indicate that consent by signing and dating the 
informed consent document in the presence of study personnel. Any patient who signs the consent 
form will be considered a “screened” patient. 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
14 
6 
INVESTIGATIONAL PLAN 
6.1 
Study Design and Duration 
The study is a prospective, randomized, open-label, blinded end-point evaluation trial.  
Patients with NVAF, ESRD, and a CHA2DS2-VASc of 2 or more (Appendix 1) will be 
randomized in a 1:1 fashion to apixaban or warfarin.  The primary outcome is International Society 
of Thrombosis and Haemostasis (ISTH) major bleeding and clinically relevant non-major 
bleeding, adjudicated by a central clinical events process.   
A total of approximately 230 patients (randomized 1:1 to apixaban and warfarin) will be 
enrolled at approximately 65 sites across the Unites States.  The maximum follow-up time will be 
approximately15 months, and the target follow-up time will be a mean of 12 months with the last 
patient enrolled into the trial having a minimum of 6 months of follow-up..   
Pharmacokinetics and pharmacodynamics analyses will be performed in a subset of 
patients to determine apixaban concentrations.  For patients enrolled using versions 13 or earlier 
of the protocol, at Day 1 visit, blood samples were collected for PK on all patients randomized to 
apixaban.  A subset of no more than 50 patients randomized to apixaban had additional PK/PD 
samples collected at Day 3 visit and at Month 1 visit. Samples were be drawn at the start of the 
hemodialysis session and at the end of the hemodialysis session.  For patients enrolled using 
version 14 of the protocol, no PK/PD samples will be collected. 
The schematic provided in Figure 6-1 summarizes the study design. 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
15 
 
  
6.2 
Study Population & Eligibility Criteria 
For entry into the study, the following criteria MUST be met. Entry waivers will not be 
granted. 
6.2.1 Inclusion Criteria 
1. Males and Females, age at least 18 years, or the local age of consent, whichever is greater.  
2. Patients will be defined as having qualify AF, if they meet any of the following criteria: 
a. AF on ECG at enrollment, 
b. two or more reports of AF from separate monitoring events at least 2 weeks apart (report 
of ECG, single lead rhythm strip such as AliveCor, inpatient telemetry, Holter monitor, 
event monitor, implantable loop recorder, pacemaker, or implantable cardioverter-
defibrillator), 
Warfarin 
(target INR 2–3)
Apixaban 5 mg oral twice daily
(2.5 mg BID in patients ≥ 80 years of age 
and/or ≤ 60 kg )
Primary outcome: ISTH major and clinically relevant non-major 
bleeding
Secondary outcomes:
• PK/PD 
• Stoke and systemic embolism
• Death
• Tolerability/persistence/adherence parameters 
Randomize
(n ≈ 230)
Open label with blinded event adjudication
RENAL-AF Trial: Study Overview
Selected inclusion criteria
•
Atrial fibrillation
•
CHA2DS2-VASc ≥2
•
Hemodialysis
•
Candidate for OAC
Selected exclusion criteria
•
Moderate or severe mitral stenosis
•
OAC needed for reason other than AF
•
Need for aspirin > 100 mg
•
Need for dual antiplatelet therapy
•
Life expectancy < 3 months
 
Figure 6-1 
Study Schematic 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
16 
c. 1 report of AF (report of ECG, single lead rhythm strip such as AliveCor, inpatient 
telemetry, Holter monitor, event monitor, implantable loop recorder, pacemaker, or 
implantable cardioverter-defibrillator) and being treated with oral anticoagulation for 
stroke prevention for atrial fibrillation at enrollment,  
d. 1 report of AF (report of ECG, single lead rhythm strip such as AliveCor, inpatient 
telemetry, Holter monitor, event monitor, implantable loop recorder, pacemaker, or 
implantable cardioverter-defibrillator) and any mention in the medical record of a second 
episode of AF, or 
e. history of cardioversion for AF and any mention in the medical record of a second episode 
of AF or being treated with oral anticoagulation for stroke prevention for atrial fibrillation 
at enrollment 
3. CHA2DS2-VASc score of ≥ 2. 
4. End-stage renal disease treated with hemodialysis for at least 3 months.  
5. Considered by the treating physician(s) to be candidate for oral anticoagulation. (i.e. patient 
does not have a reversible cause for AF) [OAC treatment naïve or subjects currently 
receiving OAC are eligible].  
6. If of childbearing potential, be willing to avoid pregnancy during the study.  
6.2.2 Exclusion Criteria 
1. Not considered by the treating physician(s) to be candidates for oral anticoagulation (for 
example, hemoglobin < 8.5g/dL, history of intracranial hemorrhage, active bleeding, 
recent gastrointestinal bleed or retroperitoneal bleed, severe hepatic impairment, or 
anaphylactic reaction to apixaban) 
2. Moderate or severe mitral stenosis 
3. Conditions other than NVAF that require anticoagulation such as mechanical prosthetic 
valve, deep venous thrombosis, or pulmonary embolism 
4. Need for aspirin at a dose > 100 mg a day or need for aspirin in combination with P2Y12 
antagonist therapy (for example clopidogrel, prasugrel, or ticagrelor) 
5. Life expectancy < 3 months  
6. Anticipated kidney transplant within the next 3 months 
7. Prisoners or others who are involuntarily incarcerated or detained 
8. Pregnant, breastfeeding, or considering pregnancy.  
9. Participation in a clinical trial of an unapproved, experimental treatment within the past 30 
days 
6.2.3 Women of Childbearing Potential & Breastfeeding Women 
For purposes of this protocol, the terminology “women of childbearing potential 
(WOCBP)” is defined as any female who has experienced menarche and who has not undergone 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
17 
surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. 
Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence 
of other biological or physiological causes. In addition, females under the age of 55 years must 
have a serum follicle stimulating hormone, (FSH) level > 40mIU/mL to confirm menopause. 
 Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The 
duration of the washout period below are suggested guidelines and the investigators should 
use their judgment in checking serum FSH levels. If the serum FSH level is > 40mIU/ml 
at any time during the washout period, the woman can be considered postmenopausal: 
o 
1 week minimum for vaginal hormonal products (rings, creams, gels) 
o 
4 week minimum for transdermal products 
o 
8 week minimum for oral products 
o 
Other parenteral products may require washout periods as long as 6 months. 
Women of childbearing potential (WOCBP) must have a negative urine (use serum if 
patient is anuric) within 24 hours prior to randomization to apixaban or warfarin. WOCBP must 
agree to follow instructions for method(s) of contraception for the duration of treatment with 
apixaban or warfarin (s) plus 5 half-lives of warfarin (8 days) or apixaban (3 days) plus 30 days 
(duration of ovulatory cycle) for a total of 38 days for warfarin and 33 days for apixaban post-
treatment completion. 
Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (s) YY plus 5 half-lives 
of warfarin (8 days) or apixaban (3 days) plus 90 days (duration of sperm turnover) for a total of 
98 days for warfarin and 93 days for apixaban post-treatment completion. 
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements.  However WOCBP must still undergo pregnancy testing. 
Investigators shall counsel WOCBP and male patients who are sexually active with 
WOCBP on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy. Investigators shall advise WOCBP and male patients who are sexually active with 
WOCBP on the use of highly effective methods of contraception. Highly effective methods of 
contraception have a failure rate of < 1% when used consistently and correctly. At a minimum, 
patients must agree to the use of one method of highly effective contraception as listed below: 
 
Male condoms with spermicide 
 
IUDs, such as ParaGard® 
 
Tubal ligation 
 
Vasectomy 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
18 
 
Complete Abstinence 
o Complete abstinence is defined as complete avoidance of heterosexual intercourse and 
is an acceptable form of contraception for all study drugs.  Acceptable alternate 
methods of highly effective contraception must be discussed in the event that the patient 
chooses to forego complete abstinence. 
 Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirena® by WOCBP 
patient or male patient’s WOCBP partner. .  Female partners of male patients participating 
in the study may use hormone based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug.  
Women who are breastfeeding are not allowed to participate in this study.  
6.2.4 Discontinuation of Patients from Treatment 
Patients may discontinue study drug for any of the following reasons: 
 Patient’s decision to stop study treatment for any reason. Should a patient decide to stop 
study treatment, we will request he or she remain in follow-up, and we will follow them 
through medical records and/or death registries.  
 Any clinical adverse event, laboratory abnormality, or intercurrent illness that, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the patient. 
 Pregnancy 
o Instruct WOCBP to contact the investigator or study staff immediately if they suspect 
they might be pregnant (e.g. missed or late menstrual period) at any time during study 
participation. Institutional policy and local regulations should determine the frequency 
of on-study pregnancy tests for WOCBP enrolled in the study. 
o The investigator must immediately notify the sponsor if a study patient becomes 
pregnant. 
o Male patients whose partners are WOCBP should contact the investigator or study staff 
immediately if a pregnancy in the female partner is suspected or confirmed. 
Institutional policy and local regulations should determine the appropriate steps. 
 Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical illness. 
 Any other study specific reasons. 
All patients who discontinue should comply with protocol-specified follow-up procedures 
outlined in Section 8. Guidance will be provided in the Study Manual on how to transition to 
standard of care anticoagulation therapy at the end of the trial.  


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
19 
6.2.5 Transition to Standard of Care Anticoagulation Therapy at End of Trial 
Prior to the day of the final dose of study drug, Principal Investigators should discuss with 
their patients, and with the patients’ treating physicians, whether to begin open-label warfarin at a 
dose judged appropriate by the treating physician; e.g. based on the clinical profile of the subject 
including age, dry body weight or hemodialysis target body weight, creatinine clearance, 
concomitant therapies or other clinical conditions.  A resource that can be used to choose initial 
dose is www.warfarindosing.org. 
For those patients that will transition to warfarin from apixaban, the day following the final 
study-mandated apixaban dose, the apixaban dose will be decreased by half (from 5mg BID to 
2.5mg BID) and warfarin initiated; the patient will take 2.5mg apixaban BID in addition to 
warfarin. This “combination” therapy will continue until an INR of at least 2.0 has been obtained. 
INR should be measured two to three days after the first warfarin dose. An appropriate adjustment 
to the open-label warfarin dose should be made with the suggestion to use an algorithm like that 
found in the study (protocol section 7.4.3) or per local standards. Once there is an INR value of 
2.0 or greater, the apixaban should be stopped, and the warfarin dosing should continue. 
7 
TREATMENTS  
7.1 
Study Treatment: Apixaban 
7.1.1 Identification 
Product descriptions, packaging/storage, and other specifications of the study drugs in the 
RENAL-AF study are summarized in Table 7-1. 
 
Table 7-1 
Study Drugs for RENAL-AF 
Product 
Description / 
Class and Dosage 
Form 
Potency 
Blinded or 
Open Label 
Packaging/ 
Appearance 
Storage 
Conditions 
(per label) 
Apixaban film 
coated tablets 
5mg 
Open label 
Commercial marketed 
presentation 
As per label 
Apixaban film 
coated tablets 
2.5mg 
Open label 
Commercial marketed 
presentation 
As per label 
Warfarin sodium 
Per provider 
Open label 
Commercial marketed 
presentation 
As per label 
 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
20 
7.1.2 Handling and Dispensing 
Apixaban should be stored in a secure area according to local regulations. The investigator 
is responsible for ensuring that it is dispensed only to study patients and only from official study 
sites by authorized personnel, as dictated by local regulations. 
If concerns regarding the quality or appearance of apixaban arise, do not dispense the 
investigational product, and contact the sponsor immediately. 
7.1.3 Drug Destruction 
Since apixaban and warfarin are both commercially available, study drug will be destroyed 
according to the local institution requirements. 
7.2 
Drug Ordering and Accountability 
Apixaban will be supplied to the investigator as part of the study materials.  Warfarin will 
be obtained by the patients from a retail pharmacy with a prescription from their prescribing 
provider, but the costs of the warfarin prescriptions will be reimbursed by the RENAL-AF trial. 
7.2.1 Initial Orders 
Initial apixaban supplies will be provided upon site activation per sponsor’s SOPs. Supplies 
will be shipped by the sponsor’s specified vendor. Additional details will be provided in the study 
reference manual.  
7.2.2  Re-Supply 
Sites should request resupply of apixaban to the sponsor’s specified vendor. Enough lead 
time should be given to ensure apixaban is on site in advance of the study visit. Additional details 
will be provided in the study reference manual.  
7.2.3 Accountability 
Apixaban documentation must be maintained that includes all processes required to ensure 
drug is accurately administered. This includes documentation of drug receipt, dispensation and 
administration records, and destruction records.  
7.3 
Method of Assigning Patients to a Treatment 
Each patient will be assigned a unique sequential patient number. Each patient that meets 
the inclusion and exclusion criteria will be randomly assigned in a 1:1 manner to apixaban or dose 
adjusted warfarin with an INR goal of 2.0-3.0.  Randomization will be stratified by investigative 
site and prior warfarin status (experienced versus naïve).  Patients will be considered warfarin 
naïve if they have never previously been on warfarin or if they have started warfarin within the 
last 30 days.  Patient randomization will occur within the electronic data capture (EDC) system.  


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
21 
Patients on warfarin at baseline will be randomized to either the apixaban or warfarin arm.  
If the patient is randomized to the warfarin arm, he or she will continue on dose adjusted warfarin 
without any transition in oral anticoagulation regimen.  If the warfarin patient is randomized to 
apixaban, warfarin will be held, and apixaban will be started once the patient's INR value is < 2.0.   
For patients on a NOAC at baseline, he or she will be randomized to either the apixaban or 
warfarin arm.  For those patients randomized to apixaban, the patient should start apixaban at the 
time of their next regularly scheduled dose of the baseline NOAC.  For those patients randomized 
to warfarin, he or she should be started on warfarin in addition to the baseline oral anticoagulant, 
with the recommendation that the NOAC be reduced to half the full dose (ie, apixaban 2.5 mg bid, 
dabigatran 75 mg bid, rivaroxaban 10 mg q d, edoxaban 30 mg q d), with plans to stop the baseline 
oral anticoagulant (and continue warfarin) once the INR level reaches 2.0.  When deciding whether 
to use this half-dose NOAC "bridge" strategy, take into account thrombotic risk, for example based 
on history of prior stroke. 
7.4 
Selection and Timing of Dose for Each Patient 
If a dose of apixaban is not taken at the scheduled time, the dose should be taken as soon 
as possible on the same day and then continue with twice daily administration as before.  The dose 
should not be doubled to make up for a missed dose. 
Apixaban can be taken with or without food. 
7.4.1 Apixaban Dose Modifications 
In patients with at least 1 of the following characteristics: age  80 years or dry body 
weight/hemodialysis target body weight  60 kg, the recommended dose of apixaban is 2.5 mg 
twice daily, and patients should receive the 2.5 mg dose at any point during the trial at which they 
have met one of these characteristics (for example, a patient with an age of 79 years at enrollment 
and body weight/hemodialysis target body weight > 60kg would receive the 5 mg dose at 
enrollment but should receive the 2.5 mg dose around their 80th birthday).  If a study patient is 
taking apixaban 5 mg twice daily and is experiencing minor bleeding, the site investigator will be 
able to contact the study leadership to discuss temporary dose adjustments to 2.5 mg twice daily.  
The dates and reason for all dose adjustments to 2.5 mg twice daily must be recorded.  Patients 
taking strong dual inhibitors of CYP3A4/P-gp (examples include ketoconazole, itraconazole, 
ritonavir, and clarithromycin) should have their dose adjusted to 2.5 mg twice daily based on the 
United States package insert.  Patients taking dual inhibitors of CYP3A4/P-gp that are not strong 
inhibitors should consider dose reduction to 2.5 mg twice daily.  If patients are already taking the 
2.5 mg dose apixaban, avoid co-administration of these medications.  Cardiologists and 
nephrologists from the study leadership will be available to discuss dosing and advise about 
potential apixaban dosing adjustments.  


