Conditions: Latent Tuberculosis Human Immunodeficiency Virus Rifamycins Causing Adverse Effects in Therapeutic Use Drug Interaction Potentiation
Keywords: Drug-drug interaction Pharmacokinetics Non-nucleoside reverse transcriptase inhibitor NNRTI LTBI Antimycobacterial
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: yes

Brief summary:
Drug therapy for persons living with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) co-infected with latent tuberculosis infection (LTBI) is complex. Anti-tuberculosis drugs used to treat LTBI often induce drug metabolizing enzymes that share the same metabolic pathway as antiretroviral drugs used for those living with HIV/AIDS. This study evaluates the drug-drug interaction (DDI) potential of an antiretroviral drug when co-administered with a common anti-tuberculosis regimen of drugs.

Detailed description:
Rifapentine (RPT) and isoniazid (INH) given once weekly for 12 weeks is commonly used for treating LTBI in adults. For people living with HIV-1, the risks of LTBI is increased. Individuals living with HIV-1 are often on chronic antiretroviral drugs that prevent immunodeficiency and complications associated with infection. Unfortunately, antiretroviral drugs are subject to many DDIs especially with RPT which induces drug clearing enzymes.

Doravirine (DOR) is a newly approved non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. Because RPT induces the metabolic pathway in which DOR is removed, there is concern that taking both concomitantly will result in an unwanted DDI leading to reduced DOR concentrations in the blood. Reduced levels will result in loss of efficacy for the drug and therefore not provide adequate viral suppression in those living with HIV. This study investigates the DDI potential of the once weekly regimen RPT and INH together with DOR in healthy volunteers.

Arms:
arm 1: Period 1: DOR twice-daily alone (Study days 1-4) and Period 2: DOR twice-daily with RPT and INH once-weekly (Study days 7-21)

Interventions: intervention 1: Doravirine (DOR) intervention 2: Rifapentine (RPT) intervention 3: Isoniazid (INH)
Intervention descriptions: intervention 1: Non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection in adults in combination with other antiretroviral agents. intervention 2: Rifamycin anti-tuberculosis agent indicated for the treatment of latent and active tuberculosis infection. intervention 3: Anti-tuberculosis agent indicated for the treatment of latent and active tuberculosis infection.

Protocol document:
Prot_SAP_000.pdf: 
DOravirine, Rifapentine and Isoniazid Interaction Study (DORIIS) 
Protocol Version: 2.0 
Protocol Date: 17 April 2019 
JeffTrial Number: 12690 
Page 1 of 48 
 
 
 
 
Clinical Protocol 
 
A Phase 1, Open-Label, Fixed-Sequence, Drug Interaction Study to Investigate the Effect of 
Once-Weekly Rifapentine and Isoniazid on the Pharmacokinetics of Steady-State Doravirine 
 
JeffTrial Protocol Number: 12690 
Merck MISP Number: 58495 
 
Principal Investigator: 
Walter K. Kraft, MD 
Department of Pharmacology & Experimental Therapeutics 
132 South 10th Street, 1170 Main Building 
Philadelphia, PA 19107 
215 -955-6086 
Co-Investigator: 
Edwin Lam, PharmD 
Department of Pharmacology & Experimental Therapeutics 
132 South 10th Street, 1170 Main Building 
Philadelphia, PA 19107 
215-955-5916 
Study Site: 
Thomas Jefferson University 
Funder: 
Merck & Co., Inc. 
Study Compounds: 
Doravirine (PIFELTRO) 
Rifapentine (PRIFTIN) 
Isoniazid 
United States 
Investigational New Drug 
(IND) Number: 
143,072 
Phase: 
1 
Protocol Date: 
16 April 2019 


DOravirine, Rifapentine and Isoniazid Interaction Study (DORIIS) 
Protocol Version: 2.0 
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Page 2 of 48 
 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................. 2 
SUMMARY OF PROTOCOL CHANGES ...................................................................................... 5 
LIST OF TABLES ...................................................................................................................... 6 
LIST OF FIGURES .................................................................................................................... 6 
LIST OF ABBREVIATIONS ........................................................................................................ 7 
PROTOCOL SUMMARY ........................................................................................................... 8 
SCHEDULE OF EVENTS .......................................................................................................... 11 
1 
INTRODUCTION ............................................................................................................ 14 
1.1 Background and Rationale ...................................................................................................... 14 
1.1.1 Background ...................................................................................................................... 14 
1.1.2 Mechanism of Interaction ................................................................................................. 15 
1.1.3 Overview of Doravirine .................................................................................................... 15 
1.1.3.1 Doravirine Clinical Experience in Healthy Volunteers .................................................. 15 
1.1.3.2 Doravirine Co-administered with Rifampin ................................................................. 15 
1.1.3.3 Doravirine Co-administered with Rifabutin ................................................................. 16 
1.1.4 Overview of Rifapentine ................................................................................................... 16 
1.1.4.1 Rifapentine Clinical Experience in Healthy Volunteers ................................................. 16 
1.1.5 Overview of Isoniazid ....................................................................................................... 16 
1.1.5.1 Isoniazid Clinical Experience in Healthy Volunteers ..................................................... 16 
1.1.6 Overview of Pyridoxine .................................................................................................... 16 
1.1.6.1 Pyridoxine Clinical Experience in Healthy Volunteers .................................................. 16 
1.2 Study Rationale ...................................................................................................................... 16 
1.2.1 Rationale for Subject Population ...................................................................................... 16 
1.2.2 Rationale for Dose Selection ............................................................................................. 17 
1.2.2.1 Doravirine ................................................................................................................. 17 
1.2.2.2 Rifapentine ................................................................................................................ 19 
1.2.2.3 Isoniazid .................................................................................................................... 19 
1.2.2.4 Pyridoxine ................................................................................................................. 19 


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1.3 Rationale for Endpoints .......................................................................................................... 19 
1.3.1 Pharmacokinetic Endpoints .............................................................................................. 19 
1.3.2 Safety Endpoints .............................................................................................................. 19 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................. 20 
2.1 Objectives .............................................................................................................................. 20 
2.1.1 Primary Objective ............................................................................................................ 20 
2.1.2 Secondary Objective ......................................................................................................... 20 
2.2 Endpoints ............................................................................................................................... 20 
2.2.1 Primary Endpoints ............................................................................................................ 20 
2.2.2 Secondary Endpoints ........................................................................................................ 20 
3 
STUDY DESIGN .............................................................................................................. 20 
4 
HEALTHY VOLUNTEER SELECTION.................................................................................. 21 
4.1 Inclusion Criteria ..................................................................................................................... 21 
4.3 Study Drug and Lifestyle Adherence ........................................................................................ 22 
4.3.1 Outpatient Phone Contact ................................................................................................ 22 
4.3.2 Outpatient Adverse Event Reporting ................................................................................. 22 
4.4 Subject Discontinuation and Withdrawal ................................................................................. 22 
4.5 Subject Replacement Strategy ................................................................................................. 23 
5 
STUDY INTERVENTIONS ............................................................................................... 23 
5.1 Treatment Drugs ..................................................................................................................... 23 
5.2 Treatment Allocation .............................................................................................................. 24 
6 
STUDY PROCEDURES .................................................................................................... 24 
6.1 Overview ................................................................................................................................ 24 
6.2 Informed Consent ................................................................................................................... 24 
6.3 Subject Recruitment and Screening ......................................................................................... 24 
6.4 Study Visit Schedule ............................................................................................................... 24 
6.4.1 Study Day - 1 .................................................................................................................... 24 
6.4.2 Study Period 1- Pharmacokinetics of Doravirine Alone ...................................................... 24 
6.4.2.2 Period 1- Study Days 2-7 ............................................................................................ 25 
6.4.3 Study Period 2- Pharmacokinetics of Doravirine and Rifapentine and Isoniazid .................. 26 
6.4.3.1 Period 2- Study Days 8-16 .......................................................................................... 26 


DOravirine, Rifapentine and Isoniazid Interaction Study (DORIIS) 
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6.4.3.2 Period 2- Study Days 17-24......................................................................................... 28 
6.4.4 Post-Study Follow-up – Approximately 7-10 days after the last dose of doravirine ............. 29 
6.5 Domiciling .............................................................................................................................. 29 
6.6 Clinical Procedures & Assessments .......................................................................................... 29 
6.6.1 Medical History ................................................................................................................ 29 
6.6.2 Physical Examination ........................................................................................................ 30 
6.6.3 12-Lead Electrocardiogram ............................................................................................... 30 
6.6.4 Vital Signs ........................................................................................................................ 30 
6.6.5 Laboratory Safety Evaluations .......................................................................................... 30 
6.6.6 Prior and Concomitant Medications Review ...................................................................... 30 
6.7 Study Restrictions ................................................................................................................... 30 
6.7.1 Diet, Fruit, and Medications Restrictions ........................................................................... 30 
6.7.2 Alcohol Restriction ........................................................................................................... 31 
6.7.3 Smoking Restriction ......................................................................................................... 31 
6.7.4 Activity Restrictions ......................................................................................................... 31 
6.8 Contraception and Pregnancy Testing ...................................................................................... 31 
6.9 Subject Identification Card ...................................................................................................... 31 
6.10 Standardized Meals .............................................................................................................. 32 
6.11 Study, Drug Dosing and Procedure Modification Permitted .................................................... 32 
6.12 Study Stopping Rules ............................................................................................................ 32 
7 
DRUG SUPPLY ............................................................................................................... 32 
8 
POTENTIAL RISKS AND BENEFITS ................................................................................... 33 
8.1 Potential Risks Associated with Doravirine .............................................................................. 33 
8.2 Potential Risks Associated with Rifapentine ............................................................................ 34 
8.3 Potential Risks Associated with Isoniazid ................................................................................. 35 
8.4 Potential Risks Associated with Pyridoxine .............................................................................. 36 
9 
SAFETY, ADVERSE EVENTS (AE) & SERIOUS ADVERSE EVENTS (SAE) ............................... 36 
9.1 Definitions .............................................................................................................................. 36 
9.1.1 Adverse Event (AE) ........................................................................................................... 37 
9.1.2 Serious Adverse Event (SAE) ............................................................................................. 38 
9.2 Assessing and Recording AEs & SAEs ....................................................................................... 38 


