Clinical trial NCT01884337
Conditions: Anticoagulation
Sponsor: Bristol-Myers Squibb
Start date: 2015-03-24; Completion date: 2018-06-04
Enrollment: 557 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary purpose of this protocol is to evaluate the safety of Apixaban in prophylaxis of Venous Thromboembolism (VTE) in Indian patients undergoing elective total knee or hip replacement

Detailed description:

Arms: arm 1: Apixaban 2.5 mg tablets by mouth twice daily, 12 days for TKR subjects or 35 days for THR subjects
Interventions: intervention 1: Apixaban
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Page:
1
Protocol Number:
CV185158
IND Number:
NA
Ex-US
Non-IND
EUDRACT Number
NA
Date:
12-Nov-2012
Revised Date
22-Jul-2014
Clinical Protocol CV185158
A Phase IV, Open-Label, Multi-center Study to Evaluate the Safety of Apixaban in Indian 
Subjects Undergoing Elective Total Knee Replacement or Total Hip Replacement Surgery 
Revised Protocol Number: 02
Incorporates amendment(s) 02
Study Director 
Robert M. Knabb, PhD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
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expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 02
22-Jul-2014
Incorporates Amendment(s) 02
Amendment 02
22-Jul-2014
This amendment incorporates the changes requested by the health 
authority of India to include ‘single clopidogel use’ as exclusion criteria 
and wording related to collection of data in case of death. 
Incorporate other minor changes to correct and/or clarify protocol 
requirements.
This revision applies to all subjects and will serve in lieu of the revised 
protocol 01.
Revised 
Protocol 01
03-Jun-2013
Incorporates Amendment(s) 01
Amendment 01
03-Jun-2013
This amendment serves to revise the design of the study from a 
randomized, active controlled parallel group design to a single arm 
design by removing the enoxaparin arm.
Incorporate other minor changes to correct and/or clarify protocol 
requirements
In addition there are editorial changes throughout the document due to 
adaptation of the previous protocol version to the new BMS Protocol 
Template
This revision applies to all subjects and will serves in lieu of the original 
protocol.
Original 
Protocol
12-Nov-2012
Not applicable
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SYNOPSIS
Clinical Protocol CV185158
Title of Study: Protocol CV185158: A Phase IV, Open-Label, Multi-center Study to Evaluate the Safety of 
Apixaban in Indian Subjects Undergoing Elective Total Knee Replacement or Total Hip Replacement Surgery
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Subjects will receive oral apixaban, 2.5 mg twice daily for 12 2 days in subjects undergoing TKR or 
35 2 days in subjects undergoing THR.
Study Phase: 4
Research Hypothesis: Apixaban 2.5 mg BID is well-tolerated for venous thromboembolism (VTE) prophylaxis in 
Indian subjects undergoing total hip or knee replacement.
Primary Objective:  Evaluate the safety of apixaban in prophylaxis of VTE in Indian patients undergoing elective 
total knee or hip replacement.
Study Design: Open-label with endpoint adjudication. Subjects with planned surgery for total knee replacement 
(TKR) or total hip replacement (THR) will be screened for inclusion up to 14 days before surgery.  Subjects will 
receive oral apixaban, 2.5 mg twice daily, with the first dose administered 12-24 hr after surgery, and continuing for 
12 2 days in subjects undergoing TKR or 35 2 days in subjects undergoing THR.
During hospitalization, subjects will be observed for signs or symptoms of venous thromboembolism or bleeding. 
After hospital discharge, subjects will be instructed to contact the investigator for adverse events including signs or 
symptoms of bleeding, deep vein thrombosis (DVT) or pulmonary embolism (PE). At the end of the intended 
treatment period and at the end of the 30-day follow-up period, the patients will come to attend an in person visit or 
a phone visit if an in person visit is not planned.
SCREENING PERIOD (up to 14 days prior to surgery)
Subjects undergoing total hip replacement or total knee replacement surgery (including revisions) without known or 
suspected hereditary or acquired bleeding or coagulation disorders who meet the inclusion/exclusion criteria are 
eligible. Screening clinical laboratory samples will be collected during this period.
↓
ENROLLMENT (from 4 days before surgery to 24 hours after surgery)
Eligible subjects (N = 500) will be assigned to apixaban 2.5 mg PO starting 12 - 24 hours after completing skin 
wound closure, then BID for 35 2 days for the subjects undergoing total hip replacement or 12 2 days for the 
subjects undergoing total knee replacement. Sites will call into the IVRS system to record whether the subject's 
planned surgery is a hip replacement or knee replacement.
↓
TREATMENT PERIOD (35 days 2 days for THR subjects or 12days 2 for TKR)
Treatment Period Visits: Day 1 (day of surgery), Day 2, Day 7 2, Day 12 2 for TKR or Day 35 2 for THR 
patients. The Day 7, 12 or 35 visit should ideally be an in-person visit.  If this is not possible, a telephone follow-up 
visit will be performed.
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While hospitalized, subjects will be evaluated daily for symptomatic VTE (DVT and/or PE) and bleeding events. 
After hospital discharge, subjects will report all AEs including, but not limited to, signs and/or symptoms suggestive 
of DVT or PE and bleeding, to the Investigator. 
↓
FOLLOW-UP PERIOD (30 days after last dose of study drug)
Follow-up Visits: The follow up visit will occur 30 days after the last dose of study drug. TKR subjects will have 
their follow-up visit at Day 42 2 days and THR subjects will have their follow up visit at Day 65 2 days. The 
follow-up visit should ideally be an in-person visit.  If this is not possible, a telephone follow-up visit will be 
performed.
Subjects will report all AEs, including those signs and/or symptoms suggestive of DVT and/or PE and bleeding, to 
the Investigator.
Study Population: Subjects Undergoing Elective Total Knee Replacement or Total Hip Replacement Surgery
Main Inclusion Criteria:
Male or female subjects over the age of 18, who are scheduled for elective total knee or hip replacement or a 
revision of at least one component of a total knee or hip replacement. Subjects must be willing and able to give 
written informed consent prior to any screening procedures. 
Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy 
throughout the treatment period of the study in such a manner that the risk of pregnancy is minimized.
Main Exclusion Criteria:
WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire treatment period 
of the study
Women who are pregnant or breastfeeding
Known or suspected, acquired or bleeding or coagulation disorder in the subject or a first degree relative
Known coagulopathy
Active bleeding or at high risk for bleeding
Brain, spinal, ophthalmologic, or major surgery or trauma within the past 90 days
Active hepatobiliary disease
Two consecutive blood pressure readings within 15-30 minutes with supine SBP > 180 mm Hg or supine 
DBP > 105 mm Hg
Hemoglobin < 9 g/dL & Platelet count < 100,000/mm3
Creatinine clearance < 30 mL/min as estimated by the method of Cockcroft and Gault 
Active hepatobiliary disease, based on an ALT or AST > 2xULN or a Total Bilirubin 1.5xULN (unless an 
alternative causative factor [eg, Gilbert’s syndrome] is identified)  
Any antiplatelet agents (including clopidogrel) other than aspirin
Vitamin K antagonist or other novel oral anticoagulant (such as rivaroxaban or dabigatran)
Ongoing unfractionated heparin or low molecular weight heparin use
Use of thrombolytics within past 7 days.
Study Assessments and Primary Endpoint:  The primary endpoint is the incidence of adjudicated major or 
clinically relevant nonmajor bleeding. Secondary endpoints include adjudicated DVT or PE and all-cause death. 
These primary and secondary endpoints will be assessed up to end of treatment + 2 days.
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Statistical Methods:  The primary objective of the study is to evaluate the safety of apixaban in prophylaxis of VTE 
in Indian patients undergoing elective total knee or hip replacement. The primary study endpoint is a composite of 
International Society on Thrombosis and Haemostasis (ISTH) major bleeding/clinically relevant non-major bleeding 
(CRNM) in subjects undergoing elective total knee or hip replacement at the end of treatment + 2 days.
Total of 500 subjects will be enrolled and allocated to apixaban. The sample size of the study is determined by
requirement of regulatory agency rather than statistical considerations. With 500 subjects and event rate of 4.36% 
for ISTH major or clinically relevant non-major bleeding, the width of the 95% CI for the event rate will be (2.6%, 
6.2%) and width of the CI is 3.6%.  
Subgroup analyses by surgery type will also be conducted.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 
 
