Conditions: Healthy Volunteers
Keywords: Antiretroviral Therapy Human Immunodeficiency Disease Drug-Drug Interactions Thrombosis Bleeding
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
Background:

Rivaroxaban and apixaban are blood thinners. People with HIV may need to take them to treat or prevent blood clots. The anti-HIV drug darunavir (DRV) can increase the amount of these blood thinners in the body. This can cause bleeding or other health problems. The drug cobicistat (COBI) is used to help anti-HIV drugs work better. Researchers want to give healthy people DRV combined with COBI to learn how it affects rivaroxaban or apixaban blood levels.

Objective:

To test blood levels of rivaroxaban or apixaban when taken with COBI and DRV/COBI.

Eligibility:

Healthy volunteers ages 18-65

Design:

Participants will be screened with:

Medical history

Physical exam

Fasting blood and urine tests. (Urine tests will be performed in females of child-bearing potential only)

Participants will have 8 visits; 3 are long (about 10-12 hours) and 5 are about 1 hour. They include:

Baseline and final visits:

Fasting blood and urine tests

Day 1 visit (long day):

Fasting blood and urine tests

Catheter placement: A needle will insert a small tube into the participant's arm vein. Blood will be drawn up to 10 times.

Dose of rivaroxaban or apixaban

Day 2 visit (short day):

Fasting blood tests

Dose of COBI

Participants will receive a bottle containing COBI tablets to take at home.

Day 7 (long day):

Fasting blood and urine tests

Catheter placement: A needle will insert a small tube into the participant's arm vein. Blood will be drawn up to 10 times.

Dose of rivaroxaban or apixaban

Dose of COBI

Day 8 (short day):

Fasting blood tests

Dose of DRV/COBI Participants will receive a bottle containing DRV/COBI tablets to take at home.

Day 13 (long day):

Fasting blood and urine tests

Catheter placement: A needle will insert a small tube into the participant s arm vein. Blood will be drawn up to 10 times.

Dose of rivaroxaban or apixaban

Dose of DRV/COBI

Day 14 (short day):

Fasting blood tests

Participants will take COBI tablets daily at home on days 3-6, and DRV/COBI on days 9 -12 during the study. They will record doses and side effects.

During the study, participants cannot:

Take most medications.

Drink alcohol, smoke, or vape

Engage in activities such as contact and extreme sports

Detailed description:
Rivaroxaban is a direct oral anticoagulant (DOAC) used for the prevention and treatment of various thromboembolic disorders. Predictable pharmacokinetic (PK) and pharmacodynamic (PD) properties, coupled with a few drug drug and food-drug interactions, distinguishes DOACs from a traditionally used anticoagulant, warfarin, allowing fixed dosing without routine coagulation monitoring. Patients with human immunodeficiency virus (HIV) are living as long as their HIV negative counterparts due to safe and efficacious antiretroviral therapy (ART). Persons with HIV are at higher risk for thromboembolic events and DOACs are a feasible option for anticoagulation in this population. However, there is a lack of drug interaction and safety data currently on the co-administration cobicistat (COBI)-boosted antiretroviral (ARV) regimens with rivaroxaban. Rivaroxaban is metabolized by cytochrome P450 isozyme (CYP) 3A4 and its absorption is modulated by permeability glycoprotein (P-gp), both of which are inhibited by the PK booster COBI. It is therefore possible that plasma concentrations of rivaroxaban may be significantly increased when co-administered together with COBI. This is of clinical concern as increased anticoagulant exposure may result in bleeding without the security of routine clinical monitoring. The purpose of this study is to determine the effects of steady state concentrations of COBI and darunavir (DRV)/COBI on the PK and PD of single oral doses of rivaroxaban.

Arms:
arm 1: Healthy participants received a single dose of rivaroxaban 10 mg orally on day 1 (phase 1) followed by cobicistat 150 mg once daily from days 2 - 7 and a single dose of rivaroxaban 10 mg on day 7 (phase 2). Participants received darunavir /cobicistat 800/150 mg once daily from days 8 - 13 followed by a single dose of rivaroxaban 10mg on day 13 (phase 3). Serial blood sampling was done on days 1, 7, and 13.

Interventions: intervention 1: Cobicistat intervention 2: Darunavir/Cobicistat intervention 3: Rivaroxaban
Intervention descriptions: intervention 1: Each tablet of Tybost contains 150 mg of cobicistat. intervention 2: Each tablet of Prezcobix contains 800 mg of darunavir and 150 mg of cobicistat. intervention 3: Each tablet of Xarelto contains 10 mg of rivaroxaban.

Protocol document:
Prot_SAP_000.pdf: 
CLOTRx.  Version 4.0   July 29, 2021 
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Impact of steady state Cobicistat and Darunavir/Cobicistat on the Pharmacokinetics and 
Pharmacodynamics of an Oral Anticoagulant (Rivaroxaban) in Healthy Volunteers 
(CLOTRx) 
 
NIH Protocol Number: 19-CC-0063 
 
Sponsored by:  
National Institute of Health (NIH) Clinical Center Pharmacy Department (CC-Pharm) 
National Institute of Allergy and Infectious Diseases (NIAID) 
Clinical Center Department of Laboratory Medicine (CC-DLM) 
 
 
Principal Investigator: 
Colleen Hadigan, MD, MPH 
Laboratory of Immunoregulation (LIR), NIAID 
Building 10, Room 11C103 
10 Center Dr 
Bethesda, MD 20814 
Phone: 301-594-5754 
Fax: 301-402-4097 
Email: hadiganc@niaid.nih.gov 
 
 
 
 
Version 4.0 
 
29 July 2021 
 
 
 
 


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TABLE of CONTENTS 
LIST OF ABBREVIATIONS ......................................................................................................... 5 
PROTOCOL SUMMARY .............................................................................................................. 7 
PRECIS ........................................................................................................................................... 9 
1 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................. 10 
1.1 
Background ................................................................................................................... 10 
1.2 
Direct Oral Anticoagulants ........................................................................................... 11 
1.2.1 
Rivaroxaban (Xarelto) ........................................................................................... 12 
1.3 
CYP3A4 and P-gp Inhibitors ........................................................................................ 13 
1.3.1 
Cobicistat (Tybost) ................................................................................................ 13 
1.3.2 
Darunavir (Prezista) ............................................................................................... 14 
1.4 
Scientific Rationale ....................................................................................................... 15 
2 
STUDY OBJECTIVES ......................................................................................................... 15 
2.1 
Primary Objective ......................................................................................................... 15 
2.2 
Secondary Objective ..................................................................................................... 15 
2.3 
Exploratory Objective ................................................................................................... 15 
3 
STUDY DESIGN .................................................................................................................. 15 
3.1 
Description of the Study Design ................................................................................... 15 
3.2 
Study Endpoints ............................................................................................................ 17 
3.2.1 
Primary Endpoints .................................................................................................... 17 
3.2.2 
Secondary Endpoints ................................................................................................ 17 
4 
STUDY POPULATION ....................................................................................................... 17 
4.1 
Rationale for Subject Selection ..................................................................................... 17 
4.2 
Recruitment Plan ........................................................................................................... 17 
4.2.1 
Recruitment of NIH Staff or Family Members of Study Team Members ................ 17 
4.3 
Subject Inclusion Criteria ............................................................................................. 18 
4.4 
Subject Exclusion Criteria ............................................................................................ 18 
4.5 
Justification for Exclusion of Special Populations ....................................................... 19 
4.5.1 
Exclusion of Pregnant Women ................................................................................. 19 
4.5.2 
Exclusion of Breastfeeding Women ......................................................................... 20 
4.5.3 
Exclusion of Children and Persons >65 Years-old ................................................... 20 
4.5.4 
Exclusion of Adults Who Cannot Consent ............................................................... 20 
5 
STUDY AGENT/INTERVENTIONS .................................................................................. 20 
5.1 
Disposition, Dispensation and Accountability .............................................................. 20 
5.2 
Formulation, Packaging and Labeling .......................................................................... 20 
5.3 
Assessment of Participant Compliance with Study Agents .......................................... 20 
5.4 
Study Agent Storage and Stability ................................................................................ 21 
5.5 
Preparation, Administration and Dosage of Study Agents ........................................... 21 
5.6 
Concomitant Medications and Procedures.................................................................... 21 
5.7 
Prohibited Medications and Procedures ........................................................................ 21 
6 
STUDY SCHEDULE ........................................................................................................... 21 
6.1 
End-of-Study Visit (7±3 days after administration of final study dose) ....................... 25 
6.2 
Early Termination Visit ................................................................................................ 25 
6.3 
Pregnancy and Follow-up Visit .................................................................................... 26 
7 
STUDY PROCEDURES/EVALUATIONS ......................................................................... 26 


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8 
POTENTIAL RISKS AND BENEFITS ............................................................................... 26 
8.1 
Potential Risks .............................................................................................................. 26 
8.1.1 
Rivaroxaban .............................................................................................................. 26 
8.1.2 
Cobicistat .................................................................................................................. 27 
8.1.3 
Darunavir/Cobicistat ................................................................................................. 28 
8.1.4 
Blood draw and IV catheter ...................................................................................... 28 
8.1.5 
Pharmacogenomic testing ......................................................................................... 28 
8.2 
Potential Benefits .......................................................................................................... 29 
9 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA ......... 29 
9.1 
Intended Use ................................................................................................................. 29 
9.2 
Storage .......................................................................................................................... 29 
9.3 
Tracking ........................................................................................................................ 29 
9.4 
Disposition at the Completion of the Protocol .............................................................. 29 
9.5 
Loss or Destruction ....................................................................................................... 29 
10 DATA SHARING PLAN ..................................................................................................... 29 
11 REMUNERATION PLAN FOR PARTICIPANTS ............................................................. 30 
12 ASSESSMENT OF SAFETY ............................................................................................... 30 
12.1 
Toxicity Scale ............................................................................................................... 30 
12.2 
Recording/Documentation and Reporting Adverse Events .......................................... 31 
12.3 
Reporting Procedures .................................................................................................... 32 
12.3.1 
Investigator Assessment of Adverse Events ......................................................... 32 
12.3.2 
Reporting to the Medical Monitor ........................................................................ 32 
12.3.3 
Reporting Procedures to the NIH IRB .................................................................. 33 
12.4 
Pregnancy ...................................................................................................................... 33 
12.5 
Type and Duration of the Follow-up of Participants after Serious Adverse Events ..... 33 
12.6 
Pausing Rules for An Individual Participant ................................................................ 33 
12.6.1 
Reporting a Pause ................................................................................................. 34 
12.6.2 
Resumption of a Paused Participant ..................................................................... 34 
12.6.3 
Discontinuation of Study Agent............................................................................ 34 
12.7 
Halting Rules for the Protocol ...................................................................................... 34 
12.7.1 
Reporting a Study Halt.......................................................................................... 34 
12.7.2 
Resumption of a Halted Study .............................................................................. 34 
12.7.3 
Discontinuation of Study Agent............................................................................ 34 
12.8 
Study Discontinuation ................................................................................................... 34 
12.9 
Premature Withdrawal of a Participant ......................................................................... 35 
12.10 
Replacement of Withdrawn Participants or Participants Who Discontinue Study 
Treatment .................................................................................................................................. 35 
13 SAFETY OVERSIGHT ........................................................................................................ 35 
13.1 
Safety Review and Communications Plan (SRCP) ...................................................... 35 
13.2 
Medical Monitor ........................................................................................................... 35 
14 STUDY MONITORING ...................................................................................................... 36 
15 STATISTICAL CONSIDERATIONS .................................................................................. 36 
15.1 
Primary Study Hypothesis ............................................................................................ 36 
15.2 
Secondary Study Hypothesis ........................................................................................ 36 
15.3 
Sample Size Justification .............................................................................................. 36 
15.4 
Description of the Analysis ........................................................................................... 37 


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16 ETHICS/PROTECTION OF HUMAN PARTICIPANTS ................................................... 38 
16.1 
Informed Consent.......................................................................................................... 38 
16.1.1 
Considerations for Consent of NIH Staff or Family of Study Team Members .... 38 
16.2 
Participant Confidentiality ............................................................................................ 38 
17 DATA HANDLING AND RECORD KEEPING ................................................................ 39 
17.1 
Data Capture and Management ..................................................................................... 39 
17.2 
Record Retention .......................................................................................................... 39 
 
LIST OF TABLES 
Table 1: Summary of Drug Interaction Studies with Rivaroxaban............................................... 13 
Table 2: Study Schedule and Procedures ...................................................................................... 22 
Table 3: Compensation Schedule.................................................................................................. 30 
Table 4: Toxicity Grading Scale for Total Bilirubin, According to the “Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Trials” ............ 31 
Table 5: Power and Sample Size (n) ............................................................................................. 37 
 
LIST OF FIGURES 
Figure 1: Study Schematic ............................................................................................................ 16 
 
LIST OF APPENDICES 
Appendix A: Scientific References ............................................................................................... 40 
Appendix B: Schedule of Procedures/Evaluations ....................................................................... 45 
Appendix C: Blood Volumes (mL) for Specimen Collection ...................................................... 47 
Appendix D: Study Initiation Calendars ....................................................................................... 48 
Appendix E: Xarelto® Prescribing Information ........................................................................... 49 
Appendix F: Tybost® Prescribing Information ............................................................................ 49 
Appendix G: Prezcobix® Prescribing Information ...................................................................... 49 
Appendix H: Prezista® Prescribing Information .......................................................................... 49 
 
 


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List of Abbreviations 
AE 
adverse event 
AF 
 
atrial fibrillation 
aPTT  
activated partial thromboplastin time 
ALT 
alanine transaminase 
APR 
Antiretroviral Pregnancy Registry 
ART 
antiretroviral therapy 
ARV 
antiretroviral 
AST 
aspartate transaminase 
AUC 
area under the concentration vs time curve 
AUC0-24hr 
area under the concentration vs time curve from 0 to 24 hours postdose 
AUC0-12hr 
area under the concentration vs time curve from time 0 to 12 hours postdose 
AUC0-∞ 
area under the concentration vs time curve from 0 to infinity; total drug exposure 
AUC0-tau 
area under the curve from 0 to the dosing interval 
AUEC0-24 
area under the effect curve from 0 to 24 hours 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
CBC/diff 
complete blood count with differential 
CC 
Clinical Center 
CL/F 
apparent oral clearance 
Cmax 
maximum total plasma concentration 
Cmin 
minimum total plasma concentration 
COBI 
cobicistat 
CPRU 
Clinical Pharmacokinetics Research Unit 
CrCl 
creatinine clearance 
CRIMSON 
Clinical Research Information Management System of the NIAID 
CYP 
cytochrome P450 isozyme 
DAIDS 
Division of AIDS 
DLM 
Department of Laboratory Medicine 
DOAC 
direct oral anticoagulant 
DOT 
directly observed therapy 
DRV 
darunavir 
DVT 
deep vein thrombosis 
eGFR 
estimate glomerular filtration rate 
ERmax  
maximum effect ratio over baseline 
FDA 
Food and Drug Administration 
FXa 
factor Xa 
GI 
gastrointestinal 
GMR 
geometric mean ratio 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HRPP 
Human Research Protections Program 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous 
LFTs  
liver function tests 