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9.3 Data Safety Monitoring Plan (DSMP) ....................................................................................... 39 
10 DATA COLLECTION, STUDY MONITORING, AND RECORD MANAGEMENT ....................... 39 
10.1 Data Collection and Reporting ............................................................................................... 39 
10.2 Study Monitoring .................................................................................................................. 39 
10.3 Investigator Study Files ......................................................................................................... 40 
10.4 Retention of Records ............................................................................................................ 40 
11 STATISTICAL AND PHARMACOKINETIC METHODS .......................................................... 40 
11.1 Sample Size Estimation ......................................................................................................... 40 
11.2 Pharmacokinetic Analysis ...................................................................................................... 40 
11.3 Safety Analysis ...................................................................................................................... 41 
12 SUPPORTING DOCUMENTATION ................................................................................... 41 
12.1 Appendix 1: Time Windows for Serial Assessments & Dosing .................................................. 41 
12.2 Appendix 2: Clinical Laboratory Tests..................................................................................... 41 
12.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up 
and Reporting .............................................................................................................................. 43 
12.3.1 Definition of AE .............................................................................................................. 43 
12.3.2 Definition of SAE ............................................................................................................ 43 
12.3.3 Additional Events Reported ............................................................................................ 44 
12.3.4 Recording AEs and SAEs .................................................................................................. 44 
13 ETHICS AND PROTECTION OF HUMAN SUBJECTS ........................................................... 46 
13.1 Institutional Review Board Review ........................................................................................ 46 
13.2 Informed Consent ................................................................................................................. 46 
13.1 Subject Confidentiality .......................................................................................................... 46 
14 SUPPLEMENTAL MATERIALS ......................................................................................... 46 
15 REFERENCES ................................................................................................................. 47 
 
 
SUMMARY OF 
PROTOCOL 
CHANGESVersion 
Date 
Description 
2.0 
17 April 2019 
1) Addition of FDA stopping rules 
2) Enrollment age increased to 60 years-old 
3) Addition of pregnancy tests 


DOravirine, Rifapentine and Isoniazid Interaction Study (DORIIS) 
Protocol Version: 2.0 
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4) Clarification of birth control use 
1.0 
18 February 2019 
Original protocol 
 
 
LIST OF TABLES 
 
Table 1: 
Doravirine pharmacokinetic parameters as a once and twice-daily regimen in 
the presence of rifabutin …………………………………………….................................... 
17 
Table 2: 
Dose,  frequency,   route  of   administration,  and  protocol  regimen  under 
investigation……………………………………………………………………………………………….... 22 
Table 3: 
Protocol required safety and other laboratory assessments………………………..... 40 
 
 
LIST OF FIGURES 
 
Figure 1: Simulated mean plasma concentration-time profiles of doravirine following 
administration of 100 mg once daily co-administered with 300 mg once-daily 
rifabutin in healthy volunteers.………………………................................................. 
16 
Figure 2: Simulated mean plasma concentration-time profiles of doravirine following 
administration of 100 mg twice daily co-administered with 300 mg once-daily 
rifabutin in healthy volunteers………………………………………………………………………. 17 
Figure 3: Dosing and sampling schedule………………………………………………………………………. 20 


DOravirine, Rifapentine and Isoniazid Interaction Study (DORIIS) 
Protocol Version: 2.0 
Protocol Date: 17 April 2019 
JeffTrial Number: 12690 
Page 7 of 48 
 
 
 
LIST OF ABBREVIATIONS 
 
AIDS 
Acquired Immunodeficiency Syndrome 
AE 
Adverse Event 
ARV 
Antiretroviral 
AUC0-24 
Area under the plasma-concentration time curve from time 0 to 24 
hours 
AUC0-inf 
Area under the plasma-concentration time curve from time 0 
extrapolated to infinity 
AUC0-last 
Area under the plasma-concentration time curve from time 0 to last 
sampled dose 
BID 
Twice daily 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cmax 
Maximum concentration observed 
CMP 
Complete Metabolic Panel 
CRU 
Clinical Research Unit at Thomas Jefferson University 
CRF 
Case report form 
Ctrough 
Trough concentration 
CYP 
Cytochrome P450 
DDI 
Drug-Drug Interaction 
DSMP 
Data Safety and Management Plan 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
FDA 
US Food and Drug Administration 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IND 
Investigational New Drug 
INH 
Isoniazid 
INSTI 
Integrase Strand Transfer Inhibitor 
LTBI 
Latent Tuberculosis Infection 
NNRTI 
Non-Nucleoside Reverse Transcriptase Inhibitor 
P-gp 
Permeability Glycoprotein 
PHI 
Protected health information 
PK 
Pharmacokinetics 
QD 
Once Daily 
RPT 
Rifapentine 
SAE 
Serious adverse event 
SS 
Steady State 
TB 
Tuberculosis 
Tmax 
Time of maximum observable plasma concentration 
UA 
Urinalysis 
β-hCG 
Beta-Human Chorionic Gonadotropin 


DOravirine, Rifapentine and Isoniazid Interaction Study (DORIIS) 
Protocol Version: 2.0 
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PROTOCOL SUMMARY 
 
Synopsis 
Antiretroviral (ARV) drug therapy for persons living with human immunodeficiency virus (HIV) 
and acquired immunodeficiency syndrome (AIDS) is multi-modal. The presence of HIV infection 
increases the risk of co-infection with tuberculosis which requires drug therapy using 
rifapentine (RPT) and isoniazid (INH). The combination of RPT/INH is well tolerated and is 
recommended as once-weekly therapy for a total of 12 weeks. RPT is an inducer of hepatic 
microsomal drug metabolizing P450 enzymes, which includes the cytochrome (CYP) 3A family 
of enzymes. Doravirine is a novel ARV for the treatment of HIV-1 infection. It is primarily 
metabolized by CYP3A. Co-administration of doravirine together with RPT may result in 
decreased doravirine exposure creating a potential for a drug-drug interaction when both 
drugs are used together. This study is designed to evaluate the pharmacokinetics of doravirine 
100 mg given twice daily in the presence of RPT/INH, and to evaluate the safety and tolerability 
of doravirine when co-administered with RPT/INH in healthy volunteers. 
Overview of Study Design 
This is a phase I, open-label, two-period, fixed-sequence, drug interaction study to evaluate 
the effect of twice-daily doravirine co-administered with RPT and INH in healthy participants. 
All participants will receive doravirine alone for 4 days given twice daily during the first period. 
Doravirine dosing will resume from days 7-21. RPT and INH will be administered on days 7, 14, 
and 21 during the second period. 
Hypothesis 
When co-administered, once-weekly rifapentine will decrease the geometric mean 
concentrations of twice-daily doravirine by 15% compared to the geometric mean trough 
concentrations of twice-daily doravirine administered alone. 
Objectives and Endpoints 
Primary Objective 
Primary Endpoint 
Compare the change in plasma exposure-time 
profile, defined as AUC(0-last), Cmax, and Ctrough, 
following multiple oral doses of twice-daily 
doravirine 100 mg co-administered with weight 
based, once-weekly RPT and INH. 
Change in pharmacokinetic parameters 
measured as AUC(0-last), Cmax, and Ctrough. 
Secondary Objective 
Secondary Endpoint 


DOravirine, Rifapentine and Isoniazid Interaction Study (DORIIS) 
Protocol Version: 2.0 
Protocol Date: 17 April 2019 
JeffTrial Number: 12690 
Page 9 of 48 
 
 
 
 
Evaluate the safety and tolerability of doravirine 
when co-administered with RPT and INH. 
Proportion of subjects with treatment- 
emergent adverse events for safety 
parameters. 
Study Population (Inclusion) 
1. Healthy male or female between 18-60 years old at the time of screening. 
2. Have a Body Mass Index (BMI) > 19 and < 33. 
3. Weigh > 45 kg but < 120 kg. 
4. Non-smoker (tobacco or electronic cigarettes). 
5. Negative QuantiFERON-TB Gold at screening. 
6. Subjects who agree to abstain from alcohol consumption throughout the duration of 
the study. 
7. Female subjects of childbearing potential must demonstrate a urine beta-hCG 
consistent with non-pregnancy at the time of the screening visit and agree to the use 
(and/or have their partner use) an acceptable method of birth-control at initial 
screening, during the time of the trial and until four weeks after the last dose of drug 
following the last treatment period. 
8. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study. 
Study Population (Exclusion) 
1. History of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary, 
dermatologic, psychiatric abnormalities or neurological (including stroke and chronic 
seizure) diseases. 
2. >500 mL blood or plasma donation in the 6 weeks prior to study start. 
3. Known anaphylactic or severe systemic reactions to any components of doravirine, 
rifapentine, isoniazid, or pyridoxine. 
4. Positive HIV, Hepatitis B or Hepatitis C virus. Evidence of prior Hepatitis B infection 
and immunity is not exclusionary. 
5. Latent or active tuberculosis infection. Documented prior fully treated latent 
tuberculosis is not exclusionary. 
6. Females who are postpartum for < 12 months. 
7. Current drug or alcohol abuse. 
8. Received study drug in another study within 4 weeks or within 5 half-lives- which ever 
occurring first- before first anticipated dose of study drug in this study. 


DOravirine, Rifapentine and Isoniazid Interaction Study (DORIIS) 
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9. Unable to refrain from use of over-the-counter, prescription (unless determined 
appropriate by the investigator), herbal or natural products, vitamins or supplements, 
or grapefruit juice/grapefruit products. 
10. Any clinical significant findings on lab, ECG, or physical exam at screening. 
Compounds Under Investigation and Doses 
Doravirine (Pifeltro) 
Class: Antiretroviral; Non-nucleoside reverse transcriptase inhibitor 
Availability: 100 mg oral tablet 
Investigational dosing: 100 mg orally twice-daily 
Rifapentine (Priftin) 
Class: Anti-tuberculosis agent 
Availability: 150 mg oral tablet 
Investigational dosing: 32.1–
49.9 kg - 750 mg 
≥50.0 kg - 900 mg (maximum) 
Isoniazid 
Class: Anti-tuberculosis agent 
Availability: 100mg and 300 mg oral tablets 
Investigational dosing: 15 mg/kg rounded up to the nearest 50 or 100 mg; 900 mg maximum 
Number of Subjects 
11 


