Conditions: HIV
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 26
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the steady state pharmacokinetics (PK) of rilpivirine (RPV) and determine the appropriate dose of RPV in combination with other antiretrovirals (ARVs) in participants aged greater than or equal to 2 to less than 12 years and to evaluate the safety and tolerability of RPV in combination with other ARVs in participants of same age group over a 48-week treatment period with primary endpoint at Week 24.

Detailed description:
Participants infected with human immunodeficiency virus type 1 (HIV-1) are routinely treated with combinations of multiple drugs which reduces HIV-1 ribonucleic acid (RNA) to undetectable levels in a substantial proportion of participants and counteracts the risk of viral resistance development. RPV is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) with in vitro activity against wild type (WT) HIV-1 and against NNRTI-resistant HIV-1 mutants. A medical need still exists for the development of age/weight appropriate formulations in children less than (\<) 12 years of age. In this study, participants will switch to RPV plus other ARVs. The primary analysis will be performed at Week 24. A participant will be considered to have completed the study if he or she has completed assessments at Week 48 of the study intervention phase. The total study duration for each participant, including screening and study intervention phases, will be approximately 54 weeks. Key efficacy assessments include determination of plasma HIV-1 RNA viral load and measurement of CD4+ cell count. Key safety assessments will include the monitoring of (serious) adverse events (\[S\]AEs) and HIV-related events, clinical laboratory tests, cardiovascular safety monitoring (vital signs and 12 lead electrocardiogram \[ECGs\]), and physical examination (including growth).

Arms:
arm 1: Participants will receive rilpivirine (RPV 25 milligram \[mg\], adjusted weight-based dose) orally once daily in combination with an investigator selected background regimen (that is investigator-selected antiretrovirals \[ARVs\] such as nucleoside/nucleotide reverse transcriptase inhibitor \[N{t}RTIs\] and integrase inhibitors) for 48 weeks.

Interventions: intervention 1: Rilpivirine intervention 2: ARV Background Regimen
Intervention descriptions: intervention 1: Rilpivirine 25 mg tablets for the 25 mg daily dose, or tablets for or a weight-adjusted dose. Administered orally once daily. intervention 2: The investigator-selected ARVs, including but not limited to N(t)RTIs (example, azidothymidine \[AZT\], abacavir \[ABC\], tenofovir alafenamide \[TAF\], or tenofovir disoproxil fumarate \[TDF\] in combination with emtricitabine \[FTC\] or lamivudine \[3TC\]), whichever are approved and marketed or considered local standard of care for children aged between 2 and \< 12 years in a particular country are to be administered. Integrase inhibitors (for example, dolutegravir \[DTG\] or raltegravir) can also be administered in combination with RPV, as appropriate.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status:Approved,  Date: 22 February 2021
Janssen Research & Development *
Clinical Protocol
A Phase 2, Open-label, Single-arm, Multicenter Study to Evaluate the Pharmacokinetics, 
Safety, Tolerability, and Efficacy of Switching to RPV Plus Other ARVs in HIV-1-infected 
Children (Aged 2 to <12 years) who are Virologically Suppressed
Protocol TMC278HTX2002; Phase 2
AMENDMENT 3
TMC278 (rilpivirine)
*Janssen Research & Development is a global organization that operates through different legal entities in various 
countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development studies may vary, 
such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag 
International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland Unlimited Company; or 
Janssen Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent these 
various legal entities; the sponsor is identified on the Contact Information page that accompanies the protocol.
US sites of this study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER: 2018-004301-32
Status:
Approved
Date:
22 February 2021
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-ERI-173250594, 16.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status:Approved,  Date: 22 February 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 3
This document
Amendment 2
18 December 2019
Amendment 1
24 April 2019
Original Protocol
14 Jan 2019
Amendment 3 (this document)
Overall Rationale for the Amendment: this amendment is created to include an optional intensive PK 
substudy at several study sites and to clarify some of the inclusion and exclusion criteria. 
Section number
and Name
Description of Change
Brief Rationale
1.1 Synopsis
4.1 Overall Design
It has been added that, at some sites, 
an optional PK substudy may be 
performed to collect intensive PK 
data in children ≥6 years with body 
weight ≥25 kg on the day of intensive 
PK (substudy), which will require 
additional assessments as specified in 
the substudy protocol.
The PK data of the substudy will be 
used in support of the refinement of a 
population PK model across age groups 
to gain a better understanding of PK 
profiles for participants included in the 
study.  
1.1 Synopsis
1.2 Schema
4.1 Overall Design
4.3 Justification for Dose
6.1 Study Interventions
Administered
6.6.2 Dose Modification 
(Adjustment) Rules
9.5 Independent Data 
Monitoring Committee 
Analyses
The RPV dose for participants with a 
body weight <20 kg was amended 
from 15 mg to 12.5 mg once daily.
The RPV dose was amended based on 
data from the first mini-cohort of 
5 children with a body weight <25 kg
in the study. This was endorsed by the 
IDMC.
6.6.2 Dose Modification 
(Adjustment) Rules
Details were added for a switch to the 
12.5-mg dose in participants <20 kg. 
It was specified that the RPV dose 
could change based on further 
analysis and IDMC 
recommendations.
To allow for flexibility in case of 
changes based on further analysis and 
IDMC recommendations.
5.1 Inclusion Criteria and 
throughout the document
The minimum body weight for 
enrollment in the study was adjusted 
from 11 to 10 kg. 
To align with the WHO weight bands 
for ARV dosing in children. 
1.3.1 General Schedule of 
Activities
5.2 Exclusion Criteria
5.4 Screen Failures
It has been clarified that retesting of 
an ECG leading to exclusion will be 
allowed once at screening. 
To align with the allowed retesting for 
laboratory abnormalities at screening.
5.2 Exclusion Criteria
It was specified that delays in QRS 
duration >90 ms were allowed if 
there are no other conduction 
abnormalities present.
Clarification.
4.3 Justification for Dose
Text on the standard allometric 
scaling factor of 0.75 was deleted.
The allometric scaling factor was 
adjusted based on emerging PK data.
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status:Approved,  Date: 22 February 2021
Section number
and Name
Description of Change
Brief Rationale
1.1 Synopsis
1.3.1 General Schedule of 
Activities
2.3.5 Overall Benefit/Risk 
Assessment
4.1 Overall Design
4.2 Scientific Rationale for 
Study Design
8.2.1 Physical Examination
8.2.4 Clinical Safety 
Laboratory Assessments
10.6 Appendix 6: Established 
and Theoretical Drug 
Interactions With Commonly 
Used Comedications and RPV
10.7 Appendix 7: Clinical 
Laboratory Tests
It has been clarified that endocrine 
assessments, adrenocorticotropic 
hormone stimulation testing, and 
Tanner staging are to be performed 
for all participants aged ≥6 to 
<12 years (including participants who 
turn 12 years old during the study).
To ensure that these assessments 
continue to be performed in 
participants turning 12 years old during 
the study.
1.1 Synopsis
1.2 Schema
1.3.2 Schedule of Activities
for Intensive Pharmacokinetic 
Sampling
1.3.3 Schedule of Activities
for Switch to Adjusted RPV 
Dose (if Applicable)
4.1 Overall Design
6.1 Study Interventions
Administered
It has been clarified that the intensive 
PK assessment can be done 2 weeks 
and 4 weeks after RPV treatment 
with the adjusted dose, instead of 
after at least 2 weeks and at least 
4 weeks since the time window is 
specified in Section 8.
To correct for the discrepancy between 
sections. 
1.1 Synopsis
8.5.3 Pharmacokinetic 
Parameters and Evaluations
Plasma concentration at 24 hours 
postdose was added to the PK 
parameters. 
PK parameter added for completeness. 
1.3.1 General Schedule of 
Activities
1.3.3 Schedule of Activities
for Switch to Adjusted RPV 
Dose (if Applicable)
4.1 Overall Design
It was added that sampling for 
endocrine assessments and ECGs are 
also to be done at follow-up visit. 
To clarify that at the follow-up visit 
any abnormal assessment can be 
retested, including endocrine 
assessments and ECGs.
10.4 Appendix 4: 
Contraceptive and Barrier 
Guidance and Collection of 
Pregnancy Information
Spermicides or spermicide-containing 
contraceptives were deleted from the 
list of contraceptives that could not 
be used as a sole method of 
contraception during the study.  
Spermicides are not to be used as 
contraceptives as this could potentially 
increase the rate of HIV-1 
transmission.
5.4 Screen Failures
It was specified that one additional 
rescreening is allowed in case 
inclusion and exclusion criteria are 
updated.
To allow for flexibility in case of 
updates to the criteria.
6.1 Study Interventions
Administered
It has been added that the content of 
the standard breakfast is to be 
recorded in the CRF.
Breakfast details will be collected in 
order to interpret the pharmacokinetic 
data as needed.
6.6.2 Dose Modification 
(Adjustment) Rules
It has been clarified that dose 
adjustments following weight loss are 
only needed upon confirmation of the 
change in weight. 
To ensure that no dose adjustments are 
made before confirmation that the 
weight loss is not due to an underlying 
condition.
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status:Approved,  Date: 22 February 2021
Section number
and Name
Description of Change
Brief Rationale
8.2.2 Vital Signs
The 5 minutes of rest in a quiet 
setting prior to the vital sign 
measurements were removed from 
the protocol. 
The 5 minutes of rest prior the vital 
sign measurements are not clinically 
important for children.
10.1 Appendix 1: 
Abbreviations and 
Trademarks
The definition of virologic response 
was removed.
The definition of virologic response 
was removed for clarification reasons 
as it was not in line with inclusion 
criterion 4.1 (virologically suppressed 
with documented evidence of at least 
2 plasma viral loads <50 HIV-1 RNA 
copies/mL), nor with the international 
guidelines considering virologic 
response as confirmed plasma viral 
load <50 HIV-1RNA copies/mL. Since 
both virologic thresholds of <50 and 
≥50 copies/mL and <400 and 
≥400 copies/mL will be used in the 
analysis (as defined in Section 3, 
Objectives and Endpoints), the Sponsor 
acknowledged that the definition of 
virologic response in Section 10.1 
could be considered potentially 
misleading.
10.6 Appendix 6: Established 
and Theoretical Drug 
Interactions With Commonly 
Used Comedications and RPV
Roxithromycim was added to the list 
of drugs with established and 
theoretical drug interactions with 
commonly used comedications and 
RPV.
To align with Section 6.5.3. 
10.6 Appendix 6: Established 
and Theoretical Drug 
Interactions With Commonly 
Used Comedications and RPV
It was specified that glucocorticoids 
were only disallowed if taken 
chronically.
To align with Section 6.5.3.
Throughout the document
Some administrative and editorial 
adjustments were made.
Clarification.
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status:Approved,  Date: 22 February 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 8
1
PROTOCOL SUMMARY ..................................................................................................................... 9
1.1
Synopsis........................................................................................................................................... 9
1.2
Schema .......................................................................................................................................... 16
1.3
Schedule of Activities..................................................................................................................... 18
1.3.1 General Schedule of Activities.................................................................................................... 18
1.3.2 Schedule of Activities for Intensive Pharmacokinetic Sampling................................................. 21
1.3.3 Schedule of Activities for Switch to Adjusted RPV Dose (if Applicable)..................................... 22
2
INTRODUCTION................................................................................................................................ 24
2.1
Study Rationale.............................................................................................................................. 24
2.2
Background .................................................................................................................................... 25
2.3
Benefit/Risk Assessment ............................................................................................................... 28
2.3.1 Known Benefits........................................................................................................................... 28
2.3.2 Potential Benefits........................................................................................................................ 28
2.3.3 Known Risks............................................................................................................................... 29
2.3.4 Potential Risks............................................................................................................................ 29
2.3.5 Overall Benefit/Risk Assessment ............................................................................................... 30
3
OBJECTIVES AND ENDPOINTS ..................................................................................................... 32
4
STUDY DESIGN ................................................................................................................................ 33
4.1
Overall Design................................................................................................................................ 33
4.2
Scientific Rationale for Study Design............................................................................................. 36
4.2.1 Study-specific Ethical Design Considerations ............................................................................39
4.3
Justification for Dose...................................................................................................................... 39
4.4
End of Study Definition................................................................................................................... 41
5
STUDY POPULATION ...................................................................................................................... 41
5.1
Inclusion Criteria ............................................................................................................................ 41
5.2
Exclusion Criteria ........................................................................................................................... 43
5.3
Lifestyle Considerations................................................................................................................. 46
5.4
Screen Failures .............................................................................................................................. 47
6
STUDY INTERVENTION................................................................................................................... 47
6.1
Study Interventions Administered .................................................................................................. 47
6.2
Preparation/Handling/Storage/Accountability ................................................................................ 49
6.3
Measures to Minimize Bias: Randomization and Blinding.............................................................50
6.4
Study Intervention Compliance...................................................................................................... 50
6.5
Concomitant Therapy..................................................................................................................... 51
6.5.1 Background Regimen ................................................................................................................. 51
6.5.2 Allowed Concomitant Therapy.................................................................................................... 53
6.5.3 Disallowed Concomitant Therapy............................................................................................... 53
6.6
Dose Modification........................................................................................................................... 54
6.6.1 Dose Evaluation Criteria............................................................................................................. 54
6.6.2 Dose Modification (Adjustment) Rules ....................................................................................... 56
6.7
Intervention After the End of the Study.......................................................................................... 56
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...............................................................................................57
7.1
Discontinuation of Study Intervention ............................................................................................ 57
7.1.1 Temporary Discontinuation......................................................................................................... 57
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status:Approved,  Date: 22 February 2021
7.1.2 Rechallenge................................................................................................................................ 57
7.2
Participant Discontinuation/Withdrawal From the Study................................................................57
7.3
Lost to Follow-up............................................................................................................................ 58
8
STUDY ASSESSMENTS AND PROCEDURES ...............................................................................59
8.1
Efficacy Assessments .................................................................................................................... 61
8.2
Safety Assessments....................................................................................................................... 61
8.2.1 Physical Examination.................................................................................................................. 62
8.2.2 Vital Signs................................................................................................................................... 62
8.2.3 Electrocardiogram....................................................................................................................... 63
8.2.4 Clinical Safety Laboratory Assessments ....................................................................................63
8.2.5 Behavior Risk Monitoring............................................................................................................ 64
8.3
Adverse Events and Serious Adverse Events ...............................................................................64
8.3.1 Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information..................................................................................................................................... 65
8.3.2 Method of Detecting Adverse Events and Serious Adverse Events .......................................... 65
8.3.3 Follow-up of Adverse Events and Serious Adverse Events ....................................................... 65
8.3.4 Regulatory Reporting Requirements for Serious Adverse Events ............................................. 66
8.3.5 Pregnancy................................................................................................................................... 66
8.3.6 HIV-related Events and HIV-related Outcomes..........................................................................66
8.4
Treatment of Overdose .................................................................................................................. 66
8.5
Pharmacokinetics........................................................................................................................... 67
8.5.1 Evaluations ................................................................................................................................. 67
8.5.2 Analytical Procedures................................................................................................................. 67
8.5.3 Pharmacokinetic Parameters and Evaluations...........................................................................67
8.6
Pharmacokinetic/Pharmacodynamic Evaluations..........................................................................68
8.7
Genetics ......................................................................................................................................... 68
8.8
Biomarkers ..................................................................................................................................... 68
8.9
Medical Resource Utilization and Health Economics ....................................................................68
8.10
Other Assessments........................................................................................................................ 69
8.10.1
Resistance............................................................................................................................ 69
8.10.2
Diaries .................................................................................................................................. 69
8.10.3
Questionnaires ..................................................................................................................... 69
9
STATISTICAL CONSIDERATIONS..................................................................................................70
9.1
Statistical Hypotheses.................................................................................................................... 70
9.2
Sample Size Determination ........................................................................................................... 70
9.3
Populations for Analyses................................................................................................................ 71
9.4
Statistical Analyses ........................................................................................................................ 71
9.4.1 Initial Participant and Disease Characteristics ...........................................................................71
9.4.2 Efficacy Analyses........................................................................................................................ 71
9.4.3 Safety Analyses .......................................................................................................................... 72
9.4.4 Pharmacokinetic Analyses.......................................................................................................... 73
9.4.5 Other Analyses ........................................................................................................................... 75
9.5
Independent Data Monitoring Committee Analyses ...................................................................... 76
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 77
10.1
Appendix 1: Abbreviations and Trademarks..................................................................................77
10.2
Appendix 2: Monitoring and Safety for Specific Toxicities.............................................................79
RASH.................................................................................................................................................... 79
ACUTE SYSTEMIC ALLERGIC REACTION .......................................................................................82
AST, ALT, AND TOTAL BILIRUBIN ELEVATION................................................................................83
PANCREATIC AMYLASE OR LIPASE ELEVATIONS......................................................................... 84
SIGNS AND SYMPTOMS OF ADRENAL INSUFFICIENCY ...............................................................85
CLINICAL HEPATITIS.......................................................................................................................... 86
NEUROPSYCHOLOGICAL SYMPTOMS ............................................................................................86
GASTROINTESTINAL NAUSEA (WITH OR WITHOUT VOMITING).................................................. 86
DIARRHEA ........................................................................................................................................... 87
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Status:Approved,  Date: 22 February 2021
OTHER TOXICITIES ............................................................................................................................ 88
SPECIFIC TOXICITIES WITH CONCOMITANT ARVS.......................................................................89
10.3
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 95
REGULATORY AND ETHICAL CONSIDERATIONS .......................................................................... 95
FINANCIAL DISCLOSURE .................................................................................................................. 98
INFORMED CONSENT PROCESS AND ASSENT FORM ................................................................. 98
DATA PROTECTION............................................................................................................................ 99
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH.................... 100
COMMITTEES STRUCTURE ............................................................................................................ 100
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA......................................... 100
DATA QUALITY ASSURANCE .......................................................................................................... 102
CASE REPORT FORM COMPLETION .............................................................................................102
SOURCE DOCUMENTS .................................................................................................................... 103
MONITORING .................................................................................................................................... 104
ON-SITE AUDITS............................................................................................................................... 104
RECORD RETENTION ...................................................................................................................... 105
STUDY AND SITE CLOSURE ........................................................................................................... 105
10.4
Appendix 4: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 106
10.5
Appendix 5: DAIDS Table ............................................................................................................ 109
10.6
Appendix 6: Established and Theoretical Drug Interactions With Commonly Used 
Comedications and RPV.............................................................................................................. 131
10.7
Appendix 7: Clinical Laboratory Tests ......................................................................................... 135
10.8
Appendix 8: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................................. 137
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS............................................................ 137
ATTRIBUTION DEFINITIONS............................................................................................................ 138
SEVERITY CRITERIA ........................................................................................................................ 138
SPECIAL REPORTING SITUATIONS ...............................................................................................139
PROCEDURES .................................................................................................................................. 139
CONTACTING SPONSOR REGARDING SAFETY...........................................................................140
PRODUCT QUALITY COMPLAINT HANDLING................................................................................141
10.9
Appendix 9: Tanner Scales.......................................................................................................... 142
10.10
Appendix 10: Pediatric European Network for the Treatment of AIDS (PENTA) 
Adherence Questionnaire ............................................................................................................ 144
STUDY ADHERENCE QUESTIONNAIRE FOR CAREGIVERS ....................................................... 144
STUDY ADHERENCE QUESTIONNAIRE FOR CHILDREN.............................................................146
10.11
Appendix 11: Palatability Questionnaire ...................................................................................... 149
PALATABILITY QUESTIONNAIRE FOR CHILDREN........................................................................ 149
10.12
Appendix 12: Swallowability Questionnaire .................................................................................150
10.13
Appendix 13: Cardiovascular Safety - Abnormalities...................................................................153
10.14
Appendix 14: Protocol Amendment History .................................................................................154
10.15
Appendix 15: CDC Growth Charts ............................................................................................... 160
REFERENCES.......................................................................................................................................... 162
INVESTIGATOR AGREEMENT ............................................................................................................... 165
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
8
Status:Approved,  Date: 22 February 2021
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Clopper Pearson 95% CI (2-Sided) for Various Assumptions.................................................. 70
Table 2:
Probability (%) of at Least 1 SAE Reported for Various Assumptions ..................................... 71
Table 3:
Summary of Rash ..................................................................................................................... 82
Table 4:
Summary of AST and ALT Elevations ......................................................................................84
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 16
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
9
Status:Approved,  Date: 22 February 2021
1
PROTOCOL SUMMARY
1.1
Synopsis
A Phase 2, Open-label, Single-arm, Multicenter Study to Evaluate the Pharmacokinetics, Safety, 
Tolerability, and Efficacy of Switching to RPV Plus Other ARVs in HIV-1-infected Children (Aged 2 to 
<12 years) who are Virologically Suppressed. 
Each participant must have a body weight of at least 10 kg (ie, the 10th percentile of the growth curve for 
body weight for healthy girls aged 2 years), be virologically suppressed (ie, human immunodeficiency virus 
[HIV]-1 ribonucleic acid [RNA] <50 copies/mL) on a stable antiretroviral (ARV) regimen for at least 
6 months at screening, and have no history of virologic failure. The participants should also lack any 
rilpivirine (RPV) resistance-associated mutations (RAMs) as evidenced by their historical HIV-1 
genotyping results, if available. Participants aged ≥2 to <6 years, however, are required to have historical 
HIV-1 genotyping results available at screening, to be provided to the sponsor. The availability of the 
historical HIV-1 genotyping results and the subtype need to be recorded in the CRF.
Rilpivirine (formerly known as TMC278 [R278474]), a diarylpyrimidine derivative, is a potent 
non-nucleoside reverse transcriptase inhibitor (NNRTI) with in vitro activity against wild type (WT) HIV-1 
and against NNRTI-resistant HIV-1 mutants. Rilpivirine as an oral formulation offers the convenience of 
once-daily dosing with potent antiviral activity and has a favorable safety and tolerability profile in adults 
and adolescents.
Rilpivirine at a dose of 25 mg once daily (qd) has been approved for treatment of ARV treatment-naïve 
HIV-1-infected adults in multiple countries, including the United States, Canada, Japan, and countries in 
the European Union, either as a single-agent 25-mg tablet (EDURANT) or as part of several fixed-dose 
combinations (ie, with the integrase inhibitor dolutegravir [DTG], with tenofovir disoproxil 
fumarate/emtricitabine [TDF/FTC], and with tenofovir alafenamide/FTC [TAF/FTC]). In most countries, 
including the United States and countries in the European Union, the indication of EDURANT is restricted 
to patients with a plasma viral load ≤100,000 HIV-1 RNA copies/mL. In several countries, including the 
United States and countries in the European Union, this indication has been extended to the pediatric 
population (ie, adolescents aged ≥12 to <18 years). The further pediatric development of RPV is ongoing.
OBJECTIVES AND ENDPOINTS
Objectives
Primary Objectives
!
To evaluate the steady-state pharmacokinetics (PK) of RPV and determine the appropriate dose of 
RPV in combination with other ARVs in participants aged ≥2 to <12 years with a body weight of 
<25 kg.
!
To evaluate the safety and tolerability of RPV in combination with other ARVs in participants aged 
≥2 to <12 years over a 24-week treatment period.
Secondary Objectives
!
To evaluate the safety and tolerability of RPV in combination with other ARVs over a 48-week 
treatment period.
!
To evaluate the efficacy of RPV in combination with other ARVs over a 24- and 48-week treatment 
period.
!
To evaluate population PK and PK/pharmacodynamic (PD) relationships for safety and efficacy of 
RPV in combination with other ARVs.
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
10
Status:Approved,  Date: 22 February 2021
!
To assess resistance in case of loss of virologic response to RPV in combination with other ARVs.
!
To evaluate treatment adherence to RPV in combination with other ARVs over a 24- and 48-week 
treatment period.
Exploratory Objectives
!
To assess the palatability of the 2.5-mg tablet formulation of RPV, if applicable.
!
To assess the swallowability of the 25-mg tablet formulation of RPV, if applicable.
!
To assess archived viral resistance, if feasible depending on available blood volume.
Endpoints
Primary Endpoints
!
Area under the plasma concentration-time curve from time of administration up to 24 hours postdose 
of RPV, as derived from the intensive PK assessments.
!
Incidence of grade 3/4 adverse events (AEs), serious adverse events (SAEs), HIV-related events 
(including acquired immune deficiency syndrome [AIDS]-defining illnesses and Stage-3-defining 
Opportunistic Illnesses in HIV Infection), and AEs leading to discontinuation of study intervention 
through 24 weeks of study treatment.
Secondary Endpoints
!
Incidence and severity of AEs/HIV-related events and their relatedness to RPV through 
24 and 48 weeks of study treatment.
!
Change from baseline over time and shift in toxicity grades/abnormalities versus reference for clinical 
laboratory parameters, electrocardiogram (ECG) parameters, vital signs, and physical examination 
through 24 and 48 weeks of study treatment.
!
Proportion of participants with HIV-1 RNA <50 and ≥50 copies/mL using the Food and Drug 
Administration (FDA) Snapshot approach through 24 and 48 weeks of study treatment.
!
Proportion of participants with HIV-1 RNA <400 and ≥400 copies/mL using the FDA Snapshot 
approach through 24 and 48 weeks of study treatment.
!
Immunologic changes, measured by cluster of differentiation (CD)4+ cell count (absolute and 
percentage relative to total lymphocytes), through 24 and 48 weeks of study treatment.
!
Pharmacokinetic parameters of RPV (other than area under the plasma concentration-time curve 
[AUC]), as derived from the intensive PK assessments.
!
Pharmacokinetic parameters of RPV, as derived by population PK modeling, through 24 and 48 weeks 
of study treatment.
!
Viral genotype at the time of virologic failure through 24 and 48 weeks of study treatment.
!
Treatment adherence, as assessed by the Pediatric European Network for the Treatment of AIDS 
(PENTA) adherence questionnaire and by study intervention accountability, through 24 and 48 weeks 
of study treatment.
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Status:Approved,  Date: 22 February 2021
Exploratory Endpoints
!
Responses to the palatability questionnaire after 2 weeks of study treatment.
!
Responses to the swallowability questionnaire after 2 weeks of study treatment.
!
Mutations in HIV-1 deoxyribonucleic acid (DNA) or in HIV-1 RNA, as assessed by retrospective 
peripheral blood mononuclear cell (PBMC)- or plasma-based analyses, through 24 and 48 weeks of 
study treatment.
Hypothesis
No formal hypothesis will be tested.
OVERALL DESIGN
This is a Phase 2, open-label, single-arm, multicenter, interventional study in HIV-1-infected participants 
(boys and girls) aged ≥2 to <12 years with a body weight of at least 10 kg to evaluate the PK, safety, 
tolerability, and efficacy of switching to RPV once daily in combination with other, investigator-selected 
ARVs.
All participants will have a screening phase aimed to be completed within 6 weeks. However, the screening 
phase can be prolonged with maximum 2 weeks in case of unforeseeable circumstances. All participants 
will receive open-label treatment for 48 weeks in the study intervention phase. Upon study completion, 
participants who continue to experience clinical benefit from treatment with RPV will be offered the 
opportunity to continue study treatment in the pediatric rollover study TMC278IFD3004. The total study 
duration for each participant, including screening and study intervention phases, will be approximately 
54 weeks. Participants who do not roll over in the pediatric study TMC278IFD3004, who withdraw from 
the study on or before the Week 48 visit (unless consent/assent is withdrawn), who have ongoing (S)AEs 
at the last study visit, or who need retesting of abnormal laboratory results, abnormal ECG, cortisol-related 
retesting, or plasma viral load/resistance testing at the last study visit will have a follow-up visit 4 weeks 
after their last study visit.
The end of study is considered as the last visit for the last participant in the study.
At some sites, an optional PK substudy may be performed to collect intensive PK data in children ≥6 years 
with body weight ≥25 kg on the day of intensive PK (substudy), which would require additional assessments 
as specified in the substudy protocol.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study. The IDMC will 
be the same committee as for the study TMC278-TiDP38-C213 (C213).
NUMBER OF PARTICIPANTS
To comply with overall regulatory requirements, approximately 40 participants (including at least 
12 participants with a body weight of <25 kg at baseline) will be enrolled in this study and in Cohort 2 
(participants aged ≥6 to <12 years) of the ongoing study C213 combined. A target of approximately 25 to 
30 participants will be enrolled in this study. The actual number of participants in this study will depend on 
the number of participants enrolled in Cohort 2 of study C213.
INTERVENTION GROUPS AND DURATION
At the time of Amendment 2 writing, the RPV dose recommendations of 25 mg and 15 mg for participants 
with a body weight ≥25 kg and <25 kg, respectively, were determined based on accumulating data and were 
endorsed by the IDMC, in order to achieve a similar exposure to RPV compared to adults. At the time of 
Amendment 3 writing, the dose for participants <20 kg was amended to 12.5 mg, based on data from the 
first mini-cohort of 5 children with a body weight <25 kg in the study, and was endorsed by the IDMC. 
NCT04012931


NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
13
Status:Approved,  Date: 22 February 2021
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
Pharmacokinetic/PD evaluations will be performed to explore the relationship between PK and 
safety/efficacy variables.
SAFETY EVALUATIONS
Key safety assessments will include the monitoring of (S)AEs and HIV-related events (including 
AIDS-defining illnesses and Stage-3-defining Opportunistic Illnesses in HIV Infection [cut-off for Stage-3 
illnesses is 6 years of age per criteria from 2014]), clinical laboratory tests (including endocrine assessments 
in participants aged ≥6 to <12 years, including participants who turn 12 years old during the study), 
cardiovascular safety monitoring (vital signs and 12-lead ECGs), and physical examination (including 
growth). In addition, an evaluation of depression will be performed using questionnaires or other means (as 
available at the site) as part of local standard of care for this population.
OTHER EVALUATIONS
Other assessments and procedures include resistance testing through HIV-1 genotyping and a retrospective 
evaluation of RAMs in PBMCs, documenting RPV intake through diary completion (only for participants 
scheduled for an intensive PK visit), treatment adherence, and palatability and swallowability assessments.
STATISTICAL METHODS
The primary analysis (with formal database lock) will be done when all participants have reached Week 24 
(or discontinued earlier). The final analysis (with formal database lock) will be done when all participants
have reached Week 48 (or discontinued earlier). A detailed Statistical Analysis Plan (SAP) for each analysis 
will be written and signed off prior to database lock.
Sample Size Calculation
No formal sample size calculation was performed. The sample size is based on overall regulatory 
requirements and the number of participants enrolled in Cohort 2 in study C213.
Efficacy Analysis
Plasma Viral Load
An outcome analysis (ie, proportion of participants with a plasma viral load <50 and <400 HIV-1 RNA 
copies/mL) will be performed using Snapshot approach. The Snapshot analysis is based on the last observed 
plasma viral load data within the visit window (ie, Weeks 24 and 48). The proportion of participants with 
virologic failure (ie, HIV-1 RNA ≥50 and ≥400 copies/mL) per Snapshot approach will be provided. 
Participants who switched ARVs for tolerability reasons not allowed per protocol will be considered as 
virologic failures for this Snapshot approach. Proportions will be expressed as percentages with Clopper 
Pearson 95% confidence interval (CI) at each time point. at each time point.
CD4+ Cell Count
The analysis will be based on observed values and on imputed values using NC=F, ie, participants who 
prematurely discontinued the study will have their CD4+ cell count following discontinuation imputed with 
the baseline value (resulting in a change of 0), and will have last-observation-carried-forward imputation 
for intermediate missing values.
Actual values and changes from baseline will be descriptively and graphically presented.
Safety Analysis
Adverse Events/HIV-related Events
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
14
Status:Approved,  Date: 22 February 2021
For each treatment-emergent AE/HIV-related event, the percentage of participants who experience at least 
1 occurrence of the given event will be tabulated per study phase (ie, screening phase, intervention phase, 
and follow-up). Separate tabulations will be made by severity and relationship to the study intervention, as 
appropriate.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue study intervention due to an AE, or who experience a grade 3/4 AE, 
an AE of special interest, or an SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be calculated for 
each laboratory analyte at baseline and for observed values and changes from baseline at each scheduled
time point. Descriptive statistics include number of observations (n), mean, standard deviation (SD), 
median, minimum, and maximum.
Frequency tabulations of the changes from baseline will be presented in pre- versus post-intervention cross-
tabulations (with classes for below, within, and above normal ranges). For the tests available, laboratory 
abnormalities will be determined using the Division of AIDS (DAIDS) grading table. Frequency tabulations 
of worst abnormality grade after baseline will be generated. As appropriate, frequency tabulations and 
listings will be provided for participants who develop a grade 3/4 laboratory abnormality.
Electrocardiogram
Descriptive statistics of ECG values and changes from baseline will be summarized at each scheduled time 
point. Descriptive statistics include number of observations (n), mean, SD, median, minimum, and 
maximum. Frequency tabulations of the abnormalities will be made.
Vital Signs
Descriptive statistics of pulse rate and blood pressure (systolic and diastolic) (supine and standing) values 
and changes from baseline will be summarized at each scheduled time point. Descriptive statistics include 
number of observations (n), mean, SD, median, minimum, and maximum. The percentage of participants
with values beyond clinically important limits will be summarized at each time point.
Physical Examination
Physical examination findings will be summarized at each scheduled time point per body system. Physical 
examination abnormalities will be listed.
Growth will be followed regularly and evaluated consistently using standardized growth charts. Descriptive 
statistics of height, height-for-age, weight, weight-for-age, body mass index (BMI), and BMI-for-age will 
be calculated at baseline and for observed values and changes from baseline at each scheduled time point. 
Descriptive statistics include number of observations (n), mean, SD, median, minimum, and maximum.
Tanner stage (for pubic hair and genitalia/breasts) will be cross-tabulated versus baseline by age. In 
addition, in girls, the occurrence of first menses during treatment will also be cross-tabulated versus 
baseline, and the date of menarche will be listed.
Pharmacokinetic Analysis
Descriptive statistics, including sample size (n), arithmetic mean, SD, (percentage of) coefficient of 
variation ([%]CV), geometric mean, median, minimum, and maximum, will be calculated for all individual 
derived PK parameters of RPV.
NCT04012931