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
22 
7.4.2 Temporary Discontinuation of Apixaban  
Discontinuing anticoagulants, including apixaban, for active bleeding, elective surgery, or 
invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should 
be avoided, and if anticoagulation with apixaban must be temporarily discontinued, therapy should 
be restarted as soon as possible. See Section 7.6.2 for additional details. 
7.4.3 Warfarin Dose Modifications 
The patient’s prescribing provider (any provider caring for the patient with primary 
responsibility for warfarin management, including providers from a warfarin clinic or providers 
other than the study investigator) in this open label study will select the warfarin dose.  The goal 
INR will be 2.0-3.0, and the patient’s provider should monitor the INR level and adjust the dose 
of warfarin accordingly.  The frequency of INR measurements are at the discretion of the 
prescribing provider; however, we recommend that INR values are drawn at least once a month 
and more frequently at the time of warfarin initiation or around INR values out of the therapeutic 
range.  All INR values will be recorded on the eCRF. 
Warfarin dosing will be daily and patients will be instructed to follow all prescribing 
instructions. Sites that are working with a clinic that have a warfarin dosing algorithm should 
continue to use that algorithm for this study.  For providers managing warfarin without a treatment 
algorithm, the treatment algorithm from the ARISTOTLE trial is listed in Table 7-2 and may be 
used as guidance for dose adjustment of warfarin in order to maximize the time in the therapeutic 
range (2.0-3.0). Prescribing providers are responsible for initial dose selection and any dose 
adjustments. Additional resources can be located at: 
 http://www.careinternet.net/caregiver/warfarin.php  
 www.warfarindosing.org 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
23 
Table 7-2 
Warfarin Dosing Algorithm from the ARISTOTLE Trial as Optional 
Guidance for Warfarin Management 
INR Value 
Action 
> 10.0 
Stop warfarin. Contact patient for examination. 
7.0-10.0 
Stop warfarin for 2 days; decrease weekly dosage by 25% or by 1 mg/day 
for next week (7 mg total); repeat lab assessments in 1 week. 
4.5-7.0 
Decrease weekly dosage by 15% or by 1 mg/day for 5 days of next week 
(5 mg total); repeat lab assessments in 1 week. 
3.0-4.5 
Decrease weekly dosage by 10% or by 1 mg/day for 3 days of next week 
(3 mg total); repeat lab assessments in 1 week. 
2.0-3.0 
No change.  
1.5-1.9 
Increase weekly dosage by 10% or by 1 mg/day for 3 days of next week 
(3 mg total); repeat lab assessments in 1 week 
< 1.5 
Increase weekly dosage by 15% or by 1 mg/day for 5 days of next week 
(5 mg total); repeat lab assessments in 1 week 
 
See Section 7.6.2 for instructions regarding temporary discontinuation for warfarin for 
surgeries or procedures.  
 
7.5 
Blinding/Unblinding 
Not applicable as study is not blinded to study staff or patients.  
7.6 
Concomitant Treatments 
7.6.1 Prohibited and/or Restricted Treatments 
Co-administration of apixaban is not recommended with drugs that increase the risk of 
bleeding (e.g., other anticoagulants, heparin (excluding any heparin that might be used for tunneled 
hemodialysis catheter locks), thrombolytic agents). 
Heparin during hemodialysis should be minimized in all patients (randomized to apixaban 
or warfarin).  If the investigator believes that a patient in the study has an indication for and would 
benefit from heparin with hemodialysis, we advise that a heparin bolus of no more than 5,000 units 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
24 
should be given at the onset of hemodialysis. If heparin is co-administered, the reason and the dose 
must be documented within the eCRF.  In place of heparin, the circuits should be flushed every 
hour during the hemodialysis session.  If a patient has thrombosis of the extracorporeal circuit 
when heparin is not used, then the patient should receive heparin in the priming solution for the 
extracorporeal circuit during the remaining dialysis sessions, while the patient is enrolled in the 
trial.  As above, the reason heparin was administered and the dose must be documented within the 
eCRF. 
7.6.2 Other Restrictions and Precautions 
Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive 
procedures with a moderate or high risk of unacceptable or clinically significant bleeding. 
Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedures 
with a low risk of bleeding or where the bleeding would be non-critical in location and easily 
controlled. Bridging anticoagulation during the 24 to 48 hours after stopping apixaban and prior 
to the intervention is not generally required. Apixaban should be restarted after the surgical or 
other procedures as soon as adequate hemostasis has been established.  If surgery or invasive 
procedures cannot be delayed, exercise appropriate caution taking into consideration an increased 
risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. 
The concomitant use of apixaban with antiplatelet agents increases the risk of bleeding. 
Patients will be excluded from the trial if there is a need for aspirin at a dose > 100 mg or aspirin 
in combination with P2Y12 antagonist therapy (for example clopidogrel, prasugrel, or ticagrelor).  
Patients may be included if they have an indication for P2Y12 antagonist therapy without the 
concomitant use of aspirin (for example, in the case of an aspirin allergy). 
Warfarin should be held 3 to 5 days (depending on the patient's INR value) prior to the 
surgery or invasive procedure with the goal of having the patient's INR value < 1.7 at the time of 
the surgery or procedure, depending on the bleeding risk of the procedure or surgery.  For surgery 
or procedures where serious bleeding risk is high, like many neurosurgeries, the INR should return 
to normal before proceeding. 
 
7.7 
Treatment Adherence and Persistence 
Persistence is defined as the duration of time from initiation to discontinuation of therapy, 
and this will be measured for apixaban and warfarin.  Adherence is defined as the extent to which 
a patient acts in accordance with the prescribed interval and dose of a dosing regimen.  Time in 
therapeutic range (TTR) will be used to monitor treatment adherence among patients on warfarin.  
Pill counts will be used to monitor treatment adherence among patients on apixaban.   


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
25 
Additionally, a single-item self-reported medication adherence question that has been 
associated with hospitalization and death in cardiovascular patients will be asked of all patients in 
order to provide a direct comparison between the adherence of the apixaban and warfarin patients:  
“Out of the past 7 days, did you miss a dose of your blood thinner?”.20  A second self-
reported adherence question will also be asked: “Over the last 30 days, how often have you taken 
your blood thinner: less than 20% (5 days or fewer), 20-80% (6 days to 23 days), or greater than 
80% (24 days or more) of the time?”.21  This data will be collected at the quarterly visits. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and procedures will be recorded within the clinical database. A schedule 
of study procedures can be located in Appendix 2. All laboratory assessments will be performed 
according to the standard of care schedule for the patient.  
8.1 
Screening & Randomization 
If needed, screening and randomization can occur on separate days (for example, if additional 
documentation needs to be collected between screening and randomization). However, once a 
patient is randomized within the system, the Day 1 visit and start of drug should occur within 3 
days or as soon as the INR value is < 2.0 in the case of patients on warfarin at the time of 
enrollment, who were randomized to apixaban (Appendix 3). Investigator or designee will: 
 Obtain written patient informed consent 
 Review inclusion and exclusion criteria to confirm patient eligibility for randomization 
 Review relevant medical history and all concomitant medications 
 Obtain vital signs 
 Measure height and dry body weight or hemodialysis target body weight 
 Perform ECG, perform a single lead rhythm strip such as AliveCor,  or obtain an ECG 
within the last 30 days prior to enrollment 
 Obtain laboratory samples (CBC, BMP, INR), or provide results from most recent 
laboratory evaluations if within the last 30 days prior to enrollment 
 Collect urine pregnancy test (for those women of childbearing potential). If patient is anuric 
a serum pregnancy test may be performed.  
 Provide pregnancy prevention counseling as outlined in Section 6.2.3 
 If patient is eligible, randomize patient via the Electronic Data Capture (EDC) system 
o Detailed instructions can be found in study reference manual  
 Dispense medication or prescription and provide instructions (Appendix 3) 
o If the patient is randomized to apixaban, he or she will receive a 3-month supply of 
study drug at the time of randomization.  


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
26 
o If the patient is randomized to warfarin, the patient’s provider (any provider caring 
for the patient with primary responsibility for warfarin management, including 
providers from a warfarin clinic or providers other than the study investigator) will 
prescribe warfarin and the patient will fill the prescription at a commercial 
pharmacy. Warfarin dose should be managed to ensure a target INR value of 2.0-
3.0. 
o For patients randomized to apixaban, when it is feasible based on the timing of 
hemodialysis, instruct the patient to take morning dose of apixaban at least 2 hours 
prior to the scheduled hemodialysis time for the Day 1 visit. If the timing of 
hemodialysis (early morning session) makes it unfeasible to  take apixaban 2 hour 
or more prior to hemodialysis, instruct the patient to take the apixaban as early as 
is feasible, and instruct patient to note the time he or she takes the dose of apixaban.  
The timing of the apixaban dose needs to be noted in the CRF.  
o For patients randomized to warfarin, instruct patient to take medication as 
prescribed.  
8.2 
Day 1 Visit (Enrollment)  
Day 1 visit is the first hemodialysis visit after the patient commences study drug treatment. 
The Day 1 visit should occur within 3 days or randomization or as soon as the INR value is < 
2.0 in the case of patients on warfarin at the time of enrollment, who were randomized to 
apixaban (Appendix 3).  
The investigator or designee will: 
 Obtain vital signs  
 For patients enrolled using protocol version 13 or earlier, obtain biomarker sample (if 
biomarker sample is not able to be drawn at the Day 1 visit, it can be drawn at a subsequent 
visit).  For patients enrolled using protocol version 14, no biomarker sample will be 
collected. 
 Review concomitant medications and record any concomitant medications potentially 
related to dialysis (hematopoietic agents), or bleeding (SSRIs, aspirin; P2Y12 antagonists 
such as clopidogrel, prasugrel, and ticagrelor; NSAIDs)   
 Assess for any AEs of special interest (thrombosis of fistula, graft, or access catheter; 
thrombosis of extracorporeal dialysis circuit; access site bleeding) that have occurred since 
time of consent 
 Assess for any SAEs, major bleeding events, clinically relevant non-major bleeding events, 
strokes, systemic emboli, or deaths since time of randomization 
 Record start and stop time of hemodialysis session  
 For patients receiving apixaban and enrolled using version 13 or earlier, PK samples were 
collected.  For patients enrolled using version 14, no PK samples will be collected. 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
27 
o Record time of the most recent apixaban dose prior to the PK sample 
o If the patient was taking apixaban at the time of enrollment, record the approximate 
date that the patient originally started their apixaban prior to enrollment in the study 
o Obtain 2 PK blood samples. PK samples are to be obtained at the start of the 
hemodialysis session, and at the end of the hemodialysis session. It is preferred if 
apixaban is taken at least 2 hours prior to the start of the hemodialysis session; 
however, if this is not feasible, the PK sample should still be taken.  For all PK 
blood samples, it is necessary to document the time at which the PK blood sample 
and the time at which the last dose of apixaban prior to the PK blood sample were 
taken.  
8.3 
Day 3 Visit (Day 3, 4, 5, or 6 depending on hemodialysis session schedule) [Appendix 
3] 
Investigator or designee will: 
 Obtain vital signs  
 Review concomitant medications and record any concomitant medications potentially 
related to dialysis (hematopoietic agents), or bleeding (SSRIs, aspirin; P2Y12 antagonists 
such as clopidogrel, prasugrel, and ticagrelor; NSAIDs)   
 Assess for any AEs of special interest (thrombosis of fistula, graft, or access catheter; 
thrombosis of extracorporeal dialysis circuit; access site bleeding) that have occurred since 
last visit 
 Assess for any SAEs, major bleeding events, clinically relevant non-major bleeding events, 
strokes, systemic emboli, or deaths since time of randomization 
 Record start and stop time of hemodialysis session  
 For patients randomized to apixaban who are participating in the PK/PD subset, which only 
includes patients enrolled using protocol version 13 or earlier 
o Record time of apixaban dose. Apixaban should be taken at least 2 hours prior to 
the start of the hemodialysis session.   
o Obtain 2 blood samples for PK/PD analysis. Samples are to be obtained at the start 
of the dialysis session, and at the end of the dialysis session.  
8.4 
Month 1 Visit (± 4 days) 
Investigator or designee will: 
 Review concomitant medications and record any concomitant medications potentially 
related to dialysis (hematopoietic agents), or bleeding (SSRIs, aspirin; P2Y12 antagonists 
such as clopidogrel, prasugrel, and ticagrelor; NSAIDs)   


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
28 
 Assess for any SAEs or AEs of special interest (thrombosis of fistula, graft, or access 
catheter; thrombosis of extracorporeal dialysis circuit; access site bleeding) that have 
occurred since last visit 
 Assess for any major bleeding events, clinically relevant non-major bleeding events, 
strokes, systemic emboli, or deaths since last visit 
 Obtain vital signs  
 Obtain laboratory measures  
o Record most recent CBC data for for all patients  
o INR for patients receiving warfarin 
 Record start and stop time of hemodialysis session  
 For patients randomized to apixaban who are participating in the PK subset, which only 
includes patients enrolled using protocol version 13 or earlier 
o Record time of apixaban dose 
o Obtain 2 blood samples for PK/PD analysis. Samples are to be obtained at the start 
of the dialysis session, and at the end of the dialysis session.  
8.5 
Month 2 (± 4 days)  
Investigator or designee will: 
 Review concomitant medications and record any concomitant medications potentially 
related to dialysis (hematopoietic agents), or bleeding (SSRIs, aspirin; P2Y12 antagonists 
such as clopidogrel, prasugrel, and ticagrelor; NSAIDs)   
 Assess for any SAEs or AEs of special interest (thrombosis of fistula, graft, or access 
catheter; thrombosis of extracorporeal dialysis circuit; access site bleeding) that have 
occurred since last visit 
 Assess for any major bleeding events, clinically relevant non-major bleeding events, 
strokes, systemic emboli, or deaths since last visit 
 Obtain vital signs  
 Obtain laboratory measures  
o Record most recent CBC data for all patients  
o INR for patients receiving warfarin 
 Record start and stop time of hemodialysis session  
8.6 
Month 3, Month 6, Month 9, and Month 12 (± 4 days) 
Investigator or designee will: 
 Review concomitant medications and record any concomitant medications potentially 
related to dialysis (hematopoietic agents), or bleeding (SSRIs, aspirin; P2Y12 antagonists 
such as clopidogrel, prasugrel, and ticagrelor; NSAIDs)   