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LMWH 
low molecular weight heparin 
MAI 
 
medical advisory investigator 
MM 
 
medical monitor 
NIAID 
National Institute of Allergy and Infectious Diseases  
NIH 
National Institutes of Health 
OATP 
organic anion transporting polypeptides 
OHSRP 
Office for Human Subjects Research Protections 
OTC 
over-the-counter 
P-gp 
permeability glycoprotein 
PD 
 
pharmacodynamics 
PE 
 
pulmonary embolism 
PI 
 
principal investigator 
PK 
pharmacokinetic(s) 
PLT 
platelet 
PO 
oral(ly) 
PT 
 
prothrombin time 
QD 
 
once daily 
RECORD 
Prevention of Venous Thromboembolic Events in Patients Undergoing Major 
Orthopedic Surgery of the lower Limbs: Clinical Trial 
ROCKET-AF Prevention of Stroke and Systemic Embolism in Patients with non-valvular Atrial 
Fibrillation: Clinical Trial 
RTV  
ritonavir 
SAE 
serious adverse event 
SCr 
serum creatinine 
SRCP 
safety review and communication plan 
t½ 
terminal elimination half-life 
tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
UP 
unanticipated problem 
V/F 
apparent oral volume of distribution 
VKAs  
vitamin K antagonists 
VTE 
 
venous thromboembolism 
WNL  
within normal limits  
 
 


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Protocol Summary 
Full Title: 
Impact of steady state Cobicistat and Darunavir/Cobicistat on the 
Pharmacokinetics and Pharmacodynamics of an Oral 
Anticoagulant (Rivaroxaban) in Healthy Volunteers 
 
Short Title: 
CLOTRx 
 
Sample Size: 
N = 12  
 
Accrual Ceiling: 
N = 40 
 
Study Population: 
Healthy volunteers ages 18-65 years 
 
Accrual Period: 
3 years 
 
Study duration: 
Start date: 01/01/2019 
 
End date: 12/31/2022 
 
Total length of individual participation: 17 to 23 days 
 
Study Design: 
This is an open-label, fixed sequence, intrasubject drug-drug 
interaction study designed to evaluate the effect of CYP3A4/P-gp 
inhibition by cobicistat and darunavir/cobicistat on the 
pharmacokinetics (PK) and pharmacodynamics (PD) of 
rivaroxaban. The study will include 12 healthy adult volunteers. 
Subjects will receive study drugs sequentially as follows: 
Phase 1: a single dose of rivaroxaban on day 1 followed by serial 
PK/PD blood sampling 
Phase 2: cobicistat once daily (days 2 to 7), followed by single 
dose of rivaroxaban and serial PK/PD blood sampling on day 7 
Phase 3: darunavir/cobicistat once daily (days 8 to 13) followed 
by single dose of rivaroxaban and serial PK/PD blood sampling 
on day 13.  
 
Study Agent/ 
Intervention Description: 
Participants will receive the following: 
 
 
-  Rivaroxaban 10 mg by mouth  
 
 
 (3 doses on days 1, 7, and 13) 
 
 
-  Cobicistat 150 mg by mouth x 6 days (days 2 to 7) 
 
 
-  Darunavir/Cobicistat 800/150 mg by mouth x 6 days  
 
 
 (days 8 to 13) 
- PK/PD blood sampling will be performed on days 1, 7 
 and 13 
 
Primary Objective: 
To characterize the single dose PK of rivaroxaban alone and in 
combination with steady-state cobicistat or darunavir/cobicistat in 
healthy volunteers.  


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Secondary Objectives: 
(1) To characterize the PD (anti–factor Xa [FXa], activated partial 
thromboplastin time [aPTT], prothrombin time [PT]/international 
normalized ratio [INR]) of rivaroxaban alone and in combination 
with cobicistat or darunavir/cobicistat in healthy volunteers.  
(2) To evaluate the safety and tolerability of coadministration of 
rivaroxaban alone and in combination with cobicistat or 
darunavir/cobicistat in healthy volunteers.  
 
Exploratory Objective: 
To assess the role, if any, of gene polymorphisms (for enzymes 
involved in transportation and hepatic metabolism of study drugs) 
on the interaction between rivaroxaban and CYP3A4/P-gp 
inhibitors, cobicistat or darunavir/cobicistat. 
 
Primary Endpoint: 
Plasma area under the concentration vs time curve from 0 to 
24 hours and 0 to infinity (AUC0-24hr, AUC0-), maximum total 
plasma concentration (Cmax), time to maximum plasma 
concentration (tmax), terminal elimination half-life (t½), apparent 
oral clearance (CL/F), apparent oral volume of distribution (V/F), 
and minimum total plasma concentration (Cmin) for rivaroxaban. 
 
Secondary Endpoints: 
(1) Area under the effect curve for factor Xa, aPTT, and PT/INR 
from 0 to 24 hours (AUEC0-24), and the maximum effect ratio over 
baseline (ERmax).  
(2) AEs and abnormal laboratory values. 
 
 


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Precis 
Rivaroxaban is a direct oral anticoagulant (DOAC) used for the prevention and treatment of 
various thromboembolic disorders. Predictable pharmacokinetic (PK) and pharmacodynamic 
(PD) properties, coupled with a few drug-drug and food-drug interactions, distinguishes DOACs 
from a traditionally used anticoagulant, warfarin, allowing fixed dosing without routine 
coagulation monitoring. Patients with human immunodeficiency virus (HIV) are living as long as 
their HIV-negative counterparts due to safe and efficacious antiretroviral therapy (ART). Persons 
with HIV are at higher risk for thromboembolic events and DOACs are a feasible option for 
anticoagulation in this population. However, there is a lack of drug interaction and safety data 
currently on the co-administration cobicistat (COBI)-boosted antiretroviral (ARV) regimens with 
rivaroxaban. Rivaroxaban is metabolized by cytochrome P450 isozyme (CYP) 3A4 and its 
absorption is modulated by permeability glycoprotein (P-gp), both of which are inhibited by the 
PK booster COBI. It is therefore possible that plasma concentrations of rivaroxaban may be 
significantly increased when co-administered together with COBI. This is of clinical concern as 
increased anticoagulant exposure may result in bleeding without the security of routine clinical 
monitoring. The purpose of this study is to determine the effects of steady state concentrations of 
COBI and darunavir (DRV)/COBI on the PK and PD of single oral doses of rivaroxaban.  
 
 
 


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1 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
1.1 
Background  
It is estimated that more than 50% of individuals infected with human immunodeficiency virus 
(HIV) are over the age of 50 years.1 These patients have a near-normal life expectancy and as a 
result, they are experiencing aging-related comorbidities (e.g., atrial fibrillation [AF], stroke, 
etc.) and polypharmacy.2,3 In addition, HIV infection itself is characterized as a hypercoagulable 
condition, with estimated prevalence of thromboembolic events up to 10 times higher than in the 
general population.4–6 Thus, even the younger individuals living with HIV still remain at a high 
risk for developing thromboembolic events. 
Before the availability of direct oral anticoagulants (DOACs), warfarin, a vitamin K antagonist 
(VKA), has been the mainstay therapy in the prevention and treatment of thrombosis in 
individuals without cancer, including those living with HIV. For individuals with cancer, the 
American College of Chest Physicians recommends the use of low molecular weight heparin 
(LMWH) over warfarin.7 Cancer, just like HIV, is also a known hypercoagulable state, leading to 
an increased risk of venous thromboembolism (VTE), with 4- to 7-fold increased risk of VTE.8,9 
VTE frequency is estimated to be 4% to 20% depending on the cancer type.10 HIV infection has 
been associated with certain forms of cancer such as Non-Hodgkin’s and Hodgkin’s 
lymphoma.11 Thus, individuals living with HIV and cancer are at a far greater risk of developing 
thrombosis than those with HIV alone. As such, effective anticoagulant therapy is necessary, 
with minimal drug-drug interaction, ease of dosing, and administration. 
Warfarin, despite its long history of use, presents with many clinical challenges. It is associated 
with a risk of bleeding and requires close monitoring for signs and symptoms of bleeding—
including monitoring for international normalized ratio (INR) for dose adjustment.12,13 In 
addition, it is subject to clinically significant drug interactions with food and drugs, including 
commonly used antiretroviral (ARV) medications.14 On the other hand, LMWH requires daily 
self-injection that can limit adherence, especially in the elderly. Thus, challenges in the use of 
both warfarin and LMWH have elicited large interest in the utilization of DOACs, such as 
rivaroxaban, that have more predictable pharmacokinetics and can be effectively administered as 
a fixed dose without routine pharmacological (e.g., plasma drug levels) or laboratory monitoring 
(e.g., blood clotting time). Multiple studies have demonstrated that the DOACs are non-inferior 
to warfarin or LMWH in preventing thrombotic events.15–19 However, DOACs also carry a 
potential for increased risk of bleeding with increased drug exposure and it is therefore important 
to identify factors that could increase their exposure, especially concomitant medications that can 
inhibit enzymes and transporters involved in their metabolism and elimination respectively. In 
the ROCKET-AF study (Prevention of Stroke and Systemic Embolism in Patients with non-
valvular Atrial Fibrillation) comparing the efficacy of rivaroxaban (n=7111) vs. warfarin 
(n=7125), the rate of major bleeds and non-major clinically relevant bleeds were 3.6%/year vs. 
3.5%/year (p=0.58), and 11.8%/year vs. 11.4%/year (p=0.35) respectively. A factor Xa reversal 
agent, andexanet alfa (AndexXa) was recently approved in May 2018 by the Food & Drug 
Administration (FDA) for patients treated with rivaroxaban or other DOACs when reversal of 
anticoagulation is needed due to life-threatening or uncontrolled bleeding.20,21 As such, the use of 
rivaroxaban is expected to further increase as clinicians may feel more comfortable at 
prescribing this DOAC with an approved antidote.  


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While new developments of efficacious anticoagulants exist, concerns for drug-drug interaction 
in patients taking pharmacokinetic (PK)-boosted HIV protease inhibitors, such as 
darunavir/cobicistat (DRV/COBI), still remain. Rivaroxaban is a substrate of CYP3A4, CYP2J2, 
permeability glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Prescribing 
information for rivaroxaban recommends a 50% and avoidance22 when taken concomitantly with 
strong dual CYP3A4 and P-gp inhibitors. These recommendations are based on drug interaction 
data using index inhibitors ketoconazole and ritonavir (RTV). COBI is a strong dual CYP3A4 
and P-gp inhibitor and is expected to significantly increase the plasma concentrations of 
rivaroxaban when co-administered together. COBI and RTV inhibit CYP3A4 with similar 
magnitude, however, they differ in their potential to inhibit P-gp, with COBI being the more 
potent inhibitor.23  
Available drug-drug interaction data between rivaroxaban and RTV describe a 2.5-fold increase 
in rivaroxaban exposure.24 However, it should be noted that RTV was dosed at 600 mg twice 
daily (BID) in these healthy volunteers, a dose that is higher than the recommended booster dose 
(100 mg) for protease inhibitor–containing regimens. RTV has been described to exhibit dose- 
and exposure-dependent inhibition with a combination of reversible and time-dependent 
mechanisms25. Through this inhibition mechanism, a lower dose of 100 mg is expected to yield a 
potential difference in rivaroxaban PK compared to the 600-mg BID dose. Additionally, RTV 
inhibits both P-gp and BCRP efflux transporters, and it is unclear whether or not its inhibition is 
also dose-dependent. Of note, there are no studies that have examined the PK interaction 
between rivaroxaban and COBI.   
We chose to study rivaroxaban not only because it is one of the most frequently prescribed as of 
2016,20 but also due to the general lack of PK data on the co-administration of this DOAC with 
COBI and COBI boosted DRV. In addition, rivaroxaban will be going generic in 2021, 
potentially making it a more attractive DOAC option for prescribers. In this study, rivaroxaban 
10-mg will be studied, as this is the clinical dose used. Additionally, rivaroxaban 10 mg is the 
commonly used dose in healthy volunteer PK studies. Higher doses of rivaroxaban have been 
used in healthy volunteer PK studies, and have been tolerable with mild to moderate AEs.  
The aims of this study include:  
1) To characterize the PK of rivaroxaban alone and in combination with a) COBI and b) 
DRV/COBI;  
2) To characterize the PD of rivaroxaban alone and in combination with a) COBI and b) 
DRV/COBI; 
3) To explore the potential influence if any, of gene expression on the interaction between 
DOACs (rivaroxaban) and strong dual CYP3A4/P-gp inhibitors (COBI and DRV/COBI). 
Genes of interest are those associated with enzymes and transporters involved in the 
metabolism and elimination of study drugs.  
1.2 
Direct Oral Anticoagulants 
In the coagulation cascade, factor Xa directly converts prothrombin to thrombin through the 
prothrombinase complex, leading to the formation of fibrin clot formation and activation of 
platelets (PLTs) by thrombin.  