DOravirine, Rifapentine and Isoniazid Interaction Study (DORIIS) 
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SCHEDULE OF EVENTS 
Procedures 
(Screening – Study day 14) 
Screening 
(Day -30) 
Pre-study 
Day 
(Day -1) 
Study 
Day 1 
Study 
Day 2 
Study 
Day 3 
Study 
Day 4 
Study 
Day 5 
Study 
Day 6 
Study 
Day 7 
Study 
Day 8 
Study 
Day 9 
Study 
Day 10 
Study 
Day 11 
Study 
Day 12 
Study 
Day 13 
Study 
Day 14 
Assessment of Eligibility 
X 
Signed Consent Form 
X 
Medical History 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory 
Pregnancy Test 
X 
X* 
X 
X 
Complete Blood Count 
X 
Xd 
Xc 
Comprehensive Metabolic 
Panel 
X 
Xd 
Xc 
QuantiFERON-TB Gold 
X 
HIV, Hepatitis B & C 
X 
Alcohol & Drug Screen 
X 
X 
Urinalysis 
X 
Clinical 
Procedur 
es 
Physical Exam¤ 
Xa 
X 
X 
Xf 
X 
Xf 
Vital Signs 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
Researc 
h Labs 
Doravirine PK 
Xb 
Xb,c 
X 
X 
Xb 
Doravirine Trough 
Treatment 
Rifapentine (weight based) 
Xe 
Xe,f 
Isoniazid (weight based) 
Xe 
Xe,f 
Pyridoxine 50 mg 
Xe 
Xe 
Doravirine 100 mg BID 
X 
X 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inpatient 
X 
X 
DC 
X 
X 
X 
X 
DC 
X 
DC 
Footnotes DC= Discharge from the Clinical Research Unit once all procedures are completed. 
a. A height and weight measurement will be taken at screening. 
b. A pre-doravirine PK will be taken prior to the AM dose. 
c. PK sampling will begin following the end of the AM dose. The 12 hour time point will be taken prior to the PM dose. PK Sampling schedule can be found in section 6.4.2.2. 
d. Safety labs will be drawn while the subjects are fasting prior to receiving doravirine. 
e. Subjects will receive isoniazid on an empty stomach and receive breakfast approximately 1 hour following the isoniazid dose. Doravirine, rifapentine and pyridoxine will be given approximately 20 
minutes after breakfast. 
f. Subjects whose weight is < 60 kg (< 130 lbs) at screening will be reweighed the day prior to isoniazid and rifapentine doses to establish the correct dose (no other physical exam). 


DOravirine, Rifapentine and Isoniazid Interaction Study (DORIIS) 
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*Pregnancy test for women of childbearing potential 
¤Physicals may be done the day prior except at the screening visit 


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Procedures (continued) 
(Study days 15 – Post-study) 
Study 
Day 15 
Study 
Day 16 
Study 
Day 17 
Study 
Day 18 
Study 
Day 19 
Study 
Day 20 
Study 
Day 21 
Study 
Day 22 
Study 
Day 23 
Study 
Day 24 
Post-study 
Follow-up 
(+7 to 10 days) 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
Laboratory 
Pregnancy Test* 
X 
Complete Blood Count 
Xb 
Xb 
X 
Comprehensive Metabolic Panel 
Xb 
Xb 
X 
Clinical 
Procedur 
es
Physical Exam¤ 
X 
Xf 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
Research 
Labs 
Doravirine PK 
Xa,c 
X 
X 
X 
Doravirine Trough 
Xc 
Xc 
Xd 
Treatment 
Rifapentine (weight based) 
Xe 
Isoniazid (weight based) 
Xe 
Pyridoxine 50 mg 
Xe 
Doravirine 100 mg BID 
X 
X 
X 
X 
X 
X 
X 
Assessment of Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inpatient 
X 
X 
X 
DC 
Footnotes 
DC= Discharge from the Clinical Research Unit once all procedures are completed. 
a. PK sampling will begin prior to the AM dose. The 12 hour time point will be taken prior to the PM dose of doravirine. PK sampling schedule can be found in section 6.4.3.2. 
b. Safety labs will be drawn while the subjects are fasting prior to receiving doravirine. 
c. Trough sampling will be prior to the AM dose. 
d. Trough sampling will be prior to the PM dose. 
e. Subjects will receive isoniazid on an empty stomach and receive breakfast approximately 1 hour following the isoniazid dose. Doravirine, rifapentine and pyridoxine will be given approximately 20 
minutes after breakfast. 
f. Subjects whose weight is < 60 kg (< 130 lbs) at screening will be reweighed the day prior to isoniazid and rifapentine doses to establish the correct dose (no other physical exam). 
*Pregnancy test for women of childbearing potential 
¤Physicals may be done the day prior except at the screening visit 


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1 
INTRODUCTION 
1.1 Background and Rationale 
1.1.1 Background 
Approximately 36.7 million people are living with Human Immunodeficiency Virus (HIV) 
worldwide with 21 million of those living with HIV receiving antiretroviral (ARV) drug therapy.1 
In those living with HIV, an estimated one-third of those individuals will be infected with 
Mycobacterium tuberculosis.2 The presence of HIV infection increases the risk of co-infection 
with tuberculosis (TB) by 20 to 37-fold compared to HIV-uninfected individuals. An alarming 19- 
fold increase since 2004 in global persons co-infected with TB and HIV has shifted the focus to 
identifying detection and treatment gaps to reduce the incidence of active TB in those living 
with HIV and acquired immunodeficiency syndrome (AIDS).3 In 2016, approximately 2 million 
persons globally were newly enrolled in HIV care. Approximately 42% of those 2 million persons 
living HIV initiated preventative treatment for TB reflecting the global increase in co-infection. 
As of 2016, approximately 85% of reported TB cases were on ARV therapy.3 
Tuberculosis (TB) infection is caused by Mycobacterium tuberculosis complex. Transmission 
occurs through inhalation of the bacterium from an infected individual and may progress into 
active infection or persist in an inactive state. In the inactive state, host defenses contain the 
tuberculosis. Patients are asymptomatic and this is called latent TB (LTBI). However, 
reactivation of the disease may occur allowing transmission to others. In immunocompromised 
individuals, such as those living with HIV/AIDS, the risk of developing active TB disease 
following LTBI is high compared to those without HIV co-infection.4,5 Following treatment for 
LTBI, the risk of progressing to active TB was reduced by as much as 62% in individuals co- 
infected with HIV.6 Similar reports have also observed reduced transmission rates.7 It is 
therefore critical to initiate treatment for LTBI in order to reduce progression to active TB 
disease and TB transmission in those living with HIV/AIDS. 
The Centers for Disease Control and Prevention (CDC) currently recommends use of one of four 
possible LTBI treatment regimens consisting of the rifamycins, rifampin, rifabutin, and 
rifapentine (RPT), and isoniazid (INH).8 INH and RPT given once-weekly under direct 
observational therapy for a duration of three months offers the shortest duration of treatment 
with comparable efficacy as the previous regimens. 
Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) currently approved 
in the United States for the treatment of HIV-1 infection in adult patients with no prior ARV 
treatment history. Doravirine is predominately metabolized by CYP3A4 with no clinically 
significant inhibition or induction of other cytochrome P450 enzymes.9 


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Doravirine is a substrate for the efflux transporter, permeability glycoprotein (P-gp), but does 
not inhibit P-gp. Doravirine is primarily metabolized by CYP3A and drugs that induce or inhibit 
CYP3A may affect the clearance of doravirine. 
1.1.2 Mechanism of Interaction 
The rifamycin family of antibiotics are notoriously known for potentiating DDIs through 
induction of cytochrome P450 drug metabolizing enzymes or drug transporters. The three 
currently US FDA marketed rifamycins include rifampin, rifabutin, and RPT.10-12 The potency of 
induction is greatest with rifampin (100%) followed by RPT (85%) and rifabutin (40%).13 
As such, clinically meaningful DDIs may present to therapeutically co-administered drugs who 
are CYP3A substrates. Enzyme induction may be time-dependent and variable depending on  
the TB regimen selected. In healthy volunteer studies, CYP3A4 induction was greatest when RPT 
was dosed daily compared to given every three days.14 
DDI studies involving RPT dosed once-weekly together with ARV drugs have also shown time- 
dependent inductive effects compared to RPT dosed daily.15,16 
1.1.3 Overview of Doravirine 
1.1.3.1 Doravirine Clinical Experience in Healthy Volunteers 
The safety and tolerability of doravirine were investigated in two single and multiple ascending 
dose studies that explored doses ranging from 6 to 1200 mg in healthy male subjects.17 
Doravirine was well tolerated at multiple doses of up to 750 mg once daily for up to 10 days. 
Headache, dizziness, nausea and fatigue were the most common reported adverse events 
related to the study drug. There were no clinically significant trends observed in laboratory 
assessments, vital signs or ECGs in healthy volunteers. 
The pharmacokinetics of doravirine is expected to be similar between healthy subjects and HIV- 
1 infected subjects. 
1.1.3.2 Doravirine Co-administered with Rifampin 
When co-administered with multiple-doses of rifampin, peak and systemic exposures were 
reduced by 57% and 78%, respectively.18 The parameter associated with virological suppressive 
efficacy, C24, was reduced by 97%. Chronic administration of rifampin was therefore concluded 
to result in loss of efficacy overtime. As such, the regulatory labeling recommends against the 
co-administration of doravirine together with rifampin. 
Doravirine was well tolerated administered alone or co-administered with rifampin. The most 
common adverse event was oropharyngeal pain reported in 2 subjects with all adverse events 
resolving by the end of study. There were no clinically meaningful changes observed in 
laboratory, vital signs or ECG in volunteers on doravirine co-administered with rifampin.18 


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1.1.3.3 Doravirine Co-administered with Rifabutin 
Following multiple doses of rifabutin in healthy volunteers, doravirine exposures and C24 were 
observed to decrease by 50% and 68%, respectively.19 Whereas the magnitude of induction 
from rifampin observed significant reductions in the exposure parameters, induction from 
rifabutin may be potentially mitigated using a dosing regimen consisting of doravirine 100 mg 
twice daily. 
Doravirine was well tolerated when co-administered with rifabutin. The most commonly 
observed adverse events were headaches, pyrexia and chromaturia and was considered related 
to rifabutin treatment.19 
1.1.4 Overview of Rifapentine 
1.1.4.1 Rifapentine Clinical Experience in Healthy Volunteers 
The 2018 update to the CDC recommendations for LTBI management have expanded the utility 
of once-weekly RPT to include those aged 2-17 years old.20 RPT is approved by the FDA for the 
treatment of pulmonary TB caused by Mycobacterium tuberculosis.10 RPT is standard of care 
and used extensively to manage LTBI or active TB infections. Doses of up to 20 mg/kg/day were 
well tolerated in healthy volunteers.21 
The most common adverse events observed in healthy volunteers (n=7) at doses used in this 
study were constipation (29%), vomiting (14%), fever (14%), dizziness (14%), hyperbilirubinemia 
(14%), and lymphopenia (28%).21 
1.1.5 Overview of Isoniazid 
1.1.5.1 Isoniazid Clinical Experience in Healthy Volunteers 
INH is the gold standard in the treatment of LTBI and active TB infection for both adult and 
children. In patients with LTBI, INH is either given alone for 6 or 9 months or together with 
rifamycins to shorten the duration of therapy. INH is approved by the FDA for the treatment of 
of all forms of tuberculosis in which organisms are susceptible.22 
INH is safe and well tolerated in healthy volunteers from doses ranging from 300-900 mg.23 
1.1.6 Overview of Pyridoxine 
1.1.6.1 Pyridoxine Clinical Experience in Healthy Volunteers 
Pyridoxine is an essential water soluble vitamin commonly sold over-the-counter as vitamin B6. 
1.2 Study Rationale 
1.2.1 Rationale for Subject Population 
The study will be conducted in healthy volunteers. The use of patient populations would be 
considered unethical based on the need to switch ARV regimens in those living with HIV to 
doravirine. Such practice would promote resistance and will be potentially exposing patients to 


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harm. Historically, this regimen has been studied in healthy volunteers in the presence of ARVs 
and is the common practice for conducting DDI studies.14,15 
1.2.2 Rationale for Dose Selection 
1.2.2.1 Doravirine 
Doravirine 100 mg twice-daily dosing was based on simulated plasma concentration-time 
profiles following co-administration of once-daily 300 mg rifabutin in healthy volunteers (figure 
1 and 2). 
Figure 1. Simulated mean plasma concentration-time profiles of doravirine following 
administration of 100 mg once daily co-administered with 300 mg once-daily rifabutin in 
healthy volunteers. 
 