NCT04012931


NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
17
Status:Approved,  Date: 22 February 2021
a
The screening phase can be prolonged with maximum 2 weeks in case of unforeseeable circumstances resulting in a maximum screening phase duration of 8 weeks.
b
In the current study and study C213 combined.
c
Intensive PK assessment after 4 weeks of study treatment.
d
The appropriateness of the RPV dose will be assessed.
e
Exposure (too high or too low) or results showing a safety or efficacy concern that could potentially be avoided by altering the RPV dose, as deemed by the sponsor upon IDMC 
recommendation. Refer to Section 6.6.1 for the dose evaluation criteria. The data may indicate that either all or some participants in certain body weight categories need an adjusted 
RPV dose. 
f
An additional intensive PK assessment will be performed after 2 weeks of treatment with the adjusted RPV dose. If after data review by the sponsor and IDMC, the RPV dose is still 
not acceptable, the process will be repeated until an acceptable RPV dose is found or the criteria for stopping are met.
g
Exposure (too high or too low) or results showing a safety or efficacy concern that cannot be avoided by altering the RPV dose, as deemed by the sponsor upon IDMC 
recommendation. Refer to Section 6.6.1 for the dose evaluation criteria.
h
For additional children only, an intensive PK assessment will be performed after 4 weeks of treatment with the RPV dose that was found acceptable in the mini-cohort.
i
After at least 12 children with a body weight of <25 kg (in the current study and study C213 combined) received 4 weeks of study treatment (or discontinued earlier), an overall 
analysis of all available data will be performed for IDMC review purposes. The same dose evaluation process as for the mini-cohort will be followed.
j
Approximately 40 participants will be enrolled in study TMC278HTX2002 and C213 Cohort 2 combined; at least 12 participants with a body weight of <25 kg at baseline in total, 
including at least 7 participants with a body weight of <20 kg at baseline.
k
Any retest, of abnormal laboratory results or plasma viral load/resistance testing, should be captured in this TMC278HTX2002 study if the participants roll over to the 
TMC278IFD3004 study.
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
18
Status:Approved,  Date: 22 February 2021
1.3
Schedule of Activities 
1.3.1
General Schedule of Activities
Screeninga Baseline
Study Intervention Phaseb
Follow-up Visitb,c
Study Assessments and Procedures
W-6
D1
W2
W4d
W8 W12 W16 W24 W32 W40 W48e
+4 Weeks 
Informed consent/assentf, demographic data, medical and 
surgical history, concomitant diseases
∀
Inclusion/exclusion criteriag,mm
∀
Xh
Historical HIV-1 genotyping result, including HIV-1 
subtypekk
X
HLA-B*5701 testingi
X
Determination of plasma HIV-1 RNA viral loadj
∀
∀
X
X
X
X
X
X
X
X
X
Samples for CD4+ cell count
∀
∀
∀
X
X
X
∀
X
X
X
Samples for viral genotypingk
X
X
X
X
X
X
X
X
X
X
PBMC samplel
X
X
X
Samples for biochemistrym,n,o
∀
∀
X
∀
X
X
X
∀
X
X
X
Xp
Samples for hematology
∀
∀
X
∀
X
X
X
∀
X
X
X
Xp
Samples for endocrine assessmentsq,r
X
X
Xs
Xp
Adrenocorticotropic hormone (ACTH) stimulation testingq,t
Reflex test
12-lead ECGu,mm
X
X
X
X
X
Xs
Xp
Vital signs (pulse rate, blood pressure)
∀
∀
X
∀
X
X
X
∀
X
X
X
X
Physical examination
∀
∀
Xv
∀w
Xw
X
Xw
∀
Xw
Xw
X
Xw
Check occurrence of first mensesx
X
X
X
X
X
X
X
X
X
X
X
Tanner stagingy
X
X
X
X
X
X
Contraceptive counselingz
X
Height/weightaa
∀
∀
X
∀
X
X
X
∀
X
X
X
X
Pregnancy testbb
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
∀
∀
X
∀
X
X
Xs
Samples for PKj,cc
X
Xdd
X
X
X
X
Diary completionee
X
Treatment adherence counseling
X
X
X
X
X
X
X
X
X
X
X
PENTA adherence questionnairell
X
X
X
X
X
∀
X
X
X
Study intervention accountability
X
X
X
X
X
X
X
X
X
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
19
Status:Approved,  Date: 22 February 2021
Screeninga Baseline
Study Intervention Phaseb
Follow-up Visitb,c
Study Assessments and Procedures
W-6
D1
W2
W4d
W8 W12 W16 W24 W32 W40 W48e
+4 Weeks 
Palatability assessmentff,gg
X
Swallowability assessmentff,hh
X
Evaluation of depressionii
X
X
X
X
X
X
X
X
X
X
Dispensation of RPV
X
X
X
X
X
X
X
X
Concomitant therapyjj
X
X
X
X
X
X
X
X
X
X
X
X
Observe/Interview for AEs/HIV-related eventsjj
X
X
X
X
X
X
X
X
X
X
X
X
a
After obtaining informed consent/assent, samples will be taken for determination of plasma HIV-1 RNA viral load and CD4+ cell count. During the screening phase, it is allowed 
to assess the plasma viral load and CD4+ cell count separately before the other screening assessments. If plasma viral load results meet the inclusion criteria and the investigator 
considers continuation of antiretroviral therapy (ART) appropriate (taking into account current treatment guidelines, including CD4+ cell count and the participant’s clinical 
status), the participant will return within 2 weeks after availability of these results for the remainder of the screening procedures. If plasma viral load results do not meet the 
inclusion criteria, the participant will be considered a screen failure. The baseline visit should be scheduled within 4 weeks after the screening visit (and within 6 weeks after 
plasma viral load and CD4+ cell count assessments, if these were assessed separately before the other screening assessments). In case of unforeseeable circumstances, the 
screening phase can be prolonged with maximum 2 weeks resulting in a maximum screening phase duration of 8 weeks.
b
Unscheduled visits may be performed for safety/tolerability reasons, including cortisol-related retesting, ECG retesting, and for determination of plasma HIV-1 RNA viral load 
results.
c
The 4-week follow-up visit is performed for participants who do not roll over in the pediatric study TMC278IFD3004, who withdraw from the study on or before the Week 48 
visit (unless consent/assent is withdrawn), who have ongoing (S)AEs at the last study visit, or who need retesting of abnormal laboratory results, abnormal ECG, cortisol-related 
retesting, or plasma viral load/resistance testing at the last study visit. Any retest of abnormal laboratory results or plasma viral load/resistance testing should be captured in this 
study if the participants roll over to study TMC278IFD3004 or if they stop the study. Additional unscheduled visits may be performed for safety/tolerability reasons, including 
cortisol-related retesting, ECG retesting, and for confirmation of plasma viral load results.
d
For participants with a body weight of <25 kg, the participants and/or their representatives should be contacted via telephone or email to assess adherence (to RPV and other 
ARVs) and to reinforce study instructions every day for at least 3 consecutive days before the intensive PK sampling. If potential AEs are detected during these telephone/email 
contacts, then an additional site visit should be scheduled, and necessary evaluations performed. If the participant has missed a dose of RPV within 10 days before the intensive 
PK visit, the visit should be rescheduled so as to achieve steady state of RPV.
e
For participants who discontinue the study before the Week 48 visit, this is the Withdrawal visit.
f
Informed consent must be obtained before any study-related activity. Participants (where appropriate, depending on age and local regulation) must be informed about the study 
and must give assent before any study-related activity.
g
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight 
Considerations.
h
The participant’s clinical status will be checked again before the first dose of study treatment. If a participant’s clinical status changes (including any available laboratory results 
or receipt of additional medical records) after screening but before the first dose of study treatment is given such that he or she no longer meets all eligibility criteria, then the 
participant should be excluded from study participation.
i
Only required for participants for whom the investigator considers abacavir (ABC) in the background regimen and not required for participants with prior documented 
HLA-B*5701 negative results. Also in case of switch to ABC during the study, the participant should test negative for HLA-B*5701 if prior documented HLA-B*5701 negative 
results are lacking. The test involves a cheek swab. No eating or drinking is allowed for 30 minutes before the swab. 
j
In case of suspected virologic failure, a sample for confirmation of plasma viral load and PK should be taken at an unscheduled visit.
k
Samples collected at the time of virologic failure, at Weeks 24 and 48, and at the Week 48/Withdrawal visit will be tested for the determination of the HIV-1 genotype, as long as 
the plasma viral load is sufficiently high. Samples collected at other time points may be selected for the determination of the HIV-1 genotype by the protocol virologist in case of 
virologic failure and based on plasma viral load.
l
A PBMC sample will be taken to allow retrospective characterization of archived viral resistance.
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
20
Status:Approved,  Date: 22 February 2021
m
Sample should be taken after overnight fasting.
n
Lipid assessments will only be performed at screening, on Day 1, and at Weeks 24 and 48.
o
A hepatitis A, B, and C test will be performed at baseline. Extra tests can be done at other visits, whenever clinically relevant.
p
For any abnormal result at the previous visit, the test should be repeated at this visit.
q
Only for participants aged ≥6 to <12 years (including for participants who turn 12 years old during the study).
r
Assessment of follicle-stimulating hormone (FSH), luteinizing hormone (LH), androstenedione, testosterone, 17-hydroxyprogesterone and dehydroepiandrosterone sulfate
(DHEAS) in conjunction with the cortisol assessment.
s
Assessments do not need to be performed at the Withdrawal visit.
t
The ACTH stimulation test needs to be conducted in case of confirmed abnormally low cortisol (<248 nmol/L [9 μg/dL] or signs or symptoms of adrenal insufficiency. It 
includes measurements of cortisol and 17-hydroxyprogesterone, measured before and 60 minutes after ACTH stimulation and needs to be conducted in the morning, between 
7h30 and 9h30. If the ACTH stimulation test is abnormal (ie, the cortisol value after ACTH stimulation is <500 nmol/L [18.1 μg/dL]), a retest needs to be performed at the next 
scheduled visit or at least within the next 8 weeks.
u
At baseline and at the intensive PK visit, the ECG should be taken predose and at the expected Cmax (ie, 4 hours after RPV intake). At Weeks 24 and 48, the ECG should 
preferably be taken at Cmax. Additional ECGs must be performed in case of start of certain concomitant medication (refer to Section 6.5.2).
v
A skin examination only.
w
A brief physical examination only.
x
Only for girls who have not yet had their first menses. Date of first menses will be noted, as applicable.
y
Tanner staging is limited to participants aged ≥6 to <12 years (including participants who turn 12 years old during the study).
z
It is the investigator’s responsibility to ensure that participants receive counseling about birth control methods and precautions to reduce the risk of transmitting HIV, as appropriate 
by age (refer to Section 10.4, Appendix 4, Contraceptive and Barrier Guidance and Collection of Pregnancy Information). Girls having their first menses during the study should 
receive counseling again.
aa
Growth will be followed using the standardized growth charts (see Section 10.15).
bb
Serum pregnancy test at screening and urine pregnancy test at the other time points (only for girls of childbearing potential). At baseline, the urine pregnancy test will be done 
before the first RPV intake. Additional serum or urine pregnancy tests may be performed for girls of childbearing potential, as determined necessary by the investigator or 
required by local regulation, to establish the absence of pregnancy at any time during study participation.
cc
Exact date and time of blood sampling and of the last 2 RPV intakes before blood sampling will be recorded on the case report form (CRF). Where possible (ie, if RPV intake 
occurs during the visit), at least on 1 occasion, the sample will be taken just before RPV intake. When additional safety monitoring ECGs are performed, a PK sample should be 
taken within 10 minutes after each of these ECGs (refer to Section 6.5.2).
dd
For participants with a body weight of <25 kg, intensive PK sampling will take place after 4 weeks of study treatment. Refer to the separate Schedule of Activities for Intensive
Pharmacokinetic Sampling for further details. For all other participants, a sparse PK sample will be taken.
ee
Participants scheduled for an intensive PK visit and/or their representatives will have to complete a diary documenting RPV intake from the start of study treatment until the 
intensive PK visit.
ff
Questionnaires will only be administered if a certified translation is available in the local language.
gg
Assessment should only be done upon administration of the 2.5-mg tablet formulation at the site.
hh
Assessment should only be done upon administration of the 25-mg tablet formulation at the site.
ii
Evaluation should be done using questionnaires or other means (as available at the site) as part of local standard of care. Any clinically relevant changes occurring during the 
study will be reported as AEs.
jj
Concomitant medication and AEs/HIV-related events (including AIDS-defining illnesses and Stage-3-defining Opportunistic Illnesses in HIV Infection) will be monitored 
throughout the study from signing of the informed consent form (ICF) onwards until the last study-related activity.
kk
For children aged ≥2 to <6 years, the availability of a historical HIV-1 genotyping and the HIV-1 subtype result should be documented in the CRF. If a historical HIV-1 
genotyping result is available for children aged ≥6 to <12 years, the subtype should be documented in the CRF as well. The historical HIV-1 genotype should be collected by the 
site monitor and provided to the sponsor.
ll
Separate PENTA adherence questionnaires are available for Children ≥ 6 years of age and for caregivers.
mm Retesting for an ECG leading to exclusion will be allowed once. 
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
21
Status:Approved,  Date: 22 February 2021
1.3.2
Schedule of Activities for Intensive Pharmacokinetic Sampling
Note: For participants with a body weight of <25 kg, as defined at baseline, intensive PK sampling
will take place after 4 weeks of study treatment. For participants who require an RPV dose 
adjustment (as per IDMC analysis), intensive PK sampling will take place after 2 weeks of study
treatment on that adjusted RPV dose (refer to Section 1.3.3).
Time
Blood Samplea
ECG, Pulse Rate, Blood Pressure
Other
Admission to site in the morning
Predose
Xb
Xc,d
Standard breakfast at site
0 h
RPV intakee
2 h
X
Resume usual diet
4 h
X
Xd
5 h
X
6 h
X
9 h
X
12 h
X
24 h
X
Discharge from unitf
a
At each indicated time point, approximately 1 mL of blood will be collected (total volume of blood drawn during the 
24-hour period will be approximately 10 mL).
b
Within 1 hour before RPV intake.
c
Within 2 hours before RPV intake.
d
Electrocardiogram and vital sign measurements should be performed preferably before blood sampling.
e
Rilpivirine dose should be taken within 40 minutes following the start of the breakfast. For participants who vomit within 
30 minutes after dosing, the dose should be readministered. Redosing is not allowed if the participant vomits more than 
30 minutes after dosing. If the participant vomits more than 30 minutes after dosing on the day of intensive PK 
evaluation, this assessment must be rescheduled.
f
In case it is not feasible for the participant to stay overnight, the participant can be discharged after the 12-hour sample
and return to the site for the 24-hour sample.
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
22
Status:Approved,  Date: 22 February 2021
1.3.3
Schedule of Activities for Switch to Adjusted RPV Dose (if 
Applicable)
Note: The following Schedule of Activities is applicable for participants with a body weight of 
<25 kg who switch to an adjusted RPV dose (as per IDMC analysis).
Study Assessments and Procedures
Study Intervention Phasea
Dose Switch Visitb,c
2 Weeks Post Dose 
Switch Visitc,d
4 Weeks Post Dose 
Switch Visitc,e
Determination of plasma HIV-1 RNA 
viral load 
∀
X
Samples for CD4+ cell count
∀
X
Samples for viral genotypingf
X
Samples for biochemistryg,h,i
X
X
Samples for hematology
∀
X
12-lead ECGj
X
Vital signs (pulse rate, blood pressure)
∀
X
Physical examination 
∀k
Xl
Check occurrence of first mensesm
X
X
Height/weightn
∀
X
Urinalysis
∀
Samples for PKo
Xp
X
Diary completionq
X
Treatment adherence counseling
X
X
X
PENTA adherence questionnairer
X
X
Study intervention accountability
X
X
Palatability assessmentr,s
X
Swallowability assessmentr,t
X
Evaluation of depressionu
X
Dispensation of RPV
X
X
Concomitant therapyv
∀
∀
X
Observe/Interview for AEs/HIV-related 
eventsv
∀
∀
X
a
Unscheduled visits may be performed for safety/tolerability reasons, including cortisol-related retesting and ECG 
retesting, for PK analysis and confirmation of plasma viral load results (in case of suspected virologic failure), and for 
the dose switch visit and/or post dose switch visits.
b
After at least 4 weeks of study treatment with the RPV dose (15 mg, 12.5 mg, or another adjusted weight-based dose) 
or, if applicable, with the adjusted RPV dose.
c
If the (post) dose switch visit is done within 1 week of the next scheduled visit as indicated in the General Schedule of 
Activities, this next scheduled visit can be cancelled but assessments of that visit will have to be performed at the (post) 
dose switch visit.
d
A re-evaluation of participants who have been treated with the adjusted RPV dose for 2 weeks (captured as 
unscheduled visits in the CRF).
e
A re-evaluation of participants who have been treated with the adjusted RPV dose for 4 weeks (captured as 
unscheduled visits in the CRF).
f
Samples collected at the time of virologic failure will be tested for the determination of the HIV-1 genotype, as long as 
the plasma viral load is sufficiently high. Samples collected at other time points may be selected for the determination 
of the HIV-1 genotype by the protocol virologist in case of virologic failure and based on plasma viral load.
g
Sample should be taken after overnight fasting.
h
Lipid assessments will not be performed.
i
Hepatitis A, B, and C tests can be done, whenever clinically relevant.
j
The ECG should preferably be taken at the expected Cmax (ie, 4 hours after RPV intake). Additional ECGs must be 
performed in case of start of certain concomitant medication (refer to Section 6.5.2).
k
A skin examination only.
l
A brief physical examination only.
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m
Only for girls who have not yet had their first menses. Date of first menses during the study will be noted, as 
applicable.
n
Growth will be followed using the standardized growth charts.
o
Exact date and time of blood sampling and of the last 2 RPV intakes before blood sampling will be recorded on the 
CRF. When additional safety monitoring ECGs are performed, a PK sample should be taken within 10 minutes after 
each of these ECGs (refer to Section 6.5.2).
p
Intensive PK sampling will take place at this visit. Refer to the separate Schedule of Activities for Intensive
Pharmacokinetic Sampling for further details.
q
Participants and/or their representatives will have to complete a diary documenting RPV intake from the start of 
treatment (with the adjusted dose) until the intensive PK visit.
r
Questionnaire will only be administered if a certified translation is available in the local language.
s
Assessment should only be done upon administration of the 2.5-mg tablet formulation.
t
Assessment should only be done upon administration of the 25-mg tablet formulation.
u
Evaluation should be done using questionnaires or other means (as available at the site) as part of local standard of care.
Any clinically relevant changes occurring during the study will be reported as AEs.
v
Concomitant medication and AEs/HIV-related events (including AIDS-defining illnesses and Stage-3-defining 
Opportunistic Illnesses in HIV Infection) will be monitored throughout the study from signing of the ICF onwards until 
the last study-related activity.
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2
INTRODUCTION
Rilpivirine (RPV, formerly known as TMC278 [R278474]), a diarylpyrimidine derivative, is a 
potent non-nucleoside reverse transcriptase inhibitor (NNRTI) with in vitro activity against 
wild type (WT) human immunodeficiency virus type 1 (HIV-1) and against NNRTI-resistant 
HIV-1 mutants. Rilpivirine as an oral formulation offers the convenience of once-daily dosing with 
potent antiviral activity and has a favorable safety and tolerability profile in adults and adolescents.
For the most comprehensive nonclinical and clinical information regarding RPV, refer to the latest 
version of the Investigator's Brochure (IB) and its Addenda for RPV, and to the EDURANT® 
prescribing information.13,21
Throughout this protocol, the term “study intervention” refers to RPV, the term “participant” refers 
to the child, and the term “representative” refers to the parent(s)/caregiver(s) and/or legally 
acceptable representative(s).
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
2.1
Study Rationale
Patients infected with HIV-1 are routinely treated with combinations of multiple drugs (highly 
active antiretroviral [ARV] therapy) including nucleoside/nucleotide reverse transcriptase 
inhibitors (N[t]RTIs), NNRTIs, protease inhibitors, pharmacokinetic (PK) boosters, integrase 
inhibitors, and fusion inhibitors. This treatment reduces HIV-1 ribonucleic acid (RNA) to 
undetectable levels in a substantial proportion of patients and counteracts the risk of viral 
resistance development. A medical need still exists for the development of age/weight-appropriate 
formulations in adolescents and children.
Rilpivirine is an NNRTI with in vitro activity against WT and NNRTI-resistant HIV-1. Rilpivirine 
at a dose of 25 mg once daily has been approved for treatment of ARV treatment-naïve 
HIV-1-infected adults in multiple countries, including the United States, Canada, Japan, and 
countries in the European Union, either as a single-agent 25-mg tablet (EDURANT) or as part of 
several fixed-dose combinations (ie, with the integrase inhibitor dolutegravir [DTG], with 
tenofovir disoproxil fumarate/emtricitabine [TDF/FTC], and with tenofovir alafenamide/FTC 
[TAF/FTC]). In most countries, including the United States and countries in the European Union, 
the indication of EDURANT is restricted to patients with a plasma viral load 
≤100,000 HIV-1 RNA copies/mL. In several countries, including the United States and countries 
in the European Union, this indication has been extended to the pediatric population 
(ie, adolescents aged ≥12 to <18 years). 
The further pediatric development of RPV is ongoing. In Cohort 2 of study 
TMC278-TiDP38-C213 (C213), an RPV dose that is safe and provides exposures similar to RPV 
exposures in adults (with a geometric mean area under the plasma concentration-time curve from 
time of administration up to 24 hours postdose [AUC24h] between 1,426 and 2,673 ng.h/mL) is
being evaluated in ARV treatment-naïve HIV-1-infected children aged ≥6 to <12 years with 
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baseline HIV-1 RNA ≤100,000 copies/mL.3 Study recruitment has been challenging as the number 
of children in this specific study population is very limited. The main reasons are that international 
treatment guidelines generally recommend to initiate antiretroviral therapy (ART) immediately 
after HIV-1 diagnosis and that many newly identified HIV-1-infected children have HIV-1 RNA 
levels significantly higher than 100,000 copies/mL. Therefore, the current study is designed to 
evaluate the PK, safety, tolerability, and efficacy of RPV in combination with other ARVs in 
virologically suppressed (ie, HIV-1 RNA <50 copies/mL) HIV-1-infected children aged 
≥2 to <12 years with a body weight ≥10 kg (ie, the 10th percentile of the growth curve for body 
weight for healthy girls aged 2 years)2 and without a history of virologic failure or documented 
resistance to RPV.
In study C213, available data for children with low body weights (<25 kg) are currently limited. 
Consequently, in the current study, intensive PK data will be gathered in HIV-1-infected children 
with a body weight of <25 kg (regardless of age) to further identify an RPV dose that provides 
exposures similar to those in adults. Depending on the RPV dose, either the oral RPV 25-mg tablet 
formulation or a not-yet-marketed oral 2.5-mg tablet formulation (to allow dose adaptation) will 
be administered.
The PK, safety, tolerability, and efficacy data over 48 weeks of treatment with RPV, administered 
as either a 25-mg dose or a weight-based dose (as applicable), will be evaluated in the entire group 
of virologically suppressed HIV-1-infected children aged ≥2 to <12 years enrolled in this study. 
These data will complement the results from Cohort 2 (children aged ≥6 to <12 years) in study
C213. With this, the overall regulatory requirements concerning the evaluation of RPV in a 
pediatric population aged ≥2 to <12 years could be fulfilled (refer to Section 4.2, Scientific 
Rationale for Study Design).
2.2
Background
Nonclinical Studies
Rilpivirine did not show a potential for genotoxicity, teratogenicity, phototoxicity, skin or eye 
membrane irritation, or delayed-type hypersensitization. The tumors observed in rodents were not 
the result of interaction of RPV with deoxyribonucleic acid (DNA) but rather due to an epigenetic 
mechanism. In addition, RPV did not affect fertility, early embryonic development, pre- and 
postnatal development, or the immune system at oral doses ranging from 160 to 1,600 mg/kg/day.
The target organs and systems of toxicity observed following oral administration of RPV were the 
adrenal cortex and the associated steroid biosynthesis (mouse, rat, dog, cynomolgus monkey), the 
reproductive organs (male and female dog), the liver (mouse, rat, dog), the thyroid and pituitary 
gland (rat), the kidney (mouse, dog), the hematopoietic system (mouse, rat, dog), and the 
coagulation system (male rat). The sensitivity of these organs or systems differed by species. In 
general, the effects were reversible. The effects on the thyroid gland in rats are considered 
species-specific and not relevant for humans.
Overall, the margin of exposure between that associated with the effects seen in animals after oral 
dosing and that of the 25-mg once-daily dose of RPV, is considered sufficient in view of the high 
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sensitivity of animals compared with humans and the lack of relevance of the animal effects for 
humans.
Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. The 
distribution of RPV into compartments other than plasma (eg, cerebrospinal fluid and genital tract 
secretions) has not been evaluated in humans. The terminal elimination half-life of RPV is 
approximately 45 hours. After single dose oral administration of 14C-RPV, on average 85% and 
6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged 
RPV accounted for on average 25% of the administered dose. Only trace amounts of unchanged 
RPV (<1% of the administered dose) were detected in urine. In vitro experiments indicate that 
RPV primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP)3A 
system. All metabolites found in humans were also found in animal species used for safety 
evaluation. The 25-mg once-daily dose of RPV is not likely to have a clinically relevant effect on 
the exposure of medicinal products metabolized by CYP enzymes, or medicinal products 
transported by P-glycoprotein.21
Clinical Studies
At the cut-off date of 19 May 2018, 39 Phase 1 studies with non-HIV-infected adults
(878 participants treated with RPV) and 1 Phase 1 study with HIV-1-infected adults
(15 participants treated with RPV) had been completed with oral RPV (sponsored by Janssen 
Research & Development). In 2 Phase 2a studies, 72 HIV-1-infected adults received oral RPV. 
One Phase 2b and 2 Phase 3 studies, in which 279 and 686 HIV-1-infected adults received oral 
RPV, respectively, have been completed.21 Additionally, data up to Week 240 are available from 
1 Phase 2 study in 36 HIV-1-infected adolescents (aged ≥12 to <18 years).4
Clinical Data and Previous Human Experience With Oral Tablet Formulation of RPV in 
Adults
Results from pooled Phase 1 studies have provided an understanding of the short-term safety and 
tolerability profile of RPV and its PK characteristics. Two Phase 2a studies demonstrated the 
short-term antiviral activity of RPV in HIV-1-infected adults and provided a strong rationale for 
further development of RPV in HIV-1-infected adults at doses of 25 to 150 mg once daily.
In the Phase 2b study in HIV-1-infected ARV treatment-naïve adults, substantial and sustained 
virologic response was observed after 96 weeks of study treatment, confirming the results of the 
primary analysis at Week 48. In the extension after Week 240, all ongoing participants maintained 
this virologic response up to the end of the study. Rilpivirine provided clear immunologic benefit 
as shown by the mean increase from baseline in cluster of differentiation (CD)4+ cell counts that 
occurred in participants treated with RPV up to Week 240. Most adverse events (AEs), including 
serious adverse events (SAEs) and AEs leading to discontinuation, emerged during the first 
48 weeks of study treatment and there were no changes in safety patterns up to the end of the study. 
The 25-mg once-daily dose of RPV offered the best benefit/risk balance for further development 
in HIV-1-infected ARV treatment-naïve adults.
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Clinical Data and Previous Human Experience With Oral Tablet Formulation of RPV in 
Adolescents (Aged ≥12 to <18 years) and Children (Aged ≥6 to <12 years)
The Phase 2 study C213 is an ongoing open-label, single-arm study in HIV-1-infected ARV 
treatment-naïve adolescents (aged ≥12 to <18 years, Cohort 1, completed) and children (aged ≥6 to 
<12 years, Cohort 2, ongoing). Participants received 48 weeks of treatment with RPV 25 mg once 
daily in combination with an investigator-selected background regimen (azidothymidine [AZT], 
abacavir [ABC], or TDF in combination with FTC or lamivudine [3TC]). Participants in Cohort 1 
were treated for an additional 4 years. The results of the Week 48 and Week 240 (final) analyses 
are available for the 36 adolescents enrolled in this cohort.
The Week 48 data showed that the 25-mg once-daily dose of RPV in adolescents resulted in similar 
RPV exposure as observed in adults.5 In addition, RPV 25 mg once daily in combination with an 
investigator-selected background regimen containing 2 N(t)RTIs was efficacious and generally 
safe and well tolerated.21
The results from the Week 240 analysis demonstrated long-term efficacy and safety. Virologic 
response (defined as confirmed plasma viral load <50 HIV-1 RNA copies/mL, time to loss of 
virologic response analysis) was achieved in 14/32 participants (43.8%). For participants with 
baseline plasma viral load ≤100,000 HIV-1 RNA copies/mL, 12/25 participants (48.0%) had 
virologic response at Week 240, compared with 2/7 participants (28.6%) with baseline plasma 
viral load >100,000 HIV-1 RNA copies/mL. Most AEs emerged in the first 48 weeks of the study 
and no new safety signal was observed thereafter. Rilpivirine did not affect pubertal development 
(as assessed by Tanner staging) or growth of adolescents. There were no new safety findings 
compared with the known RPV safety profile in HIV-1-infected adults.4
The recruitment of children aged ≥6 to <12 years in Cohort 2 is ongoing. The PK data in children 
(Cohort 2) supplemented with all available data in adolescents (Cohort 1) will allow dose selection 
for the current study (refer to Section 4.3, Justification for Dose).
2.3
Benefit/Risk Assessment
2.3.1
Known Benefits
The results of this study will establish the RPV dose recommendations for HIV-1-infected children
aged ≥2 to <12 years.
2.3.2
Potential Benefits
The establishment of a pediatric RPV dose is an important step towards the development of a 
pediatric fixed-dose combination with RPV.
Potential benefits of switching to an RPV-based regimen can be expected as treatment with RPV 
in combination with 2 NRTIs showed an improved safety profile in adults compared with an 
EFV-based regimen in the Phase 3 studies C209 and C215 (refer to Section 2.2, Background). In 
addition, oral RPV may show improved palatability versus ritonavir-boosted lopinavir syrup.7
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Improved palatability in children is important as it plays a pivotal role in achieving patient 
acceptance and therefore compliance to treatment.
As no control arm is included in the current study, these potential benefits will not be directly 
assessed.
2.3.3
Known Risks
Every medication can have undesirable effects.
The safety assessment is based on the Week 96 pooled data from 1,368 participants in the Phase 3
controlled studies C209 and C215 in HIV-1-infected ARV treatment-naïve adults, of whom 686 
received the 25-mg once-daily dose of RPV (refer to Section 2.2, Background). 
Grade 3 or 4 adverse drug reactions (ADRs) were reported in 3.6% of participants treated with 
RPV. By grouped term, the most frequently reported ADRs were headache (15.5%), nausea
(14.6%), insomnia (10.5%), dizziness (10.2%), abnormal dreams (8.9%), rash (7.4%), 
abdominal pain (7.1%), depression (6.9%), fatigue (5.7%), and vomiting (5.4%). Adverse drug 
reactions of at least grade 2 reported in at least 2.0% of adults treated with RPV were, by grouped 
term: depression (4.1%), headache (3.5%), insomnia (3.5%), transaminases increased (2.8%), rash 
(2.3%), and abdominal pain (2.0%).21 Most ADRs occurred in the first 48 weeks of study 
treatment.13
There were no additional ADR terms identified in adults in the (pooled) Phase 1, Phase 2a, and 
Phase 2b (up to 240 weeks) studies, nor in the post-Week 96 analyses of the Phase 3 studies.21
Furthermore, no new safety signal was identified in adolescents (Cohort 1 in the pediatric study 
C213) after 240 weeks of study treatment when compared with the known RPV safety profile in 
HIV-1-infected adults.4
2.3.4
Potential Risks
As with all clinical studies requiring blood sampling, there are risks associated with venipuncture
and multiple blood sample collection. Blood drawing may cause pain, tenderness, bruising, 
bleeding, dizziness, vasovagal response, syncope, and, rarely, infection at the site where the blood 
is drawn. 
Virologic failure and development of resistance are known to occur in ART containing an 
NNRTI and can result in the loss of treatment options from this class and of other constituents of 
the ART. In participants treated with RPV, a higher rate of overall treatment resistance and 
cross-resistance to the NNRTI class was observed compared to control. In the Phase 3 studies, the 
risk of virologic failure was greater in participants with a baseline plasma viral load 
>100,000 HIV-1 RNA copies/mL than in participants with a baseline plasma viral load 
≤100,000 HIV-1 RNA copies/mL. The greater risk of virologic failure for participants treated with 
RPV was observed in the first 48 weeks of study treatment, while low rates of virologic failure 
(similar to the control) were observed from Week 48 to Week 96. Participants who experienced 
virologic failure had an increased risk of developing NNRTI and/or N(t)RTI resistance. In the 
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Phase 2 study in adolescents, no new information on the resistance profile of RPV was identified 
in the Week 48 resistance analysis.11,21
The concomitant use of RPV and other drugs may result in potentially significant drug 
interactions, some of which may lead to loss of therapeutic effect of RPV and possible 
development of resistance.13
Body fat redistribution/accumulation, including central obesity, dorsocervical fat enlargement 
(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and ‘cushingoid 
appearance’ have been observed in patients receiving ART. The mechanism and long-term 
consequences of these events are unknown. A causal relationship has not been established.21
Immune reconstitution inflammatory syndrome has been reported in participants treated with 
combination ART, including RPV. During the initial phase of combination ART, participants
whose immune system responds may develop an inflammatory response to indolent or residual 
opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis 
jiroveci pneumonia, and tuberculosis), which may necessitate further evaluation and treatment. 
Autoimmune disorders such as Graves’ disease have also been reported to occur in the setting of 
immune reconstitution inflammatory syndrome; however, the time to onset is more variable, and 
these events can occur many months after treatment initiation.21
2.3.5
Overall Benefit/Risk Assessment
Accumulated data from completed and ongoing studies indicate that the benefit/risk balance for 
RPV clinical studies is positive.
Although there are potential benefits (refer to Section 2.3.2), there is no known direct benefit 
expected for HIV-1-infected participants in the current study (refer to Section 2.3.1).
Several safety measures have been proposed to minimize risk to participants, including:
!
Utilization of selection criteria which exclude participants who may potentially be at higher 
risk of an AE (refer to Section 5, Study Population).
!
Utilization of withdrawal criteria (refer to Section 7.2, Participant Discontinuation/Withdrawal 
From the Study). If a participant discontinues study intervention and withdraws from the study 
before the end of the study intervention phase (except when due to withdrawal of 
consent/assent), the Week 48/Withdrawal visit and 4-week follow-up visit assessments should 
be obtained.
!
Participants experiencing rash, acute systemic allergic reactions, aspartate aminotransferase 
(AST)/alanine aminotransferase (ALT) elevations, pancreatic amylase or lipase elevations, 
clinical hepatitis, nausea, diarrhea, neuropsychological symptoms, signs and symptoms of 
adrenal insufficiency, or other toxicities will be closely monitored, as specified in the protocol 
(refer to Section 10.2, Appendix 2, Monitoring and Safety for Specific Toxicities).
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!
For participants who do not roll over in the pediatric study TMC278IFD3004, any clinically 
significant abnormalities persisting at the last study visit will be followed up by the investigator 
until resolution or until a clinically stable endpoint is reached (refer to Section 8.2, Safety 
Assessments).
!
An Independent Data Monitoring Committee (IDMC) will evaluate the safety data on an 
ongoing basis.
!
In participants with a body weight of <25 kg, the appropriate RPV dose will be investigated in 
more detail and reviewed by the sponsor and the IDMC.
!
Safety evaluations will be done at several time points throughout the study (refer to Schedule 
of Activities). Blood samples for biochemistry, hematology, and endocrine assessments (only 
for participants aged ≥6 to <12 years, including participants who turn 12 years on the study),
and urine samples for urinalysis will be collected, and adrenocorticotropic hormone (ACTH)
stimulation testing (only for participants aged ≥6 to <12 years, including participants who turn 
12 years on the study) will be performed if required (refer to Section 1.3.1, General Schedule 
of Activities). Vital signs and 12-lead electrocardiograms (ECGs) will be recorded and 
physical examinations, including Tanner staging in participants aged ≥6 to <12 years
(including participants who turn 12 years on the study) and height and weight measurements,
will be performed. In addition, depression will be evaluated. Treatment can be stopped or 
interrupted at the investigator’s discretion (refer to Section 7, Discontinuation of Study 
Intervention and Participant Discontinuation/Withdrawal).
!
To avoid the accumulation of resistance-associated mutations (RAMs) and to allow timely 
study withdrawal, frequent plasma HIV-1 RNA viral load monitoring will be performed in 
addition to real-time plasma-based viral resistance testing in case of loss of virologic response. 
To minimize the risk of re-emergence of archived viral resistance, participants will only be 
enrolled if no documented genotypic evidence of resistance to RPV or to the selected 
background ARVs is present (refer to Section 5.2, Exclusion Criteria).
!
Additional ECGs will be performed in case of start of certain concomitant medication (refer to 
Section 6.5.2).
!
The blood sample collection scheme is designed to perform safety, tolerability, and efficacy 
evaluations and to accurately and completely describe the PK of RPV with a minimum number 
of blood samples being collected. The total blood volume to be collected is considered to be an 
acceptable amount over this time period from the population in this study (refer to
Section 4.2.1, Study-specific Ethical Design Considerations). The use of indwelling catheters 
is encouraged for the intensive PK sampling to minimize discomfort and distress due to 
repeated venipunctures for blood sampling. Furthermore, local anesthetics can be used at the 
blood sampling site.
!
Pregnancy and breastfeeding (if applicable/appropriate by age) are exclusion criteria. In 
addition, all participants are required to use contraceptive methods, as detailed in Section 5.
More detailed information about the known and expected benefits and risks of RPV may be found 
in the IB for RPV and its Addenda, and in the EDURANT prescribing information.13,21
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3
OBJECTIVES AND ENDPOINTS
OBJECTIVES
Primary Objectives
!
To evaluate the steady-state PK of RPV and determine the appropriate dose of RPV in 
combination with other ARVs in participants aged ≥2 to <12 years with a body weight of 
<25 kg.
!
To evaluate the safety and tolerability of RPV in combination with other ARVs in participants 
aged ≥2 to <12 years over a 24-week treatment period.
Secondary Objectives
!
To evaluate the safety and tolerability of RPV in combination with other ARVs over a 
48-week treatment period.
!
To evaluate the efficacy of RPV in combination with other ARVs over a 24- and 48-week 
treatment period.
!
To evaluate population PK and PK/pharmacodynamic (PD) relationships for safety and 
efficacy of RPV in combination with other ARVs.
!
To assess resistance in case of loss of virologic response to RPV in combination with other 
ARVs.
!
To evaluate treatment adherence to RPV in combination with other ARVs over a 24- and 
48-week treatment period.
Exploratory Objectives
!
To assess the palatability of the 2.5-mg tablet formulation of RPV, if applicable.
!
To assess the swallowability of the 25-mg tablet formulation of RPV, if applicable.
!
To assess archived viral resistance, if feasible depending on available blood volume.
ENDPOINTS
Primary Endpoints
!
Area under the plasma concentration-time curve from time of administration up to 24 hours 
postdose of RPV, as derived from the intensive PK assessments.
!
Incidence of grade 3/4 AEs, SAEs, HIV-related events (including acquired immune deficiency 
syndrome [AIDS]-defining illnesses and Stage-3-defining Opportunistic Illnesses in HIV 
Infection), and AEs leading to discontinuation of study intervention through 24 weeks of study 
treatment.
Secondary Endpoints
!
Incidence and severity of AEs/HIV-related events and their relatedness to RPV through 
24 and 48 weeks of study treatment.
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!
Change from baseline over time and shift in toxicity grades/abnormalities versus reference for 
clinical laboratory parameters, ECG parameters, vital signs, and physical examination through 
24 and 48 weeks of study treatment.
!
Proportion of participants with HIV-1 RNA <50 and ≥50 copies/mL using the Food and Drug 
Administration (FDA) Snapshot approach through 24 and 48 weeks of study treatment.
!
Proportion of participants with HIV-1 RNA <400 and ≥400 copies/mL using the FDA 
Snapshot approach through 24 and 48 weeks of study treatment.
!
Immunologic changes, measured by CD4+ cell count (absolute and percentage relative to total 
lymphocytes), through 24 and 48 weeks of study treatment.
!
Pharmacokinetic parameters of RPV (other than area under the plasma concentration-time 
curve [AUC]), as derived from the intensive PK assessments.
!
Pharmacokinetic parameters of RPV, as derived by population PK modeling, through 
24 and 48 weeks of study treatment.
!
Viral genotype at the time of virologic failure through 24 and 48 weeks of study treatment.
!
Treatment adherence, as assessed by the Pediatric European Network for the Treatment of 
AIDS (PENTA) adherence questionnaire and by study intervention accountability, through 
24 and 48 weeks of study treatment.
Exploratory Endpoints
!
Responses to the palatability questionnaire after 2 weeks of study treatment.
!
Responses to the swallowability questionnaire after 2 weeks of study treatment.
!
Mutations in HIV-1 DNA or in HIV-1 RNA, as assessed by retrospective peripheral blood 
mononuclear cell (PBMC)- or plasma-based analyses, through 24 and 48 weeks of study 
treatment.
Refer to Section 8, Study Assessments and Procedures, for evaluations related to endpoints.
HYPOTHESIS
No formal hypothesis will be tested.
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2, open-label, single-arm, multicenter, interventional study in HIV-1-infected 
participants (boys and girls) aged ≥2 to <12 years with a body weight of at least 10 kg to evaluate 
the PK, safety, tolerability, and efficacy of switching to RPV once daily in combination with other, 
investigator-selected ARVs (refer to Section 6.5.1).
To comply with overall regulatory requirements, approximately 40 participants (including at least 
12 participants with a body weight of <25 kg at baseline) will be enrolled in this study and in
Cohort 2 (participants aged ≥6 to <12 years) of study C213 combined. A target of approximately 
25 to 30 participants will be enrolled in this study. The actual number of participants in this study 
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will depend on the number of participants enrolled in Cohort 2 of study C213. The participants 
with a body weight of <25 kg and ≥25 kg will be enrolled in parallel.
Each participant needs to be virologically suppressed (ie, HIV-1 RNA <50 copies/mL) on a stable 
ARV regimen for at least 6 months at screening and needs to have no history of virologic failure. 
In addition, the participants should lack any RPV RAMs as evidenced by their historical HIV-1 
genotyping results, if available. Participants aged ≥2 to <6 years, however, are required to have 
historical HIV-1 genotyping results available at screening, to be provided to the sponsor. The 
availability of the historical HIV-1 genotyping results and the subtype need to be recorded in the 
CRF. For participants aged ≥6 to <12 years, the availability of historical HIV-1 genotyping results 
should be recorded in the CRF. More details on the study population are provided in Section 5.
Rilpivirine (25 mg, 15 mg, 12.5 mg, or another adjusted weight-based dose) will be orally 
administered once daily in combination with an investigator-selected background regimen 
containing other ARVs such as N(t)RTIs and integrase inhibitors. Protease inhibitors and ARVs 
requiring a PK booster, however, are disallowed from baseline onwards (refer to Section 6.5 for 
an overview of allowed and disallowed concomitant therapy).In participants with a body weight 
of <25 kg, an intensive PK assessment will be performed after 4 weeks of study treatment to 
evaluate the appropriateness of their RPV dose. If the RPV dose needs to be adjusted, an additional 
intensive PK assessment will be performed after 2 weeks of treatment with the adjusted RPV dose 
to evaluate the dose modification. Refer to Figure 1 for a schematic overview of the study and the 
dose evaluation process. For the dose evaluation criteria, refer to Section 6.6.1.
At some sites, an optional PK substudy may be performed to collect intensive PK data in children 
≥6 years with body weight ≥25 kg on the day of intensive PK (substudy), which would require 
additional assessments as specified in the substudy protocol. 
The decision to modify the RPV dose for a specific group of participants will be made by the 
sponsor upon IDMC recommendation. 
 