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1.2.1 Rivaroxaban (Xarelto) 
Rivaroxaban is a potent and highly selective oral direct factor Xa inhibitor, indicated for the 
treatment and prevention of thrombosis. Rivaroxaban is FDA approved for (1) reducing the risk 
of stroke and systemic embolism in patients with nonvalvular AF, (2) for the treatment of deep 
venous thrombosis (DVT) and pulmonary embolism (PE), (3) for reducing the risk of recurrence 
of DVT and PE, and (4) for prophylaxis of DVT, which may lead to PE in patients undergoing 
knee or hip replacement surgery. For AF, the recommended dosage is 20 mg once daily, or 15 
mg for patients with creatinine clearance (CrCl) of 15-50 mL/min. For treatment of DVT/PE, the 
recommended dose is 15 mg BID with food for the first 21 days, followed by 20 mg once daily 
with food for the remainder of the treatment period. For long-term reduction in the risk of 
recurrence of DVT and PE, the recommended dose is 10 mg once daily. The bioavailability of 
rivaroxaban is dose dependent, with the 10-mg dose having a bioavailability of 80%-100%, with 
or without food. The solubility of rivaroxaban is rate limiting beyond 15 mg and therefore it is 
recommended that doses beyond 15 mg be administered with food. In fasted conditions, the 
bioavailability of 20-mg dose is 66%. Rivaroxaban area under the concentration vs time curve 
(AUC) and maximum total plasma concentration (Cmax) were dose proportional, independent of 
food up to 10 mg. Under fasting conditions, AUC and Cmax for the 15-mg and 20-mg doses 
increased with dose, but were less than dose proportional.26 However, AUC and Cmax were dose 
proportional for rivaroxaban doses of 10 mg, 15 mg, and 20 mg in the fed state. In addition, there 
was no relevant accumulation observed in a multiple dose escalation study,27 indicating that 
rivaroxaban concentrations after a single dose can be considered representative for steady-state 
concentrations. The peak plasma concentration is achieved approximately 2-4 hours following 
oral intake, with a terminal elimination half-life (t½)of 5-9 hours in healthy subjects ages 
20-45 years old, and 11-13 hours in the elderly (ages 60-76). Rivaroxaban is eliminated both by 
renal and non-renal pathways, with 36% of unchanged drug recovered in the urine, and 7% in the 
feces. Non-renal metabolism includes CYP3A4/5 (18%), 2J2 (14%), and hydrolysis (14%), with 
no active circulating metabolites. It is a substrate of the efflux transporters P-gp and BCRP. The 
product label recommends that concomitant use of rivaroxaban with strong dual P-gp and 
CYP3A4 inhibitors should be avoided.22 Rivaroxaban does not inhibit or induce CYP450 
enzymes or the drug transporters. 
Maximum inhibition of factor Xa (FXa) occurred 1-4 hours after administration of rivaroxaban 
1.25-80 mg, with the half-life for the biological effect of 6-7 hours. After 24 hours, FXa 
activities had not returned to baseline for doses above 5 mg. Inhibition of FXa activity was found 
to be dose dependent over a dose range of 5-80 mg. Inhibition of factor Xa activity and 
prolongation of prothrombin time (PT) were also strongly correlated with plasma concentrations 
(r=0.949, r=0.935, respectively).27 In addition, concentration-dependent changes in other PD 
measures such as PT and prothrombinase-induced clotting time were observed. PT 
measurements increased linearly with rivaroxaban concentrations, and this relationship was 
similar in both healthy subjects and patients with non-valvular AF. Increase in PT resulted in an 
increase in major bleeding events, while the probability of ischemic stroke was found to be 
independent of PT.20  
Rivaroxaban exposure in elderly subjects is generally higher than that in younger subjects, 
without relevant changes in Cmax,27,28 a finding also reported in a previous study.29 Increase in 
AUC (1.5-fold higher) in the elderly was largely due to reduced renal function, however, dose 
adjustment is not required based solely on age.22,29 Similar increases in PD markers were 


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observed (factor Xa activity and PT) as it is expected with the well-established correlation 
between rivaroxaban plasma concentrations and both factor Xa activity and PT prolongation. 
Extremes in body weight (<50 kg or >120 kg) had a less than 25% effect on the PK of 
rivaroxaban and did not require a dose adjustment.22 
Refer to section 8.1.1 (Potential Risks of rivaroxaban) for more information on the side effects of 
rivaroxaban. 
1.2.1.1 Select Drug Interaction Studies Between Rivaroxaban and Dual CYP3A4/P-gp 
Inhibitors 
 
Table 1: Summary of Drug Interaction Studies with Rivaroxaban 
Concomitant Drug 
Change in 
rivaroxaban PK 
Change in 
rivaroxaban PD 
Ketoconazole 200 mg PO daily days 1-4. 
Rivaroxaban 10 mg PO day 4. 
N=1224 
Cmax: 53% 
AUC: 82% 
CL/F: 45% 
t1/2:  22 % (5.7 hrs) 
Not measured 
Rivaroxaban 10 mg PO daily days 1-10. 
Ketoconazole 400 mg PO daily days 6-10. 
N=2024 
Cmax: 72% 
AUC: 158% 
CL/F: 61% 
CLRS: 44% 
t1/2:  35% (6.5 hrs) 
Not measured 
Rivaroxaban 10 mg PO days 1 & 8. 
Ritonavir 600 mg PO BID days 3-8 
N=18 (12 for PK analysis)24 
Cmax: 55% 
AUC: 153% 
CL/F: 60% 
CLRS: 82% 
t1/2:  21% (6.9 hrs) 
Not measured 
 
1.3 
CYP3A4 and P-gp Inhibitors 
1.3.1 Cobicistat (Tybost) 
COBI is a PK enhancer used in combination with certain ARV drugs to increase their exposure 
and peak plasma concentrations, and prolong half-life. COBI has no activity against HIV.30 It is 
primarily metabolized by CYP3A4, with minor contribution by CYP2D6. The t½ of COBI is 3 to 
4 hours, with 86.2% excreted in feces and 8.2% in urine. It is a potent inhibitor of CYP3A4 and 
P-gp.30 In addition, COBI inhibits BCRP, organic anion transporting polypeptides (OATP1B1, 
OATP1B3)30 responsible for drug uptake, and MATE1, a transporter involved in the tubular 
secretion of creatinine.31 Consequently, a modest increase in SCr (not more than 0.4 mg/dL) is 
observed when patients are started on a COBI-based therapy. However, this modest decline in 
estimated glomerular filtration rate (eGFR) does not affect actual renal glomerular function.30 Its 
inhibition properties allow for less frequent dosing, lower pill burden, reduced variability of 
systemic drug exposure, and improved drug efficacy.32 When co-administered with CYP3A4 
and/or P-gp substrates (victim), COBI (perpetrator) is expected to increase the concentration of 
the victim drug. COBI has been shown to have limited effect on activating pregnane X receptor, 
which regulates expression of metabolizing enzymes, and thus induction of these enzymes is 


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unlikely,33 a phenomenon observed with the other PK booster, ritonavir. Currently COBI, at a 
dose of 150 mg, is used to boost the plasma concentrations of the protease inhibitors darunavir, 
atazanavir, and the integrase inhibitor elvitegravir. It is available as a co-formulation with 
atazanavir (Evotaz), darunavir (Prezcobix and Symtuza [in combination with other 
ARVs]), and elvitegravir (as Genvoya and Stribild in combination with other ARV agents). It 
is also available as a single agent (Tybost). Refer to section 8.1.2 (Potential Risks of 
Cobicistat) for more information on the side effects of COBI. 
1.3.2 Darunavir (Prezista) 
DRV (Prezista) is an HIV protease inhibitor approved by the FDA in 2006. It is also available 
as a fixed dose combination with COBI (DRV/COBI 800/150 mg), with the brand name 
Prezcobix, approved in 2015, and DRV/COBI/tenofovir alafenamide/emtricitabine 
(Symtuza, 2018). In combination with other ARVs, it is indicated for the treatment of HIV-1 
infection in adults.34 DRV is chiefly metabolized by CYP3A4, with minor contribution by 
CYP2D6. Following oral administration, maximum plasma concentration is achieved within 
approximately 4 to 4.5 hours for DRV and 4 to 5 hours for COBI, under fed conditions.35 The t½ 
of DRV and COBI are 7 and 4 hours, respectively when administered together. Both DRV and 
COBI are bound to plasma protein, approximately 95% and 97% to 98%, respectively. Both 
drugs are eliminated via renal and non-renal pathways. Renal elimination accounts for 13.9% 
and 8.2% for DRV and COBI respectively. Non-renal elimination, mainly fecal, accounts for 
79.5% and 86.2% for DRV and COBI respectively. DRV is both a substrate for and a modulator 
of P-gp. Some studies have demonstrated that DRV is an inhibitor, with P-gp inhibition similar 
to that of verapamil, a known moderate dual CYP3A4/P-gp inhibitor.36,37 Other studies have also 
shown that it is capable of inducing P-gp.38,39 COBI is strong dual inhibitor of CYP3A4 and 
P-gp. Subsequently, co-administration of DRV/COBI with substrates of CYP3A4 and P-gp may 
be of significant clinical concern.  
Prior to the approval of Prezcobix, DRV was coadministered with RTV (DRV/RTV) and 
COBI separately. In clinical trials and post-marketing surveillance of DRV/RTV, the most 
frequent AEs occurring in ≥5% of individuals included diarrhea, nausea, rash, headache, 
abdominal pain, and vomiting.35 Long-term studies with co-formulated DRV/COBI have shown 
similar AEs to those observed with DRV/RTV and COBI alone.35,40 In short-term PK studies, 
DRV/COBI has been well tolerated, with similar AEs to those reported in long-term clinical 
studies.41,42 Mild-to-moderate rash occurred within the first four weeks of starting therapy, but 
resolved with continued administration.35 Warnings with the use of DRV/COBI include 
drug-induced hepatitis (0.5%), liver failure (notably in patients with pre-existing liver 
dysfunction), severe skin reactions accompanied by fever and/or transaminase elevation (0.4%), 
Stevens-Johnson Syndrome (<0.1%), and elevation of SCr due to inhibition of tubular secretion 
by COBI.35 This increase in SCr is not associated with an actual decrease in renal function. 
However, patients who experience an increase over 0.4 mg/dL from baseline should be 
monitored. 
In the 3rd phase of this study, the combination product, DRV/COBI will be used.  
Refer to section 8.1.3 (Potential Risks of Darunavir/Cobicistat) for more information on the side 
effects of DRV/COBI. 


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1.4 
Scientific Rationale 
COBI is a strong dual inhibitor of CYP3A4 and P-gp and is expected to increase the plasma 
concentrations of rivaroxaban. COBI is used to boost the plasma concentrations of protease 
inhibitors DRV and atazanavir, and integrase strand transfer inhibitor elvitegravir. To date, the 
impact of COBI, alone or in combination with other ARVs, on the PK of rivaroxaban has not 
been studied. Hence, the purpose of this study is to determine the magnitude of change in 
exposure of rivaroxaban when given alone and in combination with COBI and DRV/COBI in 
healthy volunteers, and to further determine if this change is clinically relevant to require a dose 
adjustment. In addition, the PK and PD of rivaroxaban will be characterized. DRV was chosen to 
be studied as it the preferred protease inhibitor per the DHHS ARV guidelines.34 Elvitegravir is 
not an inhibitor of CYP3A4 nor P-gp, and is therefore not expected to interact with rivaroxaban, 
and thus will not be studied. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To characterize the PK of single-dose rivaroxaban when administered alone and in combination 
with COBI or DRV/COBI in healthy volunteers.  
2.2 
Secondary Objective 
1. To characterize the PD of rivaroxaban alone and in combination with COBI or 
DRV/COBI in healthy volunteers. 
2. To assess safety and tolerability of rivaroxaban in combination with COBI or DRV/COBI 
in healthy volunteers. 
2.3 
Exploratory Objective 
To explore the potential influence, if any, of gene expression (genes associated with CYP450 
enzymes and drug transporters) on the interaction between rivaroxaban and strong dual 
CYP3A4/P-gp inhibitors (COBI, DRV/COBI) 
3 
STUDY DESIGN 
3.1 
Description of the Study Design 
This is an open-label, non-randomized, three-period, fixed sequence, drug-drug interaction PK 
study in healthy volunteers >18 years of age. The study will evaluate the impact of steady state 
concentrations of COBI and DRV/COBI on the PK and PD of rivaroxaban. A schematic of the 
study design is presented in Figure 1. This study will involve administering these drugs to 
12 volunteers participating in 3 phases as follows. 
Rivaroxaban 10 mg PO, single dose (days 1, 7, 13), COBI 150 mg PO daily (days 2 to 7), 
DRV/COBI 800/150 mg PO daily (days 8 to 13). 
Phase 1 consists of administration of rivaroxaban alone on day 1, with intense PK/PD sampling. 
Phase 2 consists of administration of COBI alone for a period of 5 days, then followed by co-
administration of rivaroxaban and COBI on the 7th day in addition to intense PK/PD sampling. 
Administration of COBI alone for 5 days prior to co-administration with rivaroxaban allows for 
achievement of steady-state COBI plasma concentrations, maximum enzyme inhibition, and 
sufficient time for rivaroxaban to wash off. Enzyme inhibition is regarded as an almost 
instantaneous effect, with maximum enzyme inhibition observed after 2 days of dosing.43 


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Immediately following phase 2, subjects will be administered DRV/COBI in phase 3 for 5 days, 
then in combination with rivaroxaban on day 13 with intense PK/PD sampling. Transition from 
phase 2 to phase 3 does not require a wash-out period. Adequate time spacing between the single 
doses of rivaroxaban is necessary to ensure that the anticoagulant are sufficiently eliminated. The 
t½ for rivaroxaban when administered alone is 5.7 to 16.3 hours when administered in 
combination with strong CYP3A4/P-gp inhibitors. As such, 5 half-lives (4 days) would be 
adequate for >97% drug elimination. DRV has a half-life of 7 hours when co-administered with 
COBI. It takes ~5 half-lives for a drug to achieve steady state. Thus, administering DRV/COBI 
for 6 days is sufficient to achieve steady state. Participants will undergo periodic serial PK blood 
draws on days 1, 7, and 13. Matched PD parameters will also be collected on the same days. 
Rivaroxaban, when dosed orally once daily as per the FDA label, reaches tmax at 2 to 4 hours 
postdose. As such, frequent sampling is necessary to closely capture tmax value.  
Figure 1: Study Schematic 
 
 
Study Timeline 
Screening: Days -89 to 0 
Baseline visit: Days -6 to 0 
PK visits: Days 1, 7, 13  
• Blood samples for plasma rivaroxaban PK: at times 0 (predose), 1, 2, 3, 4, 6, 8, 10, and 
24 hours postdose. Rivaroxaban is dosed once a day in subjects. It has linear PK 
properties, which can also predict PK parameters in multiple dosing. 
• Safety labs drawn with predose sample on days 1, 7, and 13 
End-of-study-visit: 7±3 days after administration of final study dose 
Total study duration (excluding screening): 17 to 23 days  
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Study Day
COBI 150mg
DRV/COBI 800/150mg
Rivaroxaban 10 mg
24 hr
PK
24 hr
PK
Trough
Trough
Trough
24 hr
PK
Phase 2
Phase 3
Phase 1


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3.2 
Study Endpoints  
3.2.1 Primary Endpoints 
The following are the primary endpoints for rivaroxaban:  
• AUC0-∞,  
• AUC0-24,  
• Cmax, 
• tmax,  
• t½,  
• CL/F, 
• V/F, 
• Cmin. 
3.2.2 Secondary Endpoints 
• The PD parameters of interest are: 
o AUEC0-24 for FXa, aPTT, and PT/INR 
o ERmax for FXa, aPTT, and PT/INR 
• AEs and abnormal laboratory values, as graded according to the Division of AIDS 
(DAIDS) AE and the Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Trials AE table (total bilirubin only). 
4 
STUDY POPULATION 
4.1 
Rationale for Subject Selection 
Healthy volunteers will be studied, as opposed to patients with HIV infection, in order to 
eliminate the influence of confounding variables (medications, HIV infection, etc.) on our study 
results. In addition, HIV patients are often on concomitant medications, which may interact with 
the study drugs being examined, and thus the final interpretation of study results could be 
affected.  
4.2 
Recruitment Plan 
This study is being conducted at a single site, the National Institutes of Health (NIH) Clinical 
Center (CC). Up to 40 participants will be screened for a total of up to 12 healthy, HIV-negative 
volunteers to enroll and complete this open-label study. Participation of all ethnic groups and 
genders will be actively encouraged. This will be done through the Office of Patient 
Recruitment, which recruits participants for volunteer studies conducted at the NIH CC. There is 
an active effort to recruit minorities and women through outreach programs in the Washington, 
DC metropolitan area. This study is not designed to assess the influence of gender, age, and/or 
ethnicity on the drug-drug interaction (if observed) between oral anticoagulants (rivaroxaban) 
and COBI or DRV/COBI. 
4.2.1 Recruitment of NIH Staff or Family Members of Study Team Members  
NIH staff and family members of the study team may be enrolled in this study as this population 
meets the study entry criteria. Neither participation nor refusal to participate in the research will 
have an effect, either beneficial or adverse, on the participant’s employment or position at the 
NIH. 