 
 
 
 
 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Screening.................................................................................................. 
3.1.2 Enrollment................................................................................................ 
3.1.3 Treatment Period ..................................................................................... 
3.1.4 Follow-up Period ..................................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
4 TREATMENTS ......................................................................................................... 
4.1 Study Treatments .............................................................................................. 
4.1.1 Investigational Product ............................................................................ 
4.1.2 Noninvestigational Product ..................................................................... 
4.1.3 Handling and Dispensing ........................................................................ 
4.2 Method of Assigning Subject Identification ..................................................... 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
4.4 Blinding/Unblinding ......................................................................................... 
4.5 Treatment Compliance ...................................................................................... 
4.6 Destruction and Return of Study Drug ............................................................. 
4.6.1 Destruction of Study Drug ....................................................................... 
4.6.2 Return of Study Drug ............................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
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5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.2 Secondary Efficacy Assessments .............................................................. 
 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Abnormalities ......................................................................... 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
7.1 Data Monitoring Committee ............................................................................. 
7.2 Independent Central Adjudication Committee ................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoint Definitions ......................................................................................... 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s).
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
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, subject recruitment materials/process (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
sponsor should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling, information to be provided to subjects and any updates. 
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The investigator or sponsor should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects, or, in those situations where consent cannot be given by 
subjects, their legally acceptable representative, are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1. Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2. Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study. 
3. Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information. 
5. If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating their 
informed consent during the study, then consent must additionally be obtained from the 
subject. 
6. Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke patients, or subjects with severe 
dementia) may only be enrolled in the study with the consent of a legally acceptable 
representative. The subject must also be informed about the nature of the study to the extent 
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compatible with the subjects’ understanding, and should they become capable, personally sign 
and date the consent form as soon as possible. The explicit wish of a subject unable to give his or 
her written consent, who is capable of forming an opinion and assessing this information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
Expected duration of the study, from first subject, first visit through last subject, last visit is 
approximately 8 months.
This study is designed to evaluate the safety of oral apixaban 2.5 mg BID following total knee 
and hip replacement surgeries. There are four study periods extending up to maximum duration 
of approximately 42 2 days for the patients undergoing total knee replacement surgery and up 
to 65 2 days for the patients undergoing total hip replacement surgery:

A screening period, of up to 14 days prior to surgery

An enrollment period: from 4 days before surgery to 1 day after surgery

A treatment period: First dose, PO, starting 12 - 24 hours after completing skin wound 
closure, then BID for 35 2 days for the subjects undergoing total hip replacement or 12 2
days for the subjects undergoing total knee replacement.

A 30-day follow-up period starting the day after the last dose of study medication.
Figure 3.1-1:
Study Design 
Screening
Enrollment
Treatment Period
Follow-up
Period
2.5 mg BID 
apixaban
TKR – 2 weeks
THR – 5 weeks
30 days
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3.1.1
Screening
The screening period will begin with a screening visit that occurs up to 14 days prior to surgery. 
Subjects undergoing elective THR or TKR surgery (including revisions) who meet the 
inclusion/exclusion criteria are eligible for study entry.
No study-related procedure may be performed until the subject has been completely informed of 
the study, has freely consented to take part in the study, and has signed and dated an informed 
consent document approved by a licensed Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC).
Blood sample and Urine pregnancy test will be collected for laboratory assessments.
The IVRS system will be contacted to obtain a unique subject number. Medical history, vital 
signs and body weight will be obtained (refer to Section 5.1 for details).
3.1.2
Enrollment
The enrollment may occur from 4 days prior to surgery to 24 hours after surgery.
Subjects who meet all the inclusion/exclusion criteria will be enrolled to the site for this visit. 
Subjects (N = 500) will be assigned to oral apixaban 2.5 mg BID 
Blood sample and Urine pregnancy test will be collected for laboratory assessments.
Sites will call into the IVRS system for assignment to apixaban 2.5 mg; sites will indicate 
whether the subject is undergoing either a TKR or THR. Either hip or knee replacement patients 
may be enrolled in any order, but BMS may place enrollment limits on either type of surgical 
patient to ensure adequate enrollment of both knee and hip surgery patients in the study.
3.1.3
Treatment Period
The day of surgery is Day 1.
The first dose of apixaban will be administered 12 - 24 hours after completing skin wound 
closure, typically in the morning of Day 2 and then BID for 35 2 days for the subjects 
undergoing total hip replacement or 12 2 days for the subjects undergoing total knee 
replacement.
While hospitalized, subjects will be evaluated on Day 1, Day 2 and discharge day for suspected 
symptomatic VTE, bleeding events or any AEs or SAEs.
At any subsequent treatment visits (Day 7 2 and Day 12 2 for TKR subjects or Day 7 2 and 
Day 35 2 for THR subjects), subjects will be instructed to report to the investigator all AEs, 
including signs and/or symptoms suggestive of VTE and any bleeding events they experienced 
since their last visit. Subjects with signs and/or symptoms of VTE at any time should return to 
the hospital/clinic and undergo appropriate diagnostic evaluation. 
If study medication is discontinued for a suspected DVT and or PE, alternative antithrombotic 
prophylaxis may be initiated per the Investigator’s discretion and standard of care. Every effort 
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must be made to confirm a suspected DVT and/or PE diagnosis before discontinuing study 
medication and initiating treatment per the Investigator’s standard of care.
Samples for laboratory assessment of hematology will be obtained on the day of discharge. 
Urine pregnancy test will be performed on Day 12 for TKR subjects and on Day 35 for THR 
subjects.
Dosing Diaries should be collected at Day 7 & Day 12 for TKR subjects and at Day 7 & Day 35 
for THR subjects.
Subjects should be encouraged to return for an in person visit on Day 7 and Day 12 for TKR and 
Day 7 and Day 35 for THR. Alternatively those visits would be performed by phone.
3.1.4
Follow-up Period
As appropriate and per the Investigator’s discretion and standard of care, alternative 
antithrombotic prophylaxis may be initiated the day after the last dose of study medication.
For subjects undergoing TKR surgery, follow-up study visit will occur on Day 42 2 and for 
subjects undergoing THR surgery, the follow up visit will occur on Day 65 2. Subjects should 
be encouraged to return for an in person follow up visit at Day 42 (TKR) or Day 65 (THR). 
Alternatively those visits would be performed by phone.
Subjects will be asked to report to the Investigator, all AEs/SAEs including those symptoms 
suggestive of DVT and/or PE and bleeding. Suspected DVT and/or PE will be evaluated using 
the appropriate diagnostic assessment.
3.2
Post Study Access to Therapy
At the end of the study, the sponsor will not continue to supply study drug to 
subjects/investigators unless the sponsor chooses to extend the study. The investigator should 
ensure that the subject receives appropriate standard of care to treat the condition under study.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Age 18 years
b) Subjects must be willing and able to give written informed consent. Consent to 
participate in the study must be obtained prior to any screening procedures.
2) Target Population
a) Subjects undergoing elective total knee or hip replacement or a revision of at least one 
component of a total knee or hip replacement.
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3) Age and Reproductive Status
a) Women of childbearing potential (WOCBP) and men must be using an acceptable 
method of contraception to avoid pregnancy throughout the study in such a manner that 
the risk of pregnancy is minimized. See Section 3.3.3 for the definition of WOCBP.
b) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational 
product. 
c) Women must not be breastfeeding
d) Sexually active fertile men must use effective birth control if their partners are WOCBP.
3.3.2
Exclusion Criteria
1) Target Disease Exceptions   
a) Known or suspected, acquired or bleeding or coagulation disorder in the subject or a first 
degree relative
b) Known coagulopathy
c) Active bleeding or at high risk for bleeding.
2) Medical History and Concurrent Diseases  
a) Brain, spinal, ophthalmologic, or major surgery or trauma within the past 90 days
b) Active hepatobiliary disease
c) Alcohol and/or substance abuse within the past year
d) Any condition, in the opinion of the Investigator, for which surgery or administration of 
an anticoagulant is contraindicated.
3) Physical and Laboratory Test Findings
a) Two consecutive blood pressure readings within 15-30 minutes with supine SBP > 180 
mm Hg or supine DBP > 105 mm Hg
b) Hemoglobin < 9 g/dL
c) Platelet count < 100,000/mm3
d) Creatinine clearance < 30 mL/min as estimated by the method of Cockcroft and Gault 
e) Active hepatobiliary disease, based on an ALT or AST > 2 x ULN or a Total Bilirubin 
1.5 x ULN (unless an alternative causative factor [eg, Gilbert’s syndrome] is identified.
4) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for 
the entire treatment period of the study
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b) Women who are pregnant or breastfeeding
c) Women with a positive pregnancy test on enrollment or prior to investigational product 
administration.
5) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated 
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Administration of any investigational drug currently or within 30 days prior to enrollment 
into this study.
6) Prohibited Treatments and/or Therapies
a) Any antiplatelet agents (including clopidogrel) other than aspirin
b) Vitamin K antagonist or other novel oral anticoagulant (such as rivaroxaban or 
dabigatran) during the treatment period
c) Ongoing unfractionated heparin or low molecular weight heparin use
d) Use of thrombolytics within past 7 days
e) Use of Fondaparinux 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and to ensure that the results of the study can be used. It is imperative that subjects fully 
meet all eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential include any female who has experienced menarche and who 
has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as: 