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
29 
 Assess for any SAEs or AEs of special interest (thrombosis of fistula, graft, or access 
catheter; thrombosis of extracorporeal dialysis circuit; access site bleeding) that have 
occurred since last visit 
 Assess for any major bleeding events, clinically relevant non-major bleeding events, 
strokes, systemic emboli, or deaths since last visit 
 Obtain vital signs 
 Obtain laboratory measures  
o Record most recent CBC data for all patients  
o INR for patients receiving warfarin 
 Assess medication compliance for apixaban: conduct pill count  
 Record responses to medication adherence questions  
 Dispense study medication (apixaban treatment group) or prescription (warfarin treatment 
group) 
 Record start and stop time of hemodialysis session  
8.7 
Month 15 or Final Visit (+ 4 days) 
Investigator or designee will: 
 Review concomitant medications and record any concomitant medications potentially 
related to dialysis (hematopoietic agents), or bleeding (SSRIs, aspirin; P2Y12 antagonists 
such as clopidogrel, prasugrel, and ticagrelor; NSAIDs)   
 Assess for any SAEs or AEs of special interest (thrombosis of fistula, graft, or access 
catheter; thrombosis of extracorporeal dialysis circuit; access site bleeding) that have 
occurred since last visit 
 Assess for any major bleeding events, clinically relevant non-major bleeding events, 
strokes, systemic emboli, or deaths since last visit 
 Obtain vital signs 
 Measure dry body weight or hemodialysis target body weight 
 Obtain laboratory measures  
o Record most recent CBC data for all patients  
o INR for patients receiving warfarin 
 Assess medication compliance for apixaban: conduct pill count  
 Record responses to medication adherence questions  
 Record start and stop time of hemodialysis session  
8.8 
Discontinuation of Patient from Study 
Patients can decide to withdraw from the study for any reason.  If the patient withdraws 
consent to be contacted for follow-up, vital status will be obtained through the patients records, 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
30 
physician, or public records. When allowed and with consent, social security number will be 
obtained as to allow obtaining vital status through National Death Index and/or Medicare. 
9 
ADVERSE EVENTS 
An Adverse Event [AE] is defined as any new untoward medical occurrence or worsening 
of a pre-existing medical condition in a patient or clinical investigation patient administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational product. 
9.1 
Safety Management 
The sponsor has engaged DCRI Safety Surveillance to oversee real-time serious adverse 
event (SAE) collection, evaluation, and expedited regulatory reporting for this study. A DCRI 
safety medical monitor will be responsible for evaluating site reported SAEs to confirm protocol 
specific serious reporting criteria, causality assessment, and expectedness compared to the product 
label. Details of this process can be found in the study-specific Safety Management Plan. 
9.2 
Suspected Adverse Reaction  
A suspected adverse reaction (SAR) is any adverse event for which there is a reasonable 
possibility that the drug caused the event. “Reasonable possibility” suggests there is a causal 
relationship between the drug and the adverse event. “Suspected adverse reaction” implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event caused 
by a drug. 
Adverse events, except as described below, will not be collected since both study drugs are 
marketed and have known and extensive safety profiles. 
9.3 
Serious Criteria 
For this protocol, a Serious Adverse Event (SAE) is any untoward medical occurrence at 
any dose that:  
 results in death 
 is life-threatening (defined as an event in which the patient was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe) 
 requires inpatient hospitalization or causes prolongation of existing hospitalization  
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
31 
 is an important medical event, defined as a medical event that may not be immediately life-
threatening or result in death or hospitalization but, based on appropriate medical and 
scientific judgment, may jeopardize the patient or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed above. Examples of such 
events include but are not limited to intensive treatment in an emergency department or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.  
 results in potential or suspected cases of liver injury including but not limited to liver test 
abnormalities, jaundice, hepatitis or cholestasis.  
 Although pregnancy, overdose, and cancer are not always serious by regulatory definition, 
these events must be submitted to the sponsor within the same time period as an SAE. 
9.3.1 Events of Special Interest 
The following events will not be included in the primary outcome, but they are clinical 
events of special interest that may relate to safety and that will be tracked and reported in the trial 
results. These adverse events are to be reported to DCRI, regardless of whether these reports are 
classified as serious or unexpected: 
 Thrombosis of fistula, graft, or access catheter 
 Thrombosis of extracorporeal dialysis circuit 
 Access site bleeding that does not meet the criteria for major or clinically relevant non-
major bleeding, as defined in Section 0  
 Other clinically overt bleeding that does not meet the criteria for major or clinically relevant 
non-major bleeding, as defined in Section 0  
 Red blood cell transfusion(s) 
9.3.2 Protocol Specific Exceptions to SAE Reporting 
The following SAEs will be collected but do not require reporting through the SAE 
reporting mechanism. These events will be captured on event-specific forms, not on the SAE form 
 Safety and efficacy outcomes that are being collected in a systematic way on the eCRF, 
such as major bleeding, clinically relevant non-major bleeding, stroke or systemic 
embolism, and mortality will be collected and recorded within the database   
 Other clinical outcomes expected to occur in patients on hemodialysis as part of the disease 
process: 
o Myocardial infarction 
o Atrial fibrillation with rapid ventricular response 
o Heart failure or fluid overload 
o Pulmonary edema 
o Transient ischemic attack  


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
32 
o Acute severe hypertension 
o Infections (including but not limited to cellulitis, osteomyelitis, and pneumonia) 
 NOTE: Outcomes that are expected to occur in patients on hemodialysis as part of the 
disease process that are not clinically relevant to the trial need not be collected or reported: 
hyperkalemia, hypoglycemia in patients with diabetes, bradycardia, peripheral arterial 
disease or gangrene, chronic obstructive pulmonary disease, constipation, hypotension, or 
long bone fracture such as femur fracture. 
 
NOTE: The following hospitalizations are not considered SAEs:  
 Visits to the emergency room or other hospital department lasting less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a life-
threatening event) 
 Elective surgery planned before or after signing consent 
 Admissions as per protocol for a planned medical/surgical procedure or elective surgeries.  
 Routine health assessments requiring admission for baseline/trending of health status (e.g. 
routine colonoscopy) 
 Medical/surgical admissions other than remedying ill health state that was planned before 
study entry. Appropriate documentation is required in these cases. 
 Admissions encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g. lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason) 
9.4 
Assessment of Adverse Event Severity  
The determination of adverse event severity rests on medical judgment of a medically-
qualified investigator. The severity of AEs will be graded using the following definitions:  
Mild: awareness of sign, symptom, or event, but easily tolerated;  
Moderate: discomfort enough to cause interference with usual activity and may warrant 
intervention;  
Severe: incapacitating with inability to do usual activities or significantly affects clinical 
status, and warrants intervention. 
9.5 
Assessment of Causal Relationship 
The causal relationship to study drug is to be determined by a physician at the site and 
should be used to assess all reportable adverse events (AEs).  
The causal relationship should be one of the following:  


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
33 
 Related: There is reasonable causal relationship between study drug administration and 
the AE 
 Not related: There is not a reasonable causal relationship between study drug 
administration and the adverse event.  
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship.  
The investigator reports causality, but the sponsor retains the final decision on causality 
when filing to the FDA. 
9.6 
Expectedness 
The expectedness of an adverse event shall be determined according to the specified 
reference document containing safety information (e.g., most current investigator’s brochure or 
product label). Any AE that is not identified in nature, severity, or specificity in the current study 
drug reference document(s) (e.g. investigator’s brochure), is considered unexpected/unlisted.  
Events that are mentioned in the investigator’s brochure or product label as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the drug, but not specifically 
mentioned as occurring with the particular drug under investigation or on the list of expected 
events (Appendix 4) in the course of illness of patients with atrial fibrillation on hemodialysis are 
considered unexpected/unlisted.  
9.7 
Adverse Event Collecting and Reporting  
Non-serious adverse events that lead to permanent discontinuation of study drug will be 
collected on the eCRF.  
Following the patient’s signing the written consent in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur after signing the written 
consent through 30 days after permanent study drug discontinuation.  If applicable, SAEs must be 
collected that relate to any later protocol-specific procedure (such as follow-up skin biopsy). 
The investigator should report any SAE occurring after these time periods that is believed 
to be related to study drug or protocol-specified procedure.  
An SAE report should be completed for any event where doubt exists regarding its status 
of seriousness.  
All Serious Adverse Events (SAEs) that occur following the subject’s written consent in 
the study through 30 days after permanent study drug discontinuation must be reported to DCRI.  
SAEs, whether related or unrelated to the study drug, and pregnancies must be reported by 
the site to DCRI within 24 hours through the electronic data capture system (EDC). DCRI will 
report the SAE to BMS within 2 business days via a protocol-specific SAE page generated through 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
34 
the EDC. Pregnancies must be reported by the site to DCRI on a Pregnancy Surveillance Form. 
NOTE: DCRI will forward any pregnancy information to BMS within 2 business days. SAE 
email address and fax number as listed are only for DCRI to report to BMS, and not for 
direct site reporting. 
SAE Email Address: Worldwide.Safety@BMS.com. 
SAE Fax Number: 609-818-3804. 
If only limited information is initially available, follow-up reports are required. Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.  
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours to DCRI 
using the same procedure used for transmitting the initial SAE report. 
All SAEs will be followed until resolution, stabilization or the event is otherwise explained. 
If the investigator believes that an SAE (that needs to be reported as such) is not related to 
study drug, but is potentially related to the conditions of the study (such as withdrawal of previous 
therapy, or a complication of a study procedure), the relationship should be specified in the 
narrative section of the SAE Form. 
All SAEs must be reported by the investigator or qualified designee within 24 hours of 
becoming aware of the event. The investigator/qualified designee will enter the required 
information regarding the SAE into the appropriate module of the eCRF, which will automatically 
result in distribution of the information to the appropriate sponsor contact. If the eCRF system is 
temporarily unavailable, the event, including the investigator-determined causality to study drug, 
should be reported via a paper back-up SAE form to DCRI. Upon return of the availability of EDC 
system, the SAE information must be entered into the eCRF within 24 hours. 
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, 
these events must submitted within the same time period (1 business day) as an SAE. 
9.7.1 SAE Reconciliation performed by DCRI 
DCRI will reconcile the clinical database SAE cases transmitted to BMS Global 
Pharmacovigilance (GPV&E). Frequency of reconciliation will be done every three months and 
once prior to study database lock. BMS GPV&E will e-mail upon request from DCRI, the GPV&E 
reconciliation report. Requests for reconciliation should be sent to aepbusinessprocess@bms.com. 
The data elements listed on the GPV&E reconciliation report will be used for case identification 
purposes. If DCRI determines a case was not transmitted to BMS GPV&E, the case will be sent 
immediately. 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
35 
9.7.2 Follow-up 
When additional relevant information becomes available, the investigator will record 
follow-up information according to the same process used for reporting the initial event as 
described above. The investigator will follow all reportable events until resolution, stabilization or 
the event is otherwise explained.  
The Sponsor or designee (e.g. DCRI Safety Surveillance) will follow all SAEs and 
pregnancies until resolution, stabilization, until otherwise explained. 
9.8 
Health Authority Reporting (US FDA IND) 
Investigators must adhere to local Health Authority Reporting Requirements. For studies 
conducted under an investigator sponsored US FDA IND, the FDA will be provided information 
on the following through the DCRI: 
 Any event that is both serious and unexpected will be reported to the Food and Drug 
Administration (FDA) as soon as possible and no later than 7 days (for a death or life-
threatening event) or 15 days (for all other SAEs) after the investigator’s or institution’s 
initial receipt of the information.  
9.8.1 Expedited events 
The Sponsor or designee will notify the FDA and all participating investigators in a written 
IND safety report of an SAR that, based on the opinion of the investigator or sponsor, is serious, 
is related to study drug, and is unexpected (per the sponsor) as soon as possible, but not later than 
15 calendar days after the sponsor has determined the serious, unexpected SAR (SUSAR) qualifies 
for expedited reporting. The sponsor will identify all safety reports previously filed with the IND 
concerning a similar SAR, and will analyze the significance of the SAR in light of the previous, 
similar reports. Follow-up reports will be sent to investigators to inform and update them about an 
important suspected adverse reaction if it significantly affects the care of the patients or conduct 
of the study. 
The site investigator will be responsible for reporting adverse events and unanticipated 
problems involving risks to patients to their local IRBs/IECs in accordance with local regulations.  
9.8.2 Non-Serious Adverse Events (NSAEs) Collecting and Reporting 
A non-serious adverse event is an AE that is not classified as serious. Non-serious adverse 
events will only be collected if they result in study drug discontinuation or if they are predefined 
outcomes (or other events of special interest) that will be collected as outcome clinical events in 
the trial eCRFs.  The collection of other non-serious adverse event (NSAE) will not be done during 
this pragmatic clinical trial.  Non-serious AEs that are collected during the study will be listed in 
the Clinical Study Report (CSR). 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
36 
9.9 
Laboratory Test Abnormalities 
The following laboratory abnormalities should be captured and reported as appropriate: 
 Any laboratory test result that is clinically significant or meets the definition of an SAE 
 Any laboratory test result abnormality that required the patient to have study drug 
discontinued  
It is expected that wherever possible, the clinical rather than the laboratory term will be 
used by the reporting investigator (e.g., use the term anemia rather than low hemoglobin value).  
Laboratory test abnormalities are provided to the sponsor via annual safety reports (if 
applicable), and interim or final study reports. 
9.10 Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a 
study patient is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (e.g. dose tapering if necessary 
for patient safety).  
The investigator must immediately notify the sponsor of this event within 24 hours and in 
accordance with SAE reporting procedures. 
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome must be reported. Any associated AEs or SAEs that occur to the mother or 
fetus/child will be recorded in the SAE eCRFs.  
Any pregnancy that occurs in a female partner of a male study patient should be reported 
to DCRI. Information on this pregnancy may also be collected on the Pregnancy Surveillance 
Form. DCRI will forward reports to BMS. 
Protocol-required procedures for study discontinuation and follow-up must be performed 
on the patient unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. 
It is expected that whenever possible, the clinical, rather than the laboratory, term would 
be used by the reporting investigator (e.g., anemia vs. low hemoglobin value).   
9.11 Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a study 
drug that is considered both excessive and medically important. All occurrences of study drug 
overdose must be reported as SAEs. 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
37 
10 DATA MONITORING COMMITTEE 
The data monitoring committee (DMC) will monitor the safety aspects of this study.  The 
DMC will consist of clinicians and one statistician. The DMC is expected to meet at approximately 
every 6-months.  The DMC charter will provide details on monitoring roles and responsibilities.   
11 CLINICAL EVENTS CLASSIFICATION 
The DCRI Clinical Events Classification (CEC) group will be responsible for blindly 
adjudicating the primary endpoint of major bleeding or clinically relevant non-major bleeding.  
The CEC will also adjudicate secondary outcomes as defined in Section 0.  Source documents will 
be collected as part of this blind, adjudication process.  The methodology used by the CEC is 
detailed in the CEC charter. 
12 STATISTICAL CONSIDERATIONS 
 