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Every effort will be made to protect participant information, but such information may be 
available in medical records and may be available to authorized users outside of the study team 
in both an identifiable and unidentifiable manner. 
The NIH investigator will provide and request that the NIH staff member review the Frequently 
Asked Questions (FAQs) for Staff Who are Considering Participation in NIH Research and the 
Leave Policy for NIH Employees Participating in NIH Medical Research Studies (NIH Policy 
Manual 2300-630-3). Considerations for consent of staff is described in section 16.1.1. 
4.3 
Subject Inclusion Criteria 
A subject will be considered eligible for this study only if all of the following criteria are met: 
1. Adults between the ages of 18 to 65 years. 
2. Body mass index between 18 to 30 kg/m2. 
3. Judged to be healthy based on medical history, physical examination, vital signs and 
clinical laboratory tests (liver function tests (LFTs: alanine transaminase [ALT], aspartate 
transaminase (AST), total bilirubin ≤ upper limit of normal [ULN] (with the exception of 
participants with Gilbert’s syndrome); albumin within normal limits (WNL)], 
eGFR>90 mL/min/1.73 m2, PLT>150,000/µL, hemoglobin (Hgb)>12 g/dL, aPTT≤ULN, 
PT≤ULN, INR≤ULN. 
4. Subject agrees to storage of specimens for future research. 
5. Negative serum or urine pregnancy test for females of child-bearing potential. 
6. For female subjects, willing to avoid pregnancy by (a) practicing abstinence or (b) using 
effective non-hormonal and/or barrier methods of birth control, as well as avoid breast 
feeding or providing breast milk to infant during the study period. (baseline visit up to 
end of study day 20±3) 
7. Willing to avoid engaging in activities such as contact sports, including extreme sports, 
that may increase the risk of bleeding through body injury or bruising, during the study 
period (baseline visit up to end of study day 20±3) 
8. Willingness to forgo drinking alcohol during the study period (baseline visit up to end of 
study day 20±3) 
9. Able to provide consent. 
4.4 
Subject Exclusion Criteria 
A subject will be ineligible for this study if one, or more, of the following criteria are met: 
1. HIV infection, as determined by standard serologic or virologic assays for HIV infection. 
2. Laboratory evidence of active or chronic hepatitis A, B or C infection. 
3. History or presence of any of the following:  
a. any major medical conditions that requires daily frequent medication or potentially 
impairs medication absorption, metabolism and elimination 
b. any other condition that may interfere with the interpretation of the study results, or 
not be in the best interest of the subject in the opinion of the Investigator.  
4. Current participation in an ongoing investigational drug protocol or use of any 
investigational drug within 30 days (based on last dose received) prior to receipt of any 
study drugs/medications. 
5. History or presence of the following: 
a. bleeding/hematologic disorders (e.g., anemia, hemophilia, etc.),  


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b. serious/major bleeding event (intracranial, gastrointestinal (GI), as assessed by 
subject interview), or 
6. current increased risk of bleeding  
7. for female subjects, menorrhagia 
8. Planned invasive or surgical procedure within (prior to or following) 28 days of study 
participation. 
9. Therapy with any prescription, over-the-counter, herbal, or holistic medications, 
including hormonal contraceptives by any route, within 5 half-lives of the agent prior to 
receipt of any study medications will not be permitted with the following exception: 
Intermittent or short-course therapy (<14 days) with prescription, vaccines or over-the-
counter medications will be reviewed by investigators on a case-by-case basis for 
potential drug interactions.  
10. Inability to obtain venous access for sample collection. 
11. Inability to swallow whole capsules and/or tablets. 
12. Pregnant female. 
13. Breastfeeding female. 
14. The presence of persistent diarrhea or malabsorption that could interfere with the 
subject’s ability to absorb drugs. 
15. Illicit drug or alcohol use 
16. Use of nicotine-containing tobacco products, including cigarettes, vaping and chewing 
tobacco. 
17. Known hypersensitivity to rivaroxaban, COBI, or DRV. 
18. History of documented hypersensitivity or allergy to sulfa. 
19. Organ transplant recipient. 
Co-enrollment guidelines: Co-enrollment in other trials is restricted, other than enrollment on 
observational studies. Study staff should be notified of co-enrollment as it may require the 
approval of the investigator.  
4.5 
Justification for Exclusion of Special Populations 
4.5.1 Exclusion of Pregnant Women 
Pregnant people are excluded from this study to reduce the confounding effects of physiological 
changes during pregnancy on PK parameters of interest. Pregnant women may also develop 
anemia as a result of frequent PK blood draw. Furthermore, the effects of rivaroxaban on the 
developing human fetus have not been well established. There are no adequate and well-
controlled studies of rivaroxaban in pregnant women. Animal studies show that rivaroxaban 
crosses the placenta.22  
Prezcobix is not recommended during pregnancy due to substantially lower exposures of DRV 
and COBI during pregnancy. In a clinical trial of 7 pregnant women receiving Prezcobix in 
combination with a background regimen, there were no new clinically relevant safety findings 
compared with known safety profile of Prezcobix in HIV-1 infected adults. There is insufficient 
data with Prezcobix in pregnant individuals from the Antiretroviral Pregnancy Registry (APR). 
DRV/RTV in combination with a background regimen is one of the recommended HIV regimens 
for pregnant women at a dose of DRV/RTV 600/100 mg BID or 800/100 mg once daily (QD), 
depending on certain clinical scenarios. Following exposure of darunavir-containing regimens 
during pregnancy, there was no difference in rate of overall birth defects for darunavir (2.7%) 


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compared with the background rate for major defects of 2.7% in a U.S reference population of 
the Metropolitan Atlanta Congenital Defects Program. Studies in animals did not show evidence 
of embryotoxicity or teratogenicity.  
There are insufficient numbers of pregnancies with exposure to cobicistat that have been 
reported to the APR to estimate the rate of birth defects. In pregnant rats, increases in 
post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 
125 mg/kg/day of COBI, while no malformations were noted at doses up to 125 mg/kg/day of 
COBI. When COBI was administered to pregnant rabbits, no maternal or embryo/fetal effects 
were noted at 100 mg/kg/day, which was a 3.8-times higher systemic exposure than human 
exposures at the recommended daily dose of COBI. 
4.5.2 Exclusion of Breastfeeding Women 
Because there is an unknown but potential risk for AEs in nursing infants secondary to exposure 
of the mother with rivaroxaban, breastfeeding participants are excluded from study participation. 
4.5.3 Exclusion of Children and Persons >65 Years-old  
This study intends to investigate the PK/PD properties and safety profiles of agents in an adult 
population, as opposed to children, as age-related metabolic and transport processes in children 
differ from those of adults. The safety and effectiveness of rivaroxaban has not been established 
in the pediatric population.22 Additionally, there is greater than minimal risk, with no benefit in 
the pediatric population. 
As in children, changes in metabolic processes as a result of aging may confound findings from 
participants older than 65 years. As this is a preliminary study, there is no potential benefit as a 
population to justify their participation. However, future investigators may include this 
population as well. 
4.5.4 Exclusion of Adults Who Cannot Consent 
Adults who are unable to provide informed consent are excluded from enrolling in this study. If a 
participant permanently loses the capacity to provide ongoing consent, then they will be 
withdrawn from the study (section 12.9). 
5 
STUDY AGENT/INTERVENTIONS 
5.1 
Disposition, Dispensation and Accountability 
Study agents will be distributed and accounted for by the NIH pharmacy according to standard 
pharmacy procedures. 
5.2 
Formulation, Packaging and Labeling 
Each bottle will be individually labeled with the patient identification number, dosing 
instructions, recommended storage conditions, the name and address of the manufacturer, and 
that the agent should be kept out of reach of children. 
5.3 
Assessment of Participant Compliance with Study Agents 
Participants will receive a memory aid card to log their doses of COBI and DRV/COBI, as well 
as to record AEs between study visits. This memory aid card will not be used as a source 
document. Each participant will receive telephone contact to remind them of appropriate 


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adherence and/or of upcoming appointments. Additionally, participants will be instructed to 
bring all study agent bottles to each study visit for pill count. 
5.4 
Study Agent Storage and Stability 
All study agents should be stored and dispensed from the NIH CC Pharmacy according to 
standard pharmacy procedures.   
5.5 
Preparation, Administration and Dosage of Study Agents 
Participants will receive once-daily dose of COBI (Tybost) 150 mg for 6 days (days 2 to 7) and 
once-daily dose of DRV/COBI (Prezcobix) 800/150 mg for 6 days (days 8 to 13). Participants 
will also receive single doses of rivaroxaban (Xarelto) 10 mg on days 1, 7, and 13 at the day 
hospital. 
Each tablet of Xarelto (Janssen Pharmaceuticals, Inc [Titusville, New Jersey]) contains 10 mg of 
rivaroxaban. Participants will be given rivaroxaban with food at 0800±2 hours on days 1, 7, and 
13 at the day hospital. 
Each tablet of Tybost (Gilead Sciences, Inc [Foster City, CA]) contains 150 mg of COBI. 
Participants will be instructed to take one tablet daily at the same time (0800±2 hours) every day 
with food at home on non-PK/PD days. At the 24-hour PK visit day, participants will be 
instructed to bring their study agent supply to the NIH Day Hospital or OP-8 Infectious Diseases 
Clinic. 
Each tablet of Prezcobix (Janssen Pharmaceuticals, Inc [Titusville, New Jersey]) contains 
800 mg of DRV and 150 mg of COBI. Participants will be instructed to take one tablet daily at 
the same time (0800±2 hours) every day with food at home on non-PK/PD days. At the 24-hour 
PK visit day, participants will be instructed to bring their study agent supply to the NIH Day 
Hospital or OP-8 Infectious Diseases Clinic. 
5.6 
Concomitant Medications and Procedures 
All concomitant prescription and nonprescription (including over-the-counter [OTC]) 
medications taken during study participation will be recorded in the Clinical Research 
Information Management System of the NIAID (CRIMSON). For this protocol, a prescription 
medication is defined as a medication that can be prescribed only by a properly 
authorized/licensed clinician. 
5.7 
Prohibited Medications and Procedures 
To minimize potential drug interactions or AEs in healthy volunteers, therapy with any 
prescription, OTC, herbal, or holistic medications, except for occasional use of acetaminophen 
(no more than 2 g/24 hours), loperamide, or antihistamines (on non-PK/PD days), will not be 
permitted throughout the study period (baseline visit up to end of study visit Day 20±3) unless 
discussed with and approved by the principal investigator (PI). In addition, subjects are not 
allowed to drink alcohol during the study period (baseline visit up to end of study visit 
Day 20±3). 
6 
STUDY SCHEDULE 
A flowchart of the study schedule is provided in Table 2. A table of the study schedule is 
provided in Appendix B, blood volumes are listed in Appendix C, and study initiation calendars 
in Appendix D.  


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Table 2: Study Schedule and Procedures 
 
Screening (Days -89 to 0) 
• Signing of informed consent 
• Vital signs 
• Medical/medication history 
• Physical examination 
• Laboratory tests (including HIV testing, viral markers for hepatitis screen 
[hepatitis B surface antigen, anti-hepatitis C antibody, anti-hepatitis A 
IgM], serum or urine pregnancy test for females of child-bearing potential, 
a basic chemistry [acute care panel], hepatic panel, mineral panel, complete 
blood count with differential [CBC/diff], aPTT, PT/INR) 
• Blood draws and serum or urine pregnancy test may be repeated as 
clinically indicated at the discretion of the medically responsible 
investigator within 14 days of initial screening 
• Counsel female subjects on ways to avoid pregnancy by a) practicing 
abstinence or b) using effective non-hormonal and/or barrier methods of 
birth control, as well as avoid breast feeding or providing breast milk to 
infant 
 
Baseline (Days -6 to 0) 
• Medical/medication history 
• Vital signs 
• Physical examination 
• Safety labsa (if not within 6 days of screening) 
• Serum or urine pregnancy test (if of child-bearing potential, if not within 
6 days of screening) 
• Counsel female subjects on ways to avoid pregnancy by a) practicing 
abstinence or b) using effective non-hormonal and/or barrier methods of 
birth control, as well as avoid breast feeding or providing breast milk to 
infant 
 
Day 1: Serial 24-hr PK/PD samplingb,c 
• Vital signs 
• Serum or urine pregnancy test (if of child-bearing potential, which must be 
negative to proceed with the study) 
• Counsel female subjects on ways to avoid pregnancy by a) practicing 
abstinence or b) using effective non-hormonal and/or barrier methods of 
birth control, as well as avoid breast feeding or providing breast milk to 
infant 
• Medical/medication history 
• Eat a standardized breakfast 
• Insertion of intravenous (IV) catheter 
• Administer rivaroxaban 10 mg with 240 mL of water at 0800 (±2 hrs)  
• Serial 24-hr blood PK/PD samples 
• Safety labsa 
• Assessment of AEs  


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• Dismiss from NIH CC following 10-hr blood draw and removal of IV 
catheter 
• Counsel subjects not to engage in activities that would increase the risk of 
bleeding, such as contact sports 
• Participant will be provided the option to stay overnight or to return the 
next day for the 24-hr blood draw.  
 