Source: Doravirine FDA Clinical Pharmacology Review 


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Figure 2. Simulated mean plasma concentration-time profiles of doravirine following 
administration of 100 mg twice daily co-administered with 300 mg once-daily rifabutin in 
healthy volunteers. 
 
Source: Doravirine FDA Clinical Pharmacology Review 
 
Table 1 shows the mean plasma pharmacokinetic values following single oral doses of 100 mg 
doravirine with once-daily 300 mg rifabutin as the 100 mg regimen and 100 mg twice-daily 
regimen at day 1 and 5. 
Table 1. Doravirine pharmacokinetic parameters as a once and twice-daily regimen in the 
presence of rifabutin. 
Source: Doravirine FDA Clinical Pharmacology Review 


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Based on non-parametric superposition and simulation using 100 mg twice-daily doravirine co- 
administered with 300 mg once-daily rifabutin, a twice-daily 100 mg doravirine regimen 
achieves similar trough, AUC0-24 and Cmax values as compared to a 100 mg once-daily dose of 
doravirine in the absence of an inducer. 
It is with this evidence that a 100 mg twice-daily doravirine dose be selected to study the 
interacting effects when co-administered with RPT. 
1.2.2.2 Rifapentine 
The dose of RPT was selected based on the CDC recommended doses for LTBI. The 
recommended dose in adults is weight based, with a maximum dose of up to 900 mg weekly. 
The recommended dose based on the range of weights is: 
 32.1-50 kg: 750 mg 
 >50 kg: 900 mg 
1.2.2.3 Isoniazid 
The dose of INH was selected based on the recommended doses for LTBI. The recommended 
dose in adults is weight based, with a maximum dose of up to 900 mg weekly. The 
recommended dose is 15 mg/kg. 
1.2.2.4 Pyridoxine 
The pyridoxine dose was selected based on the recommended doses for concurrent INH 
administration in LTBI. Pyridoxine is given to persons taking INH to reduce the risk of 
neuropathy. It is not anticipated that pyridoxine will impact the potential for DDI, it is safe and 
administered routinely with INH in clinical practice. The recommended dose is 50 mg daily. 
1.3 Rationale for Endpoints 
1.3.1 Pharmacokinetic Endpoints 
Blood samples will be collected for doravirine PK analysis at pre-dose (0 hour), 0.5, 1, 1.5, 2, 3, 
6, 12, 24, 36, 48 and 72 hours post dose on study days 4-7 (when doravirine is given alone) and 
21-24 (following co-administration with RPT/INH). Doravirine trough concentrations will be 
taken on study days 15, 16, and 20. 
The PK parameters prior to co-administration and following will be estimated using non- 
compartmental analysis. With patients on ARVs, drug concentrations determine efficacy 
(virological suppression). Therefore, the pharmacokinetic parameters associated with efficacy 
(Ctrough, Cmax, and AUC) will be compared prior to and following co-administration of RPT/INH. 
1.3.2 Safety Endpoints 
Safety for doravirine, INH, and RPT has been extensively studied and is well established. This 
study will observe the safety and tolerability of co-administration of doravirine, INH and RPT in 


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healthy volunteers. Given the extensive experience of all three drugs, it is not expected that the 
current study will be sensitive to detect new or uncommon safety events associated with co- 
administration. 
 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 Objectives 
2.1.1 Primary Objective 
 Compare the change in plasma exposure-time profile, defined as AUC(0-last), Cmax, and 
Ctrough, following multiple oral doses of twice-daily doravirine 100 mg co-administered 
with weight based, once-weekly RPT and INH in healthy HIV-negative adult volunteers.
2.1.2 Secondary Objective 
 Evaluate the safety and tolerability of doravirine when co-administered with rifapentine 
and INH in healthy HIV-negative adult volunteers. 
2.2 Endpoints 
2.2.1 Primary Endpoints 
 Change in the doravirine plasma exposure-time profile, as defined by AUC(0-last), Cmax, 
and Ctrough.
2.2.2 Secondary Endpoints 
 Proportion of subjects experiencing adverse event(s) characterized by type, frequency, 
severity, timing and laboratory abnormalities- and tolerability of the co-administered 
drugs.
 
3 
STUDY DESIGN 
This is a prospective, phase I, single-center, open-label, fixed-sequence, two-period, 
pharmacokinetic study investigating the effect of RPT and INH on the pharmacokinetics of 
doravirine. 
Eleven healthy male or female adult subjects will be enrolled. Subjects will receive reference 
drug (doravirine 100 mg given as one 100 mg tablet twice-daily) for four study days during the 
first period. For the second period beginning on study day 7 (first week of perpetrator drug 
dosing), a weight-based dose of RPT/INH and pyridoxine 50 mg will be administered together 
with doravirine 100 mg twice daily. 
Combination RPT/INH and pyridoxine 50 mg will be administered weekly (study days 14 and 21) 
while doravirine 100 mg will be dosed twice-daily from study day 7 onward to study day 21. 


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Figure 3: Dosing and sampling schedule. 
 
4 
HEALTHY VOLUNTEER SELECTION 
4.1 Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study. 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Healthy male or female between 18-60 years old at the time of screening. 
2. Have a Body Mass Index (BMI) > 19 and < 33. 
3. Weigh > 45 kg but < 120 kg. 
4. Non-smoker (tobacco or electronic cigarettes). 
5. Negative QuantiFERON-TB Gold at screening. 
6. Subjects who agree to abstain from alcohol consumption throughout the duration of the 
study. 
7. Female subjects of childbearing potential must demonstrate a urine beta-hCG 
consistent with non-pregnancy at the time of the screening visit and agree to the use 
(and/or have their partner use) of an acceptable method of birth-control at initial 
screening, during the time of the trial, and until four weeks after the last dose of drug 
following the last treatment period. 
8. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study. 


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4.2 Exclusion Criteria 
Subjects with any of the following characteristics or conditions will not be included in the study: 
1. History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, 
hepatic, immunological, renal, respiratory, genitourinary, dermatologic, psychiatric 
abnormalities or neurological (including stroke and chronic seizure) diseases. 
2. >500 mL blood or plasma donation in the 6 weeks prior to study start 
3. Known anaphylactic or severe systemic reactions to any components of doravirine, 
rifapentine, isoniazid or pyridoxine. 
4. Positive HIV, Hepatitis B or Hepatitis C virus. Evidence of prior Hepatitis B infection and 
immunity is not exclusionary. 
5. Latent or active tuberculosis infection. Documented prior fully treated latent 
tuberculosis is not exclusionary. 
6. Females who are postpartum < 12 months. 
7. Current drug or alcohol abuse. 
8. Received study drug in another study within 4 weeks or within 5 half-lives, which ever 
occurring first, before first anticipated dose of study drug in this study. 
9. Unable to refrain from use of over-the-counter, prescription (unless determined 
appropriate by the investigator), herbal or natural products, vitamins or supplements, or 
grapefruit juice/grapefruit products. 
10. Any clinical significant findings on lab, ECG or physical exam at screening. 
4.3 Study Drug and Lifestyle Adherence 
Enrolled subjects must be willing and able to adhere to the following lifestyle restrictions during 
the course of the study in order to be eligible for participation: 
1. Refrain from the use of alcohol and illicit drugs throughout the study duration 
2. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary 
supplements, unless at the opinion of the investigator, not compromise the safety of the 
subject 
4.3.1 Outpatient Phone Contact 
Subjects will be contacted by a CRU staff to ensure adherence to their evening doravirine doses. 
4.3.2 Outpatient Adverse Event Reporting 
CRU staff will assess for AEs during the outpatient phone calls. 
4.4 Subject Discontinuation and Withdrawal 
Subjects may withdraw consent at any time for any reason. In addition, a subject may be 
withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons. Subjects who miss any treatment 
dose will be discontinued from the study at the discretion of the investigator. Any subject who 


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suffers a serious safety adverse events possibly- or probably-related-to study intervention will 
be discontinued. 
4.5 Subject Replacement Strategy 
If a subject discontinues from the trial, a replacement subject may be enrolled if deemed 
appropriate by the investigators. The replacement subject will generally receive the same 
treatment or treatment sequence (as appropriate) as the subject being replaced. 
 
5 
STUDY INTERVENTIONS 
5.1 Treatment Drugs 
The treatment drugs used in this study are doravirine, rifapentine, isoniazid, and pyridoxine. 
Table 2 highlights the dose, frequency, route of administration, and protocol regimen under 
investigation. 
Table 2: Dose, frequency, route of administration, and protocol regimen under investigation 
 
Drug 
Dose 
Dosage 
Form 
Dosing Frequency 
Route of 
Administration 
Protocol 
Regimen 
Doravirine 
100 mg 
Tablet 
1 tablet twice daily 
Oral 
Twice daily 
administration 
on study days 
1-4 and 7-21 
Rifapentine 
150 mg 
Tablet 
Weight Based Once Weekly 
Dosing: 
32.1–49.9 kg - 750 mg (5 tablets) 
≥50.0 kg - 900 mg (maximum – 6 
tablets) 
Oral 
Once weekly 
administration 
on study days 
7, 14, and 21 
Isoniazid 
300 mg 
Tablet 
Weight Based Once Weekly 
Dosing: 
15 mg/kg rounded up to the 
nearest 50 or 100 mg (900 mg or 3 
tablets maximum) 
Oral 
Once weekly 
administration 
on study days 
7, 14, and 21 
Pyridoxine 
50 mg 
Tablet 
1 tablet once weekly 
Oral 
Once weekly 
administration 
on study days 
7, 14, and 21 


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5.2 Treatment Allocation 
Subjects will be screened using a screening number (SN) beginning consisting of an alpha- 
numeric code starting with SN 1001. Allocation numbers will begin with 201. Replacement 
subjects will begin with allocation 301. 
 