12.1 Sample Size Determination 
No confirmatory statistical hypothesis testing is pre-specified, and the explotorary analyses 
will be detailed in a separate statistical analysis plan (SAP). The SAP will be based on deriving 
the point estimates and 95% CIs for the pairwise comparisons of the primary endpoint, as well as 
other clinical outcomes of interest. These comparisons will be presented as a two-sided 95% CI on  
the observed relative risk (hazard ratio). For the primary endpoint, Kaplan-Meier cumulative risk 
curves will be constructed and log-rank test will be used.  
The trial will randomize approximately 230 patients in a ratio of 1:1 to warfarin or apixaban 
treatment groups.  Radomization will be stratified by investigative site and prior warfarin status 
(experienced versus naïve).  The study will be conducted at about 65 sites in the United States.  
The primary endpoint is major bleeding or clinically relevant non-major bleeding.   
Due to a lower recruitment rate than anticipated in the early stage in the trial, the sample 
size was reduced from 760 (see protocol version 13, Section 12.1) to 230 patients.  Due to lack of 
statistical power with a total of 230 patients, the current analytic plan  has been changed from a 
formal non-inferiority testing followed by superiority testing to an exploratory analytic plan with  
no confirmatory statistical hypothesis testing.  If the upper 95% CI on the relative risk of the 
primary outcome excludes 1.40, this will be considered evidence of non-inferiority of apixaban.  
However, if the 95% CI excludes unity,  this would be considered evidence of superiority.   
The 30% event rate in warfarin patients is based on the fact that the major bleeding rate for 
patients in ARISTOTLE with an estimated creatinine clearance of 30mL/min, who were 
randomized to warfarin, was approximately 10% at 1-year.17  The major or clinically relevant non-
major bleeding rate would be estimated to be 20% at 1 year for patients with an estimated 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
38 
creatinine clearance of 30mL/min based on the fact that clinically relevant non-major bleeding in 
ARISTOTLE occurred at the same rate as major bleeding.9  Similarly the rate of major bleeding 
was 13% in ARISTOTLE patients 75 years or older with an estimated creatinine clearance less 
than or equal to 30mL/min.22  In the ROCKET trial, the rate of major or clinically relevant non-
major bleeding in patients with an estimated creatinine clearance of 30-49mL/min was 18% per 
year.23  The assumption is that there is approximately 1.5 times more bleeding in hemodialysis 
patients relative to patients with an estimated creatinine clearance of 30mL/min.  This is further 
supported by a 34% rate of non-access site major bleeding among warfarin patients, which was 
noted in a retrospective analysis of hemodialysis patients with AF.11  
 
12.2 Populations for Analyses 
The primary outcome will be calculated based on an intention to treat (ITT) 
methodology. The ITT approach uses all randomized patients analyzed by treatment assigned.  A 
sensitivity analysis is planned using the “modified intention to treat (mITT)”. The mITT 
population uses all randomized patients who received at least 1 dose of study therapy analyzed 
by randomized treatment.      
The DMC may choose to look at the ‘safety’ population defined as the mITT population 
analyzed by the initial drug received.  Details will be provided in the DMC SAP. 
12.3 Outcome Definitions 
The primary outcome is major bleeding or clinically relevant non-major bleeding.  Major 
bleeding described below is adapted from the International Society on Thrombosis and Hemostasis 
(ISTH) definition in order to be relevant for this specific AF ESRD patient population treated with 
hemodialysis. 
A major bleeding event is defined as: 
 Acute clinically overt bleeding (including access site related bleeding) accompanied by 
one or more of the following: 
o A decrease in hemoglobin of 2g/dL or more with overt bleeding (over a period 
deemed by the events review process to be consistent with bleeding) 
o A transfusion of 2 or more units of packed red blood cells in the setting of an overt 
bleeding event (over a period deemed by the events review process to be consistent 
with bleeding) 
o Bleeding at a critical site 
 Intracranial 
 Intra-spinal 
 Intraocular 
 Pericardial 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
39 
 Intra-articular 
 Intramuscular with compartment syndrome 
 Retroperitoneal 
 Fatal bleeding 
 
Clinically relevant non-major bleeding event: 
 Acute or sub-acute clinically overt bleeding (including access site related bleeding) that 
does not meet criteria for major bleeding and results in: 
o Hospital admission for bleeding 
o Physician guided medical or surgical treatment for bleeding 
o A change in antithrombotic therapy 
 
Safety events of special interest: these events will not be included in the primary endpoint, 
but they are safety events of special interest that will be tracked. These events are defined in section 
9.3.1. 
This is primarily a safety outcome trial. The efficacy outcomes are secondary outcomes, as 
listed below.  
 Stroke: Diagnosis of stroke will require the abrupt onset of focal neurological symptoms 
lasting at least 24 hours.  It is strongly recommended (but not required) that a neurologist 
evaluation supports the diagnosis of stroke.  An imaging procedure such as a head CT scan 
or MRI should support the diagnosis of stroke, as made by the neurologist.  All strokes will 
be classified as stroke of unknown cause, ischemic, or hemorrhagic.  
 Systemic embolism: Clinical history consistent with an acute loss of blood flow to a 
peripheral artery, which is supported by evidence of embolism from surgical specimens, 
autopsy, angiography, ultrasound, or other objective testing. 
 All-cause mortality: Deaths will be classified as either cardiovascular or non-
cardiovascular.  All deaths will be assumed to be cardiovascular unless a non-
cardiovascular cause can be clearly provided 
12.4 Analyses 
12.4.1 Demographics and Baseline Characteristics 
Frequency distribution and summary statistics for demographic and baseline variables will 
be presented by treatment group and for all patients combined.  Key demographic and baseline 
variables to be summarized include: geographic region, age, sex, race/ethnicity, vintage (time since 
initiation of dialysis), height, dry body weight or hemodialysis target body weight, Quételet’s 
(body mass) index (BMI), vital signs, prior warfarin status (experienced versus naïve), risk factors 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
40 
for stroke, risk factors for bleeding, comorbid conditions, baseline medications, and atrial 
fibrillation type. 
12.4.2 Analysis for Primary Safety Endpoint 
The primary objective is to assess the safety of  apixaban as compared to warfarin on the 
primary safety outcome defined as time to first occurrence of major bleeding or clinically relevant 
non-major bleeding during the study period among all randomized patients.  The Cox proportional 
hazards model, stratified by prior warfarin status (experienced versus naïve) on the intent to treat 
(ITT) population will be used as the primary analysis to evaluate the endpoint. This analysis will 
be repeated after adjusting for clinically important baseline characteristics to be specified in the 
statistical analysis plan (SAP).   
The validity of the proportional hazard assumption underlying the Cox survival analysis 
will be tested using appropriate statistical methods. If required, additional appropriate survival 
analysis techniques will be employed as sensitivity analyses. Evaluation of the primary safety 
outcomes will include events which occurred from the randomization date to the month 15 visit or 
the date of final assessment where all elements of the outcome of interest were evaluated if that is 
prior to the month 15 visit, regardless of the time interval between patient discontinuation of study 
drug and final contact. If patients do not have any events throughout the study, they will be 
censored on the date of final assessment where all elements of the outcome of interest were 
evaluated.     
Subgroup analyses will be performed to further evaluate apixaban effect. Relevant 
subgroups, including age, sex, race, aspirin use, concomitant medications, and medical history, 
will be examined and will be pre-specified in greater detail in the Statistical Analysis Plan (SAP). 
Hazard ratios and 95% confidence intervals will be reported for each subgroup, as well as p-values 
for the tests of interaction between treatment and each subgroup. 
In addition to the ITT populations, the analyses for the primary safety endpoint will be 
performed on the mITT. Additional details will be provided in the SAP, which will be developed 
prior to the first DMC analysis and finalized prior to study completion.  
12.4.3 Efficacy Analyses 
Event rates for the following secondary outcomes will be summarized by treatment group: 
 Ischemic stroke 
 Hemorrhagic stroke 
 Stroke of unknown cause 
 Systemic embolism 
 All-cause death 
 Composite of stroke or systemic embolism 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
41 
 Composite of stroke, systemic embolism, major bleeding, and all-cause mortality 
Cox proportional hazards models will be used to estimate the hazard ratios and two-sided 
95% confidence intervals for each of these secondary outcomes. 
12.4.4 Persistence and Adherence Analyses 
A single-item self-reported medication adherence question that has been associated with 
hospitalization and death in cardiovascular patients will be asked of all patients in order to provide 
a direct comparison between the adherence of the apixaban and warfarin patients: “Out of the past 
7 days, did you miss a dose of your blood thinner?”20 
A second self-reported adherence question will also be asked: “Over the last 30 days, how 
often have you taken your blood thinner: less than 20% (5 days or fewer), 20-80% (6 days to 23 
days), or greater than 80% (24 days or more) of the time?”21 This data will be collected at the 
quarterly visits. 
The TTR will be determined by the modified Rosendaal method of linear interpolation 
between each pair of measured INR values.25    
More details on the statistical methods and analyses will be provided in the statistical 
analysis plan (SAP).   
12.4.5 Pharmacokinetic and Pharmacodynamic Analyses 
Samples will be obtained from a subset of patients randomized to apixaban, under versions 
13 or earlier of the protocol, to characterize apixaban PK/PD levels in hemodialysis patients with 
atrial fibrillation. No patients enrolled under version 14 of the protocol will have PK/PD samples 
collected.  Details for analyses will be specified in a separate PK/PD SAP.  
 Pharmacokinetic Measures: 
o Samples collected as described in Study Assessments and Procedures will be 
analyzed to determine apixaban plasma concentration. Listing of the apixaban 
plasma concentrations will be provided. 
o Data from the current study may be pooled with historical data to provide individual 
PK parameters (e.g., CL/F, Vc/F, KA) in order to approximate Cmax, Cmin, and 
AUC (TAU) for each patient from a PPK model. Modeling results will be reported 
separately. 
 Pharmacodynamic Measures: 
o Samples collected as described in Study Assessments and Procedures will be 
analyzed by a one-step chromogenic anti-FXa assay. Listing of the anti-FXa 
activities will be provided. 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
42 
12.4.6 Biomarker Analyses 
At the Day 1 visit, a blood sample will be collected from a subset of patients, enrolled using 
versions 13 or earlier of the protocol, and stored for later measurement of selected biomarkers.  If 
the biomarker sample is not able to be drawn at the Day 1 visit, it can be drawn at a subsequent 
visit.  Blood samples will be analyzed for biomarkers such as, but not limited to, NTproBNP, hsTn, 
GDF-15.  The biomarker evaluation will be used to characterize the risk of clinical outcomes, such 
as bleeding, in patients with NVAF and ESRD on hemodialysis.  No patients enrolled using version 
14 of the protocol will have a blood sample collected.   
13 STUDY MANAGEMENT 
13.1 Compliance with the Protocol 
The study shall be conducted as described in this approved protocol. The sponsor is the 
sole authority of the content of this protocol and any revisions to the protocol will be at the 
sponsor’s discretion. The site investigator will not implement any deviation or change to the 
protocol without prior review and documented approval of the amendment from the appropriate 
IRB, except when necessary to eliminate an immediate hazard(s) to study patients. 
13.2 Records Retention  
13.2.1 Study and Source Document Records Retention 
The investigator must retain all study records and source documents for a minimum of 2 
years or longer, if notified by the sponsor, following the completion of the study, unless local 
regulations and institutional policies require a longer storage period.  
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall 
be transferred to a mutually agreed upon designee (e.g., another investigator, IRB). Notice of such 
transfer will be given in writing to the sponsor.  
13.2.2 Study Drug Records  
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product is maintained at each study site where study drug and non-investigational 
product(s) is/are inventoried and dispensed. Records or logs must comply with applicable 
regulations and guidelines and should include: 
o amount received and placed in storage area 
o amount currently in storage area 
o label ID number or batch number  
o amount dispensed to and returned by each patient, including unique patient identifiers 
o amount transferred to another area/site for dispensing or storage 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
43 
o non-study disposition (e.g., lost, wasted)  
o amount destroyed at study site, if applicable 
o dates 
and 
initials 
of 
person 
responsible 
for 
Investigational 
Product 
(IP) 
dispensing/accountability, as per the Delegation of Authority Form. 
13.3 Destruction of Investigational Product  
Study drugs are to be destroyed on site. It is the investigator’s responsibility to ensure that 
arrangements have been made for disposal, and that procedures for proper disposal have been 
established according to applicable regulations, guidelines, and institutional procedures. 
Appropriate records of the disposal must be maintained.  