Day 2: 24-hr trough and COBI dosing 
• Return to NIH CC for 24-hr postdose PK sample 
• Medical/medication history 
• Vital signs  
• Blood sample for pharmacogenomic testing  
• Administer COBI 150 mg at 0800 (±2 hrs) with a well-balanced meal  
 after collection of 24-hr PK/PD sample 
• Assessment of AEs 
• COBI 150 mg, 6-day supply (9 tablets) dispensed from NIH CC Pharmacy 
(+3 tablets to allow for minor scheduling variances) 
• Receive memory aid log (to serve as reminder of dosing schedule, and 
document of self-reported AEs) 
• Counsel female subjects on ways to avoid pregnancy by a) practicing 
abstinence or b) using effective non-hormonal and/or barrier methods of 
birth control, as well as avoid breast feeding or providing breast milk to 
infant 
Day 2 – 6: COBI dosing days 
• COBI 150 mg once daily at 0800 (±2 hrs) with food 
• Administration recorded on the provided dosing log 
Day 7: Serial 24-hr PK samplingb 
• Vital signs 
• Serum or urine pregnancy test (if of child-bearing potential, which must be 
negative to proceed with the study) 
• Counsel female subjects on ways to avoid pregnancy by a) practicing 
abstinence or b) using effective non-hormonal and/or barrier methods of 
birth control, as well as avoid breast feeding or providing breast milk to 
infant 
• Medical/medication history 
• Review memory aid card and conduct COBI pill count 
• Eat a standardized breakfast 
• Insertion of IV catheter 
• Administer rivaroxaban 10 mg COBI 150 mg with 240 mL of water at 0800 
(±2 hrs)  
• Serial 24-hr blood PK/PD samples 
• Safety labsa 
• Assessment of AEs  
• Collect any remaining COBI and return to NIH CC Pharmacy for discard 
• Dismiss from NIH CC following 10-hr blood draw and removal of IV 
catheter 


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• Counsel subjects not to engage in activities that would increase the risk of 
bleeding, such as contact sports 
• Participant will be provided the option of staying overnight or to return the 
next day for the 24-hr blood draw 
 
Day 8: 24-hr trough and DRV/COBI dosing 
• Return to NIH CC for 24-hr postdose PK/PD sample 
• Medical/medication history  
• Vital signs 
• Administer DRV/COBI 800/150 mg at 0800 (±2 hrs) with a well-balanced 
meal after collection of 24-hr PK/PD sample 
• Assessment of AEs 
• DRV/COBI 800/150 mg, 6-day supply (9 tablets) dispensed from NIH CC 
Pharmacy (+3 tablets to allow for minor scheduling variances) 
• Counseling female subjects on ways to avoid pregnancy by a) practicing 
abstinence or b) using effective non-hormonal and/or barrier methods of 
birth control, as well as avoid breast feeding or providing breast milk to 
infant 
Day 8 – 12: DRV/COBI dosing days 
• DRV/COBI 800/150 mg once daily at 0800 (±2 hrs) with food 
• Administration recorded on the provided dosing log 
Day 13: Serial 24-hr PK samplingb 
• Vital signs 
• Serum or urine pregnancy test (if of child-bearing potential, which must be 
negative to proceed with the study) 
• Counsel female subjects on ways to avoid pregnancy by a) practicing 
abstinence or b) using effective non-hormonal and/or barrier methods of 
birth control, as well as avoid breast feeding or providing breast milk to 
infant 
• Medical/medication history 
• Review memory aid card and conduct DRV/COBI pill count 
• Eat a standardized breakfast 
• Insertion of IV catheter 
• Administer rivaroxaban 10 mg and DRV/COBI 800/150 mg with 240 mL 
of water at 0800 (±2 hrs)  
• Serial 24-hr blood PK/PD samples 
• Safety labsa 
• Assessment of AEs 
• Collect any remaining DRV/COBI and return to NIH CC Pharmacy for 
discard 
• Dismiss from NIH CC following 10-hr blood draw and removal of IV 
catheter 
• Counsel subjects not to engage in activities that would increase the risk of 
bleeding, such as contact sports 
• Participant will be provided the option to stay overnight or to return the 
next day for the 24-hr blood draw 


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Day 14: 24-hr trough  
• Collection of 24-hr postdose PK/PD sample 
• Medical/medication history 
• Vital signs 
• Assessment of AEs 
• Counsel female subjects on ways to avoid pregnancy by a) practicing 
abstinence or b) using effective non-hormonal and/or barrier methods of 
birth control, as well as avoid breast feeding or providing breast milk to 
infant 
 
End of Study Visit (Day 20 ±3 days) 
• Medical/medication history 
• Vital signs  
• Physical examination 
• Safety labs 
• Assessment of AEs 
 
a Safety labs will be collected at baseline, with the time 0 (predose) PK/PD sample (days 1, 7, 
and 13) and at the end of study visit. Assessments will include serum or urine pregnancy test for 
females of child-bearing potential; a basic chemistry (acute care panel including Na, K, CO2, 
anion gap, BUN, SCr, eGFR, glucose, albumin), hepatic (including AST, ALT, alkaline 
phosphatase, total bilirubin, direct bilirubin), and mineral panel (Ca, Mg, Phos) and complete 
blood count with differential [WBC, RBC, Hgb, HCT, PLTs, differential]. PD measurements 
will be time matched with PK collection for both the purpose of PK correlation as well as safety 
assessment on days 1, 2, 7, 8, 13, and 14. PD measures include anti-factor Xa, aPTT, and 
PT/INR. Additional safety labs will be assessed at the discretion of the medically responsible 
investigator, without additional blood draw. 
b 24-hr plasma PK/PD sampling times will occur at the following times: 0 (predose), 1, 2, 3, 4, 5, 
6, 8, 10, and 24 (±2) hours postdose. The participant will be discharged after collection of the 
10-hour postdose sample, to then return for the 24-hour postdose sample collection the following 
day. PD blood samples will be collected at the same times as PK samples, but in a separate tube.  
c Day 1 will always be scheduled for a Wednesday or Thursday to ensure that other study visits 
also occur on weekdays  
6.1 
End-of-Study Visit (7±3 days after administration of final study dose) 
Participants will return to the NIH CC for a final follow-up visit 7 (±3) days after the end of final 
study drug. AEs will be assessed, vital signs measured, and blood for safety labs. Participants 
who can become pregnant will have a serum or urine pregnancy test. Participation ends after this 
visit. 
6.2 
Early Termination Visit 
If participants terminate the study early, they will be asked to return for drawing end-of-study 
labs (7±3 days after the final dose of any study drug[s]) and will receive a physical exam and AE 
assessment. 


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6.3 
Pregnancy and Follow-up Visit 
Participants who become pregnant while on study will discontinue study agents and procedures 
and will be instructed to follow-up with their physician for prenatal care; they will also be 
followed to delivery for purposes of safety monitoring for this study. 
7 
STUDY PROCEDURES/EVALUATIONS 
Blood draw: The amount of blood drawn for research purposes will be within the limits allowed 
for adult research participants by the NIH CC (Medical Administrative Policy 95-9, Guidelines 
for Limits of Blood Drawn for Research Purposes in the Clinical Center: http://cc-
internal.cc.nih.gov/policies/PDF/M95-9.pdf). Blood samples will be used for the following: 
• Screening labs (see section 6).  
• 24-hour plasma PK/PD of rivaroxaban 
• Pregnancy testing 
• Safety labs: safety panel (acute care, hepatic and mineral), CBC/diff. These safety labs 
are the same as the safety labs listed in section 6, Study schedule (Table 2) 
o Results of safety lab assessments will be reviewed as they become available, with 
appropriate clinical follow-up through resolution as necessary for any abnormal 
results. 
Pharmacogenomics: A single blood sample (10 mL) on day 2 will be collected for 
pharmacogenomic testing (targeted sequencing).   
Urine: Urine samples will be used for pregnancy testing. 
8 
POTENTIAL RISKS AND BENEFITS 
8.1 
Potential Risks 
Potential research-related risks to study participants include adverse effects of study medications, 
alone or in combination (rivaroxaban, COBI and/or DRV/COBI) and AEs associated with blood 
collection by venous catheter insertion or venipuncture in the face of anticoagulation. 
8.1.1 Rivaroxaban 
In clinical trials and post-marketing surveillance, the most frequent AEs with rivaroxaban were 
bleeding complications.22 In the ROCKET-AF trial, whereby 7111 subjects with nonvalvular AF 
received rivaroxaban (15 mg or 20 mg orally [PO] QD) to reduce the risk of stroke and systemic 
embolism, the bleeding rate (percent per year) was 3.6% for major bleeding (defined as overt 
bleeding associated with a decrease in Hgb≥2g/dL, a transfusion ≥2 units of packed red blood 
cells or whole blood, bleeding at a critical site, or with a fatal outcome) compared to 3.5% with 
warfarin. Among the major bleeding categories, GI bleeding rate (upper GI, lower GI, and rectal 
bleeding) was the highest in rivaroxaban group (2%) compared to warfarin group (1.2%). The 
risk of bleeding was increased in subjects who were ≥75 years and those with reduced CrCl 
(<50 mL/min). Drug discontinuation due to bleeding events was higher in the rivaroxaban group 
than in warfarin group (4.3% vs. 3.1%). The incidence of discontinuation for non-bleeding 
adverse events was similar in both treatment groups. 


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In EINSTEIN trial, whereby 6962 subjects received rivaroxaban (15 mg PO BID×21 days, then 
20 mg PO QD) to reduce the risk of recurrence of DVT and/or PE, major bleeding events 
occurred in 1% of subjects in the rivaroxaban group compared to 1.7% in the enoxaparin/VKA 
group. Other bleeding categories include clinically relevant non-major bleeding of 8.6% 
(compared to 8.7% with enoxaparin/VKA). For any bleeding event, 28.3% was reported in 
rivaroxaban group versus 28% in enoxaparin/VKA group. 
Drug discontinuation due to bleeding events was higher in rivaroxaban group than in 
enoxaparin/VKA group (1.7% vs. 1.5%).  
In the RECORD trial (Prevention of Venous Thromboembolic Events in Patients Undergoing 
Major Orthopedic Surgery of the lower Limbs), whereby 4487 subjects received rivaroxaban 
(10 mg PO QD) for prophylaxis of DVT following hip or knee replacement surgery, any 
bleeding event was reported in 5.8% of subjects (compared to 5.6% in enoxaparin group), with 
major bleeding events reported at 0.3%. 
Rivaroxaban should be discontinued at least 24 hours before invasive/surgical procedures. In 
case of overdose, there is the potential of hemorrhagic complications. Andexanet alfa, a specific 
anti–factor Xa agent for the reversal of rivaroxaban activity is available.21 In PK studies (doses 
ranging from 2.5 to 80 mg), rivaroxaban was safe and tolerable.26,27 In a food effect PK study, of 
the 24 healthy subjects who received rivaroxaban 10 mg PO×1, 10 subjects experienced 
treatment-related AEs. All drug related AEs were of mild intensity (subcutaneous bleeding, 
headaches, pain in both knees, neck pain, epistaxis), with exception of two moderate AEs 
(drug-related headache and non–drug-related lipase elevation). In the same study, in subjects 
who received rivaroxaban 20 mg PO×1, 9/23 subjects experienced treatment-related AEs of mild 
intensity. All treatment-related AEs were resolved by the end of the study.  
The risk of bleeding will be minimized to subjects in the current investigation, as subjects will 
receive rivaroxaban 10 mg as 3 separated single doses. 
(Refer to Appendix E for Xarelto® prescribing information.) 
8.1.2 Cobicistat 
COBI is generally well tolerated. In clinical trials, the most frequent adverse reaction after 
prolonged administration of COBI, albeit in conjunction with other ARV medications, were GI 
events (nausea, diarrhea).44(p2),45,46 COBI has been show to increase SCr (mean change 
0.14±0.13 mg/dL), usually within the first 2 weeks of therapy, due to the inhibition of tubular 
secretion of creatinine; glomerular function is not believed to be affected.45–47 Patients who 
experience a confirmed increase in SCr>0.4 mg/dL from baseline should be closely monitored.30 
In PK studies, COBI was tolerable.41,47,48 Most AEs judged to be related to study medications 
were mild to moderate. Three exceptions include: a single subject who reported left upper 
extremity discoordination (grade 3) during daily doses of COBI, a single subject who reported 
rash (grade 3) during daily doses of COBI with DRV, and a single subject who reported a severe 
rash during daily doses of COBI with atazanavir.41,44,47 All AEs resolved upon discontinuation of 
study drug. Commonly reported AEs included nervous (headache, somnolence, abnormal 
dreams) and integumentary (rash) system AEs, which resolved by the completion of the study. 
Because subjects in the current investigation will receive COBI limited to 6 days, the risk to 
subjects is expected to be slightly above minimal.  
(Refer to Appendix F for Tybost® prescribing information.)  