Amenorrhea ≥ 12 consecutive months without another cause and a documented serum 
follicle stimulating hormone (FSH) level > 35 mIU/mL or 

Women with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35 mIU/mL or
NOTE: FSH level testing is not required for women 62 years old with amenorrhea 
of 1 year

Women on hormone replacement therapy (HRT).
Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin 
patches, or implanted or injectable products), or mechanical products such as an intrauterine 
device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are 
practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be 
of childbearing potential.
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3.4
Concomitant Treatments
Medications required for the treatment of underlying medical conditions are allowed, with the 
exception of those listed below.
3.4.1
Prohibited and/or Restricted Treatments
Prohibited Therapies
Prohibited medications are listed in the Exclusion Criteria (see Section 3.3.2 item 6a to 6e).
Use of pneumatic compression devices and tourniquets must be discontinued at the completion 
of skin wound closure and are not permitted throughout the treatment period.
Anti-thrombotic prophylaxis may be continued during the follow-up period per the Investigator’s 
discretion and standard of care.
Restricted Therapies During the Treatment Period
Subjects are allowed to use the following therapies during the study at the investigator’s 
discretion:

Oral cox-2 selective (eg, celecoxib [Celebrex]) and short-acting NSAIDs for joint pain are 
permitted although not encouraged (acetaminophen/paracetamol or opiods are the preferred 
methods for systemic pain management) 

Parenteral 
ketorolac 
or 
parecoxib 
is 
permitted 
although 
not 
encouraged 
(acetaminophen/paracetamol or opiods are the preferred methods for systemic pain 
management)

Aspirin > 165 mg/day is prohibited

Herbal medications are permitted, provided the subject has permission from the Investigator

Metformin should be temporarily discontinued at the time of, or prior to, procedures in which 
intravascular iodinated contrast material is used and then withheld for at least 48 hours 
subsequent to the procedure (eg, venograms).

Epidurals should be removed at least 5 hours prior to administration of the first dose of 
apixaban.
All concomitant medication use must be noted on the appropriate e-CRFs.
3.4.2
Other Restrictions and Precautions
The following precautions and restrictions must be followed to preserve study integrity and 
subject safety:

Subject should comply with prescribed dosing schedule

Subjects should be cautioned that any new prescriptions, or over-the-counter medications, 
including herbal medications, should be discussed thoroughly with the Investigator prior to 
initiation.
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Study medication must be discontinued for subjects experiencing a severe adverse event, (eg, 
myocardial infarction) which may require the use of open-label anticoagulants (eg, LMWH), 
antiplatelet agents, thrombin inhibitors (eg, hirudin), glycoprotein IIb/IIIa antagonists or other 
antithrombotic agents, either with or without interventions (eg, percutaneous coronary 
intervention). The treating physician should be made aware that when study medication 
(apixaban) is administered at the protocol-specified doses, routine coagulation tests such as 
Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively 
insensitive measures of activity and, therefore, unsuitable for monitoring. If treatment of a severe 
adverse event is indicated, the treating physician may consider using the agent(s) listed above at 
the lowest recommended therapeutic dose for the first 12 hours following discontinuation of 
study medication.
Discontinuation of Subjects from Treatment: Subjects MUST discontinue investigational product 
(and noninvestigational product at the discretion of the investigator) for any of the following 
reasons:

Withdrawal of informed consent (subject’s decision to withdraw for any reason)

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the subject

Pregnancy

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness

Signs and/or symptoms suggestive of DVT in the operated and/or nonoperated leg which 
are confirmed by ultrasound and/or venography

Signs and/or symptoms suggestive of PE which are confirmed by diagnostic assessment, 
eg, V/Q scan, pulmonary angiogram, CT scan (including spiral), and as indicated, 
additional confirmatory tests 

Subject has clinical jaundice at any time 

Subject has specific elevated liver function test (LFTs) results

Subject has a severe adverse event that may require the use of anticoagulants, antiplatelet 
agents, thrombin inhibitors, glycoprotein IIB/IIIa antagonists or other thrombotic agents