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
44 
14 GLOSSARY OF TERMS 
Term 
Definition 
Adverse Reaction 
An adverse event that is considered by either the 
investigator or the sponsor to be related to the 
investigational product 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (i.e., not previously described in the 
Investigator Brochure), or that could be associated with 
the study procedures.  
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction as 
termed by the European Clinical Trial Directive 
(2001/20/EC).  
Unexpected Adverse 
Reaction 
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g., 
Investigator Brochure for an unapproved investigational 
product) 
 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
45 
15 LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AF 
Atrial fibrillation 
BMS 
Bristol-Myers Squibb 
CEC 
Clinical Events Classification 
eCRF 
(electronic) Case Report Form 
EDC 
Electronic Data Capture 
ESRD 
End stage renal disease 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
HCG 
Human Chorionic Gonadotropin 
HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
ISR 
Investigator-Sponsored Research 
ITT 
Intent to treat 
NCI 
National Cancer Institute 
NSAE 
Non-Serious Adverse Event 
NVAF 
Non-valvular atrial fibrillation 
RDW 
Red Cell Distribution Width 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
46 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TIA 
Transient ischemic attack 
TTR 
Time in Therapeutic Range 
WOCBP 
Women of Child-Bearing Potential 
 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
47 
16 REFERENCES 
1. Wizemann V, Tong L, Satayathum S, Disney A, Akiba T, Fissell RB, Kerr PG, Young 
EW, Robinson BM. Atrial fibrillation in hemodialysis patients: clinical features and 
associations with anticoagulant therapy. Kidney Int 2010;77(12):1098-106. 
2. Olesen JB, Lip GY, Kamper AL, Hommel K, Kober L, Lane DA, Lindhardsen J, Gislason 
GH, Torp-Pedersen C. Stroke and bleeding in atrial fibrillation with chronic kidney disease. 
N Engl J Med 2012;367(7):625-35. 
3. Nigwekar SU, Bhan I, Turchin A, Skentzos SC, Hajhosseiny R, Steele D, Nazarian RM, 
Wenger J, Parikh S, Karumanchi A, Thadhani R. Statin use and calcific uremic 
arteriolopathy: a matched case-control study. Am J Nephrol 2013;37(4):325-32. 
4. Yang F, Chou D, Schweitzer P, Hanon S. Warfarin in haemodialysis patients with atrial 
fibrillation: what benefit? Europace 2010;12(12):1666-72. 
5. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased 
risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 
2009;20(10):2223-33. 
6. Shah M, Avgil Tsadok M, Jackevicius CA, Essebag V, Eisenberg MJ, Rahme E, 
Humphries KH, Tu JV, Behlouli H, Guo H, Pilote L. Warfarin use and the risk for stroke 
and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 
2014;129(11):1196-203. 
7. Granger CB, Chertow GM. A pint of sweat will save a gallon of blood: a call for 
randomized trials of anticoagulation in end-stage renal disease. Circulation 
2014;129(11):1190-2. 
8. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum 
A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, 
Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-
Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, 
Lewis G, Afzal R, Yusuf S. Apixaban in patients with atrial fibrillation. N Engl J Med 
2011;364(9):806-17. 
9. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi 
HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, 
Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, 
Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, 
Verheugt FW, Zhu J, Wallentin L. Apixaban versus warfarin in patients with atrial 
fibrillation. N Engl J Med 2011;365(11):981-92. 
10. Product Monograph PrELIQUIS (apixaban). In: Inc PC, (ed); 2011. 
11. Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW. Dabigatran and 
Rivaroxaban Use in Atrial Fibrillation Patients on Hemodialysis. Circulation 2015. 
12. Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with 
moderate chronic kidney disease. Clin J Am Soc Nephrol 2011;6(11):2599-604. 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
48 
13. Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, Hart RG, Eckardt KU, 
Kasiske BL, McCullough PA, Passman RS, DeLoach SS, Pun PH, Ritz E. Cardiovascular 
disease in chronic kidney disease. A clinical update from Kidney Disease: Improving 
Global Outcomes (KDIGO). Kidney Int 2011;80(6):572-86. 
14. Reinecke H, Brand E, Mesters R, Schabitz WR, Fisher M, Pavenstadt H, Breithardt G. 
Dilemmas in the management of atrial fibrillation in chronic kidney disease. J Am Soc 
Nephrol 2009;20(4):705-11. 
15. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke 
in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146(12):857-67. 
16. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin 
initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc 
Nephrol 2011;6(11):2662-8. 
17. Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, Keltai M, Lanas 
F, Lopes RD, Lopez-Sendon J, Granger CB, Wallentin L. Efficacy of apixaban when 
compared with warfarin in relation to renal function in patients with atrial fibrillation: 
insights from the ARISTOTLE trial. Eur Heart J 2012. 
18. US Renal Data System. USRDS 2014 Annual Data Report: Atlas of Chronic Kidney 
Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National 
Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 
2014. http://www.usrds.org/adr.aspx. United States Renal Data System Web site. Accessed 
June 2, 2015. 
19. Elliott MJ, Zimmerman D, Holden RM. Warfarin anticoagulation in hemodialysis patients: 
a systematic review of bleeding rates. Am J Kidney Dis 2007;50(3):433-40. 
20. Wu JR, DeWalt DA, Baker DW, Schillinger D, Ruo B, Bibbins-Domingo K, Macabasco-
O'Connell A, Holmes GM, Broucksou KA, Erman B, Hawk V, Cene CW, Jones CD, 
Pignone M. A single-item self-report medication adherence question predicts 
hospitalisation and death in patients with heart failure. J Clin Nurs 2014;23(17-18):2554-
64. 
21. Gonzalez JS, Schneider HE, Wexler DJ, Psaros C, Delahanty LM, Cagliero E, Safren SA. 
Validity of medication adherence self-reports in adults with type 2 diabetes. Diabetes Care 
2013;36(4):831-7. 
22. Halvorsen S, Atar D, Yang H, De Caterina R, Erol C, Garcia D, Granger CB, Hanna M, 
Held C, Husted S, Hylek EM, Jansky P, Lopes RD, Ruzyllo W, Thomas L, Wallentin L. 
Efficacy and safety of apixaban compared with warfarin according to age for stroke 
prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J 
2014;35(28):1864-72. 
23. Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, Paolini JF, Hankey 
GJ, Mahaffey KW, Patel MR, Singer DE, Califf RM. Prevention of stroke and systemic 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
49 
embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial 
fibrillation and moderate renal impairment. Eur Heart J 2011;32(19):2387-94. 
24. Farrington CP, Manning G. Test statistics and sample size formulae for comparative 
binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. 
Stat Med 1990;9(12):1447-54. 
25. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the 
optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993;69(3):236-9. 
26. Savaysa ® (edoxaban) [package insert] Daiichi Sankyo, Inc,, Parsippany, NJ. September 
2016. 


Protocol No. CV185-450 
RENAL-AF 
Vers. 14, 12 September 2018 
IND No. 128055 
 
 
50 
17 APPENDICES 
Appendix 1: CHA2DS2-VASc Score 
 
C: 
Congestive Heart Failure (1 point) 
H: 
Hypertension (1 point) 
A2: 
Age ≥ 75 years (2 points) 
D: 
Diabetes mellitus (1 point) 
S2: 
Stroke or TIA (2 points) 
V: 
Vascular disease: previous MI, peripheral arterial disease or aortic plaque 
(1 point) 
A: 
Age 65-74 years (1 point) 
Sc: 
Female sex (1 point) 
 


Protocol No. CV185-450 
RENAL-AF 
Vers. 13, 6 February 2018 
IND No. 128055 
 
 
51 
Appendix 2: Schedule of Procedures 
Procedure 
(Screening & 
Randomization) 
Day 11 
Day 32 (Day 3, 
4, 5, or 6) 
Month 1        
(± 4 days) 
Month 2     
(± 4 days) 
Month 3, 6, 9, 12  
(± 4 days) 
Month 15 (+ 4 
days) or  Final 
Visit 
Informed Consent 
X 
 
 
Eligibility review 
X 
 
 
Medical History Review 
X 
 
 
 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
Dry body weight or 
hemodialysis target body 
weight 
X 
 
 
 
X 
ECG4 
X 
 
 
 
SAE, AEs of special interest, 
and bleeding event assessment 
X5 
X 
X 
X 
X 
X 
X 
Con med assessment 
X 
X 
X 
X 
X 
X 
X 
Pregnancy prevention 
counseling 
X 
 
 
 
Randomize in EDC system  
X 
 
 
 
 
 
 
Dispense or prescribe and 
instruct on use of drug 
X 
 
 
X 


Protocol No. CV185-450 
RENAL-AF 
Vers. 13, 6 February 2018 
IND No. 128055 
 
 
52 
Procedure 
(Screening & 
Randomization) 
Day 11 
Day 32 (Day 3, 
4, 5, or 6) 
Month 1        
(± 4 days) 
Month 2     
(± 4 days) 
Month 3, 6, 9, 12  
(± 4 days) 
Month 15 (+ 4 
days) or  Final 
Visit 
Medication Compliance 
Assessment 
 
 
 
X 
X 
Record start and stop time of 
hemodialysis session 
 
X 
X 
X 
X 
X 
X 
Record time of apixaban dose 
 
X 
X 
X 
 
 
 
CBC6 
X 
 
X 
X 
X 
X 
BMP 
X 
 
 
 
INR7 
X 
 
X 
X 
X 
X 
Urine or serum β-hCG8   
X 
 
 
 
 
Pharmacokinetic Sample9 
 
X 
X 
X 
 
 
 
Biomarker Sample10 
 
X 
 
 
 
 
 
 
1 Visit should occur within 3 days of randomization or as soon as the INR value is < 2.0 in the case of patients on warfarin at the time of enrollment, who 
were randomized to apixaban 
2 Visit may occur on Day 3, 4, 5, or 6 depending on hemodialysis session 
3 Resting blood pressure, pulse, respiratory rate, and temperature  
4 After resting for ≥ 5 minutes, at enrollment or within 30 days of enrollment.  May include a single lead rhythm strip such as AliveCor. 
5 SAEs that occur anytime after consent, including between consent and randomization, must be reported 


Protocol No. CV185-450 
RENAL-AF 
Vers. 13, 6 February 2018 
IND No. 128055 
 
 
53 
6 Includes hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC), red cell distribution width (RDW). Results from most recent standard 
of care draw may be used, if results are not > 30 days old.  
7 Includes International Normalized Ration (INR). INR should be performed at least monthly for patients randomized to warfarin, and at screening and 
randomization for all patients.  
8 If positive, patient is not eligible to participate. If patient is anuric, a serum pregnancy test can be performed.  
9 At Day 1 visit, PK samples are to be collected for all patients randomized to apixaban: at the start of the hemodialysis session and at the end of the 
hemodialysis session. A sub-set of 50 patients randomized to the apixaban arm will have additional PK samples, and a PD sample, drawn at the Day 3 
(between day 3 and day 6) and Month 1 visits. Samples are to be collected at the start of the hemodialysis session, and at the end of the hemodialysis 
session. This is only for patients enrolled using versions 13 or earlier of the protocol.  No samples will be collected for patients enrolled using version 14 
of the protocol. 
10 If the biomarker sample is not able to be drawn at the Day 1 visit, it can be drawn at a subsequent visit.  This is only for patients enrolled using versions 
13 or earlier of the protocol.  No samples will be collected for patients enrolled using version 14 of the protocol. 
 
 


Protocol No. CV185-450 
RENAL-AF 
Vers. 13, 6 February 2018 
IND No. 128055 
 
 
54 
Appendix 3: Timing of First Dose, Day 1, and Day 3 
  
Patient enrolled in 
RENAL-AF
On NOAC at time of 
enrollment
Randomized to warfarin
1st dose of warfarin: at 
the same time as next 
dose of NOAC after 
randomization along 
with half of the NOAC 
dose
Day 1: First dialysis visit 
after starting warfarin 
(within 3 days of 
randomization)
Day 3: Second dialysis 
visit after starting 
warfarin (3-6 days after 
randomization)
Randomized to apixaban
1st dose of apixaban: in 
place of the previous 
NOAC on the day of the 
first dialysis session 
after randomization 
(preferably 2 hours 
before dialysis) 
Day 1: First dialysis visit 
after starting apixaban
(within 3 days of 
randomization)
Day 3: Second dialysis 
visit after starting 
apixaban (3-6 days after 
randomization)
On warfarin at time of 
enrollment
Randomized to warfarin
1st dose of warfarin: at 
the same time as next 
dose of warfarin after 
randomization
Day 1: First dialysis visit 
after randomization 
(within 3 days of 
randomization)
Day 3: Second dialysis 
visit after 
randomization (3-6 days 
after randomization)
Randomized to apixaban
1st dose of apixaban: as 
soon as INR is 
determined to be < 2.0 
after randomization
Day 1: First dialysis visit 
after starting apixaban
Day 3: Second dialysis 
visit after starting 
apixaban
Not on oral 
anticoagulant at time of 
enrollment
Randomized to warfarin
1st dose of warfarin: as 
soon as patient has 
warfarin (within 3 days 
of randomization)
Day 1: First dialysis visit 
after starting warfarin 
(within 3 days of 
randomization)
Day 3: Second dialysis 
visit after starting 
warfarin (3-6 days after 
randomization)
Randomized to apixaban
1st dose of apixaban: 
the morning of the first 
dialysis session after 
randomization 
(preferably 2 hours 
before dialysis) 
Day 1: First dialysis visit 
after randomization 
(within 3 days of 
randomization)
Day 3: Second dialysis 
visit after 
randomization (3-6 days 
after randomization)


Protocol No. CV185-450 
RENAL-AF 
Vers. 13, 6 February 2018 
IND No. 128055 
 
 
55 
Appendix 4: Expected Events in Patients on Hemodialysis 
 
 Myocardial infarction 
 Atrial fibrillation with rapid ventricular response 
 Heart failure or fluid overload 
 Pulmonary edema 
 Transient ischemic attack  
 Acute severe hypertension 
 Infections (including but not limited to cellulitis, osteomyelitis, and pneumonia) 
 Hyperkalemia 
 Hypoglycemia in patients with diabetes 
 Bradycardia 
 Peripheral arterial disease or gangrene 
 Chronic obstructive pulmonary disease 
 Constipation 
 Hypotension 
 Long bone fracture such as femur fracture 
 

SAP_001.pdf: 
1 
Statistical Analysis Plan for 
RENAL-AF 
Final Version 1.0 
Date: 04JUN2019 
BMS PROTOCOL NUMBER: CV185-450
NCT02942407 
RENal hemodialysis participants ALlocated apixaban versus warfarin in Atrial Fibrillation 
(RENAL-AF) Randomized Clinical Trial 
Author of SAP:  Dianne Gallup/Hussein Al-Khalidi 
Co-principal Investigators:  Christopher Granger and Glenn M. Chertow 
CONFIDENTIAL 
 This document contains information that is privileged or confidential and may not be disclosed unless 
such disclosure is required by applicable laws and regulations. The information in this document is the 
property of the Duke Clinical Research Institute (DCRI) and may not be reproduced, published, or 
disclosed to others without written authorization from DCRI. 


2 
 
Table of Contents 
1.0 
Introduction ..................................................................................................................................... 6 
1.1. 
Study Objectives ........................................................................................................................ 7 
1.2. 
Study Design .............................................................................................................................. 7 
1.3. 
Sample Size and Power ............................................................................................................. 9 
1.4. 
Schedule of Major Assessments and Data Sources ................................................................... 9 
2.0 
Analysis Populations ........................................................................................................................ 9 
2.1    Intent-to-treat (ITT) Population ..................................................................................................... 9 
2.3     Modified Intention to Treat (mITT) and Safety Populations .......................................................... 10 
3.0 
BACKGROUND CHARACTERISTICS .................................................................................................. 10 
3.1 
Disposition of Participants ...................................................................................................... 10 
3.2 
Demographic and Baseline Characteristics ............................................................................. 11 
3.3 
Medical History ........................................................................................................................ 11 
4.0 
METHODS OF ANALYSES ................................................................................................................ 11 
4.1     
General Principles .................................................................................................................... 11 
4.2     
Time to Event Analyses ............................................................................................................ 13 
4.3     
Censoring ................................................................................................................................. 13 
4.4     
Handling of Missing Data ......................................................................................................... 14 
4.5     
Assessment of Model Assumptions ........................................................................................ 15 
5.0 
PRIMARY SAFETY AND ALL EFFICACY ............................................................................................. 15 
5.1     
Primary Outcome ..................................................................................................................... 15 
5.1.1  
Non-inferiority Exploratory Analysis of Primary Outcome ................................................. 16 
5.1.2 
Key Supportive Analysis for Exploratory Analysis of Non-inferiority of Primary Outcome 17 


3 
 
5.1.3 
Superiority Exploratory Analysis of Primary Outcome ....................................................... 17 
5.1.4 
Covariate Adjusted Analysis of Primary Outcome .............................................................. 17 
5.1.5   
Subgroup Analysis ............................................................................................................... 17 
5.2 
Secondary Outcomes ............................................................................................................... 18 
5.2.1   
Analysis of Secondary Outcomes ........................................................................................ 19 
5.3 Events of Special Interest ............................................................................................................... 20 
5.4   
Other Clinical Outcomes of Interest ........................................................................................ 20 
6.0 
Pharmacokinetics (PK) and Pharmacodynamics (PD) of Apixaban ................................................ 21 
7.0 
Safety and Tolerability Analysis ..................................................................................................... 21 
7.1 
Adverse Events (AEs)/Serious Adverse Experiences (SAEs) ........................................................... 21 
7.2   Laboratory Data ............................................................................................................................ 22 
7.3   
Extent of Study Medication Exposure ..................................................................................... 22 
7.3.1  
Study Medication Persistence ............................................................................................. 22 
7.3.2   
Self-reported Compliance ................................................................................................... 23 
7.3.3   
Apixaban Adherence ........................................................................................................... 23 
7.3.4 
Warfarin Adherence ............................................................................................................ 23 
7.4 
Medications ............................................................................................................................. 24 
7.5  
Investigator reported events ................................................................................................... 25 
8.0 
DMC AND INTERIM ANALYSIS ........................................................................................................ 25 
9.0 
REFERENCES ................................................................................................................................... 26 
Appendix I:  Schedule of Procedures .......................................................................................................... 27 
Appendix II:  Table of Contents of CSR........................................................................................................ 30 
 