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8.1.3 Darunavir/Cobicistat 
The fixed-dose tablet combination of DRV and COBI was FDA-approved in January 2015.35 
Prior to approval, DRV coadministered with RTV (DRV/RTV) and COBI had been used 
separately in the clinical setting. In clinical trials and post-marketing surveillance of DRV 
coadministered with RTV, the most frequent AEs occurring in ≥5% of individuals were diarrhea 
(9%), headache (7%), rash (6%), and abdominal pain (6%).35 Long-term studies with the 
coformulation of DRV/COBI have shown similar AEs to those observed with DRV/RTV and 
COBI alone.35,40 In short-term PK studies, DRV/COBI has been well tolerated, with similar AEs 
to those reported in long-term clinical studies.41,42 Mild-to-moderate rash usually occurs within 
the first four weeks of starting therapy, but typically resolves with continued administration.35 
Warnings with the use of DRV/COBI include drug-induced hepatitis (0.5%), liver failure 
(notably in patients with pre-existing liver dysfunction), severe skin reactions accompanied by 
fever and/or transaminase elevation (0.4%), Stevens-Johnson Syndrome (<0.1%), and elevation 
of SCr due to inhibition of tubular secretion by COBI.35 This increase in SCr is not associated 
with an actual decrease in glomerular renal function. However, patients who experience an 
increase over 0.4 mg/dL from baseline should be monitored. Additionally, patients with a known 
sulfa allergy should be monitored after initiating DRV/COBI as DRV contains a sulfonamide 
moiety. Incidence of rash between subjects with and without a history of sulfonamide allergy 
was similar in clinical trials. Other serious AEs associated with long-term use of protease 
inhibitors include new onset of diabetes mellitus, exacerbation of pre-existing diabetes mellitus, 
hyperglycemia, fat redistribution, and increased bleeding in patients with hemophilia.  
The above-mentioned serious reactions are reported in patients on chronic therapy after 24 to 
96 weeks on daily dosing of DRV/COBI. These patients are infected with HIV-1, are on other 
drugs that may contribute to the serious reactions, and often have other co-morbidities. As 
subjects in this study will be healthy volunteers and exposure to DRV/COBI will be limited to 
6 days, the risk to subjects is expected to be slightly above minimal. The first dose of 
DRV/COBI will be administered by a nurse under direct observation, and subjects will be 
observed for 0.5 to 1 hour, should any immediate reactions occur. In addition to assessing AEs 
during PK/PD days, close monitoring will be provided through phone calls in between PK/PD 
study visits, as well as safety follow-up (7±3 days after last study drug). 
(Refer to Appendix G for Prezcobix® prescribing information.) 
8.1.4 Blood draw and IV catheter 
The risks of drawing blood include pain, bruising, bleeding, and, rarely, fainting or infection. 
Insertion of an IV catheter for collection of blood can also result in inflammation of the skin and 
vein. 
8.1.5 Pharmacogenomic testing  
There are no foreseeable risks with pharmacogenomic testing. Results of pharmacogenomic 
testing will not be clinically validated or become a part of the participant’s medical record at the 
NIH, and will not be returned to participants. Research records containing this information are 
maintained in a secure manner as described in section 16.2.  


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8.2 
Potential Benefits 
This is not a therapeutic trial; therefore, study participants will not experience direct benefits 
from their participation. However, the results of this study may help in the care of patients 
receiving these or similar medications in the future. 
9 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, AND DATA 
9.1 
Intended Use 
Samples, specimens, and data collected under this protocol will be used to assess plasma 
concentrations of rivaroxaban. PD markers in plasma of these drugs will also be assessed. 
Genetic testing will be performed. Method development for drug assays (rivaroxaban) and 
sample processing will be performed by the Clinical Pharmacokinetics Research Unit (CPRU) 
lab. Assay for PD markers will be performed by the Department of Laboratory Medicine (DLM) 
here at NIH.  
9.2 
Storage 
Samples collected for PK assessments will be stored at −80°C in a locked freezer in the CPRU 
lab. Other samples collected under this study may be stored at the National Cancer Institute  at 
Frederick Central Repository and at DLM. Samples and data will be stored using codes assigned 
by the investigators or their designees. All stored computer data will be password protected. 
Only investigators will have access to the samples and data. 
9.3 
Tracking 
Samples acquired under this protocol will be tracked using a database located on a 
password-protected computer. Data will be stored and maintained in CRIMSON database. 
9.4 
Disposition at the Completion of the Protocol 
In the future, other investigators (both at NIH and outside) may wish to use these samples and/or 
data for research purposes. If the planned research falls within the category of “human subjects 
research” on the part of the NIH researchers, IRB review and approval will be obtained. This 
includes the NIH researchers sending out coded and linked samples or data and getting results 
that they can link back to their subjects. 
9.5 
Loss or Destruction 
Any loss or unanticipated destruction of samples (for example, due to freezer malfunction) or 
data (for example, misplacing a printout of data with identifiers) that meets the definition of a 
reportable event will be reported to the NIH IRB according to HRPP Policy 801.  
Additionally, participants may decide at any point not to have their samples stored. In this case, 
the PI will destroy all known remaining samples and report what was done to both the participant 
and to the IRB. This decision will not affect the individual’s participation in this protocol or any 
other protocols at NIH. 
10 DATA SHARING PLAN 
Human data generated in this study will be shared for future research as follows: 
• De-identified data in an NIH-funded or approved public repository. 


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• Identified data in the Biomedical Translational Research Information System (BTRIS, 
automatic for activities in the CC). 
• De-identified or identified data with approved outside collaborators under appropriate 
agreements. 
• Through publications and/or public presentations. 
Data will be shared before, at the time of or shortly after publication. 
This study is not expected to generate the amount of genetic data that triggers the NIH Genomic 
Data Sharing Policy, which applies to all NIH-funded research that generates large-scale human 
or non-human genomic data, as well as the use of these data for subsequent research. 
11 REMUNERATION PLAN FOR PARTICIPANTS 
Participants will be compensated for their time and inconvenience per study visit as described in 
the following table: 
Table 3: Compensation Schedule 
Compensation schedule 
Screening 
$50 
Baseline 
$50 
Days 1-2 
$400 
Days 7-8 
$400 
Days 13-14 
$400 
Day 20 
$50 
Total 
$1350 
If the participant requires additional clinical follow-up outside of scheduled study visits based on 
medical advisory investigator discretion, then the participant may be compensated an amount 
consistent with NIH CC policies and guidelines for additional follow-up visits/procedures. 
Subjects who do not complete all study procedures will receive compensation that has been 
prorated based on the extent of their participation. Volunteers who complete all study procedures 
will be compensated a maximum total of $1350. Payment will be issued after the final study visit 
in each arm. Travel and/or lodging expenses may be provided as per PI discretion. 
12 ASSESSMENT OF SAFETY 
Information regarding expected side effects from the study drugs is taken from the 
manufacturers’ package inserts and published studies. The risk to volunteers is considered to be 
slightly above minimal since exposure to rivaroxaban will be limited to 3 single doses; exposure 
to COBI and DRV/COBI will be limited to 6 days each respectively. The protocol does involve 
blood drawing. 
12.1 Toxicity Scale 
The Investigator will grade the severity of each AE according to the “DAIDS Table for Grading 
the Severity of Adult and Pediatric Adverse Events” most recent Version 2.1, July 2017, which 
can be found at: https://rsc.tech-res.com/docs/default-source/safety/division-of-aids-(daids)-
table-for-grading-the-severity-of-adult-and-pediatric-adverse-events-corrected-v-2-
1.pdf?sfvrsn=2.  


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Some Grade 1 lab parameters on the DAIDS Toxicity Table fall within the NIH lab reference 
range for normal values. These normal values will not be reported as Grade 1 AEs.  
Total bilirubin will be graded according to the “Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Trials”, as indicated in the table below. 
The full table can be accessed through the following link: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/ucm091977. Only the total bilirubin 
measure (not direct or indirect bilirubin individually) will be used to determine whether pausing 
rules have been met. Direct and indirect bilirubin measures will still be collected as AEs.  
Table 4: Toxicity Grading Scale for Total Bilirubin, According to the “Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Trials” 
Serum Test 
Mild            
(Grade 1) 
Moderate        
(Grade 2) 
Severe      
(Grade 3) 
Potentially Life 
Threatening      
(Grade 4) 
Total bilirubin – when 
accompanied by any 
increase in LFTs (eg, 
AST, ALT) increase by 
factor. 
1.1-1.25 x ULN 
1.26-1.5 x ULN 
1.51-1.75 x ULN 
> 1.75 x ULN 
Total bilirubin – when 
LFTs (eg, AST, ALT) are 
all normal; increase by 
factor. 
1.1-1.5 x ULN 
1.6-2.0 x ULN 
2.0-3.0 x ULN 
> 3.0 x ULN 
ALT = alanine transaminase; AST = aspartate transaminase; LFT = liver function test; ULN = upper limit 
of normal. 
All other laboratory and clinical AEs that occur in a subject will be assessed for severity and 
classified into one of the categories below: 
• Grade 1 (Mild): Event requires minimal or no treatment and does not interfere with the 
subject’s daily activities. 
• Grade 2 (Moderate): Event results in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• Grade 3 (Severe): Event interrupts a subject’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually incapacitating. 
• Grade 4 (Life threatening): Any adverse drug experience that places the subject or 
participant, in the view of the Investigator, at immediate risk of death from the reaction as 
it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, 
might have caused death. 
• Grade 5 (Death) 
12.2 Recording/Documentation and Reporting Adverse Events 
At each contact with the participant, starting from the time the informed consent form is signed 
through the end of the final study visit, information regarding AEs will be elicited by appropriate 
questioning and examinations. All events, both expected/unexpected and related/unrelated, will 
be immediately documented in the subject’s medical record/source document, recorded in 
CRIMSON, and reported as outlined below. Source documents will include progress notes, 
laboratory reports, consult notes, phone call summaries, survey tools, and data collection tools. 


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Source documents will be reviewed in a timely manner by the research team. All reportable AEs 
that are identified will be recorded in CRIMSON. The start date, the stop date, the severity of 
each reportable event, and the PI’s judgment of the AE’s relationship and expectedness to the 
study agent/intervention will also be recorded in CRIMSON. If a diagnosis is clinically evident 
(or subsequently determined), the diagnosis rather than the individual signs and symptoms or lab 
abnormalities will be recorded as the AE. 
12.3 Reporting Procedures  
12.3.1 Investigator Assessment of Adverse Events 
The medical advisory investigator (MAI) and the PI will assess all AEs with respect to 
Seriousness (criteria listed above), Severity (intensity or grade) [using the specified toxicity 
tables] and Causality (relationship to study agent and relationship to research) according to the 
following guidelines. 
12.3.1.1 Causality 
Causality: likelihood that the event is caused by the study agent(s) will be assessed considering 
the factors listed under the following categories: 
• Definitely related 
o reasonable temporal relationship 
o follows a known response pattern 
o clear evidence to suggest a causal relationship 
o there is no alternative etiology 
• Probably Related 
o reasonable temporal relationship 
o follows a suspected response pattern (based on similar agents) 
o no evidence of a more likely alternative etiology 
• Possibly Related 
o reasonable temporal relationship 
o little evidence for a more likely alternative etiology 
• Unlikely Related 
o does not have a reasonable temporal relationship 
OR 
o good evidence for a more likely alternative etiology 
• Not Related 
o does not have a temporal relationship 
OR 
o definitely due to an alternative etiology 
Note: Other factors (e.g., dechallenge, rechallenge) should also be considered for each causality 
category when appropriate. Causality assessment is based on available information at the time of 
the assessment of the AE. The investigator may revise the causality assessment as additional 
information becomes available. 
12.3.2 Reporting to the Medical Monitor 
A medical monitor (MM) has been appointed for oversight of safety in this clinical study (see 
Safety Oversight, section 13.) 


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12.3.3 Reporting Procedures to the NIH IRB 
• Assessment of Safety 
AEs and other reportable events are defined in Policy 801: Reporting Research Events. 
• Reporting Procedures 
Unanticipated problems, non-compliance, and other reportable events will be reported to the NIH 
IRB according to Policy 801. 
• Reporting to the NIAID Clinical Director 
The PI will report UPs, major protocol deviations, and deaths to the NIAID Clinical Director 
according to institutional timelines. 
12.4 Pregnancy 
Although pregnancy itself is not an AE, events occurring during pregnancy, delivery, or in the 
neonate (e.g., congenital anomaly/birth defect) may be AEs or SAEs. 
In the event a participant or female partner of a participant becomes pregnant, prenatal care will 
not be provided by the study and the following steps will be taken: 
• Discontinue the study agents and procedures but continue to follow-up until delivery for 
safety. 
• Enroll in ARV pregnancy registry (APR). 
• Report to the MM and the IRB as required. 
• Advise research participant to notify the obstetrician of study participation and study 
agent exposure. 
12.5 Type and Duration of the Follow-up of Participants after Serious Adverse Events 
SAEs that have not resolved by the end of the follow-up period will be followed until final 
outcome is known. If it is not possible to obtain a final outcome for an SAE (e.g., the participant 
is lost to follow-up), then the reason a final outcome could not be obtained will be recorded by 
the investigator in CRIMSON.  
12.6 Pausing Rules for An Individual Participant 
Pausing is the suspension of administration of study agent to a single participant. The pausing 
criteria for a single participant in this study include any of the following: 
• A participant experiences a >Grade 3 AE that is possibly, probably, or definitely related 
to a study agent  
• A participant experiences a Grade 2 AE of transaminase elevations that is possibly, 
probably, or definitely related to the study agents. 
• Any safety issue that the site investigator determines should pause administration of a 
study agent to a single participant. 