Subject has an increased risk of bleeding complications eg persistent bleeding after 
surgery or difficult (more than 2 failed attempts) or traumatic (bloody spinal fluid) 
lumbar puncture.
All subjects who discontinue should comply with protocol specified follow-up procedures as 
outlined in Section 5. The only exception to this requirement is when a subject withdraws 
consent for all study procedures or loses the ability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
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If a subject was withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate case report form (CRF) page.
All subjects who discontinue study medication prematurely and have received at least one dose 
of post-surgical oral study medication should be encouraged to return for an in person visit on 
Day 7, Day 12 (TKR) or Day 35 (THR) and follow up visit at Day 42 (TKR) or Day 65 (THR). 
Alternatively those visits would be performed by phone.
Subjects who require a revision of their hip or knee replacement during the study's treatment 
period should have their apixaban stopped at least 48 hours before their revision surgery.
Patients who withdraw consent for treatment with study drug should still receive follow-up for 
adverse events and outcomes unless they withdraw consent for follow-up as well.
If a subject is lost to follow-up, every effort should be made to contact the subject and perform 
these procedures. At minimum the vital status should be collected.
4
TREATMENTS
All protocol-specified investigational and non-investigational products are considered study 
drug. The following table (Table 4.1-1) describes the study drug used.
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4.1
Study Treatments
 
 
 
 
 
 
 
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as follows:
A pharmaceutical form of an active substance being tested or used as a reference in a clinical 
study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) in a way different from the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Apixaban 2.5 mg will be the only investigational product in this study.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is apixaban.
4.1.2
Noninvestigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
In this protocol, noninvestigational product(s) is/are: Not applicable for this study.
4.1.3
Handling and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the sponsor immediately.
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations.
Apixaban tablets should be stored at below 30°C. 
4.2
Method of Assigning Subject Identification
At screening, each subject will be assigned a unique sequential number by the Interactive Voice 
Response System (IVRS). The IVRS will be available 24 hours per day, seven days a week. The 
subject number will consist of a unique 5-digit number which is assigned sequentially within a 
study (starting with 00001) by the IVRS. This number will be used for identification throughout 
the study and will not be used for any other subject.
After meeting inclusion/exclusion criteria, subjects eligible for the treatment will be assigned 
prior to surgery to apixaban 2.5 mg by the IVRS. 
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4.3
Selection and Timing of Dose for Each Subject
Study medication for this study is defined as apixaban 2.5 mg tablets. Subjects will receive 
apixaban tablets.

The first oral dose will be given 12 - 24 hours after completing skin wound closure, typically 
in the morning of Day 2, followed by BID dosing for 12 ± 2 days in subjects undergoing 
TKR or 35 ± 2 days in subjects undergoing THR.

Study subjects will take one tablet in the morning and one tablet in the evening.
4.4
Blinding/Unblinding
Not applicable.
4.5
Treatment Compliance
Prior to leaving the hospital, subjects or their caregivers will be instructed on timing and proper 
methods of study medication administration
4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
If study drugs (those supplied by the sponsor or sourced by the investigator) are to be destroyed 
on site, it is the investigator’s responsibility to ensure that arrangements have been made for the 
disposal, procedures for proper disposal have been established according to applicable 
regulations, guidelines and institutional procedures, and appropriate records of the disposal have 
been documented. The unused study drugs can only be destroyed after being inspected and 
reconciled by the responsible BMS Study Monitor.
4.6.2
Return of Study Drug
Study drug will not be returned. All unused and/or partially used study drug may be destroyed on 
site providing the site has an applicable standard operating procedure on file.
If the site is not able to destroy the study medication, the Study Monitor should be contacted to 
organize the study drug return.
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5
STUDY ASSESSMENTS AND PROCEDURES 
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline for TKR Subjects (CV185158)
Procedure - TKR Subjects
Screening
Visit
Enrollment
Treatment Period
Follow 
up
Period
Notes
Days
Pre-
Surgery
1-14
Pre-Surgery
-4 days to 
+24 hours
Surgery
Day 1
Day 2
Hospital 
Discharge
Day 7 
2 
days
Day 
12 2 
days
Day 42 
2 days
Informed Consent
X
Inclusion/Exclusion Criteria
X
Medical History
X
Weight & Age & Gender
X
Vital Signs (SBP/DBP & HR)
X
Contact IVRS
X
X
At screening, after obtaining 
signed informed consent form, 
contact IVRS to obtain subject 
number; At enrollment, contact 
IVRS for assignment to 
apixaban 2.5 mg
Dispense Study Medication
X
Discharge Instructions
X
Review Medication 
Compliance
X
X
X
AE/SAE Assessment
X
X
X
X
X
X
X
Lab: for SAE’s related to liver 
failure/jaundice/hepatitis:  local  
lab hepatitis panels and full 
LFT’s (AST, ALT, T.Biliruin, 
D. bilirubin, GGT, AP, 
PT/aPTT/INR) must be 
performed; for bleeding related 
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Table 5.1-1:
Screening Procedural Outline for TKR Subjects (CV185158)
Procedure - TKR Subjects
Screening
Visit
Enrollment
Treatment Period
Follow 
up
Period
Notes
Days
Pre-
Surgery
1-14
Pre-Surgery
-4 days to 
+24 hours
Surgery
Day 1
Day 2
Hospital 
Discharge
Day 7 
2 
days
Day 
12 2 
days
Day 42 
2 days
SAE’s, analysis of  CDC, 
PT/aPTT/INR must be 
performed by the local lab.
Symptomatic VTE 
Assessment
X
X
X
X
X
X
X
Local Lab: Serum Creatinine 
LFT’s (AST, ALT,TBILI) & 
CBC
X
X
Local Lab: Hb
X
X
X
Dosing Diaries to be collected
X
X
Pregnancy Test
X
X
X
X
WOCBP only
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Table 5.1-2:
Screening Procedural Outline for THR Subjects (CV185158)
Procedure - THR Subjects
Screening
Visit
Enrol-
lment
Treatment Period
Follow 
up
Period
Notes
Days
Pre-
Surgery
1-14
Pre-
Surgery
-4 days 
to +24 
hours 
after 
surgery
Surgery
Day 1
Day 
2
Hospital 
Discharge
Day 7 
2 
days
Day 
35 
2 
days
Day 65 
2 
days
Informed Consent
X
Inclusion/Exclusion Criteria
X
Medical History
X
Weight & Age & Gender
X
Vital Signs (SBP/DBP & HR)
X
Contact IVRS
X
X
At screening, after obtaining 
signed informed consent form, 
contact IVRS to obtain subject 
number; At enrollment, 
contact IVRS for assignment 
to apixaban 2.5 mg
Dispense Study Medication
X
Discharge Instructions
X
Review Medication Compliance
X
X
X
AE/SAE Assessment
X
X
X
X
X
X
X
Lab: for SAE’s related to liver 
failure/jaundice/hepatitis:  
local  lab hepatitis panels and 
full LFT’s (AST, ALT, 
T.Biliruin, D. bilirubin, GGT, 
AP, PT/aPTT/INR) must be 
performed; for bleeding 
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Table 5.1-2:
Screening Procedural Outline for THR Subjects (CV185158)
Procedure - THR Subjects
Screening
Visit
Enrol-
lment
Treatment Period
Follow 
up
Period
Notes
Days
Pre-
Surgery
1-14
Pre-
Surgery
-4 days 
to +24 
hours 
after 
surgery
Surgery
Day 1
Day 
2
Hospital 
Discharge
Day 7 
2 
days
Day 
35 
2 
days
Day 65 
2 
days
related SAE’s, analysis of  
CDC, PT/aPTT/INR must be 
performed by the local lab.
Symptomatic VTE Assessment
X
X
X
X
X
X
X
Local Lab: Serum Creatinine LFT’s 
(AST, ALT,TBILI) & CBC
X
X
Local Lab: Hb
X
X
X
Dosing Diaries to be collected
X
X
Pregnancy Test
X
X
X
X
WOCBP only
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5.2
Study Materials
BMS will supply the sites with the following materials:

Daily dosing diaries to be used to record study medication taken

Subject discharge instruction cards

Electronic case report forms

Sample source documentation worksheets

Patient Emergency card.
5.3
Safety Assessments
Bleeding is the primary safety outcome measure. Bleeding AEs/SAE/s will be assessed by the 
investigator at every post-surgery visit. At discharge from the hospital, impress upon the subject 
and/or caregiver the importance of contacting the Investigator immediately if subject experiences 
signs of clinically over bleeding during the treatment period or the follow-up period. These 
bleeding AEs/SAEs will be evaluated by the clinical events adjudication committee.
Acute clinically overt bleeding is defined as new onset, visible bleeding or signs or symptoms 
suggestive of bleeding with confirmatory imaging techniques which can detect the presence of 
blood (eg, US, CT, MRI).
All acute clinically overt bleeding events will be adjudicated by the ICAC as a major bleeding 
event, a clinically relevant nonmajor bleeding event or neither.
The definition of major bleeding described below is adapted from the International Society on 
Thrombosis and Hemostasis (ISTH) definition.
Major Bleeding Event is defined as a bleeding event that is:

Acute clinically overt bleeding accompanied by one or more of the following:

A decrease in hemoglobin (Hb) of 2 g/dL or more over a 24-hour period

A transfusion of 2 or more units of packed red blood cells

Bleeding that occurs in at least one of the following critical sites:

Intracranial

Intra-spinal

Intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular 
bleed)

Pericardial

An operated joint and requires re-operation or intervention

Intramuscular with compartment syndrome

Retroperitoneal.

Bleeding that is fatal.
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Clinically Relevant Nonmajor Bleeding event is defined as a bleeding event that is:

Acute clinically overt bleeding

Does not satisfy additional criteria required for the bleeding event to be defined as a major 
bleeding event and meets at least one of the following criteria.

Epistaxis (nose bleed):

Subject seeks medical attention from a physician

Subject visits an emergency room

Bleeding requires an intervention, eg, nasal pack

Single bleeding episode persists for 5 minutes or more.

Gastrointestinal Bleed:

Vomit containing frank blood or coffee ground material which tests positive for blood

Endoscopically confirmed bleeding

Frank blood per rectum or melenic stools.

Hematuria:

Overt, spontaneous bleeding

Bleeding (bloody urine) persists for 24 hours or more after instrumentation.

Bruising/ecchymosis:

Any bruise which is assessed as “unusual” (eg, greater than expected following surgery).

Hemoptysis:

Expectoration of blood or blood-stained sputum.

Hematoma:

Overt blood collection associated with the surgical wound
Presence of a hematoma is demonstrated radiographically, eg, US, CT, MRI, and a drop 
in hemoglobin is present with no external evidence of bleeding.
Fatal Bleeding Event is defined as a bleeding event that the ICAC determines is the primary 
cause of death or contributes directly to death.
5.4
Efficacy Assessments
No specific diagnostics are required for evaluating asymptomatic VTE's. However, patients with 
signs or symptoms suggestive of deep vein thrombosis (DVT) or pulmonary embolism (PE) must 
be evaluated with the clinically appropriate imaging techniques, including compression 
ultrasound (CUS) or venography for suspected DVT, or VQ scanning or spiral CT for suspected 
PE. Additional diagnostics performed outside the efficacy assessments and outside SAE 
reporting need not be part of the study report but should be maintained as part of the medical 
record.
An independent events adjudication committee will evaluate these reports of VTEs as well as of 
deaths. All deaths will be adjudicated regardless of whether they seem related to VTE's or not. In 
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case of death, all efforts should be made to determine the cause of death which is aligned to the 
BMS process on data collection, obtaining autopsy reports or verbal information from family.
5.4.1
Primary Efficacy Assessment
The composite of VTE/all cause death will include all adjudicated symptomatic pulmonary 
embolisms and deep vein thromboses. Statistical details will be described in the Statistical 
Analysis Plan as a separate document.
5.4.2
Secondary Efficacy Assessments
Not Applicable.
5.5
Other Assessments 
VTE's that are discovered as part of incidental findings (such as CT scans for other parts of the 
body), will not be counted towards the efficacy endpoint but will be adjudicated and reported 
separately.
6
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 subject 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.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A serious AE (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject 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 (see 
NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
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result in hospitalization.)  Potential drug induced liver injury (DILI) is also considered an 
important medical event.  (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs.  (See Section 
6.1.1 for reporting pregnancies.)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered "important medical event" or event life 
threatening)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy)

medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative).
6.1.1
Serious Adverse Event Collection and Reporting
Following the subject’s written consent to participate 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 during the screening period 
and within 30 days of discontinuation of dosing. 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. 
If the investigator believes that an SAE is not related to the 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 Report 
Form.
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SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms).  When using paper forms, the reports 
are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: See Contact Information list.
SAE Facsimile Number: See Contact Information list.
For studies capturing SAEs/pregnancies through electronic data capture (EDC), electronic 
submission is the required method for reporting. The paper forms should be used and submitted 
immediately, only in the event the electronic system is unavailable for transmission. When paper 
forms are used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): See Contact Information 
list.
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 BMS (or designee) 
using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.  In case of death, all efforts should be 
made to determine the cause of death which is aligned to the BMS process on data collection, 
obtaining autopsy reports or verbal information from family.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug, or those that are present at the end of study 
treatment as appropriate. All identified nonserious AEs must be recorded and described on the 
nonserious AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Abnormalities
The following laboratory abnormalities should be captured on the nonserious AE CRF Page or 
SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 
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
Any laboratory abnormality that required the subject to have the study drug discontinued or 
interrupted

Any laboratory abnormality that required the subject to receive specific corrective therapy.
It is expected that wherever possible, the clinical, rather than the laboratory term would be used 
by the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety). Protocol-required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 6.1.1 for reporting details.).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 6.1.1 for reporting details).
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Potential drug induced liver injury is defined as 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic.
6.7
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious AE, 
as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
7.1
Data Monitoring Committee
Not Applicable.
7.2
Independent Central Adjudication Committee
The Independent Central Adjudication Committee (ICAC) will be responsible for validating 
outcome events as specified in the protocol and according to guidelines using standardized 
criteria.
The ICAC reviews and adjudicates all suspected symptomatic DVT, PE, major bleeds, clinically 
relevant non-major bleeds, minor bleeds, thrombocytopenia and causes of death.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The sample size of the study is determined by requirement of regulatory agency rather than 
statistical considerations. With 500 subjects in the apixaban arm and event rate of 4.36% for 
ISTH major or clinically relevant non-major bleeding, the width of the 95% CI for the event rate 
will be (2.6%, 6.2%) and width of the CI is 3.6%.
8.2
Populations for Analyses
The term “treatment period” refers to the period between the first administration of study 
medication (post-surgery oral apixaban) and two days after the last administration of study 
medication (end of treatment). The “treatment period” will be the basis for the summaries of 
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safety and efficacy. Summaries of safety and efficacy data will include all subjects receiving any 
study medication.
8.3
Endpoint Definitions
Primary Endpoint: 
The primary study endpoint is a composite of International Society on Thrombosis and 
Haemostasis (ISTH) major bleeding/clinically relevant non-major bleeding (CRNM) in subjects 
undergoing elective total knee or hip replacement at the end of treatment + 2 days, where ISTH 
major bleeding is