4 
 
 
LIST OF ABBREVIATIONS 
 
 
ACE 
Angiotensin converting enzyme 
ARB 
Angiotensin II receptor blocker 
AE 
Adverse event 
AF 
Atrial fibrillation 
β-hCG 
Beta-human chorionic gonadotropin 
BID 
Bis in Die (i.e. twice a day) 
BMI 
Body mass index 
BMS 
Bristol-Myers Squibb 
CBC 
Complete blood count 
CEC 
Clinical events classification 
CI 
Confidence interval 
CSR 
Clinical study report 
  DBP 
Diastolic blood pressure 
DCRI 
Duke clinical research institute 
DMC 
Data monitoring committee 
eCRF 
Electronic case report form 
ESRD 
End-stage renal disease 
HR 
Hazard ratio 
INR 
International normalized ratio 
ISTH 
International society of thrombosis and haemostasis 
ITT 
Intent-to-treat 
KM 
Kaplan-Meier 
mITT 
Modified intention to treat 
MedDRA 
Medical dictionary for regulatory activities 
MI 
Myocardial infarction 
NOAC 
Non-vitamin K antagonist oral anticoagulants 


5 
 
NVAF 
Non-valvular atrial fibrillation 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per protocol 
PROBE 
Prospective, randomized, open-label, blinded end-point 
PI 
Principal investigator 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SOC 
System organ class 
TBD 
To be determined 
TESAE 
Treatment emergent serious adverse experiences 
TIA 
Transient ischemic attack 
TTR 
Time in therapeutic range 
VKA 
Vitamin K antagonists 
 
 
 
 
 
 
 
 


6 
 
1.0 Introduction 
RENAL-AF is a prospective, randomized, open-label, blinded end-point evaluation trial (PROBE).  The 
protocol states that a total of approximately 230 patients (randomized 1:1 in the apixaban and warfarin 
arms) will be enrolled at approximately 65 sites across the Unites States; however, due to slow 
enrollment, the trial was stopped early and a total of 155 participants were randomized at 42 sites within 
the United States.  Due to the trial terminating early, duration of treatment will vary depending on when 
the participant was randomized.  The plan at the time of the writing of this SAP is that all treatment will 
end within a week of July 5, 2019.  Therefore, duration of treatment will be a maximum of 15 months, 
and the target is a mean follow-up of approximately 12 months with the last patient enrolled into the trial 
having a 6 months of follow-up.  The study will assess the impact of apixaban compared to warfarin on 
the effect of major or clinically relevant non-major bleeding in participants with end-stage renal 
disease (ESRD) on hemodialysis with atrial fibrillation (AF), meaning atrial fibrillation without 
moderate or severe mitral stenosis. The reader of this Statistical Analysis Plan (SAP) is also 
encouraged to read the final clinical trial protocol (BMS Protocol CV185-450, Version 14 dated 12 
September 2018) which  provides  detail  on  the  conduct  of  the  study,  the  operational  aspects  of  
clinical assessments and the timings of individual participant assessments.  The reader is also encouraged 
to read the Clinical Endpoints Committee Charter (Version 4.0, Dated 07Feb2019) which outline the 
definitions of those endpoints that will be adjudicated. 
 
This SAP contains definitions of analysis populations, derived variables and details on the statistical 
methods for the analyses and summaries of study data that are to be performed to help support the 
completion of the final statistical report for the RENAL-AF trial. Specifications of tables, figures, and 
data listings are contained in a separate document however, an initial table of contents can be found in 
Appendix II of this document.   
 
A Data Monitoring Committee (DMC) will monitor this study based on a separate DMC Charter. A 
separate DMC SAP will be provided for monitoring safety of the participants by the DMC. 
 
Outcomes that are adjudicated by a blinded clinical events classification (CEC) committee, the process 
for which is governed by CEC charter referenced in the protocol, will be referred to as “adjudicated” 
events in the SAP.  The term “outcome” is used throughout this document  as  synonymous  with  the  
term  “endpoint”  used  in  the  clinical trial protocol.  The following outcomes are adjudicated by the 
blinded CEC committee in RENAL-AF: Bleeding (ISTH major, clinically relevant non-major, or 
minor), stroke (hemorrhagic, ischemic, or undetermined), transient ischemic attack (TIA), systemic 
embolism, and death (cardiovascular, non-cardiovascular, or undetermined). CEC data takes 
precedence over investigator data when both are available. 


7 
 
1.1. 
Study Objectives 
 
Primary Objective 
To assess the safety of apixaban versus warfarin regarding International Society of Thrombosis and 
Haemostasis (ISTH) major bleeding or clinically relevant non-major bleeding events in participants 
with NVAF and ESRD on hemodialysis. 
Secondary Objectives 
The secondary objectives are to: 
1. Evaluate stroke and systemic embolism event rates with warfarin and apixaban in patients 
with NVAF and ESRD on hemodialysis. 
2. Evaluate mortality rates with warfarin and apixaban in patients with NVAF and ESRD on 
hemodialysis. 
3. Evaluate persistence (meaning the duration of time from initiation to discontinuation of 
therapy) of and adherence (meaning the extent to which a patient acts in accordance with 
the prescribed interval and dose of a dosing regimen) to warfarin and apixaban in patients 
with NVAF and ESRD on hemodialysis. 
4. Evaluate the pharmacokinetics and pharmacodynamics of apixaban in ESRD NVAF 
patients on hemodialysis. 
Other Objectives 
Other objectives will include analysis of outcomes and treatment effect according to levels of 
cardiovascular biomarkers at baseline.   
 
1.2. 
Study Design 
The study is a prospective, randomized, open-label, blinded end-point evaluation trial.  Participants with 
NVAF, ESRD, and a CHA2DS2-VASc (defined in Appendix 1 of CSP) of 2 or more will be randomized 
in a 1:1 ratio to apixaban or warfarin, stratified by investigative site and prior warfarin status (experienced 
versus naïve).  Participants are considered warfarin naïve if they have never previously been on warfarin or 
if they have started warfarin within the last 30 days.  Those participants randomized to apixaban who are 
>= 80 years old or dry body weight/hemodialysis target body weight  60 kg should receive 2.5 mg 
apixaban BID at any point during the trial at which they have met one of these characteristics; otherwise, 


8 
 
participants will receive 5 mg BID.  If a study participant is taking apixaban 5 mg BID and is experiencing 
minor bleeding, the site investigator will be able to contact the study leadership to discuss temporary dose 
adjustments to 2.5 mg BID. Participants taking strong dual inhibitors of CYP3A4/P-gp (examples include 
ketoconazole, itraconazole, ritonavir, and clarithromycin) will be asked by the site investigator to reduce 
their dose of apixaban to 2.5mg twice daily based on the United States package insert..  Site investigators 
should consider dose reduction to 2.5 mg twice daily for participants taking dual inhibitors of CYP3A4/P-
gp that are not strong inhibitors.  If participants are already taking the 2.5-mg dose apixaban, the site 
investigator should avoid co-administration of these medications.  
For those participants randomized to warfarin, the participant’s prescribing provider (any provider caring 
for the patient with primary responsibility for warfarin management, including providers from a warfarin 
clinic or providers other than the study investigator) will select the warfarin dose.  The goal INR will be 
2.0-3.0, and the participant’s provider should monitor the INR level and adjust the dose of warfarin 
accordingly.  The frequency of INR measurements are at the discretion of the prescribing provider; 
however, it is recommended that the INR values are drawn at least once a month and more frequently at the 
time of warfarin initiation or around INR values out of the therapeutic range.   
The primary outcome is ISTH major bleeding and clinically relevant non-major bleeding, adjudicated by 
a central blinded clinical events adjudication process.   
Unless the participant specifically wrote a letter stating that they refused to allow any further information 
or data capture, including retrospectively through medical records, every effort will be made to obtain as 
much information as possible through the end of study/month 15 visit. 
Samples will be obtained from a subset of patients randomized to apixaban, under versions 13 or earlier 
of the protocol, to characterize apixaban PK/PD levels in hemodialysis patients with atrial fibrillation. No 
patients enrolled under version 14 of the protocol will have PK/PD samples collected. On day 1, blood 
samples will be collected for PK analysis on all participants randomized to apixaban. A subset of no more 
than 50 participants randomized to apixaban will have additional PK/PD samples collected at Day 3 visit 
and Month 1 visit. Samples will be drawn pre-hemodialysis and post-hemodialysis.  The PK/PD analysis 
is not within the scope of this SAP. 
 
 


9 
 
Selected biomarkers will be collected from a subset of patients at the day 1 visit, enrolled using versions 
13 or earlier of the protocol, and stored for later analysis.  If the biomarker sample is not able to be drawn 
at the Day 1 visit, it can be drawn at a subsequent visit.  The biomarker analysis is not within the scope of 
this SAP. 
1.3. 
Sample Size and Power 
Due to a lower recruitment rate than anticipated in the early stage in the trial, the sample size was reduced 
from 760 (protocol version 13, section 12.1) to 230 patients providing a lack of statistical power thus 
making the analysis outlined in this SAP exploratory.  The actual sample size, due to early termination of 
the trial due to slow enrollment, was 155. 
Additional details can be found in the clinical study protocol (CSP). 
1.4. 
Schedule of Major Assessments and Data Sources 
 
Outcomes, serious adverse event and adverse events of special interest data are collected at day1, day 3 
(day 3, 4, 5, or 6) and monthly through month 3 and then quarterly through end of study/month 15 visit.  
SAEs that occur any time after consent, including between consent and randomization, must be reported 
on the eCRF.  All laboratory assessments will be performed according to the standard of care schedule for 
the patient.  See Appendix I for a full schedule of procedures.  All data for the final statistical report will 
be obtained from the IBM Clinical Development data base in which the eCRF was developed. 
 
 2.0 
Analysis Populations 
 
Those participants for whom no written informed consent was obtained will be excluded from all 
analyses. 
 
 
2.1    Intent-to-treat (ITT) Population 
 
The ITT population consists of all unique randomized participants regardless of their compliance with 
the study protocol. Participants are analyzed in the treatment group to which they were randomized.  
Unless otherwise noted, the ITT population will be utilized for the analysis outlined in this SAP.   


10 
 
 
2.3     Modified Intention to Treat (mITT) and Safety Populations 
 
The “Safety population” is synonymous with the “Modified Intention to Treat (mITT) population” as 
defined in the CSP and may be utilized interchangeably throughout the final study SAP.  The Safety 
population will consist of all randomized participants who received at least 1 dose of study medication.  
This population can be analyzed by randomized treatment or actual treatment received.  “Actual 
treatment received” is defined as the initial treatment received.   
 
Unless otherwise noted, the mITT population will be analyzed by randomized treatment. 
  
3.0 
BACKGROUND CHARACTERISTICS 
3.1 
Disposition of Participants 
 
 
Disposition data will be summarized for all randomized participants by treatment group and overall.   
 
Disposition data will include: 
 
• 
Inclusion in each of the two study populations 
 
• 
Participants completing study alive 
 
 
Participants who died during the study. 
 
 
Participants who were lost to follow up 
 
 
Participants who withdrew consent for further study participation  
 
 
Participants who were lost to follow-up for whom the primary outcome was evaluated. 
 
 
Participants who permanently discontinued assigned study drug and reason for permanent 
discontinuation. 
 
 
 


11 
 
3.2 
Demographic and Baseline Characteristics 
 
The demographic, baseline clinical and anthropometric characteristics collected in the study will be 
summarized by treatment and overall for ITT population. 
 
Key demographic and baseline variables to be summarized include but are not limited to the following: 
age, sex, race/ethnicity, vintage (time since initiation of dialysis), height, dry body weight, Quételet’s 
(body mass) index (BMI), vital signs, prior warfarin status (experienced versus naïve) and the following 
baseline medications:  ACE inhibitor/ARB, amiodarone, beta-blocker, aspirin, clopidogrel, digoxin, 
calcium channel blocker, statin, and non- steroidal anti-inflammatory agent. 
3.3 
Medical History 
 
Participant medical history, as collected on the eCRF, will be summarized by treatment and overall within 
ITT population.  This summary will include, but not limited to, the following:  prior warfarin status 
(experienced versus naïve), prior NOAC (experienced vs naïve), MI, clinically relevant or spontaneous 
bleeding, fall within previous year, type of atrial fibrillation, stroke, TIA, chronic heart failure, most recent 
left ventricular ejection fraction (normal, mild dysfunction, moderate dysfunction, or severe dysfunction), 
diabetes, chronic hypertension, and CHA2DS2-VASc score. 
Renal and dialysis history will also be summarized by treatment and overall within ITT population. 
4.0 METHODS OF ANALYSES 
 
4.1     
General Principles 
 
All analyses included in this SAP will be performed using SAS v9.4 or higher (SAS 
Institute Inc., Cary, NC). 
 
A safety follow-up will be performed 30 days after permanent treatment discontinuation, at which time, 
indicators as to whether or not events occurred as well as AE/SAEs are collected.  If this safety follow-up 
occurs after the end of study/Month 15 visit, the information collected will not be used in the analysis 
outlined in this SAP but may be displayed as listings when indicated. 
 
Descriptive statistics for categorical variables will be presented using counts and percentages per 
treatment group and overall.    Percentages will be displayed through the first decimal place.  Percentage 


12 
 
will be calculated based on number of participants with non-missing values for the variable.  In the event 
that the summary displayed is for a subcategory (“child”) of a main category (“parent”), the denominator 
for the “child” will be based on the non-missing observations for the “parent” (e.g., Anti-platelet (Y/N) 
is a ‘parent’ question and type of anti-platelet (e.g. aspirin) is a ‘child’ question.  The denominator for 
aspirin will be number of participants who answered yes/no to the anti-platelet question). 
 
Descriptive statistics for continuous variables will include the following:  the number of participants, 
mean, standard deviation, median, 25thand 75th quartiles, minimum and maximum as appropriate and all 
summary data will be displayed through the 1st decimal place.  In the event no meaningful information 
is available through the first decimal place (e.g., 0.01), the statistician in consultation with the PI or 
designee will determine the most relevant number of decimals to display.    Summaries of continuous 
characteristics will be based on non-missing observations.  
 
Unless otherwise specified in this document, relative study day is defined as the (assessment date of a 
measurement– randomization date) if assessment date is prior to randomization date and will be defined as 
(assessment date of measurement – randomization date) + 1 if assessment date is on/after date of 
randomization.  Using this derivation, the day of randomization will be considered study day 1.   
 