 
Refer to Section 6 for further information on the study intervention. Criteria for discontinuation of 
the study intervention and participant discontinuation/withdrawal from the study are listed in 
Section 7. 
The participants will continue the study intervention and ARV background regimen (through the 
data review periods, if applicable) until they all reach a total treatment duration of 48 weeks (or 
discontinue earlier). Dose adjustments of RPV due to changes in body weight, if applicable, are 
allowed. 
All participants will have a screening phase aimed to be completed within 6 weeks. However, the 
screening phase can be prolonged with maximum 2 weeks in case of unforeseeable circumstances. 
All participants will receive open-label treatment for 48 weeks in the study intervention phase. 
Upon study completion, participants who continue to experience clinical benefit from treatment 
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Status:Approved,  Date: 22 February 2021
with RPV will be offered the opportunity to continue study treatment in the pediatric rollover study
TMC278IFD3004. The total study duration for each participant, including screening and study 
intervention phases, will be approximately 54 weeks. Participants who do not roll over in the 
pediatric study TMC278IFD3004, who withdraw from the study on or before the Week 48 visit
(unless consent/assent is withdrawn), who have ongoing (S)AEs at the last study visit, or who need 
retesting of abnormal laboratory results, abnormal ECG, cortisol-related retesting, or plasma viral 
load/resistance testing at the last study visit will have a follow-up visit 4 weeks after their last 
study visit. Any retest of abnormal laboratory results or plasma viral load/resistance testing should 
be captured in this study if the participants roll over to study TMC278IFD3004.
Pharmacokinetic parameters will be derived from the intensive PK assessments performed in 
participants with a body weight of <25 kg.
 
Key safety assessments will include the monitoring of (S)AEs and HIV-related events (including 
AIDS-defining illnesses and Stage-3-defining Opportunistic Illnesses in HIV Infection [cut-off for 
Stage-3 illnesses is 6 years of age per criteria from 2014]),1 clinical laboratory tests (including 
endocrine assessments in participants aged ≥6 to <12 years, including participants who turn 
12 years old during the study), cardiovascular safety monitoring (vital signs and 12-lead ECGs), 
and physical examination (including growth). In addition, an evaluation of depression will be 
performed using questionnaires or other means (as available at the site) as part of local standard of 
care for this population (refer to Section 8.2).
Key efficacy assessments include determination of plasma HIV-1 RNA viral load and 
measurement of CD4+ cell count (refer to Section 8.1).
Other assessments and procedures include resistance testing through HIV-1 genotyping and a 
retrospective evaluation of RAMs in PBMCs, documenting RPV intake through diary completion 
(only for participants scheduled for an intensive PK visit), treatment adherence, and palatability
and swallowability assessments (refer to Section 8.10).
Details on the timing of the study intervention administration and assessments are given in the 
Schedule of Activities.
The same IDMC as for the study C213 will be commissioned for this study. Refer to Committees 
Structure in Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight Considerations,
for details. IDMC analyses will be conducted as described in Section 9.5. The primary analysis 
(with formal database lock) will be done when all participants have reached Week 24 (or 
discontinued earlier) followed by a final analysis (with formal database lock) when all participants
have reached Week 48 (or discontinued earlier).
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Status:Approved,  Date: 22 February 2021
4.2
Scientific Rationale for Study Design
Study Design
An open-label study design in which participants receive multiple doses of a certain study 
intervention up to steady state is a widely accepted design for studies in which a primary objective 
is to assess the steady-state PK parameters (ie, an objective measure) and to determine the 
appropriate dose of that study intervention. The PK data in children with a body weight of <25 kg
gathered in this study (combined with the PK data in children with a body weight of <25kg in 
study C213) will allow for comparison with historical data obtained in adults to determine if
similar exposures as those in adults are achieved. For this study, AUC24h of a selected RPV dose 
under fed and steady-state conditions will be the primary PK parameter. The target geometric mean 
AUC24h for RPV in this study population is between 80% and 150% of the observed geometric 
mean AUC24h for RPV in HIV-1-infected adults from the Phase 3 PK substudies of C209 and C215 
(ie, between 1,426 and 2,673 ng.h/mL).3 Pharmacokinetic data from adolescents will also be 
considered in the evaluation.5 While the AUC24h for RPV will be the primary PK parameter, the 
maximum observed plasma concentration (Cmax) and the (trough) plasma concentration at the 
beginning (C0h) and/or end (ie, at 24 hours postdose [C24h]) of the RPV dosing interval will also 
be considered. 
In this study, participants will switch to RPV plus other ARVs. This approach is supported by 
several studies indicating that switching to an RPV-containing ARV regimen is non-inferior in 
terms of safety, tolerability, efficacy, and the occurrence of virologic failure.6,9,17
Several safety measures have been proposed to minimize risk to participants (as described in 
Section 2.3.5, Overall Benefit/Risk Assessment) because only limited data are available on safety 
and tolerability in children aged ≥2 to <12 years. The primary objective will be the evaluation of 
safety and tolerability of RPV in combination with other ARVs in all participants. In addition, for 
participants with a body weight of <25 kg, the appropriateness of the RPV dose will first be 
assessed in a mini-cohort of at least 5 participants. Only when the results are deemed satisfactory 
by the sponsor upon IDMC recommendation (ie, satisfactory exposure and results not showing 
any safety or efficacy concern), additional participants with a body weight of <25 kg will be 
recruited (refer to Figure 1).
Study Population
Due to the medical need for the development of novel potent ARVs and age/weight-appropriate 
formulations in children (refer to Section 2.1, Study Rationale), HIV-1-infected children (boys and 
girls) aged ≥2 to <12 years will be enrolled. The recruitment of ARV treatment-naïve children in 
Cohort 2 in the ongoing study C213 is challenging (refer to Section 2.1).4 Therefore, recruitment 
in the current study is facilitated by enrolling participants who are virologically suppressed on a 
stable ARV regimen. The actual number of participants in this study will depend on the number 
of participants enrolled in Cohort 2 in study C213 (refer to Section 4.1).
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Status:Approved,  Date: 22 February 2021
Children with HIV-infection are known to often present with a stunted growth and a low body 
weight compared with healthy children, even more so if additional risk factors for growth 
impairment are present.33 To ensure that a representative fraction of the HIV-1-infected pediatric
population can be studied, children with a body weight as of 10 kg (ie, the 10th percentile of the 
growth curve for body weight for healthy girls aged 2 years)2 are allowed to enter the study.
In clinical studies, hypersensitivity reactions have been reported in approximately 5% of adult and 
pediatric participants receiving ABC.30 Since the risk for developing such reactions has been 
linked to the presence of the human leukocyte antigen (HLA)-B*5701 allele,28 participants without 
prior documented HLA-B*5701 negative results for whom the investigator considers ABC in the 
background regimen should test negative for HLA-B*5701 at screening to limit the risk of 
hypersensitivity reactions (refer to Section 10.2, Appendix 2, Monitoring and Safety for Specific 
Toxicities, for details). If a switch to an ABC-containing background regimen is planned during 
the study (due to intolerance, refer to Section 10.2), an HLA-B*5701 test has to be performed to 
determine eligibility to start ABC treatment (unless prior documented negative results are 
available).
Study Intervention Administration
The combined use of multiple ARVs in HIV-1-infected participants is currently recommended due 
to the inherent high mutation rate of HIV.8,10 Therefore, all participants will receive an 
investigator-selected background regimen in addition to RPV (refer to Section 6.5). Consistent 
with the treatment guidelines for ART, sensitivity to the chosen ARVs will be established at 
screening using historical HIV-1 genotyping results. Participants aged ≥6 to <12 years are not 
required to have historical HIV-1 genotyping results available at screening due to limited 
availability of historical HIV-1 genotyping results for participants in this age group, especially in 
the developing countries, and the expected fading of HIV-1 mutations.16,22,23,25
The 25-mg once-daily dose of RPV has been approved for oral treatment of ARV treatment-naïve 
HIV-1-infected adults and adolescents in multiple countries. The appropriate RPV doses to be used 
across the whole body weight range will be further established in this study.
 
.
Pharmacokinetic evaluations have shown that RPV is better absorbed following oral 
administration with food (refer to Section 2.2, Background). Therefore, RPV intake should occur 
with a meal.
Data collected over 24 weeks (primary analysis) are deemed a reasonable basis to adequately 
establish safety, tolerability, and efficacy.15 Longer-term safety, tolerability, and efficacy data will 
be reported after an additional 24-week treatment period at Week 48 (final analysis).
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Status:Approved,  Date: 22 February 2021
Study Assessments
To ensure that RPV steady-state is achieved after switching from the original ARV regimen, the
24-hour intensive PK assessment will be performed after 4 weeks of study treatment. The blood 
sample collection scheme was designed to accurately and completely describe the PK of RPV with 
a minimum number of blood samples being collected.
To avoid the accumulation of RAMs and to allow timely study withdrawal, frequent plasma viral 
load monitoring will be performed in addition to real-time plasma-based viral resistance testing in 
case of loss of virologic response. Samples for determination of CD4+ cell count will be taken in 
addition to the plasma viral load samples. 
Nonclinical studies demonstrated changes in adrenal hormones (refer to Section 2.2, Background). 
As a precaution, clinical laboratory evaluations will also include endocrine assessments in 
participants aged ≥6 to <12 years (including participants who turn 12 years old during the study) 
to verify whether any clinically relevant adrenal or gonadal effects of RPV are observed (refer to
Section 8.2.4). 
Delusions and inappropriate behavior have been reported in participants receiving licensed 
NNRTIs, predominantly in participants with a history of mental illness or substance abuse. In study 
C213, 19.4% of ARV treatment-naïve HIV-1-infected adolescents aged ≥12 to <18 years receiving 
the 25-mg once-daily dose of RPV were reported with depression at the Week 48 analysis cut-off. 
To proactively assess the risk of depression in participants treated with RPV, an evaluation will be 
done using questionnaires or other means (as available at the site) as part of local standard of care 
for this population. This will determine who needs to be referred for a complete mental health 
assessment by a mental health professional. Any clinically relevant changes occurring during the 
study will be reported as AEs.
Drug adherence is critical to the success of any treatment regimen. In addition, in the current study, 
suboptimal adherence to RPV has an impact on the PK assessments of RPV. Moreover, poor 
adherence to the background ARV regimen while remaining on only RPV (ie, virtual 
monotherapy) could not only lead to incomplete suppression of viral replication and treatment 
failure, but also potentially result in the emergence of a drug-resistant virus. There is evidence that 
adherence problems occur frequently in children. In a randomized treatment study, caregivers 
reported that 30% of children missed 1 or more doses of ARVs in the preceding 3 days.36 These 
findings illustrate the difficulty of maintaining high adherence levels, and underscore the need to 
work in partnership with families to make adherence assessment, education, and support integral 
components of care. In the current study, compliance to RPV and the background ARVs will be 
assessed by the PENTA adherence questionnaire. Compliance to RPV will also be assessed via 
pill count (study intervention accountability). If a participant’s intake of RPV or background ARVs 
is not according to the protocol, the investigator will take the necessary measures to ensure future 
adherence to the protocol.
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Status:Approved,  Date: 22 February 2021
Understanding the palatability and/or swallowability of the study intervention for children is 
important as it plays a pivotal role in achieving patient acceptance and therefore compliance to 
treatment. Palatability and swallowability will be assessed using a questionnaire by documenting 
the participant’s reaction when he or she is given the study intervention (refer to Sections 10.11
and 10.12, respectively).
4.2.1
Study-specific Ethical Design Considerations
Potential participants and/or their representatives will be fully informed of the risks and requirements 
of the study and, during the study, participants and/or their representatives will be given any new 
information that may affect their decision to continue participation. They will be told that their 
consent/assent to participate in the study is voluntary and may be withdrawn at any time with no 
reason given and without penalty or loss of benefits to which they would otherwise be entitled. Only 
participants and/or their representatives who are fully able to understand the risks, benefits, and 
potential AEs of the study, and provide their consent/assent voluntarily will be enrolled.
When referring to the signing of the informed consent form (ICF), the term representative refers to 
the parent(s)/caregiver(s) and/or legally acceptable representative(s) of the child with authority to 
authorize participation in research. For each participant, his or her parent(s) (preferably both parents, 
if available) or legally acceptable representative(s), as required by local regulations, must give 
written consent (permission) according to local requirements after the nature of the study has been 
fully explained and before the performance of any study-related assessments. Assent must be 
obtained from children (minors) capable of understanding the nature of the study, typically 
participants aged ≥7 years, depending on the institutional policies. Minors who assent to a study and 
later withdraw that assent should not be maintained in the study against their will, even if their 
representatives still want them to participate (refer to Section 10.3, Appendix 3, Regulatory, Ethical, 
and Study Oversight Considerations).
This study is being conducted to obtain data needed to assist in further pediatric development of 
RPV and establishing dose adjustment guidance in children. The primary ethical concern is that
this study will be performed in HIV-1-infected participants who will switch from an effective, 
suppressive ARV regimen to an RPV-based regimen still under investigation in this population. 
Known and potential benefits/risks are described in Section 2.3. Participants will receive financial 
compensation for travel expenses.
The total blood volume to be collected over a 30-day period is considered to be an acceptable 
amount over this time period from this study population based upon pediatric standards.14,19,37
4.3
Justification for Dose
 
 
 
 
 
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Status:Approved,  Date: 22 February 2021
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Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
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Status:Approved,  Date: 22 February 2021
 
 
4.4
End of Study Definition
A participant will be considered to have completed the study if he or she has completed 
assessments at Week 48 of the study intervention phase. Participants who prematurely discontinue 
study intervention for any reason before completion of the study intervention phase will not be 
considered to have completed the study.
The end of study is considered as the last visit for the last participant in the study. The final data 
from the study site will be sent to the sponsor (or designee) after completion of the final participant 
visit at that study site, in the time frame specified in the Clinical Trial Agreement.
5
STUDY POPULATION
Screening for eligible participants will be performed within 6 weeks before administration of the 
study intervention. Refer to Section 5.4, Screen Failures, for conditions under which the repeat of 
any screening procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate sponsor 
representative and resolve any issues before enrolling a participant in the study. Waivers are not 
allowed. 
For a discussion of the statistical considerations of participant selection, refer to Section 9.2, 
Sample Size Determination.
5.1
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1.
Aged ≥2 to <12 years at screening.
2.
Criterion modified per Amendment 3
2.1 Weighing at least 10 kg at screening.
3.
Have documented chronic HIV-1 infection.
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Status:Approved,  Date: 22 February 2021
4.
Criterion modified per Amendment 1 and Amendment 2
4.1 On a stable ARV regimen for at least 6 months prior to screening and virologically 
suppressed with documented evidence of at least 2 plasma viral loads <50 HIV-1 RNA 
copies/mL: one within 2-12 months prior to screening and one at screening.
Note: single viral loads ≥50 HIV-1 RNA copies/mL (‘blips’) are allowed after viral 
suppression (confirmed viral load <50 HIV-1 RNA copies/mL) within 12 months prior 
to screening, provided a subsequent viral load measurement is <50 HIV-1 RNA 
copies/mL (or HIV-1 RNA undetectable by a local HIV-1 RNA test) prior to or at
screening. 
5.
Criterion deleted per Amendment 1. 
6.
Parent(s) (preferably both if available or as per local requirements) (or the participant’s 
legally acceptable representative[s]) must sign an ICF indicating that he or she 
understands the purpose of and procedures required for the study and is willing to allow 
the child to participate in the study. Assent is also required from participants capable of 
understanding the nature of the study (typically aged ≥7 years), as described in the 
Informed Consent Process in Section 10.3, Appendix 3, Regulatory, Ethical, and Study 
Oversight Considerations.
7.
Can comply with the protocol requirements.
8.
Can switch from any ARV class.
9.
Never been treated with a therapeutic HIV vaccine.
10.
Otherwise healthy and medically stable on the basis of physical examination, medical 
history, vital signs, and 12-lead ECG performed at screening. If there are abnormalities, 
they must be consistent with the underlying illness in the study population. This 
determination must be recorded in the participant’s source documents and initialed by 
the investigator.
11.
Otherwise healthy on the basis of clinical laboratory tests performed at screening. If the 
results of biochemistry, hematology, or urinalysis are outside the normal reference 
ranges, the participant may be included only if the investigator judges the abnormalities 
or deviations from normal to be not clinically significant or to be appropriate and 
reasonable for the study population. This determination must be recorded in the 
participant’s source documents and initialed by the investigator.
12.
Historical HIV-1 genotyping result at screening for children aged ≥2 to <6 years (and 
for children aged ≥6 to <12 years if a historical HIV-1 genotyping result is available at 
screening) must demonstrate sensitivity to RPV and to the selected background ARVs.
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Status:Approved,  Date: 22 February 2021
13.
Girls are eligible to participate if they are not pregnant (refer to Section 10.4,
Appendix 4, Contraceptive and Barrier Guidance and Collection of Pregnancy 
Information) and not breastfeeding.
14.
Girls of childbearing potential must have a negative highly sensitive serum β-human 
chorionic gonadotropin test at screening.
15.
Heterosexually active girls of childbearing potential must practice a highly effective 
method of contraception (failure rate of <1% per year when used consistently and 
correctly) and agree to remain on a highly effective method while receiving study 
treatment and for at least 30 days after last RPV intake (refer to Section 10.4, 
Appendix 4, Contraceptive and Barrier Guidance and Collection of Pregnancy 
Information).
16.
Heterosexually active boys must practice a highly effective method of contraception 
(failure rate of <1% per year when used consistently and correctly) and agree to remain 
on a highly effective method while receiving study treatment and for at least 30 days 
after last RPV intake. All HIV-1-infected boys are advised to use a condom to reduce 
the risk of transmitting HIV (refer to Section 10.4, Appendix 4, Contraceptive and 
Barrier Guidance and Collection of Pregnancy Information).
17.
Can adhere to the lifestyle restrictions (refer to Section 5.2).
5.2
Exclusion Criteria 
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
1.
Have previously documented HIV-2 infection.
2.
Have known or suspected acute (primary) HIV-1 infection.
3.
Taken any disallowed concomitant therapies within 4 weeks before the planned first 
dose of study intervention (refer to Section 6.5, Concomitant Therapy). 
4.
A positive HLA-B*5701 test at screening (when the investigator considers ABC in the 
background regimen). In case of a positive test, ABC cannot be administered, but 
instead, the investigator can select another ARV in the background regimen. 
HLA-B*5701 testing is not required for participants with prior documented negative 
results.
5.
Any current or history of adrenal disorder.
6.
Any active clinically significant diseases (eg, pancreatitis, cardiac dysfunction, active 
and significant psychiatric disorders, clinical suspicion of adrenal insufficiency, and 
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Status:Approved,  Date: 22 February 2021
hepatic impairment) or findings at screening or medical history that, in the 
investigator’s opinion, would compromise the outcome of the study.
7.
A history of virologic failure to ARVs with or without availability of an HIV-1 
genotype result at the time of failure.
8.
Documented genotypic evidence of resistance to RPV or to the selected background 
ARVs from historical data available in the source documents (ie, at least 1 NNRTI 
RAM from the following list compiled on the basis of the list of the International 
Antiviral Society United States of America [IAS-USA] NNRTI RAMs39 and other 
relevant publications). 
A098G
V106M
Y181C
G190S
L100I
V108I
Y181I
G190T
K101E
E138A
Y181V
P225H
K101P
E138G
Y188C
F227C
K101Q
E138K
Y188H
M230I
K103H
E138Q
Y188L
M230L
K103N
E138R
G190A
P236L
K103S
V179E
G190C
K238N
K103T
V179D
G190E
K238T
V106A
V179T
G190Q
Y318F
9.
A known clinically significant allergy, hypersensitivity, or intolerance to RPV or its 
excipients (refer to the latest version of the IB for RPV)21or to the selected background 
ARVs. 
10.
Criterion modified per Amendment 1
10.1 Received an investigational intervention (including investigational vaccines) 
containing an active substance or used an invasive investigational medical device 
within 90 days before the planned first dose of study intervention.
11.
Enrolled in clinical studies that include any blood sampling with a volume >50 mL 
taken within 6 months before the planned first administration of RPV, specimen 
collection, or other 
interventional procedure. Concurrent participation in 
non-interventional observational studies is allowed as long as there is no impact on the 
objectives of this study. Data collected in this study can be reported in the observational 
study.
12.
Any condition (including but not limited to the abuse of alcohol or drugs 
[eg, barbiturates, opiates, cocaine, cannabinoids, amphetamines, and benzodiazepines]) 
for which, in the opinion of the investigator, participation would not be in the best 
interest of the participant (eg, compromise the well-being) or that could prevent, limit, 
or confound the protocol-specified assessments.
13.
A life expectancy of less than 6 months.
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Status:Approved,  Date: 22 February 2021
14.
Any currently active AIDS-defining illness or Stage-3-defining Opportunistic Illnesses 
in HIV Infection (cut-off for Stage-3 illnesses is 6 years of age per criteria from 2014).1
Note: An AIDS-defining illness not clinically stabilized for at least 30 days will be 
considered as clinically active.
Note: Primary and secondary prophylaxis for an AIDS-defining illness is allowed in 
case the medication used is not part of the disallowed medication (refer to 
Section 6.5.3).
15.
Any grade 3/4 laboratory abnormality at screening according to the Division of AIDS 
(DAIDS) grading table (refer to Section 10.5, Appendix 5, DAIDS Table), except for a 
selection of abnormalities:
a) grade 3 absolute neutrophil count
b) grade 3 platelets
c) grade 3 glucose elevation in diabetics
d) asymptomatic grade 3 pancreatic amylase elevation
e) asymptomatic grade 3 triglyceride / cholesterol / glucose elevation
f)
asymptomatic grade 4 triglyceride elevation
Note: Retesting of abnormal screening values that lead to exclusion will be allowed 
only once for each laboratory test using an unscheduled visit during the screening 
phase (to reassess eligibility).
16.
Active tuberculosis or being treated for tuberculosis with rifamycins at screening.
17.
The following ECG findings at screening, if judged clinically significant by the 
investigator: abnormal pulse rate and QRS intervals; rhythm abnormalities; evidence 
of acute ischemic changes.
18.
Criterion modified per Amendment 3
18.1 One or more of the following risk factors for QTc prolongation:
a) a confirmed prolongation of QT/QTc interval, eg, repeated demonstration of 
QT interval corrected for heart rate according to Bazett’s formula (QTcB) or 
Fridericia’s formula (QTcF) ≥450 ms in the screening ECG.
b) pathological Q-waves (defined as Q-wave >40 ms or depth >0.4-0.5 mV).
c) evidence of ventricular pre-excitation.
d) electrocardiographic evidence of complete or incomplete left bundle branch 
block or complete or clinically significant incomplete right bundle branch 
block.
e) evidence of second or third degree heart block.
f)
intraventricular conduction delay with QRS duration >90 ms, unless this is the 
only conduction abnormality, and no other conduction abnormalities are 
present.
g) bradycardia as defined by sinus rate <50 bpm.
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Status:Approved,  Date: 22 February 2021
h) personal or family history of long QT syndrome.
i)
personal history of cardiac disease (including congenital heart disease), or
symptomatic arrhythmias, with the exception of sinus arrhythmia; personal 
history of asymptomatic arrhythmias is excluded if the asymptomatic 
arrhythmia is clinically significant in the opinion of the investigator.
j)
syncopal episodes if repeated, unexplained, and unrelated to emotional distress
k) risk factors for Torsade de Pointes (TdP) (eg, heart failure, hypokalemia, and 
hypomagnesemia).
Note: Retesting of an abnormal screening ECG that leads to exclusion will be allowed 
only once using an unscheduled visit during the screening period (to reassess 
eligibility).
19.
Acute clinical hepatitis at screening.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a participant's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study intervention is given 
such that he or she no longer meets all eligibility criteria, then the participant should be excluded 
from participation in the study. Section 5.4, Screen Failures, describes options for retesting and 
rescreening. The required source documents to support meeting the enrollment criteria are noted 
in Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight Considerations.
5.3
Lifestyle Considerations
Potential participants must adhere to the following lifestyle restrictions during the course of the 
study to be eligible for participation:
1.
Refer to Section 6.5, Concomitant Therapy for details regarding prohibited and 
restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements) (refer to Sections 5.1
and 5.2, respectively).
Participants scheduled for an intensive PK visit must adhere to the following meals and dietary
restrictions (as appropriate for the participant’s age) until the last PK sample at the intensive PK 
visit has been taken:
1.
Consumption of Seville oranges, grapefruit or grapefruit juice, apple juice, orange juice, 
and citrus fruits is not permitted from 7 days before RPV intake on the day of the 
intensive PK sampling until the last PK sample at the intensive PK visit has been taken.
2.
Quinine-containing products (eg, tonic water and bitter lemon) are not permitted from
24 hours before RPV intake on the day of the intensive PK sampling until the last PK 
sample at the intensive PK visit has been taken. 
NCT04012931