Fatal or

Bleeding in a critical organ, such as brain, spine, eye, retroperitoneum, joint, heart sac, or 
skeletal muscle (and resulting in compartment syndrome), or

Bleeding that results in a fall of hemoglobin  of 2 g/dL or more or transfusion of 2 units or 
more of packed red cells or whole blood within 24 hours 
and CRNM bleeding is bleeding that 

Is clinically acute and overt

Does not satisfy criteria as a major bleed but requires medical intervention, such as a visit to 
a physician’s office, emergency room, or urgent care center for epistaxis.
Secondary Endpoints:
The secondary endpoint will be: The composite of VTE/all cause death at the end of treatment + 
2 days, where VTE is the combination of deep vein thrombosis and non-fatal pulmonary 
embolism.
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Frequency distribution and summary statistics for demographic and baseline variables will be 
presented by treatment group and for all subjects combined. Key demographic and baseline 
variables to be summarized include: age, gender, race, vital signs (systolic blood pressure, 
diastolic blood, pressure, and heart rate), medical history, knee or hip replacement surgery 
experience, intra-operative details, and post-surgical patient care characteristics. The summary 
will be presented for all subjects.
8.4.2
Efficacy Analyses
The event rates and their 95% confidence intervals of composite of venous thromboembolism 
(VTE) and all cause death during the treatment period will be summarized. Subgroup analyses 
by surgery type will also be conducted.
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8.4.3
Safety Analyses
Bleeding is the primary safety outcome measure. The event rate of adjudicated major bleeding or 
clinically relevant non-major bleeding events during the treatment period will be summarized. 
Subgroup analyses by surgery type will also be conducted.
An additional analysis will summarize all adjudicated major bleeding or clinically relevant non-
major bleeding occurring during the treatment period, which begins with the first dose of study 
medication.
In addition, an analysis of major or clinically relevant non-major bleeding events will look at the 
bleeding events that occur prior to the administration of apixaban. Additional details will be 
provided in the Statistical Analysis Plan. 
The incidence of adverse events and of marked abnormalities in clinical laboratory tests will be 
summarized by treatment group for both the treatment and follow-up period. 
All adverse events that are serious or that result in discontinuation of study therapy will be 
described in depth. K-M estimator will be used to estimate the rate of early discontinuation due 
to any reason.
8.4.4
Other Analyses 
Not Applicable.
8.5
Interim Analyses
Not Applicable.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects.
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

Bristol-Myers Squibb

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
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If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by the sponsor, whichever is longer. The investigator must contact BMS prior to 
destroying any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by the sponsor) is maintained at each study site where 
study drug is inventoried and dispensed. Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage area

amount currently in storage area
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
label ID number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

non-study disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to the sponsor

retain samples for bioavailability/bioequivalence, if applicable 

dates 
and 
initials 
of 
person 
responsible 
for 
Investigational 
Product 
(IP) 
dispensing/accountability, as per the Delegation of Authority Form.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data reported on the CRF that are derived from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. 
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by the sponsor. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by a qualified physician who is an investigator or subinvestigator. 
For electronic CRFs, review and approval/signature is completed electronically through the BMS 
electronic data capture tool. The investigator must retain a copy of the CRFs including records of 
the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by the sponsor. User accounts are not to be shared or reassigned to other individuals.
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9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected considering the following criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to the sponsor. Any 
publications or abstracts arising from this study require approval by the sponsor prior to 
publication or presentation and must adhere to the sponsor’s publication requirements as set forth 
in the approved clinical trial agreement (CTA). All draft publications, including abstracts or 
detailed summaries of any proposed presentations, must be submitted to the sponsor at the 
earliest practicable time for review, but at any event not less than 30 days before submission or 
presentation unless otherwise set forth in the CTA. Sponsor shall have the right to delete any 
confidential or proprietary information contained in any proposed presentation or abstract and 
may delay publication for up to 60 days for purposes of filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the 
investigator or BMS as related to the investigational 
product
Unexpected Adverse Reaction
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved 
investigational product)
Expected Adverse Event  
An event that is described or mentioned in the 
applicable (current version) or the prescribing 
information for the drug (eg, Investigator Brochure for 
an investigational product, approved local label for a 
marketed product).  
Serious Adverse Event
Serious adverse event defined as any untoward medical 
occurrence that at any dose: results in death; is life 
threatening (defined as an event in which the subject 
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; is an important medical event (defined as a 
medical event(s) that may not be immediately life 
threatening or result in death or hospitalization but, 
based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require 
intervention [eg, medical, surgical] to prevent one of the 
other serious outcomes listed in the definition above). 
Examples of such events include, but are not limited to, 
intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization.). For 
reporting purposes only, BMS also considers the 
occurrence of pregnancy, overdose (regardless of 
association with an AE), and cancer as important 
medical events.
Investigational Product
An investigational product, also known as 
investigational medicinal product in some regions, is: A 
pharmaceutical form of an active substance* being 
tested or used as a reference in a clinical study, 
including products already with a marketed 
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Term
Definition
authorization but used or assembled (formulated or 
packaged) in a way different from the authorized form, 
or used for an unauthorized indication, or when used to 
gain further information about the authorized form.
* The only investigational product is apixaban.  
Noninvestigational Product  
Support, escape (rescue) or diagnostic medications 
(marketed form), concomitant medications.
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11
LIST OF ABBREVIATIONS
Term
Definition
ACC  
American College of Cardiology  
AE  
adverse event  
ALT  
alanine aminotransferase  
ANC  
Absolute neutrophil count  
aPTT  
activated partial thromboplastin time  
AST  
aspartate aminotransferase  
BA/BE  
bioavailability/bioequivalence  
BID  
twice daily  
BMI 
Body Mass Index  
BMS  
Bristol-Myers Squibb  
BUN  
blood urea nitrogen  
CBC  
complete blood count  
CHF  
Congestive heart failure  
CK 
creatine kinase  
CK-MB  
Creatine kinase MB subunit  
CFR  
Code of Federal Regulations of the United States of America 
CRNM 
clinically relevant non-major bleeding
CRP 
C-reactive protein  
CT  
Computer tomography  
CUS  
compression ultrasound  
DBP  
Diastolic blood pressure  
DSMB  
Data Safety Monitoring Board  
DVT  
deep-vein thrombosis  
ECG  
electrocardiogram  
e-CRF  
electronic case report form  
ERC  
Ethics Review Committee  
ESR  
Expedited safety report  
FSH  
follicle-stimulating hormone  
GGT  
gamma-glutamyl transpeptidase  
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Term
Definition
HAV  
hepatitis A virus  
Hb  
hemoglobin  
HbsAg  
hepatitis B surface antigen  
HBC  
hepatitis B core antigen  
HCG  
human chorionic gonadotropin  
HCV  
hepatitis C virus  
HIV  
Human Immunodeficiency Virus  
HRT  
hormone replacement therapy  
ICAC  
Independent Central Adjudication Committee  
IEC  
International Ethics Committee  
INR  
International normalized ratio  
IRB 
Institutional Review Board  
ITT  
intent-to-treat  
IVRS  
Interactive Voice Response System  
kg 
kilogram  
LFT  
liver function test  
LMWH  
low molecular weight heparin  
MedDRA  
Medical Dictionary for Regulatory Activities  
MCV  
Mean Corpuseular Volume  
MH  
Mantel-Haenszel  
MCH  
Mean Corpuseular Hemoglobin  
MCHC  
Mean Corpuseular Hemoglobin Concentration  
MI 
myocardial infarction  
MRI 
Magnetic Resonance Imaging  
NSAIDs  
Non-Steroidal Anti-Inflammatory Drugs  
PCI  
percutaneous coronary intervention  
PE  
pulmonary embolism  
PO  
Per os (Latin by mouth)  
PT  
Prothrombin time  
RBC  
Red blood cell  
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Term
Definition
QD  
once daily  
SAE  
serious adverse event  
SBP  
Systolic blood pressure  
SGOT  
Serum Glutamic Oxaloacetic Transaminase  
SGPT  
Serum Glutamic Pyruvic Transaminase  
THR  
Total hip replacement  
TKR        
total knee replacement
ULN  
Upper limit of normal  
US  
Ultrasound  
VKA  
Vitamin K antagonist  
VTE  
Venous thromboembolism  
V/Q  
Ventilation perfusion scan  
WBC  
White blood cell  
WOCBP  
women of childbearing potential  
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SAP_001.pdf: 
Official Title of Study: 
 