6 
STUDY PROCEDURES 
6.1 Overview 
Procedures to be performed at each visit are summarized on the table of scheduled events. It 
may be necessary to perform study procedures at unscheduled time points if deemed clinically 
necessary by the investigator. Additional evaluations/testing may be deemed necessary by the 
investigator and or sponsor for reasons related to subject safety. Trial procedures should be 
completed as close to the prescribed/scheduled time as possible. 
6.2 Informed Consent 
Consent must be documented by the subject’s dated signature on a consent form along with 
the dated signature of the person conducting the consent discussion. A copy of the signed and 
dated consent form will be given to the subject before participation in the trial. The subject will 
be informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the trial. The informed consent will adhere 
to institutional review board (IRB) requirements, applicable laws and regulations. 
6.3 Subject Recruitment and Screening 
Within approximately 3 weeks prior to randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements. Informed consent will be obtained from 
subjects who elect to participate in the study. Consent form must be signed before any study 
related procedures are done. Subjects will be asked to fast from food and drinks, except water, 
for at least 8 hours prior to the screening visit labs being drawn. 
6.4 Study Visit Schedule 
In addition to the procedures and assessments detailed below- adverse events and concomitant 
medication review will be assessed. Any nonscheduled procedures required for urgent 
evaluation of safety concerns take precedence over all routine scheduled procedures. 
6.4.1 Study Day - 1 
Subjects will be admitted to the CRU in the evening. Concomitant medications and adverse 
event assessments will be reviewed. A urine drug screen and serum alcohol will be obtained as 
well as pregnancy test for females of childbearing potential 
6.4.2 Study Period 1- Pharmacokinetics of Doravirine Alone 
Pharmacokinetic sampling windows are detailed in Appendix 1. 
6.4.2.1 Period 1- Study Day 1 


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 Vital signs and physical exam pre-dose 
 Pre-dose PK 
 Administer one tablet of 100 mg doravirine orally twice daily with 240 mL of water; 
twice daily will be 12 hours apart (AM and PM dose) 
 Assess for adverse events 
6.4.2.2 Period 1- Study Days 2-7 
 Study Day 2: 
o Dosing (AM): Subjects will be dosed with 100 mg doravirine in the AM with 240 
mL of water 
o Assessments (AM): AEs and concomitant medication review. 
o PK: No PK taken 
o Dosing (PM): Subjects will be given their PM dose of 100 mg doravirine with 240 
mL of water to take at home with instructions. 
o Subjects will be discharged from the CRU following all procedures 
 
 Study Day 3: 
o Dosing (AM): Subjects will return to the CRU in the morning for their 100 mg 
doravirine AM dose 
o Assessments (AM): Subjects will be assessed for AEs and concomitant 
medications 
o PK: No PK 
o Subjects will be readmitted back to the CRU on the evening of study day 3 
o Dosing (PM): Subjects will be given their PM dose of 100 mg doravirine 
administered with 240 mL of water in the CRU 
o Assessments (PM): AEs and concomitant medications will be reviewed 
 
 Study day 4: 
o Assessments (AM): Vital signs, AE, concomitant medications, physical exam, will 
be obtained pre-dose. Breakfast will be given pre-AM doravirine dose. 
o DOSE (AM): AM dose of 100mg Doravirine will be given with 240ml of water 
approximately 20mins after breakfast. 
o PK: A PK will be drawn prior to the AM dose of doravirine. Subsequent PK will be 
drawn at 0.5, 1, 1.5, 2, 3 and 6 hours post Day 4 AM dose. 
o PK (PM): A 12 hour post (Day 4 AM) dose PK will be drawn. 
o Assessments (PM): AEs 
o Dose (PM): Administer PM doravirine 100 mg dose with 240 mL of water. 
 
 Study day 5: 
o PK: A 24 hour post (Day 4 AM) dose PK will be drawn. 
o Dose: No doravirine dosed. 


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o Assessments: AEs, concomitant medications and safety labs (CBC and CMP). 
o Study day 5 PK (PM): A 36 hour post (Day 4 AM) dose PK will be drawn. 
 
 Study day 6: 
o PK: A 48 hour post (Day 4 AM) dose PK will be drawn. 
o Dose: No doravirine dose. 
o Assessments: AEs and concomitant medications. Subjects < 60kg will be 
weighed. See footnote f. page 11. 
o Discharge from the CRU on the morning of study day 6 after all procedures are 
completed. 
o Readmit subjects on the evening of study day 6. A Pregnancy test will be 
performed for women of childbearing potential. 
 
 Study day 7: 
o PK: A 72 hour post (Day 4 AM) dose PK will be drawn. 
o Assessments: AEs, concomitant medications, and vital signs will be obtained for 
all subjects. 
o Dose (AM): Isoniazid 15mg/kg will be dosed orally on an empty stomach after 
the assessments above. Breakfast will be provided approximately 1 hour after 
isoniazid dose. Doravirine 100 mg, rifapentine (weight based) and pyridoxine 50 
mg will be dosed orally approximately 20 minutes after breakfast with 240 mL of 
water. 
o Subjects will remain in the unit 2 hours post-dose to assess for any adverse 
reactions. Subjects will be discharged from the unit after 2 hours, however 
subjects may be kept longer per investigator discretion. 
o Dosing (PM): Subjects will be given their PM dose of 100 mg doravirine with 240 
mL of water to take at home with instructions. 
 
6.4.3 Study Period 2- Pharmacokinetics of Doravirine and Rifapentine and Isoniazid 
Pharmacokinetic sampling windows are detailed in Appendix 1. 
6.4.3.1 Period 2- Study Days 8-16 
 Study Days 8 – 16 
o Study day 8: 
 Subjects will arrive to the CRU in the morning. 
 Assessments: Subjects will have a physical exam, vital signs and 
laboratory safety blood drawn (CBC and CMP) 
 Dose (AM): A 100 mg dose of doravirine will be given with 240 mL of 
water. 
 Dosing (PM): Subjects will be given their PM dose of 100 mg doravirine 
with 240 mL of water to take at home with instructions. 


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 PK: No PK 
 
o Study days 9-13: 
 Subjects will arrive to the CRU each morning. 
 Assessments: AEs and concomitant medications will be assessed prior to 
AM doses each morning. 
 Dose (AM): A 100 mg dose of doravirine will be given with 240 mL of 
water. Subjects will be discharged after the procedures. 
 Dosing (PM): Subjects will be given their PM dose of 100 mg doravirine 
with 240 mL of water to take at home with instructions. 
 PK: No PK 
 Study Day 13 PM: Subjects will be admitted to the CRU. A pregnancy test 
will be performed for women of childbearing potential. 
 Assessments: AEs and concomitant medications. Subjects < 60kg will be 
weighed. See footnote f. page 11. 
 Dosing (PM): Subjects will be given their PM dose of 100 mg doravirine 
with 240 mL of water. 
 PK: No PK 
 
o Study day 14: 
 Assessments: Subjects will have their vital signs taken and assessed for 
AEs and concomitant medications prior to AM dosing. 
 Dose (AM): Isoniazid 15 mg/kg will be dosed on an empty stomach after 
the procedures above. Breakfast will be provided approximately 1 hour 
after isoniazid dose. Doravirine 100 mg, rifapentine (weight based) and 
pyridoxine 50 mg will be dosed with 240 mL of water approximately 20 
minutes after breakfast. 
 Subjects will remain in the unit 2 hours post-dose to assess for any 
adverse events. Subjects will be discharged from the unit after 2 hours, 
however subjects may be kept longer per investigator discretion 
 Subjects will be discharged following all procedures above 
 Dosing (PM): Subjects will be given their PM dose of 100 mg doravirine 
with 240 mL of water to take at home with instructions. 
 PK: No PK 
 
o Study day 15: 
 Subjects will arrive to the CRU in the morning. 
 Assessments: AEs, concomitant medications, physical exam and safety 
lab draws (CBC & CMP) prior to AM dose. 
 PK: A doravirine trough level will be taken prior to the morning dose. 


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 Dose (AM): Doravirine 100 mg will be administered with 240 mL of 
water. 
 Dose (PM): Subjects will be given their PM dose of 100 mg doravirine 
with 240 mL of water to take at home with instructions. 
 
o Study day 16: 
 Subjects will arrive to the CRU in the morning 
 Assessments: AEs and concomitant medications. 
 PK: A doravirine trough level will be taken prior to the morning dose. 
 Dose (AM): Doravirine 100 mg will be administered with 240 mL of water 
 Dose (PM): Subjects will be given their PM dose of 100 mg doravirine 
with 240 mL of water to take at home with instructions. 
 
6.4.3.2 Period 2- Study Days 17-24 
Pharmacokinetic sampling windows are detailed in Appendix 1. 
 Study days 17-20: 
o Subjects will arrive to the CRU in the morning 
o Assessments: AEs and concomitant medications 
o PK: No PK on study days 17 and 18 
o Study day 20: 
 
PK: A doravirine trough level will be taken prior to the morning dose. 
 Assessments: Subjects < 60kg will be weighed. See footnote f. page 11. 
o Dose (AM): Doravirine 100 mg will be administered with 240 mL of water. 
o Subjects will be admitted to the CRU on the evening of study day 20 
o Assessments: AEs and concomitant medications, a pregnancy test will be 
performed for women of childbearing potential. 
o Dose (PM): Administered PM doravirine 100 mg dose with 240 mL of water 
 
 Study day 21: 
o Assessments (AM): Vital signs, AE, concomitant medications, physical exam will 
be obtained pre-dose. 
o PK (Pre-dose): A PK will be drawn prior to the AM dose of doravirine. 
o Dose (AM): Isoniazid 15 mg/kg will be dosed on an empty stomach after the 
procedures above. Breakfast will be provided approximately 1 hour after 
isoniazid dose. Doravirine 100 mg rifapentine (weight based) and pyridoxine 50 
mg will be dosed with 240 mL of water approximately 20 minutes after breakfast 
o PK (Post-dose): Subsequent PK will be drawn at 0.5, 1, 1.5, 2, 3 and 6 hours post 
Day 21 AM dose. 
o PK: A 12 hour post (day 21 AM) dose PK will be drawn, prior to the Day 21 PM 
dose of doravirine. 