TMC278 (rilpivirine)
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Status:Approved,  Date: 22 February 2021
3.
Alcohol-containing products are not permitted from 24 hours before RPV intake on the 
day of the intensive PK sampling until the last PK sample at the intensive PK visit has 
been taken.
5.4
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not enrolled into 
the study, the date seen and age at initial informed consent will be used.
Retesting
Any grade 3/4 laboratory abnormalities or ECG abnormalities at screening that lead to exclusion
are allowed to be retested once as described in exclusion criteria 15 and 18 in Section 5.2. Retesting 
will take place during an unscheduled visit in the screening phase.
Rescreening
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. In case the inclusion or exclusion criteria are updated, a participant may be 
rescreened one additional time. Participants who are rescreened will be assigned a new participant 
number, undergo the informed consent process, and then restart a new screening phase.
6
STUDY INTERVENTION
6.1
Study Interventions Administered
Two formulations of RPV may be used in this study:
!
The commercially available RPV (EDURANT) is formulated as an oral film-coated tablet 
(formulation GFI-314585-CA-026), containing 27.5 mg of RPV as the hydrochloric acid salt 
R314585, equivalent to 25 mg of RPV as the free base.
The study intervention (RPV 25 mg, 15 mg, 12.5 mg or another adjusted weight-based dose) will 
be provided as tablets for oral administration. Participants will be instructed to take (or their 
representatives to administer) their assigned dose of the study intervention orally each day in 
combination with an investigator-selected background regimen for 48 weeks. 
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Status:Approved,  Date: 22 February 2021
The 25-mg tablets should be taken as a whole, and cannot be chewed, broken, or crushed.
 
 
 
Participants who require an RPV dose below 25 mg will start on the 2.5-mg tablet formulation. 
The tablets must be dispersed prior to use. Their RPV dose will be adjusted according to the final 
dosing schedule by weight bands as they gain weight. If participants increase in weight such that 
they require an RPV 25-mg dose, they can change to the 25-mg tablet formulation. The RPV dose 
will be taken preferably with the main meal of the day, and each dose will be separated by 
approximately 24 hours.
In participants with a body weight of <25 kg, intensive PK sampling will be performed after 
4 weeks of treatment with the RPV dose administered at baseline, or, if applicable, after 2 weeks 
of treatment with the adjusted RPV dose(s). For practical reasons, the last 3 days before the 
intensive PK sampling, participants must take the RPV dose in the morning with breakfast. 
Participants will be confined to the study site in the morning of the intensive PK sampling day and 
will receive a standard breakfast. Rilpivirine should be taken within 40 minutes following the start 
of the breakfast. Approximately 2 hours after RPV intake, participants may resume their usual diet.
If more practical, participants can switch the RPV intake to another time of the day after the 
intensive PK sampling, as long as the RPV intake is always with a meal. The meals and dietary 
restrictions mentioned in Section 5.3, Lifestyle Considerations, should be respected. The exact 
date and time of the last 2 RPV intakes before the intensive PK visit and of the RPV intake on the 
intensive PK visit should be recorded in the case report form (CRF), as well as the exact date and 
time of PK sampling and the start and stop times and content details of the standard breakfast.
For details on background medications, refer to Section 6.5.1. Temporary discontinuation of all 
ARVs during the study intervention phase will be allowed only in the event of suspected toxicity 
as described in Section 7.1.1. Criteria for discontinuation of study intervention and participant
discontinuation/withdrawal from the study are provided in Section 7.2.   
Study intervention administration must be captured in the source documents and the CRF. 
Study-site personnel will instruct participants and their representatives on how to store study 
intervention for at-home use as indicated for this protocol (refer to Section 6.2).
Rilpivirine will be manufactured and provided under the responsibility of the sponsor. Refer to 
latest version of the IB for RPV for a list of excipients.21 The excipients used in both formulations 
are safe for administration in the pediatric population participating in the study. Specific detailed 
dosing and administration instructions will be provided in the pharmacy manual/study-site 
investigational product and procedures manual, which will be provided before the start of the 
study. Rilpivirine will be packed in individual, child-resistant participant kits under responsibility of 
the sponsor. Each kit will contain information and will be labeled as required per Good 
Manufacturing Practice (GMP) Annex 13 and per local/country regulatory requirements. Labels 
must remain affixed to the individual participant kit. No medication can be repacked or relabeled 
without prior approval from the sponsor.
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Status:Approved,  Date: 22 February 2021
In case a participant missed the RPV intake, and this is noticed within 12 hours of the time of usual 
intake, the participant should take the missed dose as soon as possible, with food. The participant 
may then continue his or her usual dosing schedule. In case a participant missed the RPV intake, 
and it is noticed more than 12 hours after the time of usual intake, the participant should not take 
that dose and simply resume the usual dosing schedule. The participant should not take a double 
dose to make up for a missed one. For participants who vomit within 30 minutes after dosing, the 
dose should be readministered. Redosing is not allowed if the participant vomits more than 
30 minutes after dosing.
For a definition of study intervention overdose, refer to Section 8.4, Treatment of Overdose.
6.2
Preparation/Handling/Storage/Accountability
The study intervention must be stored at controlled temperatures ranging from 59°F to 86°F (15°C 
to 30°C) unless otherwise specified, and in the original packaging. Refer to the pharmacy 
manual/study-site investigational product and procedures manual for additional guidance on study 
intervention preparation, handling, and storage. Study intervention will be administered to the 
participant by the representative if the participant is deemed unable to self-administer the medication.
Should a deviation in storage conditions occur for RPV, then the study site should refrain from any 
further dispensation of the affected medication and provide the study-site monitor immediately with 
the following information:
!
Study number
!
Reference and batch number(s)
!
Kit number
!
Study site number
!
Temperature log (including date and duration of the deviation, minimum temperature below 
and/or maximum temperature above the specified range, that the medication was exposed to) 
and used units (°C or °F)
Deviations in storage conditions will be evaluated by the sponsor and the study site will receive 
notification whether the affected medication can continue to be used.
The investigator is responsible for ensuring that all study intervention received at the site is 
inventoried and accounted for throughout the study. The dispensing of study intervention to the 
participant, and the return of study intervention from the participant (if applicable), must be 
documented on the study intervention accountability form. Participants or their representatives
must be instructed to return all original containers, whether empty or containing study intervention.
The study intervention will be stored and disposed of according to the sponsor’s instructions. 
Study-site personnel must not combine contents of the study intervention containers.
Study intervention must be handled in strict accordance with the protocol and the container label, 
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study intervention, and study intervention returned by the 
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Status:Approved,  Date: 22 February 2021
participant, must be available for verification by the sponsor’s study-site monitor during on-site 
monitoring visits. The return to the sponsor of unused study intervention, or used returned study 
intervention for destruction, will be documented on the study intervention return form. When the 
study site is an authorized destruction unit and study intervention supplies are destroyed on-site, 
this must also be documented on the study intervention return form.
Study intervention should be dispensed under the supervision of the investigator or a qualified 
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be 
supplied only to participants. Returned study intervention must not be dispensed again, even to the 
same participant. Whenever a participant brings his or her study intervention to the study site for 
pill count, this is not seen as a return of supplies. Study intervention may not be relabeled or 
reassigned for use by other participants. The investigator agrees neither to dispense the study 
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
6.3
Measures to Minimize Bias: Randomization and Blinding
This is a single-arm study, randomization is not applicable.
As this is an open-label study, blinding procedures are not applicable.
6.4
Study Intervention Compliance
Study-site personnel will maintain a log of all study intervention received. Study intervention 
supplies for each participant will be inventoried and accounted for.
Compliance to RPV and the background ARVs will be assessed by the PENTA adherence 
questionnaire (refer to Section 8.10.3 for more information). Compliance to RPV will also be 
assessed via pill count (study intervention accountability), as documented on the study intervention 
accountability form. If a participant’s intake of study intervention or background ARVs is not 
according to the protocol, the investigator will take the necessary measures to ensure future 
adherence to the protocol.
To optimize compliance to both RPV and the background ARVs, adherence counseling should be 
planned by the investigator/study-site personnel with the participant and his or her representative
at the screening visit to discuss the individual issues that may affect each participant’s chances of 
successfully adhering to treatment. Counseling should address the implications of suboptimal 
adherence for each participant. At the baseline visit, a second adherence counseling session should 
take place and clear instructions need to be given regarding regimen intake. A compliance check 
(eg, review of the PENTA adherence questionnaire or study intervention accountability) and
additional treatment adherence counseling should take place at every subsequent study visit.
The representative of participants scheduled for an intensive PK visit, and participants as well if 
appropriate, will also have to complete a diary documenting RPV intake from the start of study 
treatment until the intensive PK visit (refer to Section 8.10.2 for more information). Participants
and/or their representatives should also be contacted via telephone or email to assess compliance
(to study intervention and background ARVs) and to reinforce study instructions every day for at 
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Status:Approved,  Date: 22 February 2021
least 3 consecutive days before the intensive PK visit. If the participant has missed a dose of RPV 
within 10 days before the intensive PK visit, the visit should be rescheduled to allow steady state 
of RPV to be reached.
6.5
Concomitant Therapy
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; nonpharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) continued at the start of the study or started during the study and different 
from the study intervention must be recorded in the CRF. Recorded information will include a 
description of the type of therapy, duration of use, dose regimen, route of administration, and 
indication. Any change in dosages of the non-ARV medication must also be reported in the CRF. 
Data on concomitant therapies will be collected up to the last study-related activity, even after 
participant withdrawal (except in case of withdrawal of consent/assent).
For any concomitant therapy given as treatment for a new condition or a worsening of an existing 
condition occurring after signing the ICF, the condition must be documented in the AE section of 
the CRF.
6.5.1
Background Regimen
The investigator-selected ARVs, including but not limited to N(t)RTIs (eg, AZT, ABC, TAF, or 
TDF in combination with FTC or 3TC), whichever are approved and marketed or considered local 
standard of care for children aged ≥2 to <12 years in a particular country, will be given as the 
coformulation or as the separate components according to local availability and use in the country 
(eg, Combivir® or 3TC/AZT, Epzicom®/Kivexa® or ABC/3TC, Truvada® or FTC/TDF).
Integrase inhibitors (eg, DTG or raltegravir) can also be administered in combination with RPV, 
as appropriate. Protease inhibitors and ARVs requiring a PK booster, are disallowed from baseline 
onwards. No dual combination of ARVs are allowed in this study.
Only branded versions of the background ARVs or generics with tentative United States FDA 
approval or World Health Organization [WHO] prequalified drugs will be prescribed by the 
investigator and reimbursed by the sponsor during the 48-week intervention phase. If these are not 
available, generic drugs approved by the local health authorities or procured by the United Nations 
(UN) international organizations (eg, United Nations International Children’s Emergency Fund 
[UNICEF]) can be allowed upon approval by the sponsor.
The selected background ARVs will be used in doses that are specified in the individual package 
inserts or for which sufficient supporting data are available for use in this age group. Applicable 
procedures and guidance based on package inserts should be respected (eg, in case of missed 
doses). The intake of the background ARVs will be according to the locally applicable procedures 
and package inserts, but preferably at the same time as RPV for ARVs with a once daily regimen. 
For ARVs with a twice daily regimen, one of the doses will be preferably taken together with RPV 
and the other dose will be taken according to the package insert. All ARVs should be started on 
the same day (ie, Day 1). For storage conditions of background ARVs, consult the respective 
package inserts.
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Status:Approved,  Date: 22 February 2021
Temporary discontinuation of all ARVs during the study intervention phase will be allowed only 
in the event of suspected toxicity as described in Section 7.1.1.
For those participants who do not tolerate the selected background ARVs, switching to alternative 
ARVs (branded versions or generics with tentative United States FDA approval and/or WHO 
prequalified drugs, or if not available, generic drugs approved by the local health authorities or 
procured by the UN international organizations upon approval by the sponsor) is allowed for some 
predefined toxicities.
A change of background regimen will be allowed in case the following AEs are reported and 
preferably after written approval from the sponsor:
!
Lactic acidosis
!
Hepatotoxicity, including severe hepatomegaly and steatosis even in the absence of marked 
transaminase elevations
!
Renal impairment
!
Anemia
!
Hypersensitivity reactions
The symptoms of intolerance to the background ARV(s) should be reported as AEs and should be 
clearly documented as leading to the change in ARV(s). 
Special considerations may be warranted for the discontinuation of certain ARVs:
!
When discontinuing ART for any reason, please take the following into consideration: 
NNRTIs, including RPV, have a long plasma elimination half-life compared to N(t)RTIs. In 
presentations and publications, it has been hypothesized that this difference in elimination 
half-life of ARVs when stopping therapy may lead to NNRTI resistance.26,31 Some experts 
recommend stopping the NNRTI first, before the other ARVs (ie, the N[t]RTI background 
regimen). Currently, however, there is no consensus on the approach to this issue either among 
the scientific community or in treatment guidelines.
!
Discontinuation of 3TC in patients with hepatitis B co-infection: severe acute exacerbations 
of hepatitis have been reported after discontinuation of 3TC in patients with chronic 
hepatitis B infection who are using this agent in their ARV regimen. Discontinuation of this 
agent for any reason in participants with chronic hepatitis B infection should be undertaken 
with caution. Careful clinical and laboratory assessment of hepatic status should be 
undertaken for at least several months in such participants. Initiation of specific 
anti-hepatitis B therapy may be required (refer to Section 10.2, Appendix 2, Monitoring and 
Safety for Specific Toxicities).
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Status:Approved,  Date: 22 February 2021
!
Participants who develop a clinically suspected hypersensitivity reaction related to ABC 
treatment must discontinue ABC treatment immediately. If a hypersensitivity reaction cannot 
be ruled out, no medicinal product containing ABC (Ziagen®, Trizivir®, or Epzicom/Kivexa) 
should be restarted. Restarting any ABC-containing product following a hypersensitivity 
reaction results in a prompt return of symptoms within hours. This recurrence of the 
hypersensitivity reaction may be more severe than on initial presentation, and may include 
life-threatening hypotension and death (refer to Section 10.2, Appendix 2, Monitoring and 
Safety for Specific Toxicities).
6.5.2
Allowed Concomitant Therapy
For coadministered therapies, the package insert should be consulted and reviewed carefully. The 
determinations listed in the respective Contraindications and Warnings and Precautions sections
must be respected to prevent any potentially serious or life-threatening drug interactions.
!
Investigator-selected background ARVs must be taken during the study.
!
H2-receptor antagonists (eg, famotidine, ranitidine, and nizatidine) should only be 
administered either at least 12 hours before or at least 4 hours after RPV intake.
!
Antacids should only be administered either at least 2 hours before or at least 4 hours after 
RPV intake.
!
If azole treatment or intake of medications associated with a risk of TdP are planned for > 2 
days, participants are subjected to additional safety monitoring: an ECG assessment taken 3 to 
7 days after start of comedication intake at Cmax, ie, 4 hours after RPV intake. A PK sample 
should be taken within 10 minutes after the ECG assessment.
!
All medications labeled as having a CYP3A4 inhibitory effect should be used with caution 
during the study (refer to Section 6.5.3 for disallowed usage). Additional safety monitoring is 
required in case of >2 days intake, as specified above.
6.5.3
Disallowed Concomitant Therapy
!
All investigational drugs (except RPV) and all investigational vaccines are disallowed from 
90 days before the baseline visit until the Week 48/Withdrawal visit.
!
The following therapies are disallowed from 4 weeks before the baseline visit until the 
Week 48/Withdrawal visit:
#
Drugs that can potentiate the activity of ARVs or have intrinsic ARV activity (but no 
indication for treatment of HIV infection): mycophenolic acid, hydroxyurea, 
hydroxychloroquine, foscarnet.
#
All disallowed medication as mentioned in the package insert of the ARV regimen.
#
Systemic chronic steroids.
!
The following anti-HIV therapies are disallowed from baseline onwards:
#
Protease inhibitors.
#
Antiretrovirals requiring a PK booster (eg, elvitegravir). 
#
NNRTIs (except for RPV).
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Status:Approved,  Date: 22 February 2021
#
Fusion inhibitors.
#
C-C chemokine receptor type 5 inhibitors.
#
Generic ARVs not tentatively approved by United States FDA, not prequalified by WHO, 
not approved by local health authorities, or not procured by UN international 
organizations (eg, UNICEF).
!
Approved vaccines are disallowed within 4 weeks before baseline, and within 4 weeks before 
a sample for plasma viral load measurement is taken.
!
The following therapies are disallowed from screening onwards:
#
All therapies labeled as having a potent CYP3A4 inducing effect (except for the ARVs 
efavirenz and nevirapine), as coadministration of RPV with these agents may result in 
decreased RPV plasma concentrations and loss of therapeutic effect. Examples include, 
but are not limited to, phenobarbital, carbamazepine, oxcarbazepine, phenytoin, 
modafinil, pioglitazone, troglitazone, rifabutin, rifampin, rifapentine, dexamethasone 
(more than a single dose), and St. John’s wort.
#
Proton pump inhibitors.
#
Tuberculosis treatment with rifamycins.
!
Chronic inhaled steroids used concomitantly with intranasal steroids are disallowed within 
30 days before baseline and within 30 days before ACTH stimulation testing.
!
For participants scheduled for an intensive PK visit, all medications labeled as having a
CYP3A4 inhibitory effect are disallowed until the last PK sample at the intensive PK visit has 
been taken, as coadministration of RPV with these agents may result in increased RPV plasma 
concentrations. Examples include, but are not limited to, ketoconazole, clarithromycin, 
erythromycin, roxithromycin, telithromycin, troleandomycin, and aprepitant. Alternative 
medications without CYP3A4 inhibitory effect should always be considered as the preferred 
option.
For details on drug interactions with RPV and specific disallowed medication, please consult 
Section 10.6, Appendix 6: Established and Theoretical Drug Interactions With Commonly Used 
Comedications and RPV.
For contraindicated therapies or therapies that are not recommended for concomitant use with the 
background regimen, the package inserts of the background ARVs should be consulted.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.6
Dose Modification
6.6.1
Dose Evaluation Criteria 
In participants with a body weight of <25 kg, intensive PK sampling will be done to further 
evaluate the most appropriate RPV dose for participants with a low body weight. Overall across 
studies TMC278HTX2002 (children aged ≥2 to <12 years with a body weight of ≥10 kg) and C213 
(Cohort 2; children aged ≥6 to <12 years), approximately 40 participants will be enrolled of which 
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Status:Approved,  Date: 22 February 2021
at least 12 participants with a body weight of <25 kg at baseline, including at least 7 participants 
with a body weight of <20 kg at baseline. To accommodate overall regulatory requirements 
concerning the evaluation of RPV in the pediatric population, the intensive PK data from this study 
TMC278HTX2002 will be combined with the data from study C213 Cohort 2. For this study, 
AUC24h of a selected RPV dose under fed and steady-state conditions will be the primary PK
parameter for determination of the acceptability of the RPV dose, but the Cmax and C0h/C24h of 
RPV will also be taken into consideration.
Dose Evaluation in the Mini-cohort
When reviewing the results of the participants in the mini-cohort, the following evaluation 
criterion will be taken into account:
!
If none of the participants on a given RPV dose has experienced a life-threatening AE 
(including death) or a grade 4 AE that is at least probably related to RPV, and ≤25% of all 
participants (ie, at most 1 participant) on a given RPV dose terminated the study intervention
due to a grade 3 or grade 4 AE that is at least possibly related to RPV, the RPV dose has 
passed the safety review. 
!
If ≤1 of the participants in the mini-cohort has an RPV AUC24h greater than the 90th percentile 
of adult values (3,513 ng•h/mL) and there are no safety concerns, the mini-cohort has passed 
the pharmacokinetic review. In case of failure, the starting dose and the expected distribution 
of RPV C0h, Cmax and AUC24h will be reviewed and an assessment will be made whether an 
RPV dose adjustment for participants under e.g., a certain body weight is warranted. 
If the RPV dose has not passed the review, the sponsor and IDMC will evaluate whether it is safe 
to continue finding an optimal RPV dose in these participants (refer to Section 6.6.2).
Dose Evaluation in at least 12 Participants
When reviewing the results of at least 12 participants with a body weight of <25 kg, the following 
evaluation criteria will be taken into account:
!
If none of the participants on a given RPV dose has experienced a life-threatening AE 
(including death) or a grade 4 AE that is at least probably related to RPV, and ≤25% of all 
participants on a given RPV dose terminated the study intervention due to a grade 3 or grade 4 
AE that is at least possibly related to RPV, the RPV dose has passed the safety review.
!
If the geometric mean AUC24h for RPV is between 80% and 150% of the observed geometric 
mean AUC24h for RPV in HIV-1-infected adults from the Phase 3 PK substudies of C209 and 
C215 (ie, between 1,426 and 2,673 ng.h/mL)3, then the RPV dose has passed the PK review. 
Note: If an individual Cmax is >440 ng/mL (1.85-fold the mean Cmax of RPV 25 mg once daily 
in healthy adults, and evaluated as not posing an increased risk for QT interval prolongation),
the RPV dose can be continued if there are no safety findings based on an overall assessment 
of the participant’s safety (eg, additional ECG with optional PK sample).
If the RPV dose has not passed the safety and/or PK review, the sponsor and IDMC will evaluate 
whether it is safe to continue finding an optimal RPV dose in these participants (refer to 
Section 6.6.2).
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Status:Approved,  Date: 22 February 2021
6.6.2
Dose Modification (Adjustment) Rules
Dose adjustment will only be considered if exposure (too high or too low) or results would show
a safety or efficacy concern that could potentially be avoided by altering the RPV dose. The 
decision to modify the RPV dose for a specific group of participants will be made by the sponsor 
upon IDMC recommendation, based on review of all available data (including intensive PK data)
after 4 weeks of study treatment. 
If an adjusted RPV dose is needed, 
 