A Phase IV, Open-Label, Multi-center Study to Evaluate the Safety of Apixaban 
in Indian Subjects Undergoing Elective Total Knee Replacement or Total Hip Replacement Surgery 
 
NCT Number: NCT01884337 
Document Date (Date in which document was last revised): July 2, 2018 


Apixaban 
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 Statistical Analysis Plan 
2-July-2018                                                      Page 1 of 12 
 
 
STATISTICAL ANALYSIS PLAN 
FOR CLINICAL STUDY REPORT 
 
A Phase IV, Open-Label, Multi-center Study to Evaluate the Safety of Apixaban  
in Indian Subjects Undergoing Elective Total Knee Replacement or Total Hip 
Replacement Surgery 
 
PROTOCOL CV185158 
 
 
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DOCUMENT HISTORY 
 
 
Version Number 
Author(s) 
Description 
1.0 
 
Original Version 
2.0 
 
1.Efficacy is not primary endpoint. There is no 
sensitivity analysis on evaluable population needed. 
Thus the definition of evaluable population and 
corresponding planned analyses were deleted now. 
2. Original treatment compliance formula is not 
accurate. It’s adjusted to current version. 
 
 
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TABLE OF CONTENTS 
DOCUMENT HISTORY.................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
1 
 
1.1 
Research Hypothesis .....................................................................................................5 
1.2 
Schedule of Analyses ....................................................................................................5 
2 
STUDY DESCRIPTION ..............................................................................................5 
2.1 
Study Design .................................................................................................................5 
2.2 
Treatment Group Assignment .......................................................................................6 
2.3 
Blinding and Unblinding ..............................................................................................6 
3 
OBJECTIVES ...............................................................................................................6 
3.1 
Primary Objective .........................................................................................................6 
3.2 
Secondary Objectives ...................................................................................................6 
4 
ENDPOINTS ................................................................................................................6 
4.1 
Primary Endpoint ..........................................................................................................6 
4.2 
Secondary Endpoint ......................................................................................................7 
5 
SAMPLE SIZE AND POWER ....................................................................................7 
6 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES .........................................................................................................7 
6.1 
Study Periods ................................................................................................................7 
6.2 
Treatment Regimens .....................................................................................................7 
6.3 
Populations for Analyses ..............................................................................................7 
7 
STATISTICAL ANALYSES .......................................................................................8 
7.1 
General Methods ...........................................................................................................8 
7.2 
Study Conduct ..............................................................................................................8 
7.3 
Study Population ...........................................................................................................8 
7.3.1 
Subject Disposition .......................................................................................................8 
7.3.2 
Demography and Baseline Characteristics ..................................................................8 
7.4 
Extent of Exposure .......................................................................................................9 
7.4.1 
Study Therapy ...............................................................................................................9 
7.4.2 
Prior and Concomitant Medications ............................................................................9 
7.5 
Efficacy .........................................................................................................................9 
7.6 
Safety ............................................................................................................................9 
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7.6.1 
Adverse Events ..............................................................................................................9 
7.6.2 
Laboratory Data .........................................................................................................10 
7.6.3 
Events of Special Interest ............................................................................................10 
8 
CONVENTIONS ........................................................................................................10 
8.1 
Safety Data Conventions ............................................................................................10 
8.2 
Baseline Measurements ..............................................................................................10 
8.3 
Day Ranges for Analysis of Time Points ...................................................................10 
8.4 
Multiple Measurements ..............................................................................................10 
9 
CONTENT OF REPORTS .........................................................................................10 
APPENDIX 1 
ANALYSIS OF SAFETY DATA - REFERENCE TO CT SOP 
109..............................................................................................................11 
 
 
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1.1 
Research Hypothesis 
Apixaban 2.5 mg twice a day in Indian patients undergoing hip or knee replacement surgery will 
provide an acceptable rate of ISTH major/CRNM bleeding. 
1.2 
Schedule of Analyses 
A final analysis will be performed after all subjects either complete the 2 weeks (for knee 
replacement subjects) or 5 weeks (for hip replacement subjects) treatment period followed by a 
30-day follow-up period, or discontinue prematurely. There is no interim analysis planned for this 
study.   
 
2 
STUDY DESCRIPTION 
2.1 
Study Design 
Expected duration of the study, from first subject, first visit through last subject, last visit is 
approximately 8 months. 
This study is designed to evaluate the safety of oral apixaban 2.5 mg BID following total knee and 
hip replacement surgeries. There are four study periods extending up to maximum duration of 
approximately 42 ± 2 days for the patients undergoing total knee replacement surgery and up to 
65 ± 2 days for the patients undergoing total hip replacement surgery: 
• A screening period, of up to 14 days prior to surgery 
• An enrollment period: from 4 days before surgery to 1 day after surgery 
• A treatment period: First dose, PO, starting 12 - 24 hours after completing skin wound closure, 
then BID for 35 ± 2 days for the subjects undergoing total hip replacement or 12 ± 2 days for 
the subjects undergoing total knee replacement. 
• A 30-day follow-up period starting the day after the last dose of study medication. 
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Figure 2.1 Study Design 
 
2.2 
Treatment Group Assignment 
Apixaban 2.5 mg bid.   
2.3 
Blinding and Unblinding 
Not applicable.   
3 
OBJECTIVES 
3.1 
Primary Objective 
To evaluate that oral administration of apixaban 2.5 mg twice a day for 2 weeks (for knee 
replacement subjects) or 5 weeks (for hip replacement subjects) is well tolerated in Indian subjects 
and produces an acceptable rate of ISTH major/CRNM bleeding. 
3.2 
Secondary Objectives  
To evaluate that oral administration of apixaban 2.5 mg twice a day for 2 weeks (for knee 
replacement subjects) or 5 weeks (for hip replacement subjects) produces an acceptable rate of the 
composite of VTE/all cause death. 
 