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12.6.1 Reporting a Pause 
If a pausing criterion is met, then a description of the AE(s) or safety issue must be reported by 
the PI within one business day to the IRB and the MM by fax or email. 
12.6.2 Resumption of a Paused Participant 
A participant who experiences any AE that meets the pausing criteria, and is possibly related to 
study drugs will not be permitted to resume the study agents but will continue to be followed for 
safety.  The PI, MAI, and MM will determine whether or not it is safe to resume administration 
of the study agent to the subject.  
12.6.3 Discontinuation of Study Agent 
A participant who does not resume study agent will continue to be followed for safety until AE 
resolution. 
12.7 Halting Rules for the Protocol 
Halting the study requires immediate discontinuation of study agents administered for all 
participants and suspension of enrollment until a decision is made whether or not to continue 
enrollment and study agent administration. The PI, MAI, and MM will determine if the study 
should be halted. The halting rules are: 
• One (or more) subject(s) experiences the same or similar Grade 4 or Grade 5 AE that is 
assessed as possibly, probably, or definitely related to rivaroxaban, COBI, or DRV/COBI  
• Two (or more) subjects experience the same or similar Grade 3 AE assessed as possibly, 
probably, or definitely related to rivaroxaban, COBI, or DRV/COBI, or  
• Three (or more) subjects experience the same or similar Grade 2 events possibly, 
probably or definitely related to rivaroxaban, COBI, or DRV/COBI (except: headache 
that requires administration of acetaminophen, diarrhea that requires the administration of 
loperamide, nausea that requires the administration of an anti-emetic, or rash). 
• Any safety issue that the PI, MAI, and/or the MM determines should halt the study. 
12.7.1 Reporting a Study Halt 
If a halting rule is met, then a description of the AE(s) or safety issue must be reported by the PI 
within one business day to the IRB and the MM by fax or email. 
12.7.2 Resumption of a Halted Study 
The PI, MAI, and MM will convene to determine an appropriate course of action (which will 
include IRB notification and consultation) before the study is allowed to resume. The PI will 
notify the IRB of the decision on resumption of the study.  
12.7.3 Discontinuation of Study Agent 
Subjects who do not resume study agent will continue to be followed for safety, until AE 
resolution.  
12.8 Study Discontinuation 
The IRB, the NIAID, and the MM, as part of their duties to ensure that research participants are 
protected, may discontinue the study at any time. Subsequent review of serious, unexpected, and 


CLOTRx.  Version 4.0   July 29, 2021 
35 
related AEs by the IRB may also result in suspension of enrollment and further trial 
interventions/administration of study agent. 
12.9 Premature Withdrawal of a Participant 
An individual participant will be withdrawn for any of the following: 
• An individual participant’s decision. (The investigator should attempt to determine the 
reason for the participant’s decision.) 
• Participant loses ability to provide ongoing informed consent. 
• Non-compliance with study procedures to the extent that it is potentially harmful to the 
participant or to the integrity of the study data. 
• The investigator determines that continued participation in the study would not be in the 
best interest of the participant. 
12.10 Replacement of Withdrawn Participants or Participants Who Discontinue Study 
Treatment 
Participants who withdraw or are withdrawn from the study prior to day 13 will be replaced. If a 
participant is replaced, all the data collected from that participant will still be included for the 
safety assessment.  
13 SAFETY OVERSIGHT 
13.1 Safety Review and Communications Plan (SRCP) 
A safety review and communication plan (SRCP) has been developed for the protocol. The 
SRCP is an internal communications document between the PI and the MM, which delineates 
the safety oversight responsibilities of the PI and MM. The SRCP also includes the overall plan 
for conducting periodic safety surveillance assessments. 
13.2 Medical Monitor 
A MM has been appointed for oversight of safety in this clinical study. The MM will be 
responsible for performing safety assessments as outlined in the SRCP. 
The MM does not have direct involvement in the conduct of the study and has no significant 
conflicts of interests as defined by NIAID policy.   
The MM will conduct independent safety monitoring and recommend appropriate action 
regarding AEs and other safety issues. The PI will send to the MM the safety reports specified in 
the SRCP. 
After each MM review, a recommendation as to whether the study is to continue as is, be 
modified, or be terminated will be discussed with the PI.  
In addition, deaths and immediately life-threatening SAEs must be reported to the MM within 
1 business day after the PI becomes aware of the event. All other SAEs must be reported to the 
MM within 3 business days of PI awareness. 
All non-SAE UPs and pregnancies will be reported by the PI to the MM at the same time they 
are submitted to the IRB.  


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The MM will be notified immediately if any pausing or halting rule is met, and the MM will 
provide a recommendation for continuation, modification, or termination of the study. 
14 STUDY MONITORING 
Accrual and safety data will be monitored by the PI and the medical advisory investigator, who 
will provide oversight to the conduct of this study. The PI will continuously evaluate 
implementation of the protocol for any unusual or unpredicted complications that occur and will 
review the data for accuracy and completeness.  
The NIH CC’s Quality Assurance Program will conduct study monitoring at least annually or 
more frequently as required. Participant consent documents, primary outcome and safety 
laboratory results, and diagnostic test results will be monitored for accuracy, correct dating, and 
agreement between case report forms and source documents. All regulatory reports, reviews and 
amendments, AEs and problem reports related to study, along with investigator credentials, 
training records, and the delegation of responsibility log will also be reviewed during monitoring 
visits. The PI will be responsible for reporting any problems to the IRB as defined in Section 
12.4, Reporting Procedures. 
15 STATISTICAL CONSIDERATIONS  
15.1 Primary Study Hypothesis 
In healthy volunteers receiving rivaroxaban concomitantly with COBI or DRV/COBI, significant 
COBI or DRV/COBI inhibition of efflux transporters (P-gp and BCRP) and CYP450 enzymes 
will be observed. Plasma levels of rivaroxaban will be significantly increased, requiring a dose 
adjustment. A significant increase in rivaroxaban levels that necessitates a dose adjustment is 
defined as a 50% or greater increase in the AUC geometric mean ratio (GMR) in combination 
with COBI or DRV/COBI compared to rivaroxaban alone (phase 2 to phase 1 and phase 3 to 
phase 1).  
15.2 Secondary Study Hypothesis 
In healthy volunteers receiving rivaroxaban concomitantly with COBI or DRV/COBI, we predict 
increase in FXa, PT, and aPTT, corresponding with increased systemic concentrations of 
rivaroxaban.  
15.3 Sample Size Justification 
Because AUC is likely to have a skewed distribution, we will transform the data using the 
natural logarithm Y=ln(AUC). Let Y1 be ln(AUC) when rivaroxaban is given alone, and Y2 be 
ln(AUC) when in combination with COBI or DRV/COBI. We will first compute a 90% 
confidence interval for the mean difference of Y2-Y1. That interval will be transformed back to 
the original (unlogged) scale to produce an estimate and confidence interval for the GMR. The 
GMR estimates the ratio of the median AUC when in combination with COBI or DRV/COBI to 
the median AUC of rivaroxaban alone.    
To compute sample size/power, we must estimate the variance, V, of Y2-Y1. It can be shown 
using the mean and variance of the lognormal distribution that V can be estimated as 
2ln(1+CV2), where CV is the intra-subject coefficient of variation. The CV of rivaroxaban is 
estimated to be 27%=0.27 based on available PK data.20 This CV corresponds to a V of 0.1407 
(=2ln(1+.272) for the log-transformed GMR of AUCs for rivaroxaban alone and in combination. 
A 50% relative increase on the original scale translates to mean difference of ln(1.50)=0.4055 for 


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37 
log-transformed AUC. Therefore, power for this procedure is equivalent to that of a one-tailed 
paired t-test of the null hypothesis that the mean difference of Y2-Y1 is 0.4055, versus the 
alternative hypothesis that it exceeds 0.4055, when the variance is 0.1407. 
If θ denotes GMR for combination vs. rivaroxaban alone, the procedure we use may be viewed 
in either of the following equivalent ways. 
1. Test the null hypothesis that θ≤1.5 versus the alternative hypothesis that θ>1.5 using a 
one-tailed test at α=0.05. If the test rejects the null hypothesis, declare the interaction 
effect to be greater than 50%.  
2. Compute the lower confidence limit of a one-sided, 90% confidence interval for θ (again 
by log transforming and then transforming back at the end). If the lower limit exceeds 
1.5, declare the interaction effect to be greater than 50%.     
Power for demonstrating a greater than 50% increase is shown in Table 5 for different true 
GMRs and sample sizes. A sample size of 12 participants provides 80% power to demonstrate at 
least a 50% increase in AUC if the true increase is 100% (true GMR=2). Power is very low if the 
true increase is 75%, but very high if the true increase is 125%. 
Table 5: Power and Sample Size (n) 
True GMR 
n=10 
n=11 
n=12 
n=13 
n=14 
n=15 
1.75 
.329 
.354 
.379 
.402 
.426 
.448 
2 
.723 
.765 
.800 
.831 
.858 
.880 
2.25 
.933 
.954 
.968 
.978 
.985 
.990 
 
A total of 12 subjects will be enrolled for this study. 
15.4 Description of the Analysis 
Rivaroxaban  PK parameters will be determined using noncompartmental methods with Phoenix 
WinNonlin® (version 7.0; Pharsight Corporation, Mountain View, CA). Cmax, tmax, and Cmin for 
rivaroxaban will be obtained directly by visual inspection of the plasma concentration vs. time 
profiles. The apparent elimination rate constant (λZ) will be determined by calculating the 
absolute value of the slope of the log-linear regression of at least 3 points of the plasma 
concentration-time plot. The t½ will be calculated as 0.693/λZ. The area under the concentration 
vs. time curve from time zero to tau hours postdose (AUC0–24, for rivaroxaban) will be calculated 
using the linear trapezoidal rule. CL/F will be calculated as 10 mg ÷ AUC0-tau. 
PK parameters (AUC0–tau, Cmax, tmax, t½, CL/F, and Cmin) for the single dose of anticoagulant 
(rivaroxaban 10 mg) will be compared alone and in combination with COBI or DRV/COBI. 
Paired t-tests will be used for comparison of the log-transformed AUC values between the 
combination and rivaroxaban alone. A one-sided p-value less than 0.05 will be claimed as 
statistically significant. GMRs (in combination vs. alone) with 90% confidence intervals will be 
calculated by exponentiating the limits of the log-transformed interval. 
Primarily, the analysis will be performed in subjects who report no missing doses. Sensitivity 
analysis will be conducted in all participants using the linear mixed effects models for the 
repeated measures data. Sensitivity analysis will also be performed in subjects that are adherent 
to the planned course of dosing.  


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16 ETHICS/PROTECTION OF HUMAN PARTICIPANTS  
16.1 Informed Consent 
Informed consent is a process where information is presented to enable persons to voluntarily 
decide whether or not to participate as a research participant. It is an ongoing conversation 
between the human research participant and the researchers which begins before consent is given 
and continues until the end of the participant’s involvement in the research. Discussions about 
the research will provide essential information about the study and include: purpose, duration, 
experimental procedures, alternatives, risks, and benefits. Participants will be given the 
opportunity to ask questions and have them answered. 
Informed consent will be obtained in person by a study team member authorized to obtain 
consent. The privacy of the subject will be maintained. Consenting investigators and the 
participant will be located in a private area (e.g., clinic consult room). The participants will sign 
the informed consent document prior to undergoing any research procedures. Consent will be 
documented with required signatures on the hard copy of the consent form. The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the informed consent 
document will be given to the participants for their records. The researcher will document the 
signing of the consent form in the participant’s medical record. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
16.1.1 Considerations for Consent of NIH Staff or Family of Study Team Members 
Informed consent will be obtained as detailed above and will comply with the requirements of 
NIH HRPP Policy 404 Research Involving NIH Staff as Subjects. 
Consent from staff members will be obtained by an individual independent of the staff member’s 
team whenever possible. When consent of that staff member is conducted, a third party will be 
present to observe the consent process in order to minimize the risk of undue pressure on the 
staff member. Similarly, for family of the study team, a study team member unrelated to the 
participant will obtain their informed consent. When consent of that staff member’s relative is 
conducted, a third party will be present to observe the consent process in order to minimize the 
risk of undue pressure on them. 
16.2 Participant Confidentiality 
All records will be kept confidential to the extent provided by federal, state, and local law. The 
study monitors and other authorized individuals may inspect all documents and records required 
to be maintained by the investigator, including but not limited to, medical records. Records will 
be kept locked and all computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the IRB, NIAID, and Office for Human 
Subjects Research Protections (OHSRP). 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the NIH. This certificate protects identifiable research information from forced 
disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
researchers and institutions from being compelled to disclose information that would identify 


CLOTRx.  Version 4.0   July 29, 2021 
39 
research participants, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to participants. 
17 DATA HANDLING AND RECORD KEEPING 
17.1 Data Capture and Management 
Study data will be maintained in CRIMSON and collected directly from participants during 
study visits and telephone calls or will be abstracted from participants’ medical records. Source 
documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary to confirm the data abstracted for this study. Data entry into CRIMSON 
will be performed by authorized individuals. The investigator is responsible for assuring that the 
data collected are complete, accurate, and recorded in a timely manner. 
17.2 Record Retention 
The investigator is responsible for retaining all essential documents in accordance with 
regulatory and institutional requirements,  International Council for Harmonisation/Good 
Clinical Practice guidelines, and the NIH Intramural Records Retention Schedule. All stored 
records will be kept confidential to the extent required by federal, state, and local law. 
Should the investigator wish to assign the study records to another party and/or move them to 
another location, the investigator will provide notification of such intent to NIAID with the name 
of the person who will accept responsibility for the transferred records and/or their new location.  
 
 


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3.  
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Evaluate and Reduce Polypharmacy and Potentially Inappropriate Prescribing in Older 
HIV-Positive Patients. Pharmacotherapy. 2017;37(12):1498-1506. doi:10.1002/phar.2043 
4.  
Saber AA, Aboolian A, LaRaja RD, Baron H, Hanna K. HIV/AIDS and the risk of deep 
vein thrombosis: a study of 45 patients with lower extremity involvement. Am Surg. 
2001;67(7):645-647. 
5.  
Saif MW, Bona R, Greenberg B. AIDS and thrombosis: retrospective study of 131 HIV-
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6.  
Klein SK, Slim EJ, de Kruif MD, et al. Is chronic HIV infection associated with venous 
thrombotic disease? A systematic review. Neth J Med. 2005;63(4):129-136. 
7.  
American College of Chest Physicians. Antithrombotic Therapy for VTE Disease. CHEST 
Guidelines and Expert Panel. February 2016. 
8.  
Ay C, Pabinger I, Cohen AT. Cancer-associated venous thromboembolism: Burden, 
mechanisms, and management. Thromb Haemost. 2017;117(2):219-230. 
doi:10.1160/TH16-08-0615 
9.  
Linkins L-A. Management of venous thromboembolism in patients with cancer: role of 
dalteparin. Vasc Health Risk Manag. 2008;4(2):279-287. 
10.  Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology 
guideline: recommendations for venous thromboembolism prophylaxis and treatment in 
patients with cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(34):5490-5505. 
doi:10.1200/JCO.2007.14.1283 
11.  Shepherd L, Ryom L, Law M, et al. Differences in Virological and Immunological Risk 
Factors for Non-Hodgkin and Hodgkin Lymphoma. J Natl Cancer Inst. December 2017. 
doi:10.1093/jnci/djx249 
12.  Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral 
anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: 
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 
2012;141(2 Suppl):e44S-e88S. doi:10.1378/chest.11-2292 