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o Assessments (PM): AEs 
o Dose (PM): Administer PM doravirine 100 mg dose with 240 mL of water 
 
 Study day 22 PK: 
o Assessments: AEs, concomitant medications and safety laboratories (CBC & 
CMP) 
o PK (AM): A 24 hour post (day 21 AM) dose PK will be drawn. 
o Dose: No dose of doravirine given 
o PM (PM): A 36 hour post (day 21 AM) dose PK will be drawn. 
 
 Study day 23 PK: 
o Assessments: AEs, concomitant medications, physical exam and vital signs 
o PK: A 48 hour post (day 21 AM) dose PK will be drawn. 
o Dose: No dose of doravirine given 
o Subjects will be discharged from the CRU following the procedures 
 
 Study day 24 PK: 
Subjects will arrive at the CRU in the morning. 
o Assessments: AEs and concomitant medications 
o PK: A 72 hour post (day 21 AM) dose PK will be drawn. 
o Dose: No dose of doravirine given 
o Subjects will be discharged from the CRU following the procedures 
NOTE: Subjects will be given a reminder phone call + 30 minutes of their scheduled dose time 
for all at home PM doses of doravirine. 
 
6.4.4 Post-Study Follow-up – Approximately 7-10 days after the last dose of doravirine. 
 Subjects will be required to follow up post study to assess for adverse events and safety 
 Safety labs will be drawn followed by a physical exam and vital signs. Comparisons will be 
drawn to pre-study. 
6.5 Domiciling 
Subjects will be admitted to the CRU as outlined in the schedule of events. 
6.6 Clinical Procedures & Assessments 
6.6.1 Medical History 
Medical history of subjects participating in the study will be obtained by the investigator or co- 
investigator(s). 


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6.6.2 Physical Examination 
The full physical examination includes evaluation of the head, eye, ear, nose and throat; the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal and neurological 
systems. The screening examination will also include height and weight for BMI calculation. 
6.6.3 12-Lead Electrocardiogram 
Subjects remain supine for at least 2 minutes prior to collection of ECG. 
6.6.4 Vital Signs 
Subjects remain supine for at least 2 minutes prior to measurement of vital signs. 
Measurements include heart rate, blood pressure and respiratory rate. Oral or tympanic 
temperature will be checked during the screening visit and if needed by the discretion of the 
physician-investigator, during and after the study. All methods of measurement (oral or 
tympanic) should be consistent for all subjects throughout the study. 
6.6.5 Laboratory Safety Evaluations 
Refer to Appendix 1 for the list of clinical laboratory tests. Laboratory tests will be performed at 
screening, during and after the study. 
 The investigator or medically qualified designee must review the laboratory report, 
document review on lab report, and record any clinically significant abnormal findings 
occurring during the study that meet the reporting requirements in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. 
 For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 days after a protocol-specified procedure, every 
attempt should be made to perform repeat assessments until the values return to 
normal or baseline or if a new baseline is established as determined by the investigator. 
6.6.6 Prior and Concomitant Medications Review 
The investigator or designated personnel will review prior medication, vitamins or supplement 
use and record prior medication taken by the subject within 4 weeks before starting the study. 
All medications, vitamins or supplements, if any, taken from screening visit until the after the 
study will be recorded. 
6.7 Study Restrictions 
6.7.1 Diet, Fruit, and Medications Restrictions 
Subjects must fast from food and drinks with the exception of water for 8 hours prior to the 
screening visit, Day 5, Day 8 , Day 15 and the follow up visit for laboratory safety tests. Subjects 
will also fast for 8 hours prior and approximately 1 hour after the Isoniazid doses on day 7, 14, 
21. Subjects will refrain from use of over-the-counter, prescription (unless determined 


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appropriate by the investigator), herbal or natural products, vitamins or supplements, or 
grapefruit juice/grapefruit products. 
 
6.7.2 Alcohol Restriction 
Alcohol consumption must be avoided throughout the entirety of the study until after the post- 
study visit. Additional alcohol tests may be performed at the judgment of the investigator if a 
there is reason to believe a subject has consumed alcohol. 
6.7.3 Smoking Restriction 
Subjects must continue to avoid smoking throughout the study up until the post-study visit. 
6.7.4 Activity Restrictions 
Subjects will avoid new, unaccustomed strenuous physical activity (i.e., weight lifting, running, 
bicycling, etc.) from the screening visit, throughout the trial until the post-trial visit. Subjects 
may participate in light recreational activities during studies (eg, watching television, reading). 
6.8 Contraception and Pregnancy Testing 
Women of childbearing potential can be enrolled. However, two (2) acceptable methods of 
contraception must be used beginning at the screening visit, throughout the trial (including 
washout period) and until 4 weeks after the last dose of trial drugs in the last treatment period. 
Acceptable methods of birth control are two (2) of the following: intrauterine device (IUD with 
or without local hormone release), implantable hormonal contraceptives (e.g. etonogestrel 
implant), diaphragm, spermicides, cervical cap, contraceptive sponge, and/or condoms. 
Abstinence is an alternative life style and subjects practicing abstinence may be included in the 
trial. Hormonal oral contraceptives are not allowed as a method of birth control in this trial. 
Female subjects of childbearing potential will be tested for urine β-human chorionic 
gonadotropin (hCG) at Screening and day -1. In the case of a positive urine β-hCG pregnancy 
test at Screening or day -1, the subject will not be enrolled in the trial. Female subjects with a 
positive urine β-hCG pregnancy test during the study (as identified on either study days 6, 13, 
and 20) will be discontinued from the study. 
6.9 Subject Identification Card 
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card after the subject provides written 
informed consent. 


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6.10 Standardized Meals 
Meals (Breakfast, lunch, dinner and snacks) will be provided to subjects during the admission 
days. 
6.11 Study, Drug Dosing and Procedure Modification Permitted 
Modifications to the dose, dosing regimen and clinical or laboratory procedures may be 
required to achieve the scientific goals of the trial objectives and/or to ensure appropriate 
safety monitoring of the study subjects. As such, some alterations from the currently outlined 
schedule may be necessary. Additional laboratory safety tests may be drawn or added to blood 
samples previously drawn to obtain additional safety information (e.g., creatinine kinase to 
evaluate elevated AST/ALT). These changes may or may not increase the number of study 
procedures for a given subject during his/her participation in the entire study. 
6.12 Study Stopping Rules 
The safety profile for isoniazid and rifapentine have been well established in combination. 
Doravirine safety has been described for the administration with other rifamycins (rifampin and 
rifabutin), without significant identification of safety signal. An independent safety physician 
will review all serious adverse events. 
 If there is a serious adverse event, possibly- or probably- related to the study 
intervention, the independent safety monitor will determine if the study will be 
permanently stopped, halted, and subsequently restarted. 
 
 If there are two serious adverse event, possibly- or probably- related to the study 
intervention, the study will be stopped. 
 
 Individual subjects who develop an AST or ALT of > 2.5 x the upper limit of normal or 
become pregnant during the study will be discontinued from the study. 
 
7 
DRUG SUPPLY 
The Thomas Jefferson University Investigational Drug Service Pharmacy will be responsible for 
maintaining appropriate records and ensure appropriate supply, handling, storage, distribution 
and usage of these materials in accordance with the protocol and applicable laws and 
regulations. 
Doravirine will be supplied by Merck & Co., Inc. Rifapentine, isoniazid, and pyridoxine will be 
purchased through the Thomas Jefferson University Hospital Pharmacy. 


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8 
POTENTIAL RISKS AND BENEFITS 
8.1 Potential Risks Associated with Doravirine 
The following most common adverse events (for All Grades) have been reported (> 5%) with the 
chronic use of doravirine in patients with HIV infection. The reported adverse event rates 
reflect chronic daily use together with other ARVs and are derived from large clinical trials in 
patients with HIV. Although these adverse event rates have been reported in patients, it may be 
possible that healthy volunteers may also experience these side effects under this protocol. 
 Central nervous system: 
o Altered sensorium (Doravirine + lamivudine + tenofovir disoproxil: 4%) 
 Defined as: altered state of consciousness, lethargy, somnolence, 
syncope 
o Sleep disorders and disturbances (Doravirine + + tenofovir disoproxil: 12%) 
 Defined as: abnormal dreams, hyposomnia, initial insomnia, insomnia, 
nightmare, sleep disorder, somnambulism 
o Dizziness (Doravirine + tenofovir disoproxil: 9%) 
o Fatigue (4-6%) 
o Headache (4-6%) 
 Gastrointestinal: 
o Nausea (5-7%) 
o Diarrhea (3-5%) 
 Laboratory abnormalities 
o Total bilirubin 1.1- < 1.6 x ULN (4-5%) 
Less commonly reported (< 2% have been reported with chronic use of doravirine in patients 
with HIV on concomitant ARVs. 
 Dermatologic 
o Rash (2%) 
 Laboratory abnormalities 
o Total bilirubin 
 1.6 - <2.6 x ULN (2%) 
 > 2.6 x ULN (<1%) 
o Creatinine (mg/dL) 
 >1.3- 1.8 x ULN or increase of >0.3 mg/dL above baseline (2-3%) 
 >1.8 x ULN or increase of 1.5 x above baseline (2%) 
o Asparate aminotransferase (IU/L) 
 2.5 - <5.0 x ULN (2-4%) 
 > 5 x ULN (<1%) 