4 
ENDPOINTS 
4.1 
Primary Endpoint 
The primary study endpoint is a composite of International Society on Thrombosis and 
Haemostasis (ISTH) major bleeding/clinically relevant non-major bleeding (CRNM) in subjects 
undergoing elective total knee or hip replacement at the end of treatment + 2 days, where ISTH 
major bleeding is 
• Fatal or 
• Bleeding in a critical organ, such as brain, spine, eye, retroperitoneum, joint, heart sac, or 
skeletal muscle (and resulting in compartment syndrome), or 
Screening
Enrollment
Treatment Period
Follow-up
Period
2.5 mg BID 
apixaban
TKR – 2 weeks
THR – 5 weeks
30 days
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• Bleeding that results in a fall of hemoglobin of 2 g/dL or more or transfusion of 2 units or more 
of packed red cells or whole blood within 24 hours 
 
and CRNM bleeding is bleeding that 
 
• Is clinically acute and overt 
• Does not satisfy criteria as a major bleed but requires medical intervention, such as a visit to a 
physician’s office, emergency room, or urgent care center for epistaxis.  
4.2 
Secondary Endpoint 
The secondary endpoint will be: The composite of VTE/all cause death at the end of treatment + 
2 days, where VTE is the combination of deep vein thrombosis and non-fatal pulmonary embolism. 
 
5 
SAMPLE SIZE AND POWER 
The sample size of the study is determined by requirement of regulatory agency rather than 
statistical considerations. With 500 subjects in the apixaban arm and event rate of 4.36% for ISTH 
major or clinically relevant non-major bleeding, the width of the 95% CI for the event rate will be 
(2.6%, 6.2%) and width of the CI is 3.6%. 
 
6 
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES  
6.1 
Study Periods 
In all listings, summaries and statistical analyses, the term 'Intended Treatment Period' refers to 
the period that starts with the enrollment.  
In all listings, summaries and statistical analyses, the term 'Treatment Period' will refer to the 
period between the first administration of study medication (post-surgery oral apixaban) and 2 
days after the last administration of study medication (end of treatment). This period will be the 
basis for the summaries of safety and efficacy. 
In all listings, summaries and statistical analyses, the term “Follow-up Period” will refer to the 
period starting after the “Treatment Period” ended through 30 days after discontinuation of study 
drug (for treated subjects). 
6.2 
Treatment Regimens 
Safety and efficacy outcomes will be summarized according to the Treated group, which subjects 
who received at least one dose of study drug.  
6.3 
Populations for Analyses 
The following populations will be used for the analyses: 
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Enrolled Population  
The Enrolled Subjects population consists of all subjects who signed informed consent. 
Treated Population 
The treated population consists of all subjects who received at least one dose of study drug during 
the treatment period. In the treated population, subjects are categorized to the As Treated group. 
Efficacy Population  
Same as Treated Population. 
 
7 
STATISTICAL ANALYSES 
Type of surgery (knee surgery or hip surgery) will be included as subgroup factor in some of the 
efficacy (Section 7.5) and all safety summaries (Section 7.6) as well as when summarizing 
demographic and baseline characteristics (Section 7.3) and extent of exposure (Section 7.4).  
7.1 
General Methods 
Refer to Section 7.1 of the Core SAP for VTE Prevention for further details on statistical methods. 
7.2 
Study Conduct 
Significant protocol deviations will be identified for all subjects who are treated. 
7.3 
Study Population 
7.3.1 
Subject Disposition 
Refer to Section 7.3.1 of the Core SAP for VTE Prevention. 
7.3.2 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all subjects combined, using 
treatment data set. All summaries will be further tabulated by stratification factor of type of surgery 
(knee or hip). Continuous variables will be summarized using mean and standard deviation. 
Categorical variables will be summarized using relative frequency. 
Key demographic and baseline variables to be summarized include: age, gender, race, vital signs 
(systolic blood pressure, diastolic blood, pressure, and heart rate), medical history, knee or hip 
replacement surgery experience, intra-operative details, and post-surgical patient care 
characteristics. 
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7.4 
Extent of Exposure 
7.4.1 
Study Therapy 
Extent of exposure to the study drug is defined as the number of the days the subject is known on 
study drug. Summary to exposure to study drug will show the distribution of the number of days 
on drug, together with the mean days of exposure, by type of surgery (knee or hip).  
Treatment compliance (TC) will also be summarized by type of surgery (knee or hip).  
For each treated subject, treatment compliance with apixaban (BID) regimen is defined as 
follows:𝑇𝑇𝑇𝑇=
100∗number of tablets taken
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑡𝑡𝑡𝑡 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑∗2−𝑘𝑘% 
where 
 
k=0, if the first dose is given the day after surgery  
 
k=1, if the first dose is given on the day of surgery. 
 
In addition, time from the end of surgery to first post-operative dose of study medication will be 
summarized by type of surgery (knee or hip). 
7.4.2 
Prior and Concomitant Medications 
Refer to Section 7.4.2 of the Core SAP for VTE Prevention. 
 
7.5 
Efficacy 
The event rates and their 95% confidence intervals of composite of venous thromboembolism 
(VTE) and all cause death based on efficacy population will be summarized. Subgroup summary 
by surgery type (knee or hip) will also be conducted. 
7.6 
Safety 
Bleeding is the primary safety outcome measure. The event rate of adjudicated major bleeding or 
clinically relevant non-major bleeding events during the treatment period will be summarized. 
Subgroup summary for bleeding by surgery type (knee or hip) will also be conducted. 
The incidence of adverse events will be summarized for both the treatment and follow-up period 
by surgery type (knee or hip). Any post-dose marked abnormalities in clinical laboratory tests will 
be listed.  
All adverse events that are serious or that result in discontinuation of study therapy will be 
described in depth. 
7.6.1 
Adverse Events 
Refer to Section 7.6.2.1 in the Core SAP for VTE Prevention. 
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7.6.2 
Laboratory Data 
Refer to Section 7.6.2.2 in the Core SAP for VTE Prevention. Hemoglobin is the parameter which 
will be summarized.   
7.6.3 
Events of Special Interest  
Refer to Section 7.6.2.4 in the Core SAP for VTE Prevention.   
 
8 
CONVENTIONS 
8.1 
Safety Data Conventions 
Refer to Section 8.1 of the Core SAP for VTE Prevention.  
8.2 
Baseline Measurements 
Refer to Section 8.2 of the Core SAP for VTE Prevention.  
8.3 
Day Ranges for Analysis of Time Points 
Subjects do not always adhere strictly to the visit schedule timing in the protocol. The day ranges 
for the summary of laboratory measurements are defined in the following tables.    
Table 8.3A:  
Day Ranges for summary of Laboratory Measurements  
Nominal Visit 
Target Day 
Day Ranges  
Screening 
Pre-Surgery 1-14 
day 
Screening to < Enrollment 
Enrollment  
Pre-Surgery -4 day 
- 24 hours 
Enrollment to < start of surgery 
Hospital discharge 
Hospital discharge 
Day 2  to < End of treatment period 
 
8.4 
Multiple Measurements 
Refer to Section 8.4 of the Core SAP for VTE Prevention.  
 
9 
CONTENT OF REPORTS 
Refer to Section 9 of the Core SAP for VTE Prevention.  
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APPENDIX 1 
ANALYSIS OF SAFETY DATA - REFERENCE TO CT SOP 109 
 
The original GD SOP 12 in Core SAP is retired and replaced by CT SOP 109.  
 
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REFERENCES 
 
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