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13.  Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and 
management of the vitamin K antagonists: American College of Chest Physicians 
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198S. doi:10.1378/chest.08-0670 
14.  Bristol-Myers Squibb Company. Coumadin Package Insert. 2017. 
15.  Bleker SM, Cohen AT, Büller HR, et al. Clinical presentation and course of bleeding events 
in patients with venous thromboembolism, treated with apixaban or enoxaparin and 
warfarin. Results from the AMPLIFY trial. Thromb Haemost. 2016;116(6):1159-1164. 
doi:10.1160/TH16-02-0137 
16.  Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with 
atrial fibrillation. N Engl J Med. 2011;365(11):981-992. doi:10.1056/NEJMoa1107039 
17.  Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial 
fibrillation. N Engl J Med. 2011;365(10):883-891. doi:10.1056/NEJMoa1009638 
18.  Prins MH, Lensing AWA, Brighton TA, et al. Oral rivaroxaban versus enoxaparin with 
vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients 
with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two 
randomised controlled trials. Lancet Haematol. 2014;1(1):e37-46. doi:10.1016/S2352-
3026(14)70018-3 
19.  Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus warfarin for 
the treatment of symptomatic venous thromboembolism. N Engl J Med. 
2013;369(15):1406-1415. doi:10.1056/NEJMoa1306638 
20.  Rivaroxaban Clinical Pharmacology Review. NDA # 202-439. 
https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/A
pprovedProducts/UCM606687.pdf. Accessed May 31, 2018. 
21.  Andexxa Package Insert. 
https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/A
pprovedProducts/UCM606687.pdf. Accessed July 9, 2018. 
22.  Janssen Pharmaceuticals.  Xarelto Package Insert January 2021.  
23.  Kumar P, Gordon LA, Brooks KM, et al. Differential Influence of the Antiretroviral 
Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein 
Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran. 
Antimicrob Agents Chemother. 2017;61(11). doi:10.1128/AAC.01201-17 
24.  Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its 
elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 
2013;76(3):455-466. doi:10.1111/bcp.12075 


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25.  Mathias AA, West S, Hui J, Kearney BP. Dose-response of ritonavir on hepatic CYP3A 
activity and elvitegravir oral exposure. Clin Pharmacol Ther. 2009;85(1):64-70. 
doi:10.1038/clpt.2008.168 
26.  Stampfuss J, Kubitza D, Becka M, Mueck W. The effect of food on the absorption and 
pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther. 2013;51(7):549-561. 
doi:10.5414/CP201812 
27.  Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and 
pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin 
Pharmacol Ther. 2005;78(4):412-421. doi:10.1016/j.clpt.2005.06.011 
28.  Kubitza D, Becka M, Roth A, Mueck W. Dose-escalation study of the pharmacokinetics 
and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin. 
2008;24(10):2757-2765. doi:10.1185/03007990802361499 
29.  Kubitza D, Becka M, Mueck W, Zuehlsdorf M. The Effect of Extreme Age, and Gender, on 
the Pharmacology and Tolerability of Rivaroxaban - An Oral, Direct Factor Xa Inhibitor. 
Blood. 2006;108(11):905-905. 
30.  Gilead Science, Inc. Tybost Package Insert. August 2020. 
31.  Lepist E-I, Zhang X, Hao J, et al. Contribution of the organic anion transporter OAT2 to the 
renal active tubular secretion of creatinine and mechanism for serum creatinine elevations 
caused by cobicistat. Kidney Int. 2014;86(2):350-357. doi:10.1038/ki.2014.66 
32.  Renjifo B, van Wyk J, Salem AH, Bow D, Ng J, Norton M. Pharmacokinetic enhancement 
in HIV antiretroviral therapy: a comparison of ritonavir and cobicistat. AIDS Rev. 
2015;17(1):37-46. 
33.  Xu L, Liu H, Murray BP, et al. Cobicistat (GS-9350): A Potent and Selective Inhibitor of 
Human CYP3A as a Novel Pharmacoenhancer. ACS Med Chem Lett. 2010;1(5):209-213. 
doi:10.1021/ml1000257 
34.  Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults 
and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults 
and adolescents. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/0. 
Accessed February 12, 2018. 
35.  Janssen Pharmaceuticals. Prezcobix Package Insert. December 2020. 
36.  Tempestilli M, Gentilotti E, Tommasi C, et al. Determination of P-glycoprotein surface 
expression and functional ability after in vitro treatment with darunavir or raltegravir in 
lymphocytes of healthy donors. Int Immunopharmacol. 2013;16(4):492-497. 
doi:10.1016/j.intimp.2013.05.003 


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37.  Fujimoto H, Higuchi M, Watanabe H, et al. P-glycoprotein mediates efflux transport of 
darunavir in human intestinal Caco-2 and ABCB1 gene-transfected renal LLC-PK1 cell 
lines. Biol Pharm Bull. 2009;32(9):1588-1593. 
38.  König SK, Herzog M, Theile D, Zembruski N, Haefeli WE, Weiss J. Impact of drug 
transporters on cellular resistance towards saquinavir and darunavir. J Antimicrob 
Chemother. 2010;65(11):2319-2328. doi:10.1093/jac/dkq324 
39.  Chan GNY, Patel R, Cummins CL, Bendayan R. Induction of P-glycoprotein by 
antiretroviral drugs in human brain microvessel endothelial cells. Antimicrob Agents 
Chemother. 2013;57(9):4481-4488. doi:10.1128/AAC.00486-13 
40.  Tashima K, Crofoot G, Tomaka FL, et al. Phase IIIb, open-label single-arm trial of 
darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected 
treatment-nave adults. J Int AIDS Soc. 2014;17(4 Suppl 3):19772. 
41.  Kakuda TN, Opsomer M, Timmers M, et al. Pharmacokinetics of darunavir in fixed-dose 
combination with cobicistat compared with coadministration of darunavir and ritonavir as 
single agents in healthy volunteers. J Clin Pharmacol. 2014;54(8):949-957. 
doi:10.1002/jcph.290 
42.  Kakuda TN, Van De Casteele T, Petrovic R, et al. Bioequivalence of a darunavir/cobicistat 
fixed-dose combination tablet versus single agents and food effect in healthy volunteers. 
Antivir Ther. 2014;19(6):597-606. doi:10.3851/IMP2814 
43.  Katzenmaier S, Markert C, Riedel K-D, Burhenne J, Haefeli WE, Mikus G. Determining 
the Time Course of CYP3A Inhibition by Potent Reversible and Irreversible CYP3A 
Inhibitors Using A Limited Sampling Strategy. Clin Pharmacol Ther. 90(5):666-673. 
doi:10.1038/clpt.2011.164 
44.  Elion R, Cohen C, Gathe J, et al. Phase 2 study of cobicistat versus ritonavir each with 
once-daily atazanavir and fixed-dose emtricitabine/tenofovir df in the initial treatment of 
HIV infection. AIDS Lond Engl. 2011;25(15):1881-1886. 
doi:10.1097/QAD.0b013e32834b4d48 
45.  DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, 
emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus 
co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 
infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Lond Engl. 
2012;379(9835):2429-2438. doi:10.1016/S0140-6736(12)60918-0 
46.  Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and 
tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment 
of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 
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9 


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47.  German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in 
subjects with normal and impaired renal function. J Acquir Immune Defic Syndr 1999. 
2012;61(1):32-40. doi:10.1097/QAI.0b013e3182645648 
48.  Mathias AA, German P, Murray BP, et al. Pharmacokinetics and pharmacodynamics of GS-
9350: a novel pharmacokinetic enhancer without anti-HIV activity. Clin Pharmacol Ther. 
2010;87(3):322-329. doi:10.1038/clpt.2009.228 
 
 


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Appendix B: Schedule of Procedures/Evaluations 
Evaluation  
Study Day 
Early 
Terminatio
n Visit 
Screening 
Baseline 
1 
2 
 5±1 
7 
8 
9±
1 
13 
14 
20±3 
  
(Day -89 to 0) 
(Day -6 – 0) 
Informed 
Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
Medical/Medi
cation History 
X 
X 
X 
X 
  
X 
X 
  
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
  
X 
X 
  
X 
X 
X 
X 
Clinical 
Assessmenta 
X 
X 
X 
X 
  
X 
X 
  
X 
X 
X 
X 
Physical 
Examination 
X 
X 
  
  
  
  
  
  
  
  
X 
X 
Telephone 
Reminder/Ass
essmentb 
  
X 
  
  
X 
  
  
X 
  
  
  
  
Acute Care 
Panel 
X 
Xc 
X 
  
  
X 
  
  
X 
  
X 
X 
Hepatic Panel 
X 
Xc 
X 
  
  
X 
  
  
X 
  
X 
X 
Mineral Panel 
X 
Xc 
X 
  
  
X 
  
  
X 
  
X 
X 
CBC/diff  
X 
Xc 
X 
  
  
X 
  
  
X 
  
X 
X 
aPTT, PT/INR  
X 
Xc 
  
  
  
  
  
  
  
  
X 
X 
Pregnancy 
Testingd 
X 
Xc 
X 
  
  
X 
  
  
X 
  
X 
X 
Anti-HIV-1/2 
X 
  
  
  
  
  
  
  
  
  
  
  
Viral Markers 
Hepatitis 
Screen 
X 
  
  
  
  
  
  
  
  
  
  
  
Study Labs 
(Rivaroxaban 
PK/PD) 
  
  
Xe 
Xf 
  
Xe 
Xf 
  
Xe 
Xf 
  
  
Study Labs 
(Pharmacogen
etic testing) 
  
  
 
Xg 
  
  
  
  
  
  
  
  


CLOTRx.  Version 4.0   July 29, 2021 
46 
Study Drug 
(rivaroxaban) 
administered 
  
  
Xh 
  
  
Xh 
  
  
Xh 
  
  
  
Study Drug 
(COBI) 
Dispensed and 
Administered 
  
  
  
Xi 
  
  
  
  
  
  
  
  
Study Drug 
(DRV/COBI) 
Dispensed and 
Administered 
  
  
  
  
  
  
Xj 
  
  
  
  
  
CBC/diff = complete blood count with differential;  aPTT = activated partial thromboplastin time;  PT = 
Prothrombin time;  INR = international normalized ratio;  PK = pharmacokinetics;  PD = pharmacodynamics;  X = 
to be performed. 
a Clinical assessment will involve AE assessments, medication reconciliations, and adherence assessments. 
b Reminder phone calls for long study visit days 1, 7 and 13. Assessment of study medication tolerability will also 
be performed. 
c Blood will only be collected at baseline if the baseline visit is more than 6 days after screening. 
d Serum or urine pregnancy test must be negative to proceed in the study. Pregnancy test will be performed at 
every PK/PD visit prior to administration of rivaroxaban.  
e Blood for plasma serial PK/PD time points. Rivaroxaban time points are 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10 and 24 
hours postdose. At each PK/PD time point, two samples will be drawn, one for PK and one for PD assessment 
(Anti factor Xa, aPTT, PT/INR). PK blood samples will be processed and stored by CPRU lab. PD blood samples 
will be processed and stored by DLM.  
f 24-hour postdose plasma trough collection.  PK blood samples will be processed and stored by CPRU lab. PD 
blood samples will be processed and stored by DLM. 
g Sample collection for pharmacogenomics will be drawn during PK time point 24 (day 2).  Send to Frederick as 
whole blood to be frozen and stored. NIH Contact: Cathy Rehm.  
h On study day visits 1, 7 and 13, rivaroxaban will be dispensed from the pharmacy and administered to the 
participant at the OP8 clinic or Day Hospital. Study drug will be administered at 0800 ± 2 hours 
i A 6-day supply (+ 3 additional tablets) of COBI 150 mg will be dispensed to the participant at Day 2 visit. 
Participant will be reminded to bring the COBI study medication supply to their next visit (Day 7). Participants 
will also be administered COBI 150 mg from the dispensed bottle under directly observed therapy (DOT).   
j A 6-day supply (+ 3 additional tablets) of DRV/COBI 800/150 mg will be dispensed to the participant at Day 8 
visit. Participant will be reminded to bring the DRV/COBI study medication supply to their next visit (Day 13).  
Participants will also be administered DRV/COBI 800/150 mg from the dispensed bottle under DOT.   
 
 
 


CLOTRx.  Version 4.0   July 29, 2021 
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Appendix C: Blood Volumes (mL) for Specimen Collection 
 
Evaluation 
Screening 
(-89 to 0 
days) 
Baselinea 
(-6 to 0) 
1 
2 
7 
8 
13 
14 
20 
±3 
Early 
Termination 
Visit 
HIV-1/2 antigen/antibody testing 
8 
 
 
 
 
 
 
 
 
 
Viral Markers Hepatitis screening 
8 
 
 
 
 
 
 
 
 
 
Acute Care Panelb 
4 
4 
4 
 
4 
 
4 
 
4 
4 
Hepatic Panel 
(4) 
(4) 
(4) 
 
(4) 
 
(4) 
 
(4) 
(4) 
Mineral Panel 
(4) 
(4) 
(4) 
 
(4) 
 
(4) 
 
(4) 
(4) 
Pregnancy Testing 
(4) 
(4) 
(4) 
 
(4) 
 
(4) 
 
(4) 
(4) 
CBC/diff 
3 
3 
3 
 
3 
 
3 
 
3 
3 
aPTT, PT/INR 
3 
3 
 
 
 
 
 
 
3 
3 
Study Labs (Rivaroxaban 
PK/PD)c 
 
 
81 
9 
81 
9 
81 
9 
 
 
Pharmacogenomicsd 
 
 
 
10 
 
 
 
 
 
 
Daily Volume (mL) 
26 
10 
88 
19 
88 
9 
88 
9 
10 
10 
Cumulative Volume (mL) 
26 
36 
124 
143 
231 
240 
328 
337 
347 
 
CBC/diff = complete blood count with differential; aPTT = activated partial thromboplastin time; PT = prothrombin time; 
INR = international normalized ratio; PK = pharmacokinetics; PD = pharmacodynamics. 
aBlood will only be collected at baseline if this visit is more than 6 days after screening. 
bA single volume of blood will be collected for acute care panel, hepatic panel, mineral panel and serum pregnancy testing. 
c Rivaroxaban serial PK/PD time points are 0 (predose), 1, 2, 3, 4, 5, 6, 8, 10, and 24 hours postdose. 
dSample collection for pharmacogenomics. Send to Frederick as whole blood to be frozen and stored. NIH Contact: Cathy Rehm.  
 
 
 


CLOTRx.  Version 4.0   July 29, 2021 
48 
Appendix D: Study Initiation Calendars 
I) 
Study Start Day: Wednesday 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
  
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Day 22 
Day 23 
Day 24 
Day 25 
Days with study visits to the NIH are bolded. 
 
II) 
Study start Day: Thursday 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
  
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Day 22 
Day 23 
Day 24 
Days with study visits to the NIH are bolded. 
 
 
 


CLOTRx.  Version 4.0   July 29, 2021 
49 
Appendix E: Xarelto® Prescribing Information 
Please refer to attachment. 
 
 
 
Appendix F: Tybost® Prescribing Information 
Please refer to attachment. 
 
 
 
Appendix G: Prezcobix® Prescribing Information 
Please refer to attachment. 
 
 
 
Appendix H: Prezista® Prescribing Information 
Please refer to attachment.