Data displayed by visit will utilize an “analysis visit” which will be derived based on windowing around the 
study day as agreed upon by the study PI or designee. 
 
A baseline value is defined as the most recent assessment taken prior to/on day of randomization.  When there 
is a missing assessment, it will not be imputed, thus, participants are excluded from any changes from baseline 
analysis for which they have a missing baseline value. 
 
Due to the anticipated small number of events, stratification by site would produce sparse data and therefore, 
the baseline hazard within each stratum would be poorly estimated with such models.  For this reason, sites 
will be pooled together and all Cox proportional hazards models will by adjusted for prior warfarin status 
(experienced vs naïve) only.   
 
Unless otherwise specified, all Kaplan-Meier rates and Kaplan-Meier curves will be performed without 
adjustment of strata or covariates. 
 
 


13 
 
4.2     
Time to Event Analyses 
 
“On-treatment” time to event will be defined as ([event date – study drug initiation date] +1 where event 
occurs prior to/at 2 days after permanent study drug discontinuation and as [appropriate censoring date 
based on analytic population – study drug initiation date] +1 where event does not occur or occurs greater 
2 days after permanent study drug discontinuation. 
 
For all other time to event analyses, unless otherwise specified in this document, time to event will be 
defined as ([event date – randomization date] +1 where event occurs and as [appropriate censoring date 
based on analytic population – randomization date] +1 where event does not occur) 
 
Treatment differences will be evaluated using a Cox proportional hazards model that includes treatment as 
an indicator variable and adjusted for prior warfarin status (experienced vs naïve), unless specified 
otherwise.  A subject will be classified as warfarin naïve if they have not previously received warfarin or 
another VKA or have initiated warfarin or another VKA within 30 days prior to randomization. 
Otherwise the subject will be classified as warfarin experienced. The data entry system will derive the 
appropriate stratum from information entered into the eCRF.  The Breslow method [3] will be used for 
handling ties. P-value and confidence intervals for the HR will be based on the Wald statistic. In addition, 
the summary tables of these analyses will include the number (%) of participants with event, Kaplan-
Meier rates as well as the 95% confidence interval by treatment monthly from randomization through the 
maximum follow-up.  Competing risks are not taken into account for any of the Cox proportional hazards 
models.  Competing risks may be taken into account as a sensitivity analysis if a considerable number of 
deaths are observed.  Kaplan-Meier curves will be produced through maximum follow up available in the 
study, with number of participants at risk indicated below the plot at specific times.  
 
4.3     
Censoring 
 
In this study we expect missing outcome data to be infrequent and every effort will be made to collect all 
information regarding the primary outcomes at the end of study/month 15 visit, even in those who have 
discontinued the study treatment.  Information at the end of study/month 15 visit can be obtained from a 
source other than direct contact with the participant (e.g., medical record, family member, etc.).    In the 
case of a medical record review, the end of study/month 15 date of assessment will be the date of most recent 
medical record reviewed. 
 
In the primary and secondary time-to-event analyses in the ITT population, participants will be censored 
at the earliest of 1) maximum of (date of last contact where all elements of the outcome of interest were assessed 
(excluding the safety follow-up visit if it occurs after the end of study/month 15 visit), 2) end of study/month 


14 
 
15 date of assessment where all elements of the outcome of interest were assessed) and 3) death date (when 
death is not part of the outcome).   Participants without any assessment of the outcome of interest will be 
censored at randomization.   
 
In time-to-event analyses in the “mITT” population, participants who have not had the event of interest 
will be censored following same rules as detailed for the ITT population.   
 
“On-treatment” time-to-event analyses will also be performed as sensitivity analyses.  The censoring date 
for these analyses will be the earliest of 1) maximum of (date of last contact where all elements of the outcome 
of interest were assessed (excluding the safety follow-up visit if it occurs after the end of study/month 15 visit), 
2) month 15 date of assessment where all elements of the outcome of interest were assessed), 3) death date 
(when death is not part of the outcome), and 4) 2 days after the permanent discontinuation of assigned study 
drug.  Participants without any assessment of the outcome of interest will be censored at study drug initiation.  
 
Unless otherwise specified, sensitivity analysis in the mITT population, if performed, will utilize the “on-
treatment” time to event/censoring described above. 
 
4.4     
Handling of Missing Data 
 
For the assessment of primary hypothesis, missing data relating to the indicator for the confirmed primary 
composite of major bleeding or clinically relevant non-major bleeding events and its components will not 
be imputed. 
 
The CEC will make every attempt to provide a complete date for the confirmed primary composite of 
major bleeding or clinically relevant non-major bleeding events; however, in the instance when the dates 
are partially missing, imputation will be performed as follows: 
 
Any partially missing date for a confirmed primary composite of major bleeding or clinically relevant 
non-major bleeding events, secondary outcomes (section 5.2), adverse events of special interest (section 
5.3), other clinical events of special interest (section 5.4), study drug initiation and termination dates at 
the time of database lock will be imputed as follows: 
 
 
If the day is missing, then the 15th of the month will be used. 
 
If missing day and month, then June 15 of provided year will be used.   
 
If year is missing, no imputation will be performed. 
 


15 
 
The aforementioned dates specified above will never be completely missing as a year will always be 
required. 
 
If the imputed portion of the date causes the date to be nonsensical (e.g.  Prior to randomization or > last 
known alive date, etc.), the imputed date will be set to the appropriate boundary (e.g. randomization or 
last known alive, respectively).  Details can be found in the analysis data set specifications.  
 
If additional partially missing dates are required for analysis, they will be imputed as described above.   
No other imputations for missing data will be performed. 
4.5     Assessment of Model Assumptions 
 
The validity of the proportional hazards assumption made in the primary analysis will be examined 
using a standard graphical methods such as Schoenfeld residual plots; if the assumption holds, the survival 
curves should be approximately parallel to each other. 
 
An additional analytical method that includes the supremum test [1] as implemented by using the ASSESS 
statement in PROC PHREG in SAS version 9.4 may be utilized.  A p-value of < 0.05 indicates violation 
of the proportional hazards assumption. 
 
If there is evidence of non-proportionality, a time dependent covariate will be included in the model to 
account for this.   
 
5.0 PRIMARY SAFETY AND ALL EFFICACY 
Definitions for major bleeding, clinically relevant non-major bleeding, stroke, systemic embolism, transient 
ischemic attack, and cause of death are defined in the CEC charter.  Unless specified otherwise, a 2-sided p-
value of < 0.05 will be considered statistically significant. 
 
5.1     
Primary Outcome 
 
The primary outcome is defined as the time from randomization to the onset of first adjudicated event in the 
composite of major bleeding/clinically relevant non-major bleeding in the ITT population or censoring date 
(as defined in section 4.3) If the event did not occur. Major bleeding includes hemorrhagic stroke as well 
as ischemic stroke with hemorrhagic transformation.   
 


16 
 
In the unlikely event that two or more confirmed outcomes occur on the same day, the following hierarchy 
will be used to ascribe the primary component of the composite: 
 
 Major bleed  
 Clinically relevant non-major bleed 
 
Event rates of the primary outcome for the ITT and mITT populations will be estimated using Cox 
proportional hazards model and Kaplan-Meier curves will be plotted for the time from randomization to 
first occurrence of the primary outcome/censored date in case of no event.by treatment group .  Participants 
at risk at quarterly time points will be displayed.   
 
5.1.1  Non-inferiority Exploratory Analysis of Primary Outcome 
Due to lack of statistical power because of a small sample size, the current analytic plan has been changed 
from a formal non-inferiority testing followed by superiority testing, as described in draft SAP version 3.5, 
dated 06DEC2017, to an exploratory analytic plan.  
The primary exploratory hypothesis is defined as: 
H0:  HR ≥ 1.4 vs. H1: HR < 1.4 
The above hypothesis will be tested at a 1-sided significance level of 0.025 in the ITT population. A 2-
sided 95% confidence interval (CI) for the hazard ratio (apixaban vs. warfarin) will be established as well 
as the p-value will be provided using the Cox Proportional Hazards model that includes treatment as a 
covariate and adjusted for prior warfarin status.  If the upper limit of the 2-sided 95% CI for the estimated 
hazard ratio (HR) from the Cox model is below the non-inferiority margin of 1.40 then this will be 
considered evidence of non- inferiority of apixaban.  
 
The analysis, as described above, will constitute the primary exploratory analyses from which treatment 
differences will be interpreted.   
 
Additionally, the aforementioned analyses will be performed in the ‘mITT’ population as a sensitivity 
analysis.   
 
 
 


17 
 
5.1.2 Key Supportive Analysis for Exploratory Analysis of Non-inferiority of Primary Outcome 
As a sensitivity analysis similar to the method described in Section 5.1.1, including Kaplan-Meier curves, 
will be conducted among mITT populations.  The ‘on-treatment’ time to event (section 4.2) and censoring 
scheme (section 4.3) will be utilized for this populations.  This analysis will compare randomized treatment 
groups.       
 
5.1.3 Superiority Exploratory Analysis of Primary Outcome 
Time from randomization to the onset of first adjudicated primary composite outcome will be analyzed 
using hazard ratios, 95% confidence intervals and p-values as in Section 5.1.1. If the upper limit of the 
2-sided 95% CI is below 1, then this will be considered evidence of superiority of apixaban.   
 
5.1.4 Covariate Adjusted Analysis of Primary Outcome 
The primary analysis, excluding Kaplan-Meier curves, will be repeated in the ITT populations after 
adjusting for the following covariates:  CHA2DS2-VASc score and baseline hemoglobin. No missing data 
imputation will be utilized for the aforementioned covariates as complete data is anticipated. 
 
5.1.5   Subgroup Analysis 
Subgroup analyses will be performed for the primary outcome among the ITT population in order to explore 
whether treatment effects on the risk of experiencing major/clinically non-relevant bleeds are consistent 
across subgroups. 
 
Pre-specified subgroups are detailed below.  For each potential modifier of treatment effect, the interaction 
of the potential modifier with randomized treatment will be examined using the Cox proportional hazards 
model adjusted for prior warfarin use. Potential modifiers expressed as continuous or ordinal variables will 
be treated as such in the Cox model. The corresponding hazard ratios, 95% CIs, and appropriate summary 
statistics will be provided. Lack of a significant interaction will imply that the differences in treatment HRs 
across subgroups are within the realm of chance and that the overall response-rates and overall HR are the 
most appropriate estimates of treatment effect within all subgroups for that factor. It is recognized that 
testing many subgroups can yield spurious false positive outcomes.  
 
Forest plots will be provided with estimated hazard ratios and 95% CIs; the CIs usually will be much wider 
and the power to detect a true difference will be low within any one subgroup owing to the smaller number 


18 
 
of participants and events. In addition, when sample sizes for subgroups are small, treatment effects cannot 
be estimated precisely.  
 
The following subgroups determined by baseline characteristics will be examined: 
 
 
Age >= 80 and/or body weight (kg) <=60  
 
Prior use of warfarin  
 
Age:  a) < 65 yrs. vs >= 65 yrs., b)  < 80 yrs. vs >= 80 yrs. 
 
Sex 
 
Myocardial infarction 
 
Peripheral arterial disease 
 
Type of atrial fibrillation: permanent  persistent or paroxysmal 
 
Prior stroke or TIA   
 
Diabetes 
 
Heart failure 
 
Hypertension 
 
CHA2DS2-VASc score: 2 vs  >=3  
 
Race:  a) White vs African American/Black vs Other and b) African American vs Other,  
 
Aspirin use within 24 hours prior to randomization   
 
Amiodarone use within 24 hours prior to randomization   
 
History of prior clinically relevant spontaneous bleeding  
 
Hemoglobin 
 
Time since dialysis initiation  
 
Time in therapeutic range prior to baseline (for participants previously treated with Warfarin) 
 
5.2 
Secondary Outcomes 
 
The secondary outcomes are defined as follows:   
 
 
Any bleed (major, clinically relevant non-major, or minor bleed) 
 
Stroke 
o Ischemic stroke  
o Hemorrhagic stroke 
o Stroke of unknown cause 
 
Systemic embolism 
 
All-cause mortality  


19 
 
 
Composite of stroke or systemic embolism  
 
Composite of stroke, systemic embolism, major bleeding, and all-cause mortality 
 
5.2.1   Analysis of Secondary Outcomes 
The analysis as described below for the following secondary outcomes will be performed in the ITT 
population:  1) Any bleed, 2) all-cause mortality, and 3) composite of stroke, systemic embolism, major 
bleeding, and all-cause mortality: 
 
A hazard ratio, 2-sided 95% confidence interval for the hazard ratio (apixaban vs warfarin), and  
p-value will be provided using the Cox Proportional Hazards model that includes treatment as 
the independent variable adjusted for prior warfarin.  
 
Kaplan-Meier event rates as well as the 95% confidence interval by treatment will be displayed 
quarterly from randomization through maximum follow-up.     
Kaplan-Meier curves will be plotted for the time from randomization to first occurrence of the 
secondary outcome of interest/censored date in case of no event (in months), by treatment group 
at randomization.  Participants at risk at each time point will be displayed. 
 
If the analysis for above cannot be performed due to small event counts, counts and percentages 
as well as a p-value from a chi-square test or fisher’s mid-p test, whichever is appropriate, will 
be displayed. 
 
Additionally, the counts and percentages of the CEC adjudicated events from randomization 
through end of study visit/month 15 in the ITT population will be calculated for the following:   
stroke, type of stroke, systemic embolism, and composite of stroke or systemic embolism.  P-
values from a chi-square test or fisher’s mid-p test, whichever is appropriate, will be displayed. 
It is recognized that results should be interpreted with caution when a relatively small number of events 
occur. 
Partial/missing event dates will be imputed in the same manner as the primary outcome described in section 
4.4. 
 
A listing of events that occur after end of study/month 15 will be displayed, if applicable.  
 


20 
 
5.3 Events of Special Interest 
 
The following events are clinical events of special interest that were investigator reported: 
 
 
Thrombosis of fistula, graft, or access catheter 
 
Thrombosis of extracorporeal dialysis circuit 
 
Access site bleeding that does not meet the criteria for acute clinically overt bleeding (defined in 
Section 12.3 of CSP) 
 
Other clinically overt bleeding that does not meet the criteria for major or clinically relevant non-
major bleeding (defined in Section 12.3 of CSP) ) 
 
Red blood cell transfusion(s) 
 
The counts and percentages for the ITT population will be calculated for the events of special interest 
which occurred from randomization through end of study/month 15.   
 
A listing of events that occur after the end of study/month 15 visit will be displayed, if applicable.  
 
5.4   
Other Clinical Outcomes of Interest 
 
The other clinical outcomes of interest (investigator reported except for TIA) are as follows: 
 
Myocardial infarction 
 
Atrial fibrillation with rapid ventricular response 
 
Heart failure or fluid overload 
 
Pulmonary edema 
 
Transient ischemic attack  
 
Acute severe hypertension 
 
Infections (including but not limited to cellulitis, osteomyelitis, and pneumonia)  
 
The counts and raw percentages from randomization through end of study/month 15 in the ITT 
population will be calculated for the outcomes described above. 
 