 
The new dose scheme 
and clear instructions on how to handle dosing will be provided to all participating sites by the 
sponsor via a written notification.
The body weight of all participants (not limited to participants with a body weight of <25 kg) will 
be measured at all scheduled visits (refer to the Schedule of Activities), and the dose may be 
adapted if the participant’s body weight changes such that it crosses into a new weight band for 
which a different RPV dose is recommended. To avoid multiple RPV dose changes based on 
fluctuations in body weight during the study, individual RPV dose adjustments for changes in 
weight band should be implemented only for increase in body weight to ≥25 kg (switch to 25 mg 
RPV dose) or decrease in body weight to < 22.5 kg (switch to 15 mg RPV dose) or decrease in 
body weight to <18 kg (switch to 12.5 mg). Appropriateness of these doses will be further 
evaluated in this study in combination with data generated from pediatric study C213. In case of 
persistent weight loss > 10% of baseline (or of the previous weight leading to a dose change during 
the study), clinical evaluation should be performed to rule out an underlying condition prior to 
proceeding to change the RPV dose. Dose change is not allowed between baseline (when weight 
is defined) and Week 4 (start of intensive PK sampling). Any dose/dosage adjustment should be 
overseen by medically-qualified study-site personnel (principal or subinvestigator). The RPV dose 
will not exceed the approved and marketed adult 25-mg dose. Dose adjustment based on changes 
in body weight does not require intensive PK sampling.
6.7
Intervention After the End of the Study
Upon study completion, participants who continue to experience clinical benefit from treatment 
with RPV will be offered the opportunity to continue study treatment in the pediatric rollover study
TMC278IFD3004 or to switch to locally available RPV (once commercially available AND 
reimbursed, OR accessible through another source [e.g. access program or government program]), 
or other locally available RPV-based regimens.
Participants who do not roll over in the pediatric study TMC278IFD3004 will be informed that 
study intervention will not be made available to them after they have completed/discontinued the 
study intervention phase and that they should return to their primary physician to determine 
standard of care.
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Status:Approved,  Date: 22 February 2021
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
The criteria for permanent discontinuation of study intervention are included in Section 7.2, 
Participant Discontinuation/Withdrawal From the Study. In case a permanent discontinuation of 
study intervention is needed, ART (ie, RPV and background regimen) should be discontinued.
The guidance on temporary discontinuation and rechallenge is provided below.
7.1.1
Temporary Discontinuation
Temporary discontinuation of all ARVs (RPV or investigator-selected background regimen)
during the intervention phase will be allowed in the event of suspected toxicity, as long as the 
temporary discontinuation is associated with and can be linked to an AE or an SAE. The 
instructions for temporary discontinuation in case of specific toxicities are provided in 
Section 10.2, Appendix 2, Monitoring and Safety for Specific Toxicities.
The maximum allowed duration of a single temporary discontinuation for toxicity reasons will be 
4 weeks and the maximum allowed cumulative duration of the temporary discontinuation for 
toxicity reasons will be 8 weeks. Participants should maintain the regular visit schedule during the 
temporary discontinuation(s). Additional unscheduled visits may be performed for safety or 
tolerability reasons. A participant may be withdrawn from the study if the maximum allowed 
durations mentioned before have been exceeded.
7.1.2
Rechallenge
Rechallenge instructions in case of specific toxicities are provided in Section 10.2, Appendix 2, 
Monitoring and Safety for Specific Toxicities.
7.2
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
!
Lost to follow-up.
!
Withdrawal of consent/assent.
!
Death.
!
Failure to comply with the protocol requirements or to cooperate with the study-site personnel.
!
Permanent discontinuation of study intervention for any reason. A participant’s study 
intervention will be automatically discontinued if:
#
The investigator or sponsor believes (eg, that for safety or tolerability reasons [eg, AE]) 
it is in the best interest of the participant to discontinue study intervention.
#
The participant becomes pregnant (refer to Section 10.4, Appendix 4, Contraceptive and 
Barrier Guidance and Collection of Pregnancy Information).
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Status:Approved,  Date: 22 February 2021
#
The participant meets at least 1 of the specific toxicities that require permanent 
discontinuation of study intervention as mentioned in the toxicity management section 
(refer to Section 10.2, Appendix 2, Monitoring and Safety for Specific Toxicities).
#
The participant experiences a grade 3/4 decrease in serum magnesium (refer to 
Section 10.5, Appendix 5, DAIDS Table).
!
Confirmed prolongation of QTcF or QTcB >500 ms or a confirmed increase in QTcF or QTcB
of ≥60 ms from baseline while receiving CYP3A4 inhibitory comedication or medication 
associated with a risk of TdP, and the QTcF or QTcB values are not normalized approximately 
1 week after the comedication treatment was stopped or if comedication treatment cannot be 
stopped (refer to Section 6.5, Concomitant Therapy).
!
Resistance observation at the time of confirmed virologic failure (defined as 2 consecutive 
plasma viral load measurements ≥200 HIV-1 RNA copies/mL).
!
Develops tuberculosis during the study.
!
Diagnosed with acute hepatitis A, B, or C infection after baseline.
!
Action as per IDMC recommendation in case results of the intensive PK data analysis and the
4-week safety, tolerability, and efficacy data review are deemed unsatisfactory by the sponsor 
upon IDMC recommendation.
When a participant withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source documents. Study intervention assigned to the withdrawn 
participant may not be assigned to another participant. Additional participants will be entered to 
aim for at least 12 participants with intensive PK data (in the current study and study C213 
combined). Additional participants may also be recruited upon request of the sponsor if the 
interpretation of the PK data is hampered (eg, poor study intervention adherence before PK 
sampling).
If a participant discontinues study intervention and withdraws from the study before the end of the 
study intervention phase, Week 48/Withdrawal visit and 4-week follow-up visit assessments 
should be obtained. If the reason for study withdrawal is withdrawal of consent/assent then no 
additional assessments are allowed.
Withdrawal From the Use of Samples in Future Research
The participant and/or his or her representative may withdraw consent/assent for use of samples 
for research (refer to Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight
Considerations). In such a case, samples will be destroyed after they are no longer needed for the 
clinical study. Details of the sample retention for research are presented in the ICF.
7.3
Lost to Follow-up
If a participant is lost to follow-up, every reasonable effort must be made by the study-site 
personnel to contact the participant and determine the reason for discontinuation/withdrawal. The 
measures taken to follow up must be documented. Refer to Section 7.2, Participant 
Discontinuation/Withdrawal From the Study.
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Status:Approved,  Date: 22 February 2021
8
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of PK, safety, tolerability, 
efficacy, and other measurements applicable to this study.
If multiple assessments are scheduled for the same time point, it is recommended that procedures 
be performed in the following sequence: ECG, vital signs, blood sampling. Blood collections for 
PK assessments should be kept as close to the specified time as possible. Other measurements may 
be done earlier than specified time points if needed. Actual dates and times of assessments will be 
recorded in the source documents and CRF.
Additional serum or urine pregnancy tests may be performed for girls of childbearing potential, as 
determined necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during participation in the study and 4 weeks after the last dose of study 
intervention. At screening, contraceptive counseling will be given as appropriate by participant’s 
age.
The total blood volume to be collected from participants will be approximately:
!
200 mL for participants of ≥2 to <6 years of age with a body weight of < 25 kg
!
224 mL for participants of ≥6 to <12 years of age with a body weight of < 25 kg
!
225 mL for participants of ≥6 to <12 years of age with a body weight of ≥ 25 kg
From each participant scheduled for an intensive PK visit, an additional blood volume of 
approximately 10 mL will be collected on the day of the visit (refer to Section 1.3.2, Schedule of 
Activities for Intensive Pharmacokinetic Sampling). From each participant requiring an ACTH 
stimulation test, an additional 4.4 mL will be collected (refer to Section 1.3.1 General Schedule of 
Activities). For each RPV dose modification as per IDMC analysis (if applicable), if the post dose 
switch visit is not done within 1 week of the next scheduled visit as indicated in the General 
Schedule of Activities (refer to Section 1.3.3, Schedule of Activities for Switch to Adjusted RPV 
Dose [if Applicable]), an additional blood volume of approximately 38.4 mL will be collected 
(including the blood volume collected during the intensive PK visit).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
Time Windows
All study visits should be scheduled relative to the baseline visit date (eg, Day 1 +14 days for 
Week 2). The study intervention phase should be 48 weeks. The following time windows are 
recommended:
!
For the Week 2 visit (including Week 2 post-switch): ±2 days
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!
For the Week 4 visit (including Week 4 post-switch):
#
For participants who are enrolled for intensive PK sampling: between Days 28 and 32
#
For all other participants: ±2 days
!
For the Weeks 8, 12, 16, 24, 32, 40, and 48 visits: ±1 week 
!
For the 4-week follow-up visit: ±4 days
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. If blood samples are collected via an indwelling cannula, an appropriate amount 
(≤1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock will be 
removed from the cannula and discarded before each blood sample is taken. After blood sample 
collection, the cannula will be flushed with 0.9% sodium chloride, United States Pharmacopeia (or 
equivalent) or sodium heparin of 10 U/mL and charged with a volume equal to the dead space 
volume of the lock. If a mandarin (obturator) is used, blood loss due to discard is not expected.
Use of local anesthetic creams is allowed to minimize the pain during the blood draw. Use of 
indwelling catheters is encouraged for the intensive PK visit to minimize discomfort and distress 
due to repeated venipunctures for blood sampling. 
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual. Samples for bioanalysis should be protected from light during sample 
processing and storage.
Study-specific Materials
The investigator will be provided with the following supplies:
!
IB
!
Pharmacy manual/study-site investigational product
!
Investigational product preparation and administration instructions for participants’ 
representative
!
Laboratory manual
!
Electronic data capture (eDC) manual
!
Central ECG machine and ECG manual
!
Any other manual, as applicable
!
Sample ICF and assent form
!
Participant diaries
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!
Study Adherence Questionnaire for Carers/Children
!
Palatability Questionnaire
!
Swallowability Questionnaire for Participant/Observer
!
Contact Information page(s)
!
Participation card
!
Warning card for ABC hypersensitivity
!
Recruitment and enrollment tools
8.1
Efficacy Assessments
At the time points specified in the Schedule of Activities, blood samples for the determination of 
plasma HIV-1 RNA viral load to assess antiviral activity and samples for the determination of 
CD4+ cell counts (absolute and percentage relative to total lymphocytes) will be taken. 
Plasma viral load levels will be measured at a central lab using a standardized HIV-1 viral load 
assay as the concentration of HIV-1 RNA in plasma. CD4+ cell counts will be measured at a central 
lab via flow cytometry. Specimen preparation procedures will be defined in the laboratory manual.
Changes from baseline in plasma viral load or in CD4+ cell counts (either increases or decreases) 
will not be reported as (S)AEs.
8.2
Safety Assessments
Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards 
until the last study-related activity. Details regarding the IDMC are provided in Committees 
Structure in Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight Considerations.
Adverse events will be reported and followed by the investigator as specified in Section 8.3, 
Adverse Events and Serious Adverse Events and Section 10.8, Appendix 8, Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting. Adverse events 
of interest are based on their relevance in the target population, their known association with other 
ARVs, and/or their potential importance demonstrated by nonclinical and clinical data with RPV,
and include endocrine events of interest, potential QTc interval prolonging events of interest, 
hepatic events of interest, neuropsychiatric events of interest, and skin events of interest.
Any clinically relevant changes occurring during the study must be recorded in the AE section of 
the CRF. For participants who do not roll over in the pediatric study TMC278IFD3004, any 
clinically significant abnormalities persisting at the last study visit will be followed by the 
investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities:
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Status:Approved,  Date: 22 February 2021
8.2.1
Physical Examination
To evaluate the participant’s eligibility, a full physical examination will be performed at screening. 
In addition, a full physical examination will be performed at the time points shown in the Schedule 
of Activities. This examination includes general appearance, eyes, ears, nose and throat, skin and 
mucous membranes (with particular attention to hyperpigmentation and hirsutism), lymph nodes,
respiratory system, cardiovascular system, gastrointestinal system, central nervous system (CNS),
peripheral nervous system, musculoskeletal system, and genitourinary system.
At several time points shown in the Schedule of Activities, only a brief physical examination will 
be performed. These assessments include general appearance, eyes, ears, nose and throat, skin and 
mucous membranes (with particular attention to hyperpigmentation and hirsutism), lymph nodes, 
respiratory system, cardiovascular system, gastrointestinal system, and CNS.
At Week 2, only a skin examination will take place.
Examinations do not include rectal or vaginal examination, unless clinically indicated.
Body weight and height will be recorded at the visits specified in the Schedule of Activities. 
Growth parameter(s), including weight and height (measured by a calibrated stadiometer 
appropriate for participants aged ≥2 years) will be followed regularly and evaluated consistently 
using standardized growth charts (refer to Section 10.15).2 Participants must be lightly clothed and 
barefoot to obtain body weight, and barefoot to measure their height. The same weighing scale and 
stadiometer will preferably be used at each visit. Body weight measurements may be used for dose 
adjustments, if applicable (refer to Section 6.6, Dose Modification).
The assessment of pubertal development will be performed by a modified Tanner assessment
consisting of a discrete visual inspection and comparison to the illustrated Tanner scales (refer to
Section 10.9, Appendix 9, Tanner Scales).18 Tanner staging is limited to participants aged ≥6 to 
<12 years (including participants who turn 12 years old during the study) and will be performed at 
the time points shown in the Schedule of Activities. For girls, it will be assessed at screening
whether they already have had their first menses. For girls who have not yet had their first menses, 
the occurrence of the first menses will be checked at every visit as part of the evaluation of pubertal 
development. 
8.2.2
Vital Signs
Pulse rate and blood pressure (systolic and diastolic) will be assessed at the time points specified 
in the Schedule of Activities, and should be performed before blood sampling. Blood pressure and 
pulse rate measurements will be assessed standing and supine with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
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Status:Approved,  Date: 22 February 2021
8.2.3
Electrocardiogram
Single ECGs will be collected at the time points specified in the Schedule of Activities, and read 
by a central ECG vendor. Whenever possible, the ECG should be taken around the expected Cmax
(ie, 4 hours after RPV intake). Additional ECGs must be performed in case of start of certain 
concomitant medications (refer to Section 6.5.2).
Instructions for the collection (eg, equipment and lead placement), transmission, and archiving of 
ECGs will be described in the ECG manual provided by the central ECG vendor. The turnaround 
time for safety alerts from the central ECG vendor to the study site is approximately 72 hours.
During the collection of ECGs, participants should be in a quiet setting without distractions 
(eg, television and cell phones). Participants can be accompanied by their representatives, if 
needed. Participants should rest in a supine position for at least 5 minutes before ECG collection 
and should refrain from talking or moving arms or legs. If blood sampling or vital sign 
measurement is scheduled for the same time point as ECG recording, the procedures should be 
performed in the following order: ECG(s), vital signs, blood sampling.
Two ECG reports will be generated by the central ECG vendor: a preliminary report and a final 
report. The final report will be reviewed by a board certified (if applicable) cardiologist from the 
central ECG vendor. Both reports will need to be interpreted for clinical significance, signed, and 
dated by the investigator, and filed in the participant’s medical record.
8.2.4
Clinical Safety Laboratory Assessments
Blood samples for biochemistry, hematology, and endocrinology (only for participants aged 
≥6 to <12 years, including participants who turn 12 years old during the study), and a random urine 
sample for urinalysis will be collected as noted in Section 10.7, Appendix 7, Clinical Laboratory 
Tests at the time points specified in the Schedule of Activities. The investigator must review the 
laboratory results generated by the central laboratory, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents.
The participants need to have fasted overnight (for at least 10 hours) before the biochemistry safety 
blood samples are drawn. Samples that were taken under nonfasted conditions and that reveal 
values that are outside the normal ranges and deemed clinically relevant for parameters that are 
affected by food intake should be retested after the participant has fasted overnight. In case of early 
withdrawal, safety blood samples may be taken at the time of dropout, even if the participant has 
not fasted for at least 10 hours.
The central laboratory will send the investigator an alert form whenever a grade 3/4 laboratory 
abnormality has been observed (refer to Section 10.2, Appendix 2, Monitoring and Safety for 
Specific Toxicities). In case a grade 3/4 laboratory abnormality occurs, a confirmatory test should 
be performed, preferably within 48 hours (if practically feasible) but no later than 72 hours after 
the results have become available.
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Status:Approved,  Date: 22 February 2021
The following laboratory abnormalities do not warrant mandatory confirmation within 48 hours:
!
asymptomatic grade 3/4 glucose or triglyceride elevations, or asymptomatic grade 3 
cholesterol elevations.
!
asymptomatic grade 3 pancreatic amylase elevations in participants with no history or 
concomitant disease of pancreatitis.
8.2.5
Behavior Risk Monitoring
There have been reports of depression when RPV has been given to some participants with HIV-1 
infection (refer to Section 2.3.3, Known Risks), as noted in the product label. The sponsor 
considers it important to monitor for such events during this clinical study.
Participants treated with RPV should be monitored appropriately and observed closely for 
depression or any other unusual changes in behavior. Consideration should be given to 
discontinuing RPV in participants who experience signs of suicidal ideation or behavior.
Families and caregivers of participants treated with RPV must be instructed to monitor participants 
for the emergence of depression and unusual changes in behavior, as well as the emergence of 
suicidal ideation and behavior, and to report such symptoms immediately to the study investigator.
Depression will be assessed at the time points specified in the Schedule of Activities using
questionnaires or other means (as available at the site) as part of local standard of care, to determine 
who needs to be referred for a complete mental health assessment by a mental health professional.
Any clinically relevant changes occurring during the study will be reported as AEs.
Also, if the study-site personnel feels that the participant has under-reported his or her symptoms, 
or if depression or suicidal ideation or behavior are suspected, the participant should be referred 
for a complete mental health assessment.
8.3
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Adverse events will be reported by the participant and/or his or her representative for the duration 
of the study.
Clinically significant changes in laboratory values, other diagnostic tests (except in case of changes 
in resistance pattern, plasma viral load, and CD4+ cell counts), and intercurrent illnesses will be 
reported as AEs.
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Status:Approved,  Date: 22 February 2021
Anticipated events will not be recorded and reported as this is the first study that includes 
participants aged <6 years. Additionally, no SAEs are anticipated in a stable HIV-1-infected 
pediatric population aged ≥2 to <12 years. All SAEs are important in understanding the safety of 
the product.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions; 
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality complaints, 
refer to Section 10.8, Appendix 8, Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.
During the entire study period, including screening and follow-up phases, specific toxicities will 
be monitored. A safety plan will be followed in case of specific toxicities (refer to Section 10.2, 
Appendix 2, Monitoring and Safety for Specific Toxicities).
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or nonserious, will be reported from the 
time a signed and dated ICF is obtained until completion of the participant’s last study-related 
procedure, which may include contact for follow-up of safety. Serious adverse events, including 
those spontaneously reported to the investigator within 30 days after the last dose of study 
intervention, must be reported using the SAE Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the SAE Form, which must 
be completed and signed by a physician from the study site, and transmitted to the sponsor within 
24 hours. The initial and follow-up reports of an SAE should be transmitted electronically or by 
facsimile (fax).
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading 
verbal questioning of the participant and representative is the preferred method to inquire about 
AE occurrence.
8.3.3
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in 
Section 10.8, Appendix 8, Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.
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Status:Approved,  Date: 22 February 2021
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute where 
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or 
sponsor where required) must report SUSARs to the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB.
8.3.5
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event 
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes 
(eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, and ectopic pregnancy) are 
considered SAEs and must be reported using the SAE Form. Any participant who becomes 
pregnant during the study must be promptly withdrawn from the study and discontinue further 
study intervention.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
8.3.6
HIV-related Events and HIV-related Outcomes 
The events or outcomes listed in the Centers for Disease Control and Prevention (CDC) Morbidity 
and Mortality Weekly Report1 will be recorded as HIV-related events (including AIDS-defining 
illnesses and Stage-3-defining Opportunistic Illnesses in HIV Infection) in the AE section of the 
CRF. 
All HIV-related events will be reported from the time a signed and dated ICF is obtained until 
completion of the participant’s last study-related procedure.
8.4
Treatment of Overdose
For this study, any dose of RPV greater than the assigned dose within the protocol-specified 
interval (refer to Study Interventions Administered in Section 6.1) will be considered an overdose.
The sponsor does not recommend specific intervention for an overdose.
In the event of an overdose, the investigator or treating physician should:
!
Contact the Medical Monitor immediately.
!
Closely monitor the participant for AE/SAE and ECG abnormalities.
!
Obtain a plasma sample for PK analysis as soon as possible from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case basis).
!
Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5
Pharmacokinetics
Blood samples will be used to evaluate the plasma PK of RPV. Plasma collected for PK may 
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or 
after the study period. Genetic analyses will not be performed on these plasma samples. Participant
confidentiality will be maintained.
8.5.1
Evaluations
Venous blood samples of approximately 1 mL will be collected for measurement of plasma
concentrations of RPV at the time points specified in the Schedule of Activities. When additional 
safety monitoring ECGs are performed in case of start of certain comedications (refer to 
Section 6.5.2, Allowed Concomitant Therapy), a PK sample should be taken within 10 minutes 
after each of these ECGs to assess the impact of the comedication on the RPV plasma levels and 
to evaluate the RPV concentration-safety relationship, if feasible. 
The exact date and time of blood sampling and of the last 2 RPV intakes before blood sampling 
must be recorded in the CRF. Participant confidentiality will be maintained. Additional 
information about the collection, handling, and shipment of biological samples can be found in the 
laboratory manual.
8.5.2
Analytical Procedures
Plasma PK samples will be analyzed to determine concentrations of RPV using a validated, 
specific, and sensitive liquid chromatography – mass spectrometry/mass spectrometry method by 
or under the supervision of the sponsor.
If needed, some plasma samples may be analyzed to document the presence of circulating 
metabolites using a qualified research method. In addition, plasma PK samples may be stored for 
future analysis of other coadministered treatments, protein binding, and the metabolite profile.
8.5.3
Pharmacokinetic Parameters and Evaluations
Intensive Pharmacokinetics
Based on the individual plasma concentration-time data, using the actual dose taken and the actual 
PK sampling times, the following PK parameters of RPV will be derived:
C0h, C24h, Cmin, Cmax, Css,av, tmax, AUC24h, CL/F, Vss/F, and FI
Other PK parameters may be estimated for exploration of the data, as appropriate.
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For the PK parameters, definitions and methods of calculation are:
C0h:
predose plasma concentration
C24h
plasma concentration at 24 hours postdose
Cmin:
minimum observed plasma concentration
Cmax:
maximum observed plasma concentration
Css,av:
average plasma concentration at steady state
tmax:
time to reach the maximum observed plasma concentration
AUC24h:
area under the plasma concentration-time curve from time of administration up to 
24 hours postdose
CL/F:
total apparent clearance at steady state, calculated by dose/AUC24h
VSS/F:
apparent volume of distribution at steady state
FI:
fluctuation index
 
 
 
 
 