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o Alanine aminotransferase (IU/L) 
 2.5 - <5.0 x ULN (3%) 
 > 5 x ULN (<1-1%) 
o Alkaline phosphatase (IU/L) 
 2.5 - <5.0 x ULN (<1%) 
o Lipase 
 1.5 - <3.0 x ULN (4-5%) 
 > 3 x ULN (1-3%) 
o Creatine Kinase (IU/L) 
 6 - <10 x ULN 2%) 
 >10 x ULN (2-3%) 
o Cholesterol, fasted (mg/dL) 
 >300 mg/dL (<1%) 
o LDL Cholesterol, fasted (mg/dL) 
 >190 mg/dL (<1%) 
o Triglycerides, fasted (mg/dL) 
 >500 mg/dL (<1%) 
8.2 Potential Risks Associated with Rifapentine 
Potential risks and adverse events are derived from studies in patients with active pulmonary 
tuberculosis and LTBI. In patients treated for active pulmonary tuberculosis, therapy consisted 
of an initial 2 month therapy of RPT twice weekly co-administered with INH, pyrazinamide and 
ethambutol. A continuation phase followed where RPT was administered once weekly together 
with INH for 120 days. As such, the reported adverse event rates may be due to other 
medications given along with RPT and prolonged exposure. Although possible, the adverse 
event profile in this study protocol will be expected to be less than those observed in clinical 
trials. 
Treatment emergent adverse events occurring in >5% of patients during the continuation phase 
(RPT once weekly) include10: 
 Hematologic 
o Neutropenia (8.5%) 
Less commonly observed adverse events occurring in <5% of patients during the continuation 
phase (RPT once weekly) include: 
 Hematologic 
o Anemia (1.6%) 
o Lymphopenia (3.2%) 


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 Eye 
o Leukocytosis (1.6%) 
o Thrombocytosis (0.3%) 
o Thrombocytopenia (1.3%) 
o Non-protein nitrogen increase (3.2%) 
 
o Conjunctivitis (0.3%) 
 Gastrointestinal 
o Dyspepsia (1.3%) 
o Vomiting (0.9%) 
o Nausea (0.6%) 
o Diarrhea (0.6%) 
 General 
o Back pain (3.5%) 
o Abdominal pain (1.3%) 
o Fever (0.3%) 
o Anorexia (2.5%) 
 Hepatic & Biliary 
o Hepatitis (RPT/INH in LTBI: 0.6%) 
o ALT increase (2.2%) 
o AST increase (2.2%) 
 Musculoskeletal 
o Arthralgia (0.9%) 
 Neurologic 
o Headache (0.9%) 
o Dizziness (0.3%) 
 Respiratory 
o Hemoptysis (1.9%) 
o Coughing (2.8%) 
 Dermatologic 
o Rash (2.5%) 
o Sweating increase (2.6%) 
o Pruritus (0.9%) 
8.3 Potential Risks Associated with Isoniazid 
Potential risks and adverse events were derived from patient populations. The most frequent 
reactions are those affecting the nervous system and the liver. The most common adverse 
event (>10%) observed in patients were increase in serum transaminases consistent with the 
signs and symptoms of acute hepatitis.22 In most instances, enzyme levels return to normal and 
generally, there is no necessity to discontinue medication during the period of mild serum 


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transaminase elevation. There is a higher frequency of INH associated hepatitis among those 
who are aged greater 35 years old, daily users of alcohol, chronic alcohol users, and black and 
Hispanic women. The CDC recommends clinical observation and not lab monitoring. In this 
study labs will be monitored which will be a sensitive detection of liver enzyme elevation. 
Nervous system reactions, particularly peripheral neuropathy, is the most common toxic effect 
and is dose-related. The risk is higher in those who are malnourished, alcoholics, and diabetics, 
none of whom will be enrolled in this study. Pyridoxine repletion is recommended to prevent 
the risk of peripheral neuropathy. 
Aside from nervous system and hepatic reactions, other adverse events include (frequency not 
provided): 
 Gastrointestinal 
o Nausea, vomiting, epigastric distress, and pancreatitis 
 Hematologic 
o Agranulocytosis; hemolytic, sideroblastic or aplastic anemia, thrombocytopenia; 
and eosinophilia 
 Hypersensitivity 
o Fever, skin eruptions (morbilliform, maculopapular, purpuric or exfoliative), 
lymphadenopathy, vasculitis, toxic epidermal necrolysis, and drug reaction with 
eosinophilia syndrome (DRESS) 
 Metabolic and Endocrine 
o Pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis and 
gynecomastia 
 Miscellaneous 
o Rheumatic syndrome and systemic lupus erythematosus-like syndrome 
8.4 Potential Risks Associated with Pyridoxine 
Pyridoxine is a water soluble vitamin that is naturally present in foods and available as a dietary 
supplement. Potential risks with pyridoxine were derived from population studies and case 
reports.24 Pyridoxine is virtually safe and commonly consumed, however high intakes of 1-6 
grams for 12-40 months can cause severe and progressive sensory neuropathy.25 The adverse 
effect profile is expected to be negligible in our protocol with the use of 50 mg weekly for 3 
weeks. 
 
9 
SAFETY, ADVERSE EVENTS (AE) & SERIOUS ADVERSE EVENTS (SAE) 
9.1 Definitions 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and assessing 
causality of AE and SAE and the procedures for completing and transmitting AE, SAE, and other 


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reportable safety event reports can be found in Appendix 2. Adverse events, SAEs, and other 
reportable safety events will be reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety events 
for outcome. 
The investigator, who is a qualified physician, will assess events that meet the definition of an 
AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality. 
9.1.1 Adverse Event (AE) 
An adverse event is defined as any untoward medical occurrence in a subject administered an 
investigational product that occurs during the conduct of a clinical trial and does not necessarily 
have a causal relationship with the study drug(s). This can be any unfavorable and unintended 
physical sign, symptom, laboratory parameter or disease entity that develops or worsens in 
severity during the course of the trial whether considered related to study drug or not. Adverse 
events can include any of the following: 
 
 All suspected adverse medication reactions. This includes events possibly related to any 
concomitant medication use 
 Physical Injuries or accidents. If a medical condition is known to have caused the injury 
or accident (e.g., a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) will be reported as two separate adverse events. 
 Abnormalities in physiological testing or physical examination (findings that require 
clinical intervention or further investigation beyond ordering a repeat [confirmatory] 
test). 
 Drug interactions 
 Onset or worsening of preexisting clinical illness 
 Laboratory or diagnostic test abnormality that require clinical intervention or further 
investigation (beyond ordering a repeat [confirmatory] test) unless they are associated 
with an already reported clinical event. A clinical laboratory abnormality should be 
documented as an adverse event if any one of the following conditions is met: 
• 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm 
the abnormality 
• 
The abnormality suggests a disease and/or organ toxicity 
• 
The abnormality is of a degree that requires active management; e.g. more 
frequent follow-up assessments, further diagnostic investigation, etc. 


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Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events. However, the medical condition for which the procedure was 
performed will be reported if it meets the definition of an adverse event. 
 
All adverse events will be assessed and recorded from the time subject is enrolled into the 
study until the post-trial visit. At each contact with the subject, the investigator or study 
personnel must seek information on adverse events by specific questioning and, as appropriate, 
by examination. Information on all adverse events, including degree of severity and relationship 
to study agent, should be recorded immediately in the source document. 
9.1.2 Serious Adverse Event (SAE) 
An SAE is an event that is not an AE per definition above, resulting in death, is life threatening, 
requires inpatient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, is a congenital anomaly or any other important 
medial events. SAEs must be reported using the Serious Adverse Event Form. All events that 
meet the definition of a serious adverse event will be reported as serious adverse events, 
regardless of whether they are protocol-specific assessments. 
9.2 Assessing and Recording AEs & SAEs 
All adverse events, whether serious or non-serious, will be reported from the time a signed and 
dated ICF is obtained until completion of the subject's last study-related procedure, which may 
include contact for follow-up of safety. 
 
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
intervention, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (e.g. cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as "upper respiratory infection"). 
 
Investigators must record in the CRF their opinion concerning the relationship of the adverse 
event to study therapy. All measures required for adverse event management must be 
recorded in the source document and reported. 
During the outpatient phase the subject will be provided with a "wallet (study) card" and 
instructed to carry this card with them for the duration of the study indicating the following: 
 Study number 
 Statement that the subject is participating in a clinical study 
 Investigator's name and 24-hour contact telephone number 
 Local sponsor's name and 24-hour contact telephone number (for medical staff only) 
 Subject number 


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9.3 Data Safety Monitoring Plan (DSMP) 
The investigators will oversee the safety of the study. This safety monitoring will include careful 
assessment and appropriate reporting of adverse events as noted above. Independent medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
An independent Medical Monitor will be assigned to this study. The medical monitor will be a 
physician who is not directly involved in the study and is not currently collaborating with the 
sponsor/investigator on any other trial and who has a working knowledge of the drugs involved 
in this study. The role of the Medical Monitor is to review all reportable AEs/SAEs including 
grading, toxicity assignments, non-reportable AEs, protocol violations/deviations, as well as all 
other safety data and activity data. The Medical Monitor may recommend reporting of adverse 
events and relevant safety data, and may also recommend suspension or termination of the 
study to the investigators and IRB. 
 
10 
DATA COLLECTION, STUDY MONITORING, AND RECORD MANAGEMENT 
10.1 Data Collection and Reporting 
Data for this study will be collected using eCRFs. The investigator and study site staff will 
receive system documentation, training, and support for the use of the eCRF. Visit-specific data 
should be entered into the eCRF and be ready for review as soon as possible, but no later than 
5 days after each visit/time point. All protocol-required information collected during the study 
must be entered by the investigator or designated representative in the source documents and 
eCRF. All data entry, modification, or deletion will be recorded automatically in an electronic 
audit trail indicating the individual subject, original value, the new value, the reason for change, 
who made the change, and when the change was made. All data changes will be clearly 
indicated with a means to locate prior values. The system will be secured to prevent 
unauthorized access to the data or the system. This will include the requirement for a user ID 
and password to enter or change data. The investigator will maintain a list of individuals who 
are authorized to enter or correct data and their system ID. The investigator or designated sub- 
investigator, following review of the data in the eCRF, will confirm the validity of each subject’s 
data by electronic signature. 
10.2 Study Monitoring 
Study progress will be monitored by the sponsor or its representative as frequently as 
necessary to ensure adequate and accurate data collection, protocol compliance, and study 
conduct in accordance with accepted regulatory requirements. The principal investigator must 
make all the subject data available to the monitor for review during the planned site monitoring 
visits. Arrangements for monitoring visits will be made in advance, except in emergency cases. 


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10.3 Investigator Study Files 
The principal investigator is responsible for maintaining all study-related documents in study 
files. The sponsor will notify the principal investigator when retention of study files is no longer 
necessary. The study will be compliant with CFR 21 312.62 and 312.57. 
10.4 Retention of Records 
Standard protocol is that essential documents should be retained until at least 2 years after the 
last approval of a marketing application and until there are no pending or contemplated 
marketing applications, or at least 2 years have elapsed since the formal discontinuation of the 
investigational product. For this investigator initiated trial, records will be stored in a secure 
location until all anticipated publications stemming from study conduct are completed. 
 