A listing of events that occur after end of study/month 15 will be displayed, if applicable.  
 


21 
 
Outcomes that are expected to occur in patients on hemodialysis as part of the disease process that are not 
clinically relevant to the trial are not collected or reported thus will not be analyzed: hyperkalemia , 
hypoglycemia in patients with diabetes, bradycardia, peripheral arterial disease or gangrene, chronic 
obstructive pulmonary disease, constipation, hypotension, or long bone fracture such as femur fracture.  
. 
 
6.0 
Pharmacokinetics (PK) and Pharmacodynamics (PD) of Apixaban 
The PK/PD analysis of Apixaban will be described in a separate analysis plan. 
7.0 
Safety and Tolerability Analysis 
There are no a priori hypotheses to be tested for safety.  Safety and tolerability will be assessed within the 
ITT population.   
7.1 
Adverse Events (AEs)/Serious Adverse Experiences (SAEs)  
All Serious Adverse Events (SAEs) that occur following the subject’s written consent through 30 days 
after permanent study drug discontinuation will be collected.   
The original term used by investigators to identify SAEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). Treatment emergent serious adverse experiences (TESAE) are defined 
as those SAEs that have a start date after the date of first study medication administration.   Outcomes 
defined in section 5 of the SAP (i.e., primary outcomes, secondary outcomes, events of special interest, and 
other clinical outcomes) are not regarded as SAEs for the safety analysis. Upon summarizing serious 
adverse events, participants will be counted only once for each preferred term. 
 
A subject level summary by treatment and overall will be displayed for treatment emergent serious adverse 
events, including the number of SAEs reported after the end of study/month 15 visit.   
 
The number and percentage of participants experiencing the types of AE/SAEs listed below as well as the 
number of events will be tabulated by system organ class (SOC) and preferred term (PT).  
 
• Treatment emergent SAEs (TESAEs).  This will be displayed by SOC and PT 
• Treatment emergent AEs that result in discontinuation of study drug  


22 
 
• Treatment emergent SAEs (TESAEs) resulting in a fatal outcome.  This will be displayed by SOC 
and PT 
 
 
All SAEs, including those collected during a 30-day safety follow-up which occurred after the participant’s 
final study visit, will be listed, indicating the site number, participant ID, assigned treatment group, age, 
gender, and race, randomization date, treatment start date, apixaban dosage, preferred term, onset date, day 
of onset relative to randomization, resolution date, duration, date of last study drug dose, day of last study 
drug dose relative to randomization date, intensity, relationship, action taken and outcome.  Additionally, 
separate listings will also be presented for participants who 1) experienced a fatal SAE and 2) any AEs 
resulting in study drug discontinuation.   
 
 
7.2   Laboratory Data 
 
Descriptive statistics will be provided by treatment for hematocrit values at each assessment time point and 
for changes from baseline.   
 
Laboratory data will be summarized for the ITT population. 
 
7.3   
Extent of Study Medication Exposure 
 
Extent of study medication exposure utilizing persistence, adherence, and self-compliance measures will 
be summarized for the ITT population. 
 
7.3.1  Study Medication Persistence 
Persistence is defined as the duration of time from initiation to permanent discontinuation of therapy.  
Persistence to study medication for the ITT population during the study period will be summarized by 
treatment and overall.  Persistence is calculated as the number of days from the date of first dose of study 
drug to the date of last dose of study drug, inclusively ((date of last dose of study drug – date of first dose 
of study drug) + 1).  This duration will not be adjusted for any period the participant may have been 
temporarily off of study drug.  Descriptive statistics will be presented by treatment group and overall. 
 
 


23 
 
7.3.2   Self-reported Compliance 
The answers to two self-reported compliance questions are obtained quarterly and each will be summarized 
by visit, treatment and overall in the ITT population.  The two questions are as follows: 
 
 
Out of the past 7 days, did you miss a dose of your blood thinner? 
 
Over the last 30 days, how often have you taken your blood thinner: less than 20% (5 days or 
fewer), 20-80% (6 days to 23 days), or greater than 80% (24 days or more) of the time? 
 
7.3.3   Apixaban Adherence  
Apixaban adherence will be summarized in the ITT population. 
Pill counts and apixaban dispensation will occur quarterly.  
Adherence to apixaban will be calculated as follows:   
 
Numerator:   # pills taken from randomization to last dose of assigned study drug. 
This will be ascertained by taking the number of pills originally in the container when dispensed 
and subtracting the number of pills remaining in the container at the quarterly visit and summing 
this value across the quarterly visits. 
 
Denominator:  # of pills expected to be taken from randomization to last dose of assigned study drug. 
This will be ascertained as follows:  2 pills a day * number of days that the participant was on 
assigned study drug 
 
The number of days that the participant is on assigned study drug is derived as follows:  (date of 
last dose of assigned study drug – date of first dose of assigned study drug) + 1, 
 
    Adherence = (numerator/denominator) * 100 
 
7.3.4 
Warfarin Adherence 
The time in therapeutic range (TTR) will be determined by the modified Rosendaal method of linear 
interpolation between each pair of measured INR values [2].  The proportion of time (counted from first 
INR value recorded on or after dosing on Day 3 until the day of discontinuation of study drug without 
considering interruptions) in which participants have an INR in the following ranges will be summarized 
in the ITT population: 


24 
 
• 
INR < 2.0, 2.0 ≤ INR ≤ 3.0, INR > 3.0 
The frequency of participants with INR in the 2.0-3.0 range for ≥ 60%, ≥ 65%, ≥ 70%, ≥ 75%, or ≥ 80% of 
time will also be summarized in the ITT population. 
Only participants who have received study drug every day for the first 3 days from study drug initiation 
will be included in these time-related summaries. The INR control measure, proportion of time in each INR 
interval, is calculated using Rosendaal’s method which assumes that the INR value between two 
measurements varies linearly from the first value to the second value 
• 
let INRi and INRi+1 be the two consecutive INR values 
• 
let Di and Di+1 be the dates associated with these two consecutive INR values, 
                      [(Di+1 - Di) = k, k>1] 
• 
assuming the linear increase or decrease between the two consecutive INR measurements, the 
unit change per day in INR is m=(INRi+1 - INRi)/ (Di+1 - Di) 
• 
the estimated INR value for the date after Di (Di+1) will be INRi + (m*1) 
• 
Similarly, the estimated INR value for the date (Di+2) will be INRi + (m*2), etc.; the estimated 
INR value on the date immediately prior to Di+1 will be INRi + (m*(k-1)). 
The estimated INR will be set to missing between Di+1 and Di if  Di+1 - Di > 56. 
Using Rosendaal’s method, each participant will have an INR measurement every day, either actual or by 
estimation through linear interpolation. The proportion of time participants have an INR within an interval 
is the number of days with INR in the interval divided by the total number of days.   
 
7.4 
Medications 
 
Medications taken at/prior to randomization will be summarized by treatment and overall. Indication of 
medication usage will be retrieved from the screening/randomization visit page. 
 
Medications taken after randomization will be summarized by treatment and overall. Indication of medication 
usage will be retrieved from the follow-up medication visit page.  If a participant took the same medication 


25 
 
more than once post-randomization, the participant will only be counted one time.  A participant must have 
an answer as to whether or not a medication was taken on at least one post-randomization form to be 
included in the denominator. 
 
Concomitant medications will be summarized in the ITT population. 
 
7.5  
Investigator reported events 
 
The following investigator reported events will be summarized by treatment in the ITT population and 
include the following: 
 
 
Any bleed composite (major bleed, clinically relevant non-major bleed, or minor bleed) and 
components as follows: 
o Major bleed 
o Clinically relevant non-major bleed 
o Minor bleed 
 
Mortality 
 
Stroke 
 
Systemic embolism 
 
Descriptive statistics will be provided for investigator reported events by treatment and overall.  
 
8.0 
DMC AND INTERIM ANALYSIS  
The data monitoring committee (DMC) will monitor the safety aspects of this study.  The DMC is expected 
to meet at least every 6-months.  The DMC charter will provide details on monitoring roles and 
responsibilities.   
While the DMC will review frequencies of bleeding events, no formal interim analysis is planned for this 
trial so no adjustment for multiple looks at the data is necessary. 
 
 


26 
 
9.0 
REFERENCES 
1. Lin, D. Y., Wei, L. J., and Ying, Z. Checking the Cox Model with Cumulative Sums of 
Martingale-Based Residuals.  Biometrika 1993; 80:557–572. 
 
2. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the optimal 
intensity of oral anticoagulant therapy.  Thromb Haemost 1993; 69(3):236-9. 
 
3. Breslow, N. E. Covariance Analysis of Censored Survival Data.  Biometrics 1974;30:89–9 
 
 
 


27 
 
Appendix I:  Schedule of Procedures 
Procedure 
(Screening & 
Randomization) Day 11 
Day 32 
(Day 3, 4, 
5, or 6) 
Month 1    
(± 4 
days) 
Month 2     
(± 4 days) 
Month 3, 
6, 9, 12  
(± 4 days) 
Month 15 
(+ 4 days) 
or  Final 
Visit 
Informed Consent 
X 
 
 
Eligibility review 
X 
 
 
Medical History 
Review 
X 
 
 
 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
Dry body weight 
or hemodialysis 
target body weight 
X 
 
 
 
X 
ECG4 
X 
 
 
 
SAE, AEs of special 
interest, and 
bleeding event 
assessment 
X5 
X 
X 
X 
X 
X 
X 
Con med 
assessment 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
prevention 
counseling 
X 
 
 
 


28 
 
Procedure 
(Screening & 
Randomization) Day 11 
Day 32 
(Day 3, 4, 
5, or 6) 
Month 1    
(± 4 
days) 
Month 2     
(± 4 days) 
Month 3, 
6, 9, 12  
(± 4 days) 
Month 15 
(+ 4 days) 
or  Final 
Visit 
Randomize in EDC 
system  
X 
 
 
 
 
 
 
Dispense or 
prescribe and 
instruct on use of 
drug 
X 
 
 
X 
Medication 
Compliance 
Assessment 
 
 
 
X 
X 
Record start and 
stop time of 
hemodialysis session 
 
X 
X 
X 
X 
X 
X 
Record time of 
apixaban dose 
 
X 
X 
X 
 
 
 
CBC6 
X 
 
X 
X 
X 
X 
BMP 
X 
 
 
 
INR7 
X 
 
X 
X 
X 
X 
Urine or serum β-
hCG8   
X 
 
 
 
 
Pharmacokinetic 
Sample9 
 
X 
X 
X 
 
 
 


29 
 
Procedure 
(Screening & 
Randomization) Day 11 
Day 32 
(Day 3, 4, 
5, or 6) 
Month 1    
(± 4 
days) 
Month 2     
(± 4 days) 
Month 3, 
6, 9, 12  
(± 4 days) 
Month 15 
(+ 4 days) 
or  Final 
Visit 
Biomarker Sample10 
 
X 
 
 
 
 
 
1 Visit should occur within 3 days of randomization or as soon as the INR value is < 2.0 in the case of patients on 
warfarin at the time of enrollment, who were randomized to apixaban 
2 Visit may occur on Day 3, 4, 5, or 6 depending on hemodialysis session 
3 Resting blood pressure, pulse, respiratory rate, and temperature  
4 After resting for ≥ 5 minutes, at enrollment or within 30 days of enrollment.  May include a single lead rhythm 
strip such as AliveCor. 
5 SAEs that occur anytime after consent, including between consent and randomization, must be reported 
6 Includes hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC), red cell distribution width 
(RDW). Results from most recent standard of care draw may be used, if results are not > 30 days old.  
7 Includes International Normalized Ration (INR). INR should be performed at least monthly for patients 
randomized to warfarin, and at screening and randomization for all patients.  
8 If positive, patient is not eligible to participate. If patient is anuric, a serum pregnancy test can be performed.  
9 At Day 1 visit, PK samples are to be collected for all patients randomized to apixaban: at the start of the 
hemodialysis session and at the end of the hemodialysis session. A sub-set of 50 patients randomized to the apixaban 
arm will have additional PK samples, and a PD sample, drawn at the Day 3 (between day 3 and day 6) and Month 1 
visits. Samples are to be collected at the start of the hemodialysis session, and at the end of the hemodialysis session. 
This is only for patients enrolled using versions 13 or earlier of the protocol.  No samples will be collected for 
patients enrolled using version 14 of the protocol. 
10 If the biomarker sample is not able to be drawn at the Day 1 visit, it can be drawn at a subsequent visit.  This is 
only for patients enrolled using versions 13 or earlier of the protocol.  No samples will be collected for patients 
enrolled using version 14 of the protocol. 
 
 


30 
 
Appendix II:  Table of Contents of CSR 
Tables 
Enrollment per Site 
Eligibility Criteria 
Subject Status  
Demographic and Baseline Characteristics 
Medical History 
Renal and Dialysis History 
Self-Reported Compliance by Visit 
Apixaban Dose 
Study Drug Adherence 
Summary of Medications Taken Pre-Randomization 
Summary of Medications Taken Post-Randomization 
Treatment Emergent Serious Adverse Events 
Treatment Emergent Serious Adverse Events by System Organ Class and Preferred Term 
Treatment Emergent Serious Adverse Events Resulting in a Fatal Outcome by System Organ Class and Preferred 
Term 
Treatment Emergent Serious Adverse Events Resulting in Discontinuation of Study Drug by System Organ Class 
and Preferred Term 
Summary Statistics by Visit for Change from Baseline in Hematocrit 
Summary of Investigator Reported Outcomes from Randomization to Month 15 
Summary of CEC Reported Outcomes from Randomization to Month 15 
Primary Safety Analysis of Major/Clinically Relevant Non-Major Bleed 
Primary Safety Analysis of Major/Clinically Relevant Non-Major Bleed in the Modified Intent to Treat Population  
Primary Safety Analysis of Major/Clinically Relevant Non-Major Bleed in the Modified Intent to Treat Population  
      Using On-Treatment Censoring 
Covariate Adjustment of Primary Safety Analysis  
Secondary Endpoint Analysis 
 
Figures  
Consort Diagram 
Kaplan-Meier Curve for Time to Major/Clinically Relevant Non-Major Bleed 
Kaplan-Meier Curve for Time to Major/Clinically Relevant Non-Major Bleed 
Kaplan-Meier Curve for Time to Major/Clinically Relevant Non-major Bleed 
Kaplan-Meier Curve for Time to Any Bleed 
Kaplan-Meier Curve for Time to Composite of Stroke, Systemic Embolism, Major bleeding, and All-cause 
Mortality 
Kaplan-Meier Curve for Time to All-cause Death 
Forest plot of Primary Safety Endpoint 


31 
 
 
Listings 
Events/Outcomes Occurring After End of Study/Month 15 Visit 
Serious Adverse events through 30-day Safety Follow-up 
Serious Adverse Events Resulting in Study Drug Discontinuation 
Serious Adverse Events Resulting in Fatal Outcome 
CEC Adjudicated All-Cause Mortality 
Additional listings may be created as needed for CSR