8.6
Pharmacokinetic/Pharmacodynamic Evaluations
Pharmacokinetic/PD evaluations will be performed to explore the relationship between PK and 
safety/efficacy variables.
8.7
Genetics
Genetics are not evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in the current study.
8.9
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this study.
CCI
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Status:Approved,  Date: 22 February 2021
8.10
Other Assessments
8.10.1
Resistance
At time points specified in the Schedule of Activities, samples for the determination of viral 
genotype will be taken. Viral genotyping will be performed centrally by a qualified provider using 
automated population-based dideoxynucleotide sequencing of the HIV-1 regions of interest. 
Genotyping of HIV-1 will only be initiated when the plasma viral load is sufficiently high. Changes 
in viral genotype will not be regarded as (S)AEs.
In addition, a PBMC sample will be taken to allow retrospective characterization of archived viral 
resistance, if needed. No human DNA analysis will be performed on these samples.
Deep sequencing and viral phenotyping may be performed retrospectively considering the amounts 
of plasma available after standard genotypic resistance testing.
8.10.2
Diaries
Participants scheduled for an intensive PK visit and/or their representatives will have to complete 
a diary (provided at baseline or at start of treatment with an adjusted dose) documenting RPV 
intake from the start of study treatment at baseline or at start of treatment with an adjusted dose 
until the day of intensive PK sampling. Study-site personnel will instruct the participants and/or 
their representatives to capture the data according to the study design and not to wait until the 
study-site visit to record information. For RPV intakes and accompanying meals at home, 
participants and/or their representatives will be asked to note the exact times of RPV intakes and 
accompanying meals (stop times). 
The investigator or study-site personnel should review the recorded data in the participant’s diary. 
Upon diary completion and review, the results of the diaries will be transcribed into the CRF by 
the study-site personnel.
8.10.3
Questionnaires
Questionnaires will only be administered if a certified translation is available in the local language.
Sites should always use the most recently provided version of the questionnaire. Depending on the 
age and literacy of the participant, the questionnaires can be completed by the participant and/or 
by his or her representative. If a participant and his or her representative have difficulties in 
completing the questionnaire, then the study-site personnel may assist. Once completed, the 
study-site personnel should review the questionnaire for completeness. The responses to the 
questionnaires will be transcribed into the CRF by the study-site personnel.
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Treatment Adherence
At all visits indicated in the Schedule of Activities, participant treatment adherence will be 
assessed by a number of sponsor-selected questions from the PENTA adherence questionnaire
(refer to Section 10.10, Appendix 10). Site staff, such as a counselor, should support the participant
or their parent(s)/caregiver(s) to complete the questionnaire together, where the participant or their 
parent(s)/caregiver(s) provides the responses to the counselor.
Palatability
The palatability of the 2.5-mg RPV tablet formulation will be assessed in a palatability 
questionnaire after a 2-week treatment period by documenting the participant’s reaction when he 
or she is given the medication (refer to Section 10.11, Appendix 11). The palatability questionnaire 
will include a 5-point hedonic facial scale. This scale is a standard tool used in clinical studies to 
assess drug palatability in children. The palatability questionnaire will be completed within 5 to 
15 minutes after RPV intake. 
Swallowability
The swallowability of the RPV 25-mg tablet formulation will be assessed in a swallowability 
questionnaire after a 2-week treatment period by documenting the participant’s reaction when he 
or she is given the medication (refer to Section 10.12, Appendix 12). The swallowability 
questionnaire will be completed within 5 to 15 minutes after RPV intake. 
9
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1
Statistical Hypotheses
No formal hypothesis will be tested.
9.2
Sample Size Determination
No formal sample size calculation was performed. The sample size is based on overall regulatory 
requirements and the number of participants enrolled in Cohort 2 in study C213.4 As described in 
Section 4.1, Overall Design, the aim is to recruit approximately 25 to 30 participants aged ≥2 to 
<12 years in the current study. 
The precision of the efficacy parameter (proportion of participants with plasma viral load
<50 HIV-1 RNA copies/mL, Snapshot approach) expressed as the 95% confidence interval (CI) is 
presented in Table 1, assuming a sample size of 25 participants and response rates between 80% 
and 95%.
Table 1:
Clopper Pearson 95% CI (2-Sided) for Various Assumptions
Sample Size (N=25)
Response Rate
80% (20/25)
84% (21/25)
88% (23/25)
94% (24/25)
95% CI
(59.3; 93.2)
(63.9; 95.5)
(74.0; 99.0)
(79.6; 99.9)
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Related to safety, Table 2 shows the probability of the occurrence of at least 1 SAE for various 
sample sizes, provided the true incidence is 1%, 5%, and 10%.
Table 2:
Probability (%) of at Least 1 SAE Reported for Various Assumptions
Sample Size (N)
True Incidence
1%
5%
10%
25
22.2
72.3
92.8
30
26.0
78.5
95.8
In study C213, the observed inter-individual variability on apparent RPV clearance was 
approximately 32%. With a sample size of 10 participants, there is >80% power to achieve 
95% CIs for apparent clearance within 70% and 140% of the geometric mean parameter estimates, 
even when assuming a higher variability (percentage of) coefficient of variation ([%]CV) of 
42%.38 Thus, at least 12 participants with a body weight of <25 kg are considered to be adequate 
for characterizing the RPV PK in that group. As recruitment for the entire group may be lengthy, 
an IDMC analysis will be done after ≥5 participants with a body weight of <25 kg have had their 
intensive PK visit and 4-week safety.
9.3
Populations for Analyses
All statistical analysis will be performed on the intent-to-treat population, defined as all 
participants who receive at least 1 dose of RPV.
9.4
Statistical Analyses
The primary analysis (with formal database lock) will be done when all participants have reached 
Week 24 (or discontinued earlier). The final analysis (with formal database lock) will be done 
when all participants have reached Week 48 (or discontinued earlier). A detailed SAP for each 
analysis will be written and signed off prior to database lock.
The results of all analyses up to Week 48 will be shared and discussed with the IDMC.
During the study, IDMC analyses will be performed to monitor PK, safety, tolerability, and 
efficacy data, and to safeguard the participants in this study (refer to Section 9.5, Independent Data 
Monitoring Committee Analyses).
9.4.1
Initial Participant and Disease Characteristics
All demographic (eg, age, height, weight, gender, body mass index, and race) and other initial 
participant characteristics (eg, physical examination, medical and surgical history, and 
concomitant diseases) will be tabulated and analyzed descriptively.
9.4.2
Efficacy Analyses
Plasma Viral Load
An outcome analysis (ie, proportion of participants with a plasma viral load <50 and <400 HIV-1 
RNA copies/mL) will be performed using Snapshot approach. The Snapshot analysis is based on 
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the last observed plasma viral load data within the visit window (ie, Weeks 24 and 48). The 
proportion of participants with virologic failure (ie, HIV-1 RNA ≥50 and ≥400 copies/mL) per 
Snapshot approach will be provided. Participants who switched ARVs for tolerability reasons not 
allowed per protocol will be considered as virologic failures for this Snapshot approach.
Proportions will be expressed as percentages with Clopper Pearson 95% CI at each time point.
CD4+ Cell Count
The analysis will be based on observed values and on imputed values using NC=F, ie, participants
who prematurely discontinued the study will have their CD4+ cell count following discontinuation 
imputed with the baseline value (resulting in a change of 0), and will have 
last-observation-carried-forward imputation for intermediate missing values.
Actual values and changes from baseline will be descriptively and graphically presented.
9.4.3
Safety Analyses
Adverse Events/HIV-Related Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities. Treatment-emergent AEs (including HIV-related 
events) are AEs with onset during the intervention phase or that are a consequence of a pre-existing 
condition that has worsened since baseline. All reported AEs will be included in the analysis. For 
each treatment-emergent AE/HIV-related event, the percentage of participants who experience at 
least 1 occurrence of the given event will be tabulated per study phase (ie, screening phase, 
intervention phase, and follow-up). Separate tabulations will be made by severity and relationship 
to the study intervention, as appropriate.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue study intervention due to an AE, or who experience a 
grade 3/4 AE, an AE of special interest, or an SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and for observed values and changes from 
baseline at each scheduled time point. Descriptive statistics include number of observations (n), 
mean, standard deviation (SD), median, minimum, and maximum.
Frequency tabulations of the changes from baseline will be presented in pre- versus 
post-intervention cross-tabulations (with classes for below, within, and above normal ranges). For 
the tests available, laboratory abnormalities will be determined using the DAIDS grading table 
(refer to Section 10.5, Appendix 5, DAIDS Table). Frequency tabulations of worst abnormality 
grade after baseline will be generated. As appropriate, frequency tabulations and listings will be 
provided for participants who develop a grade 3/4 laboratory abnormality.
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Descriptive statistics of the actual values and changes from baseline of the endocrine assessments 
(cortisol, follicle-stimulating hormone [FSH], luteinizing hormone [LH], androstenedione, 
testosterone, and dehydroepiandrosterone sulfate [DHEAS]) will be generated. 
Results of reflex ACTH testing will be listed.
Electrocardiogram
Descriptive statistics of ECG values and changes from baseline will be summarized at each 
scheduled time point. The ECG parameters analyzed are heart rate, PR interval, QRS interval, RR 
interval, QT interval, QTcB, and QTcF.20 Descriptive statistics include number of observations (n), 
mean, SD, median, minimum, and maximum. Frequency tabulations of the abnormalities will be 
made. Refer to Section 10.13, Appendix 13, Cardiovascular Safety – Abnormalities, for the 
definition of the ECG abnormalities.
Vital Signs
Descriptive statistics of pulse rate and blood pressure (systolic and diastolic) (supine and standing) 
values and changes from baseline will be summarized at each scheduled time point. Descriptive 
statistics include number of observations (n), mean, SD, median, minimum, and maximum. The 
percentage of participants with values beyond clinically important limits will be summarized at 
each time point. Refer to Section 10.13, Appendix 13, Cardiovascular Safety – Abnormalities, for 
the definition of the vital signs abnormalities.
Physical Examination
Physical examination findings will be summarized at each scheduled time point per body system.
Physical examination abnormalities will be listed.
Growth will be followed regularly and evaluated consistently using standardized growth charts. 
Descriptive statistics of height, height-for-age, weight, weight-for-age, body mass index (BMI), 
and BMI-for-age will be calculated at baseline and for observed values and changes from baseline 
at each scheduled time point. Descriptive statistics include number of observations (n), mean, SD, 
median, minimum, and maximum.
Tanner stage (for pubic hair and genitalia/breasts) will be cross-tabulated versus baseline by age. 
In addition, in girls, the occurrence of first menses during treatment will also be cross-tabulated 
versus baseline, and the date of menarche will be listed.
9.4.4
Pharmacokinetic Analyses
Intensive Pharmacokinetics
Pharmacokinetic and statistical analyses of the results will be done using WinNonlin 
Professional™ (Pharsight Corporation, Mountain View, California, United States), Microsoft 
Excel® (Microsoft Redmond, Washington, United States), and SAS (SAS Institute Inc. Cary, NC, 
United States). A noncompartmental model with extravascular input will be used for the PK 
analysis.
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Data will be listed for all participants with available plasma concentrations. Participants will be 
excluded from the intensive PK analysis if their data do not allow for accurate assessment of the 
PK (eg, incomplete administration of the study intervention; missing information of dosing and 
sampling times; vomiting; concentration data not sufficient for PK parameter calculation).
Actual sampling times will be checked for major aberrations. In case a major aberration occurs for 
an actual sampling time (ie, >20% deviation from the scheduled time), this plasma concentration 
will be excluded from descriptive statistics in the plasma concentration table.
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All participants and samples excluded from the analysis will 
be clearly documented in the study report.
Descriptive statistics, including sample size (n), arithmetic mean, SD, (%)CV, geometric mean, 
median, minimum, and maximum, will be calculated for all individual derived PK parameters of
RPV.
For each participant, plasma concentration-time data will be graphically presented. Similarly, 
graphs of the mean plasma concentration-time profiles and overlay graphs with combined 
individual plasma concentration-time profiles will be produced. Pharmacokinetic parameters will 
be subjected to an exploratory graphical analysis including various transformations in order to get 
a general overview.
 
 
 
 
 
 
 
 
 
 
 