11 
STATISTICAL AND PHARMACOKINETIC METHODS 
11.1 Sample Size Estimation 
Sample size was calculated from the published variability on doravirine 200 mg trough 
concentrations in HIV-infected subjects following multiple doses (Geometric mean = 964 
nmol/L; 95% CI: 694 – 1340).26 Using a significance level of 5% with a two-sided paired t-test, a 
sample size of 11 provided greater than 80% power to detect a change of 15% in doravirine 
(paired log-mean 6.87 versus 6.71) trough concentrations. 
The standard deviation of the paired difference was calculated assuming independence 
between the reference (doravirine alone) and co-administrated doravirine and 
rifapentine/isoniazid. The standard deviation of the paired difference was assumed to be 0.12 
for both the reference and the RPT/INH co-administered with doravirine group. 
11.2 Pharmacokinetic Analysis 
Plasma concentrations of doravirine will be used to calculate the pharmacokinetic parameters 
for each subject in the presence or absence of multiple doses of RPT/INH. Analysis for the 
primary pharmacokinetic objective will be conducted via a non-compartmental analysis. 
Parameters of interest include the area under the concentration-time point from time zero 
extrapolated to infinity (AUC0-inf), AUC0-last maximum concentration (Cmax), minimum 
concentration at 12 hours (surrogate for efficacy), time to maximum concentration (Tmax), 
apparent oral clearance (CL/F) and the apparent half-life (t1/2) for each subject. The AUC0-last will 
be computed using the linear-up, log-down trapezoidal integration method. A log-linear 
regression using the least-squares method will be employed to estimate other parameters of 
interest including the terminal half-life generated from the plasma concentration time-curve. 
The primary endpoint will be pharmacokinetic and therefore be measured as the exposure 
parameters AUC0-last, Cmax and Ctrough 


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Doravirine pharmacokinetic parameter estimates computed before and after RPT/INH exposure 
will be compared using a paired student’s t-test. Statistical significance will be defined as a p- 
value <0.05. Geometric mean ratios and 90% confidence intervals will be calculated for RPT/INH 
and doravirine administrations (i.e. RPT/INH co-administered with multiple-dose 100 mg twice- 
daily doravirine compared to a multiple-dose doravirine 100 mg twice-daily alone). 
Results for the primary pharmacokinetic objective will be reported in summary tables and 
figures. Subject demographics and treatment related adverse events will be summarized and 
tabulated. 
11.3 Safety Analysis 
Safety and tolerability assessments will be clinically reviewed for any clinical adverse events and 
include safety lab, vital signs, and physical exam beyond the pre-defined limit of change. 
Assessment will be performed for all subjects enrolled into this study. 
Safety results will be summarized and tabulated using descriptive statistics. Results will be 
reported as the proportion of subjects experiencing an adverse event. 
 
 
12 
SUPPORTING DOCUMENTATION 
12.1 Appendix 1: Time Windows for Serial Assessments & Dosing 
Sampling Window 
 
 
 
 
 
 
 
Dosing Window 
Dosing Timepoint (Hours) 
Dosing Window (Minutes) 
(doravirine) on study day 1 AM dose 
0 hour 
All other doses 
+/- 30 minutes from actual 0 hour time 
 
12.2 Appendix 2: Clinical Laboratory Tests 
 Tests detailed in table 3 will be performed by Thomas Jefferson University Hospital – 
Clinical Chemistry Laboratories 
Sampling Timepoint (Hours) 
Sampling Window (Minutes) 
Pre-dose (doravirine) on study day 1 
-120 minutes to 0 hour 
0 hour (Pre-dose) 
-10 minutes to +10 minutes 
> 0 hour – 4 hours 
-10 minutes to +10 minutes 
> 4 hours – 24 hours 
-10 minutes to +10 minutes 
> 24 hours – 72 hours 
-15 minutes to +15 minutes 
Trough concentrations 
-30 minutes to +30 minutes 


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 Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 3: Protocol required safety and other laboratory assessments. 
 
Laboratory 
Assessment 
Parameter 
Hematology 
 Platelet count 
 Hemoglobin 
 Hematocrit 
 WBC with differential 
 Partial thromboplastin time 
 Prothrombin time 
Chemistry 
 Albumin 
 Calcium 
 Chloride 
 Bicarbonate 
 Potassium 
 Sodium 
 Creatinine 
 Total Bilirubin 
 Direct bilirubin (If total bilirubin is elevated above the upper limit of 
normal) 
 Total protein 
 Blood urea nitrogen 
 Glucose 
 Aspartate Aminotransferase (AST) 
 Alanine aminotransferase (ALT) 
 Alkaline phosphatase 
Urinalysis 
 Specific gravity 
 Microscopic examination (if blood or protein is abnormal) 
 Blood 
 Glucose 
 Specific gravity 
Other Laboratory 
Tests 
 Follicle Stimulating Hormone (FSH) 
 Urine  human chorionic gonadotropin ( hCG) 
 Serology (Hepatitis B surface antigen [HBsAg] and hepatitis C virus 
antibody). Hepatitis C viral load may additionally be assessed as 
confirmation for participants with a positive antibody test 
 Human immunodeficiency virus screen 
 QuantiFERON-TB Gold Tuberculosis screen 


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12.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting 
12.3.1 Definition of AE 
 An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the procedural study intervention, whether or not considered related to 
the procedural study intervention 
 An AE can therefore any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the procedural study intervention 
Events meeting the AE definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, vital signs, or measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator 
 New conditions detected or diagnosed after conduct of the procedural study 
intervention even though it may have been present before the start of the study 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of a concomitant 
medication 
 For all reports of overdose (whether accidental or intentional) with an associated AE, 
the AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported 
using the terminology “accidental or intentional overdose without adverse effect.” 
Events NOT meeting the AE definition 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
12.3.2 Definition of SAE 
 If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
 An SAE is defined as any untoward medical occurrence that: 
 Urine drug screen to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines 
 Blood alcohol level 


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o Results in death 
o Is life threatening 
 The term “life-threatening” in the definition of “serious” refers to an 
event in which the participant was at risk of death at the time of the 
event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe 
o Requires inpatient hospitalization or prolongation of existing hospitalization 
 Hospitalization is defined as an inpatient admission, regardless of length 
of stay, even if the hospitalization is a precautionary measure for 
continued observation. (Note: Hospitalization for an elective procedure 
to treat a pre-existing condition that has not worsened is not an SAE. A 
pre-existing condition is a clinical condition that is diagnosed prior to 
study intervention and is documented in the participant’s medical 
history. 
o Results in persistent or significant disability/incapacity 
12.3.3 Additional Events Reported 
In addition to the above criteria, AEs meeting either of the below criteria, although not serious 
per ICH definition, are reportable: 
 Is a cancer 
 Is associated with an overdose of medication 
12.3.4 Recording AEs and SAEs 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g. hospital progress notes, laboratory and diagnostic reports) related to the event. The 
investigator will record all relevant AE/SAE information on the AE CRFs at each examination. 
The investigator will attempt to establish a diagnosis of the vent based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity/toxicity 
 An event is definied as “serious” when it meets at least 1 of the pre-defined outcomes 
as described in the definition of an SAE, not when it is rated as severe 
 The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
o Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort, and not interfering with everyday activities 
o Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities 


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o Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category used for 
rating the intensity of an event; and both AE and SAE can be assessed as severe 
Assessment of causality 
The determination of the likelihood that the study intervention caused the AE will be provided 
by an investigator who is a qualified physician. The investigator’s signed/dated initials on the 
source document that supports the causality noted on the AE form, ensures that medically 
qualified assessment of causality was done. This initialed document must be retained for the 
required regulatory time frame. The criteria below are intended as reference guidelines to 
assist the investigator in assessing the likelihood of a relationship between the study 
intervention and the AE based upon the available information. 
The following components are to be used to assess the relationship between the study 
intervention and the AE: 
 Time Course: Did the AE follow in a reasonable temporal sequence from the study 
intervention? 
 Likely Cause: Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors. 
 Consistency with study intervention: Is the clinical/pathological presentation of the AE 
consistent with previous knowledge regarding the procedural study intervention? 
The assessment of relationship will be reported on the case report forms/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. Use the following scale of criteria as guidance (not all 
criteria must be present to be indicative of a procedural study intervention relationship). 
 Yes, there is a reasonable possibility of study intervention relationship: 
o The temporal sequence of the AE onset relative to the study intervention is 
reasonable. The AE is more likely explained by the study intervention than by 
another cause 
 No, there is not a reasonable possibility of procedural study intervention relationship: 
o Temporal sequence of the AE onset relative to study intervention is not 
reasonable OR the AE is more likely explained by another cause than the study 
Follow up of an AE or SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 


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13 
ETHICS AND PROTECTION OF HUMAN SUBJECTS 
13.1 Institutional Review Board Review 
The principal investigator must provide the IRB with all appropriate materials, including a copy 
of the patient informed consent form. The study will not be initiated until the principal 
investigator obtains written approval of the protocol and the patient ICF from the IRB. 
Appropriate reports on the progress of this study will be made by the principal investigator to 
the IRB and medical monitor in accordance with government regulations. 
13.2 Informed Consent 
The ICH Tripartite Guideline for Good Clinical Practice establishes the general requirements for 
informed consent. Each subject will be provided with oral and written information in a language 
they can understand that describes the nature and duration of the study. Before undergoing 
screening, each subject must consent in writing to study participation. The subject will sign and 
personally date the patient ICF. The person rendering consent will also sign and personally date 
the ICF as the person who obtained the consent of the subject. Each subject will receive a copy 
of his or her signed ICF. 
13.1 Subject Confidentiality 
All records will be kept in a locked filing cabinet located in the offices of the Department of 
Pharmacology and Experimental Therapeutics in 1170 Main Building. All computer entry and 
networking programs will be performed with coded numbers only; no PHI will be entered into 
the eCRF. Clinical information will not be released without written permission of the patient, 
except as necessary for monitoring by the medical monitor, IRB, or the FDA, or other medical 
practitioner to ensure the safety and appropriate medical management of the patient in the 
event of a AE/ SAE. 
 
14 
SUPPLEMENTAL MATERIALS 
These documents are relevant to the protocol, but they are not considered part of the protocol. 
They are stored and modified separately. As such, modifications to these documents do not 
require protocol amendments. 
 Case Report Forms 
 Biospecimen sample chain of custody forms, shipment 
 Source Documents 
 Laboratory and Specimen Handling Manual 
 Pharmacy Manual 
 Data Management Plan 
 Pharmacokinetic Analysis Plan 
 DSMP 


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15 
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