 
CCI
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Pharmacokinetic/Pharmacodynamic Analyses
Efficacy and safety parameters will be subjected to a PK/PD analysis. Various efficacy and safety 
parameters will be linked to the PK of RPV applying graphical tools and, if feasible, statistical 
models.
9.4.5
Other Analyses
Resistance
Results from viral genotyping in plasma or in proviral DNA (archived resistance), as applicable, 
will be tabulated and described, particularly for participants with virologic failure. 
Individual mutations identified via viral genotyping will be reported relative to the HIV-1 WT
reference sequence.
Diaries
A participant listing will be created for participants who are enrolled for intensive PK sampling, 
with the date and time of RPV intake from the start of study treatment until the day of intensive 
PK sampling, based on the information entered in the participant diary.
Questionnaires
Treatment Adherence
Participant listings will be created so that adherence can be checked on an individual basis. 
Treatment adherence will be summarized based on study intervention accountability as the amount 
of RPV doses taken versus amount of RPV doses supposed to be taken. Descriptive statistics
include number of observations (n), mean, SD, median, minimum, and maximum. In addition, the 
proportion of participants that are adherent (ie, adherence ≥95%) will be summarized.
The responses to the PENTA adherence questionnaire will be tabulated at each time point (refer 
to Section 10.10, Appendix 10). Treatment adherence will be further summarized per time point 
based on a “worst case” combination of results for a number of sponsor-selected questions, 
categorizing participants into “treatment adherent” and “treatment nonadherent”.
Palatability
The responses to the palatability questionnaire will be tabulated.
CCI
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Swallowability
The responses to the swallowability questionnaire will be tabulated.
9.5
Independent Data Monitoring Committee Analyses
An IDMC will be established to monitor and review PK, safety, tolerability, and efficacy data on 
an ongoing basis and to ensure the continuing safety of the participants enrolled in this study, as 
noted in Committees Structure in Section 10.3, Appendix 3, Regulatory, Ethical, and Study 
Oversight Considerations. The IDMC will evaluate the appropriateness of the RPV dose for 
participants with a body weight of <25 kg and will make recommendations regarding the 
continuation, modification, or termination of the study (refer to Section 4.2, Scientific Rationale 
for Study Design). The IDMC will be the same committee as for the study C213 and will include 
at least 1 HIV specialist and at least 1 statistician.
The following analyses will be shared and discussed with the IDMC:
!
The analyses (no formal database lock) when participants in the mini-cohort (in the current 
study and study C213 combined) received at least 4 weeks of treatment with the RPV dose
(25 mg, 15 mg, 12.5 mg or another adjusted weight-based dose) (or discontinued earlier). 
!
The analyses (no formal database lock) when at least 12 participants with a body weight of 
<25 kg (in the current study and study C213 combined) received at least 4 weeks of treatment 
with the RPV dose (25 mg, 15 mg, 12.5 mg or another adjusted weight-based dose) (or 
discontinued earlier).
!
The analysis (no formal database lock) when all participants have reached 12 weeks of study 
treatment (or discontinued earlier).
!
The analyses (formal database lock) when all participants have reached 24 (primary analysis) 
and 48 weeks (final analysis) of study treatment (or discontinued earlier).
Details will be described in the IDMC charter.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Abbreviations and Trademarks
3TC
lamivudine
ABC
abacavir
ACTH
adrenocorticotropic hormone
ADR
adverse drug reaction
AE
adverse event
AIDS
acquired immune deficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ART
antiretroviral therapy
ARV
antiretroviral
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC24h
area under the plasma concentration-time curve from time of administration up to 24 hours 
postdose
AZT
azidothymidine
BMI
body mass index
C0h
predose plasma concentration
C24h
plasma concentration at 24 hours postdose
CL/F
total apparent clearance at steady state
Cmax
maximum observed plasma concentration
Cmin
minimum observed plasma concentration
Css,av
average plasma concentration at steady state
CD
cluster of differentiation
CDC
Centers for Disease Control and Prevention
CI
confidence interval
CNS
central nervous system
CRF
case report form(s) (paper or electronic as appropriate for this study)
CV
coefficient of variation
CYP
cytochrome P450
d4T
stavudine
DAIDS
Division of AIDS
ddI
didanosine
DHEAS
dehydroepiandrosterone sulfate
DNA
deoxyribonucleic acid
DTG
dolutegravir
ECG
electrocardiogram
eDC
electronic data capture
EFV
efavirenz
eGFR
estimated glomerular filtration rate
FDA
Food and Drug Administration
FI
fluctuation index
FSH
follicle-stimulating hormone
FTC
emtricitabine
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GMP
Good Manufacturing Practice
HDL
high-density lipoprotein
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
IAS-USA
International Antiviral Society United States of America
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
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IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
intravenous(ly)
LDL
low-density lipoprotein
LH
luteinizing hormone
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
NNRTI
non-nucleoside reverse transcriptase inhibitor
N(t)RTI
nucleoside/nucleotide reverse transcriptase inhibitor
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamic(s)
PENTA
Pediatric European Network for the Treatment of AIDS
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
QTcB
QT interval corrected for heart rate according to Bazett’s formula
QTcF
QT interval corrected for heart rate according to Fridericia’s formula
RAM
resistance-associated mutation
RBC
red blood cell
RNA
ribonucleic acid
RPV
rilpivirine
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SUSAR
suspected unexpected serious adverse reaction
TAF
tenofovir alafenamide
TDF
tenofovir disoproxil fumarate
TdP
Torsade de Pointes
tmax
time to reach the maximum observed plasma concentration
ULN
upper limit of normal
UN
United Nations
UNICEF
United Nations International Children’s Emergency Fund
VSS/F
apparent volume of distribution at steady state
WBC
white blood cell
WHO
World Health Organization
WT
wild type
Definitions of Terms
BMI
Body weight (kg) / [height (m)]²
CL/F
Dose divided by AUC24h
eGFR
k x height (cm) / plasma creatinine (Pcr) (mg/dL) with k = 0.55 in children aged 2-12 years, 
0.55 in adolescent girls aged 13-21 years, and 0.70 in adolescent boys aged 13-21 years
QTcB
QTcB = QT x (1000/RR)b where b = 1/2
QTcF
QTcF = QT x (1000/RR)b where b = 1/3
Virologic Failure
Suspected Virologic 
Failure
Confirmed Virologic 
Failure 
Lack or loss of virologic response
HIV-1 RNA ≥ 200 copies/mL after confirmed HIV-1 RNA of <50 copies/mL
2 consecutive HIV-1 RNA plasma viral load measurements ≥200 copies/mL
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10.2
Appendix 2: Monitoring and Safety for Specific Toxicities 
Guidelines in this section are applicable for the entire study period, including the screening and 
follow-up phases. An overview of the laboratory ranges to assign grading to a laboratory value is 
provided in Section 10.5, Appendix 5, DAIDS Table.
For grade 3 or 4 laboratory abnormalities, participants should have a confirmatory 
measurement, preferably within 48 hours after the laboratory results become available to 
the site. This management scheme is for confirmed laboratory abnormalities and not for 
isolated events.
The following laboratory abnormalities do not warrant mandatory confirmation within 48 hours:
!
Asymptomatic grade 3 or 4 glucose or triglyceride elevations, or asymptomatic grade 3 
cholesterol elevations
!
Asymptomatic grade 3 pancreatic amylase elevations in participants with no history or 
concomitant disease of pancreatitis
All grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities resulting in an 
increase of 2 DAIDS grades from baseline will be followed until return to baseline or within 
1 grade from baseline. Certain long-term AEs of ART cannot be followed to resolution within the 
setting of this study; in these cases, follow-up will be the responsibility of the investigator, which 
will be agreed upon with the sponsor.
For participants reporting rash, allergic reaction, AST/ALT and total bilirubin elevations, 
pancreatic amylase/lipase elevations, clinical hepatitis, neuropsychological symptoms, 
gastrointestinal nausea, diarrhea, signs and symptoms of adrenal insufficiency, or other toxicities 
the following actions should be taken:
RASH
Participants who have a history of a grade 2 or 3 rash may be at increased risk for RPV-related 
skin reaction and should therefore be monitored closely during the first 4 weeks of study treatment.
All the information regarding rash occurring after the first intake of study intervention needs to be 
reported in the Rash section of the CRF within 24 hours and the study site monitor needs to be 
informed. Rash occurring before the first intake of study intervention is to be reported as AEs 
(refer to Section 8.3).
Any skin change should be evaluated with specific attention for systemic symptoms, mucosal 
involvement, laboratory abnormalities (including eosinophilia and increases in ALT/AST), and 
vital sign changes such as decreases in blood pressure or fever. 
In case of rash, safety blood samples need to be taken, which are to be processed by the local 
laboratory. These samples need to be taken during the unscheduled visits as described below. The 
following parameters need to be tested: AST, ALT, gamma-glutamyl transferase (GGT), alkaline 
phosphatase (ALP), bilirubin (total, direct, and indirect), creatinine, and a complete blood cell 
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count (including hemoglobin, hematocrit, red blood cell [RBC] count, white blood cell [WBC]
count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelet count). 
If the etiology of the rash is clear, and is not related to RPV, as in the case of concomitant illness, 
skin infection, or trauma, standard management should be undertaken. Examples include herpes 
zoster, cutaneous fungal infections, acne, cuts, or burns. The event should be followed up as an 
infection/regular AE and be reported on the AE pages of the CRF.
Dermatologist fees for evaluating participants who experience rash will be reimbursed by the 
sponsor.
Grade 1 Rash
Participants may continue ART and may be treated symptomatically until the rash resolves. 
Cetirizine (antihistamine), topical corticosteroids, or antipruritic agents may be prescribed. The 
participant and/or his or her representative should be advised to contact the investigator 
immediately if there is any worsening of the rash, if any systemic signs or symptoms worsen, or if 
mucosal involvement develops. 
Referral to a dermatologist is optional. 
Participants and/or their representatives should be informed that they should visit the site
immediately when they notice any rash. For close follow-up, unscheduled visits will also be 
performed on 1 and 7 days after occurrence of any rash. If rash is unresolved after 7 days, 
additional unscheduled visits can be performed at the investigator’s discretion until resolution. 
Grade 2 Rash
Participants may continue ART. Antiretroviral therapy may also be continued for any grade 2 rash 
with an increase in ALT/AST (<2x baseline) provided the participant is followed weekly with 
repeated testing. For participants with a grade 2 rash and elevations of ALT/AST >2x baseline but 
<5x upper limit of normal (ULN), ART should be interrupted and should only be restarted when 
the cutaneous reaction has resolved.
The participant and/or his or her representative should be advised to contact the investigator 
immediately if the rash fails to resolve (after more than 2 weeks), if there is any worsening of the 
rash, if any systemic signs or allergic symptoms develop, or if mucosal involvement develops. 
Cetirizine (antihistamine), topical corticosteroids, or antipruritic agents may be prescribed.
Referral to a dermatologist is optional. 
Participants and/or their representatives should be informed that they should visit the site
immediately when they notice any rash. For close follow-up, unscheduled visits will also be 
performed on 1 and 7 days after occurrence of any rash. If rash is unresolved after 7 days, 
additional unscheduled visits can be performed at the investigator’s discretion until resolution. 
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Grade 3 Rash
Participants will permanently discontinue ART and will be withdrawn from the study. No 
rechallenge is allowed.
A biopsy should be taken within 24 hours (either by the investigator or the dermatologist) and a 
dermatologist should be consulted as soon as possible, preferably also within 24 hours.
Biopsies will be analyzed locally. The sponsor may have a central analysis performed by a selected 
pathologist. For this purpose, the local slides may be requested; after analysis, they will be returned 
to the site.
Participants and/or their representatives should be informed that they should visit the site
immediately when they notice any rash. For close follow-up, unscheduled visits will also be 
performed as follows: daily for the first 5 days after occurrence, weekly until resolution. In 
addition, extra unscheduled visits can be performed at the investigator’s discretion. 
If on day 1 (initial rash evaluation visit, when investigator notices the rash for the first time) there 
are no increases in ALT/AST noted and there is no progression of rash (eg, rash increases in size 
or spreads to other parts of the body or additional blisters/vesicles/ulcerations develop) during the 
first 5 days then safety blood samples should also be taken on Day 5. 
If on day 1 the ALT/AST are ≥2x baseline and ≥5x ULN, then safety blood samples should be 
taken daily for the first 5 days.
If on day 5 the ALT/AST are ≥2x baseline and ≥5x ULN, then safety blood samples should be 
taken at least weekly until resolution of ALT/AST abnormalities.
At the investigator’s discretion, ALT/AST can be measured more frequently. 
Grade 4 Rash
Participants will permanently discontinue ART and will be withdrawn from the study. No 
rechallenge is allowed.
A biopsy should be taken within 24 hours (either by the investigator or the dermatologist) and a 
dermatologist should be consulted as soon as possible, preferably also within 24 hours.
Biopsies will be analyzed locally. The sponsor may have a central analysis performed by a selected 
pathologist. For this purpose, the local slides may be requested; after analysis, they will be returned 
to the site.
Participants and/or their representatives should be informed that they should visit the site
immediately when they notice any rash. For close follow-up, unscheduled visits will also be 
performed as follows: daily for the first 5 days after occurrence, weekly until resolution. In 
addition, extra unscheduled visits can be performed at the investigator’s discretion. Participants 
should be hospitalized whenever medically appropriate for management of grade 4 rashes. 
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If on day 1 (initial rash evaluation visit, when investigator notices the rash for the first time) there 
are no increases in ALT/AST noted and there is no progression of rash (eg, rash increases in size 
or spreads to other parts of the body or additional blisters/vesicles/ulcerations develop) during the 
first 5 days then safety blood samples should also be taken on Day 5. 
If on day 1 the ALT/AST levels are ≥2x baseline and ≥5x ULN, then safety blood samples should 
be taken daily for the first 5 days.
If on day 5 the ALT/AST levels are ≥2x baseline and ≥5x ULN, then safety blood samples should 
be taken at least weekly until resolution of ALT/AST abnormalities. 
At the investigator’s discretion, the ALT/AST levels can be measured more frequently. 
Table 3:
Summary of Rash
DAIDS Toxicity Grade
Investigator Action
Rechallenge Instructions
Grade 1
May continue ART
NA
Grade 2
May continue ART
NA
Grade 3
Discontinue ART
No
Grade 4
Discontinue ART
No
NA=not applicable
ACUTE SYSTEMIC ALLERGIC REACTION
Management will be at the discretion of the investigator, taking into account the following 
protocol-defined procedures, and should follow generally accepted medical standards.
Participants with ABC in their background regimen and developing an acute systemic allergic 
reaction should be evaluated for the possibility of ABC hypersensitivity reaction and follow the 
instructions related to clinically suspected hypersensitivity to ABC (refer to Hypersensitivity 
Reactions).
Grade 1 Acute Systemic Allergic Reaction
Participants may continue ART. The participant and/or his or her representative should be advised 
to contact the investigator immediately if there is any worsening of the localized urticaria, or if 
any systemic signs or symptoms develop.
Antihistamines, topical corticosteroids, or antipruritic agents may be prescribed as long as these 
are in line with the package inserts of the background ARVs or the (dis)allowed medication for 
RPV as indicated in Section 6.5.
Grade 2 Acute Systemic Allergic Reaction
Participants may continue ART. If there is any worsening of the allergic reaction, the participant
and/or his or her representative should be advised to contact the investigator immediately, ART 
will be discontinued and the participant will be withdrawn from the study.
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Antihistamines, topical corticosteroids, or antipruritic agents may be prescribed as long as these 
are in line with the package inserts of the background ARVs or the (dis)allowed medication for 
RPV as indicated in Section 6.5.
Grade 3 and Grade 4 Acute Systemic Allergic Reaction
Participants will permanently discontinue ART and will be withdrawn from the study (refer to
Section 7). Participants will be treated as clinically appropriate. Standard management should be 
undertaken.
AST, ALT, AND TOTAL BILIRUBIN ELEVATION
Management will be at the discretion of the investigator, taking into account the following 
protocol-defined procedures (also refer to Table 4), and should follow generally-accepted medical 
standards. This management scheme is for confirmed laboratory abnormalities and not for isolated 
events.
Grade 1 AST or ALT Elevation and Grade 2 AST or ALT Elevation with Grade 1 or 2 
Total Bilirubin Elevation
Participants may continue ART.
Grade 3 AST or ALT Elevation with Grade 1 or 2 Total Bilirubin Elevation
Participants are to interrupt ART, except if they are co-infected with hepatitis A, B, or C (see 
below). Upon resolution of the laboratory abnormality to at least the lower grade level (at most 
grade 2), the participant may resume ART under the guidance of the investigator and preferably 
after the investigator has consulted with a sponsor’s physician.
If a participant is required to interrupt ART due to a grade 3 AST or ALT elevation, and after 
restarting ART he or she has a recurrence of grade 3 or grade 4 AST or ALT elevation, then he or 
she will permanently discontinue ART and will be withdrawn from the study (refer to Section 7).
For participants with concomitant hepatitis A, B, or C:
Warning: Severe acute exacerbations of hepatitis B have been reported in participants who are 
co-infected with hepatitis B virus and HIV and have discontinued FTC, TAF, TDF, or 
3TC. Hepatic function should be monitored closely in these participants, with both 
clinical and laboratory follow-up for at least several months. If appropriate, initiation 
of anti-hepatitis B therapy may be warranted.
If a participant is diagnosed with acute viral hepatitis during the study, then he or she must be 
withdrawn from the study immediately and the necessary follow-up visits performed (refer to
Section 7). Participants with chronic hepatitis B or C co-infection will be allowed to continue ART
if they develop a grade 3 elevation in AST or ALT, provided that ALP is not elevated to grade 2 
or higher and total bilirubin is not elevated to grade 3 or higher, and they do not have signs and 
symptoms of clinically active hepatitis. Signs and symptoms of active hepatitis include, but are 
not limited to, fatigue, malaise, anorexia, nausea, dark urine and clay-colored stools, bilirubinuria, 
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jaundice, and liver tenderness. If signs or symptoms of clinically active hepatitis occur, or if AST 
or ALT increases to grade 4, then the participant will permanently discontinue ART and will be 
withdrawn from the study (refer to Section 7).
If a participant co-infected with hepatitis B or C experiences grade 3 elevation in AST or ALT, 
ART will be interrupted. If after restarting ART, the participant has a recurrence of grade 3 
increase in AST or ALT, he or she may continue ART provided that ALP is not elevated to grade 2 
or higher and total bilirubin is not elevated to grade 3 or higher, and he or she does not have signs 
and symptoms of clinically active hepatitis. If signs or symptoms of clinically active hepatitis 
occur, or if AST or ALT increases to grade 4, then ART will be permanently discontinued and the 
participant will be withdrawn from the study (refer to Section 7). If for the hepatitis B or C 
co-infected participant treatment is interrupted a second time because of a grade 3 elevation in 
AST or ALT, ART will be permanently discontinued and the participant will be withdrawn from 
the study (refer to Section 7).
Grade 3 AST or ALT Elevation With at Least Grade 3 Total Bilirubin Elevation or 
Grade 4 AST or ALT Elevation
Participants will permanently discontinue ART and will be withdrawn from the study (refer to
Section 7).
Table 4:
Summary of AST and ALT Elevations
DAIDS Toxicity Grade 
Investigator Action
Rechallenge Instructions
Grade 1
May continue ART if total bilirubin is ∃grade 2
NA
Grade 2
May continue ART if total bilirubin is ∃grade 2
NA
Grade 3
If total bilirubin is ∃grade 2:
Interrupt ART until toxicity ∃grade 2;
If co-infected with hepatitis B or C, ART may be 
continued if ALP is ∃grade 2, bilirubin is ∃grade 3, 
and asymptomatic.
Allowed once
If recurrence after restart 
of ART, discontinue ART
permanently
If total bilirubin is > grade 2:
Discontinue ART (refer to Section 7)
No
Grade 4
Discontinue ART (refer to Section 7)
No
NA=not applicable
PANCREATIC AMYLASE OR LIPASE ELEVATIONS
For confirmed asymptomatic grade 1 and grade 2 pancreatic amylase and/or lipase elevations, and 
confirmed asymptomatic grade 3 pancreatic amylase elevations with no history or concomitant 
disease of pancreatitis, participants should be carefully evaluated and followed closely.
For confirmed asymptomatic grade 4 elevations of pancreatic amylase or confirmed asymptomatic 
grade 3 or grade 4 elevations of lipase, participants should interrupt ART until pancreatic amylase 
returns to grade ≤3 or lipase returns to grade ≤2, at which time ART could be reintroduced. If after 
reintroduction of ART asymptomatic grade 4 elevations of pancreatic amylase or asymptomatic 
grade 3 or 4 lipase levels recur, ART will be permanently discontinued and the participant will be 
withdrawn from the study (refer to Section 7).
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SIGNS AND SYMPTOMS OF ADRENAL INSUFFICIENCY
Clinical signs and symptoms of adrenal insufficiency may include, but are not limited to, tiredness, 
weakness, mental depression, headache, anorexia, weight loss, dizziness, orthostatic hypotension, 
abdominal cramps, diarrhea, electrolyte disturbances, hypoglycemia, mild normocytic anemia, 
lymphocytosis, eosinophilia, loss of body hair in women, hyperpigmentation, and hirsutism. 
Pigmentation and hirsutism are evaluated at the scheduled physical examinations (refer to
Section 1.3). 
In case of clinical signs or symptoms, or laboratory abnormalities (other than cortisol) indicative 
for adrenal insufficiency, an ACTH stimulation test should be done as soon as possible during an 
unscheduled visit. For additional details about the ACTH stimulation test and other endocrine 
assessments, refer to Section 10.7, Appendix 7, Clinical Laboratory Tests.
If the unscheduled ACTH test is performed further to the presence of signs and symptoms of 
adrenal insufficiency (as listed above), and the participant does not achieve a cortisol value 
%500 nmol/L (18.1 &g/dL) on at least 1 of the time points of cortisol measurement during the 
ACTH stimulation test (ie, morning basal cortisol or 60 minutes after ACTH stimulation), this 
should be discussed with the sponsor, taking into account other possible confounding factors 
(eg, concomitant medication, AEs,…), and the participant may discontinue ART and be withdrawn 
from the study if considered appropriate (refer to Section 7).
Appropriate clinical follow-up, including further endocrine evaluations, should be installed. The 
sponsor will seek external endocrinological advice should this be deemed appropriate or at request 
of the investigator. To this extent an external pediatric endocrinology expert will be available for 
the full duration of the study. In case of clinical signs or symptoms of adrenal insufficiency and an 
abnormal ACTH stimulation test it may be decided by the investigator and after consultation with 
the sponsor to discontinue ART if this is in the best interest of the participant. Other measures 
could be to start substitution therapy as appropriate. This may be the administration of 
glucocorticoids at the time of stressful events such as surgery or short or longer-term 
glucocorticoid substitution. In case of acute adrenal insufficiency participants may be 
hypovolemic, hyponatremic, or hyperkalemic. In such case initial therapy may consist of 
intravenously (IV) administered saline and dextrose. In a hypotensive participant, a 20 mL/kg 
bolus of isotonic sodium chloride solution given over the first hour may be necessary to restore 
the blood pressure. This bolus may be repeated if the blood pressure remains low. After results for 
the participant’s electrolytes, blood sugar, and cortisol are obtained, a single dose of 
dexamethasone may be administered without interfering with the cortisol response to cosyntropin 
or analogues, and an ACTH stimulation test should be performed. If adrenal insufficiency is 
diagnosed based on the results, substitution with glucocorticoids may need to be installed. The 
need for glucocorticoid replacement needs to be balanced between the need to prevent symptoms 
of adrenal insufficiency and the need to allow the participant to grow at a normal rate since excess 
replacement with glucocorticoid diminishes growth velocity. In case of reduced aldosterone 
secretion, mineralocorticoid replacement might also be required.
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CLINICAL HEPATITIS
Nonviral Hepatitis
Participants should be monitored for the development of signs and symptoms of hepatitis, which 
include, but are not limited to, fatigue, malaise, anorexia, nausea, dark urine and clay-colored 
stools, bilirubinuria, jaundice, liver tenderness, with or without initially abnormal serum 
transaminase levels.
Participants with these signs and symptoms should seek medical attention immediately and hepatic 
parameters should be tested. Antiretroviral therapy must be permanently discontinued and the 
participant will be withdrawn from the study if the hepatitis is considered at least possibly related 
to RPV in the opinion of the investigator (refer to Section 7).
Viral Hepatitis
If acute viral hepatitis is diagnosed during the study, the participant should be permanently 
withdrawn from the study (refer to Section 7).
NEUROPSYCHOLOGICAL SYMPTOMS
Participants and/or their representatives should be informed that RPV may cause dizziness, 
insomnia, somnolence, and/or abnormal dreams (refer to Section 2.3.3) and instructed that if 
participants experience these symptoms they should avoid potentially hazardous tasks such as 
operating machinery.
There have been reports of delusions and inappropriate behavior in participants receiving licensed 
NNRTIs, especially in participants with a history of mental illness or substance abuse. Severe acute 
depression (including suicidal ideation/attempts) has also been infrequently reported. At all visits 
indicated in the Schedule of Activities (refer to Section 1.3) an evaluation will be done using 
questionnaires or other means (as available at the site) as part of local standard of care for this 
population, to assess whether the participant needs to be referred for a complete mental health 
assessment by a mental health professional (refer to Section 8.2.5). Participants who experience 
symptoms of depression and/or their representatives should contact the investigator immediately 
as discontinuation of ART may be required. Investigators should refer participants experiencing
such symptoms for immediate psychiatric evaluation/medical intervention. 
In case of grade 3 and grade 4 alterations in personality behavior or in mood, ART must be 
permanently discontinued and the participant will be withdrawn if the neuropsychological 
symptoms are considered at least possibly related to RPV in the opinion of the investigator (refer 
to Section 7).
GASTROINTESTINAL NAUSEA (WITH OR WITHOUT VOMITING)
Although common, nausea following initiation of ART usually subsides or resolves during the 
first few weeks of treatment.
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Participants with ABC in their background regimen and developing gastrointestinal nausea should 
be evaluated for the possibility of ABC hypersensitivity reaction and follow the instructions related 
to clinically suspected hypersensitivity to ABC (refer to Hypersensitivity Reactions).
Grade 1 and Grade 2 Nausea
Participants may continue ART and may be treated as needed with anti-emetics given orally or by 
suppository.
Grade 3 Nausea
Participants will interrupt ART. The participant will be treated as needed with anti-emetics given 
orally or by suppository. Antiretroviral therapy may be resumed when the nausea resolves to 
grade ∃2. 
If grade 3 nausea recurs after resuming ART despite the use of anti-emetics, participants will 
permanently discontinue ART and will be withdrawn from the study (refer to Section 7).
Grade 4 Nausea
Participants will permanently discontinue ART and will be withdrawn from the study (refer to
Section 7).
DIARRHEA
Participants with ABC in their background regimen and developing diarrhea should be evaluated 
for the possibility of ABC hypersensitivity reaction and follow the instructions related to clinically 
suspected hypersensitivity to ABC (refer to Hypersensitivity Reactions).
Grade 1 and Grade 2 Diarrhea
Participants may continue ART. Loperamide or diphenoxylate can be administered.
Grade 3 Diarrhea
Participants will interrupt ART. Antiretroviral therapy may be resumed when the diarrhea resolves 
to grade ∃2.
If grade 3 diarrhea recurs after resuming ART despite the use of appropriate medication, 
participants will permanently discontinue ART and will be withdrawn from the study (refer to
Section 7).
Grade 4 Diarrhea
Participants will permanently discontinue ART and will be withdrawn from the study (refer to
Section 7).
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OTHER TOXICITIES
Grade 1
Participants may continue ART.
Grade 2
Participants may continue ART based on the investigator’s clinical judgment.
Grade 3
Participants should interrupt ART and may resume ART when the AE or laboratory abnormality 
resolved to within 1 grade level of the participant’s baseline but not higher than grade 2.
The following exceptions apply:
!
Participants with pre-existing diabetes who experience a glucose elevation of grade 3 (refer 
to Grade 3 or 4 Hyperglycemia).
!
Participants who experience asymptomatic glucose, triglyceride, or cholesterol elevations of 
grade 3 (refer to Grade 3 or 4 Hyperglycemia and Grade 3 or 4 Hypertriglyceridemia and 
Grade 3 Hypercholesterolemia).
!
Participants who experience asymptomatic pancreatic amylase elevations of grade 3 with no 
history or concomitant disease of pancreatitis.
!
Participants who experience an AE that is considered not related or doubtfully related to RPV.
Grade 4
Participants will permanently discontinue ART and will be withdrawn from the study (refer to
Section 7).
Exceptions are, unless clinical assessment foresees an immediate health risk to the participant:
!
Participants with pre-existing diabetes who experience a glucose elevation of grade 4 (refer
to Grade 3 or 4 Hyperglycemia).
!
Participants who experience asymptomatic glucose or triglyceride elevations of grade 4 (refer 
to Grade 3 or 4 Hyperglycemia and Grade 3 or 4 Hypertriglyceridemia and Grade 3 
Hypercholesterolemia).
!
Participants who experience confirmed pancreatic amylase and lipase elevations of grade 4 
(refer to PANCREATIC AMYLASE OR LIPASE ELEVATIONS).
!
Participants who experience a
grade 4 AE (except
rash, allergic reaction, or 
neuropsychological event) that is considered not related or doubtfully related to RPV.
Note: This management scheme is for confirmed laboratory abnormalities and not for isolated 
events.
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SPECIFIC TOXICITIES WITH CONCOMITANT ARVS
The information below does not imply that the following AEs are only related to concomitant 
ARVs, since a contribution of RPV cannot be excluded.
Grade 3 or 4 Hyperglycemia
Management decisions should be based on fasted results. If elevated glucose levels are from a 
nonfasting blood draw, the draw should be repeated after a 10-hour fast. 
Participants who experience asymptomatic glucose elevations of grade 3 or 4 and participants with 
pre-existing diabetes may continue ART unless clinical assessment foresees an immediate health 
risk to the participant. 
Participants without pre-existing diabetes and with persistent grade 3 or 4 glucose elevations 
(despite appropriate antidiabetic medication/management) should permanently discontinue ART
and be withdrawn from the study (refer to Section 7). Appropriate clinical management of 
hyperglycemia must be started in a timely fashion.
Grade 3 or 4 Hypertriglyceridemia and Grade 3 Hypercholesterolemia
Management decisions should be based on fasted results. If elevated triglyceride or cholesterol 
levels are from a nonfasting blood draw, the draw should be repeated after a 10-hour fast.
Participants who experience asymptomatic triglyceride elevations of grade 3 or 4 or cholesterol 
elevations of grade 3 may continue ART.
Hypertriglyceridemia and hypercholesterolemia should be treated according to the specific 
guidelines for treating HIV-infected participants. Appropriate clinical management of cholesterol 
in the setting of HIV infection should be started in a timely fashion. Investigators may choose to 
initiate treatment with fenofibrate, gemfibrozil, clofibrate, niacin, or a 3-hydroxy-3-methylglutaryl 
coenzyme A reductase inhibitor, in addition to the usual counseling on diet and exercise. These 
medications should be introduced with caution as they may have overlapping adverse effects. 
Moreover, niacin has the propensity to worsen the control of blood sugar in participants with 
diabetes mellitus or a history of hyperglycemia.
Hypersensitivity Reactions
In clinical studies, approximately 5% of participants receiving ABC developed a hypersensitivity 
reaction, which in rare cases has been proven fatal.30
At screening, all participants without prior documented HLA-B*5701-negative results in whom 
the investigator considers ABC in the background regimen will be tested for HLA-B*5701. In 
those participants where HLA-B*5701 is positive, ABC cannot be administered.28
Also in case of switch to ABC during the study, the participant should test negative for 
HLA-B*5701 (unless prior documented negative results are available). 
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It should also be noted that restricting ABC treatment to HLA-B*5701-negative participants (so 
excluding participants where HLA-B*5701 is positive) does not completely eliminate the risk of 
hypersensitivity reactions.
Description of the ABC Hypersensitivity Reaction
The ABC hypersensitivity reaction is characterized by symptoms indicating multi-organ 
involvement. The majority of participants have fever and/or rash.
Symptoms can occur at any time during ABC treatment, but usually appear within the first 6 weeks 
(median time to onset: 11 days). The symptoms worsen with continued therapy and can be 
life-threatening, and usually resolve shortly after discontinuation of ABC.
Frequently observed signs and symptoms include fever; rash; malaise or fatigue; gastrointestinal 
symptoms such as nausea, vomiting, diarrhea, or abdominal pain; and respiratory symptoms such 
as dyspnea, sore throat, or cough. Other signs and symptoms include myalgia, arthralgia, oedema, 
pharyngitis, headache, paresthesia, and myolysis. 
Physical findings may include rash (usually maculopapular or urticarial), lymphadenopathy, and
mucous membrane lesions (conjunctivitis, mouth ulceration). Abnormal chest x-ray findings may 
also be present (predominantly infiltrates, which can be localized).
Laboratory abnormalities may include elevated liver function tests (such as hepatic transaminases), 
increased creatine phosphokinase or creatinine levels, and lymphopenia. 
Anaphylaxis, hypotension, liver failure, renal failure, adult respiratory distress syndrome, and
respiratory failure may occur as well.
Some participants with hypersensitivity were initially thought to have respiratory disease 
(pneumonia, bronchitis, pharyngitis), a flu-like illness, gastroenteritis, or reactions to other 
medications. This delay in diagnosis leads to a more severe hypersensitivity reaction or death. 
Therefore, the diagnosis of hypersensitivity reaction should be carefully considered for 
participants presenting with symptoms of these diseases. No ABC should be administered if a 
hypersensitivity reaction cannot be ruled out.
Management of ABC Hypersensitivity Reactions
Participants developing signs or symptoms possibly linked with a hypersensitivity reaction and/or 
their representatives must immediately contact the participant’s doctor. 
If a hypersensitivity reaction is diagnosed or if hypersensitivity cannot be ruled out (even when 
other diagnoses are possible [respiratory diseases, flu-like illness, gastroenteritis, or reactions to 
other medications]), the participant must immediately discontinue ABC treatment. The 
ABC-containing ARVs will be replaced by alternative ARVs. The participant and/or his or her 
representative should be asked to return all unused supplies of the ABC-containing ARVs for 
disposal to prevent an accidental rechallenge.
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Symptomatic support for ABC hypersensitivity may be indicated such as the administration of IV
fluids to participants who develop hypotension. Antihistamines or corticosteroids have been used
to manage ABC hypersensitivity; however, there are no clinical data demonstrating their benefit
in the management of the hypersensitivity reaction. 
Laboratory and other investigations which may be useful in the evaluation and treatment of ABC 
hypersensitivity include, but are not limited to, measurement of ALT, AST, creatine 
phosphokinase, serum creatinine, and WBC differential count, and chest x-ray (if respiratory 
symptoms are present).
Special Considerations Following an Interruption of ABC Treatment
If ABC treatment has been interrupted and restarting is under consideration, the reason for 
interruption should be evaluated to ensure that the participant did not have symptoms of a 
hypersensitivity reaction. Restart of ABC treatment must be done only if access to appropriate 
medical care is readily available. If interruption was preceded by a single key symptom of 
hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal symptoms, or a respiratory 
symptom), restarting of any ABC-containing ARV should be done only under direct medical 
supervision. 
Essential Participant Information
Participants will be provided a warning card listing the common signs of a hypersensitivity 
reaction and will be instructed to carry this card with them at all times.
Investigators must ensure that participants and/or their representatives are fully informed regarding 
the following information on the hypersensitivity reaction:
!
Participants and/or their representatives must be made aware of the possibility of a 
hypersensitivity reaction to ABC that may result in a life-threatening reaction or death.
!
At screening, all participants without prior documented HLA-B*5701 negative results in 
whom the investigator considers ABC in the background regimen will be tested for 
HLA-B*5701. In those participants where HLA-B*5701 is positive, ABC cannot be 
administered.28 In addition, in case of switch to ABC during the study, the participant should 
test negative for HLA-B*5701 (unless prior documented negative results are available).
!
Participants developing signs or symptoms possibly linked with a hypersensitivity reaction 
and/or their representatives must immediately contact the participant’s doctor. 
!
Participants who are hypersensitive to ABC and/or their representatives will be reminded that 
the participants must never take any ABC-containing ARV again. 
!
Participants who have experienced a hypersensitivity reaction will be asked to return all 
unused supplies of the ABC-containing ARVs for disposal to prevent an accidental 
rechallenge.
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!
Participants who have stopped taking an ABC-containing ARV for any reason (particularly 
due to possible adverse reactions or illness) and/or their representatives must be advised to 
contact the participant’s doctor before restarting.
Reporting of Hypersensitivity Reaction
All cases of ABC hypersensitivity should be reported as SAEs (refer to Section 8.3).
Lactic Acidosis
The relevance of asymptomatic lactate elevations during ART is unclear. Therefore, routine lactate 
monitoring is not currently recommended and serum lactate evaluation is not part of the routine 
safety evaluations for this study. However, lactate monitoring should be performed at the local 
laboratory if there is a clinical suspicion of lactic acidosis (see description below).
Lactic acidosis syndrome, sometimes fatal and often associated with evidence of hepatic steatosis, 
is a recognized but rare complication of N(t)RTI therapy. Current knowledge regarding this 
syndrome is incomplete. Obesity and prolonged N(t)RTI exposure may be risk factors. 
Lactic acidosis frequently involves nonspecific symptoms such as fatigue, weakness, and fever, 
but in the majority of cases also involves symptoms suggestive of hepatic dysfunction such as 
nausea, vomiting, abdominal or epigastric discomfort, abdominal distension, hepatomegaly, and 
new onset elevated liver enzymes. 
A high index of suspicion may be required to diagnose this condition. Alternatively, it is possible 
that unwarranted concern may be raised by overinterpretation of lactic acid levels. N(t)RTI toxicity 
is only 1 cause of lactic acidosis. Type "B" lactic acid elevations or those without clinically 
apparent tissue hypoxia are also seen in the context of diabetes mellitus, uremia, liver disease, 
infections, malignancies, alkaloses, and drug and toxin ingestion of such substances as ethanol, 
methanol, ethylene glycol, and salicylates.
The following case definition of lactic acidosis will be used in this study:
Symptomatic Hyperlactatemia
New, otherwise unexplained, and persistent (%2 weeks) occurrence of at least 1 of the following 
symptoms:
!
Nausea and vomiting
!
Abdominal pain or gastric discomfort
!
Abdominal distention
!
Increased hepatic transaminases
!
Unexplained fatigue
!
Dyspnea
!
Lactate level ≥2x ULN confirmed by repeat lactate level analysis
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Note:
All lactate levels ≥2x ULN should be repeated as soon as possible (local laboratory), 
generally within 1 week. If the second result confirms hyperlactatemia, participants 
should immediately interrupt their ART. Standard management should be initiated 
with follow-up to resolution. If causality is related to the background regimen only 
and NOT to RPV, N(t)RTIs must be changed. If causality is related to RPV, ART 
will be discontinued and participants will be withdrawn.
Processing of the lactate sample needs to be done according to strict guidelines both in the 
preparation of the participant (ideally, fasting and with no recent exercise) and in the blood 
drawing/processing procedure (ideally, blood drawn without a tourniquet, no hand clenching, and 
blood drawn into a chilled tube and processed immediately) to minimize false lactate elevations.
Renal Complications
Renal safety will be monitored by evaluating serum creatinine levels, estimated glomerular 
filtration rate (eGFR), serum chemistry, and urinalysis at the visits indicated in the General 
Schedule of Activities (refer to Section 1.3.1).
If eGFR is decreased with ≥30% from baseline, the value must be confirmed by repeat testing 
within 72 hours using an unscheduled visit. A sample for bioanalysis of RPV should be taken at 
the time of the unscheduled visit. If the decrease in eGFR is confirmed, ART interruption may be 
considered at the discretion of the investigator. If the abnormality is not confirmed, the participant
may continue ART with close follow-up by the investigator. 
Unscheduled visits may be used to monitor renal function more closely. Long-term follow-up of 
participants who develop nephrotoxicity should be discussed with the sponsor. Participants who 
change their background regimen or permanently discontinue ART due to nephrotoxicity must 
attend scheduled, unscheduled, or post-study follow-up visits to characterize resolution of renal 
abnormalities. Follow-up visits (scheduled, unscheduled, or post-study) will be conducted every 
4 weeks and must be maintained until stabilization for 3 months with fluctuations of eGFR of 
<20% or return to baseline levels.
Pancreatitis
Pancreatitis must be considered whenever a participant receiving didanosine (ddI) (with or without 
concomitant administration of TDF) and/or stavudine (d4T) develops abdominal pain and nausea, 
vomiting, or elevated pancreatic amylase or lipase. Treatment with ddI, and/or TDF, and/or d4T 
should be interrupted until the diagnosis of pancreatitis is excluded. The participant experiencing 
pancreatitis can, however, be rechallenged with the ARV background regimen if pancreatitis is 
considered not related to this treatment.
In case the pancreatitis is considered at least possibly related to RPV, ART must be permanently 
discontinued and the participant will be withdrawn from the study (refer to Section 7). 
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Peripheral Neuropathy
Participants should be monitored for the development of peripheral neuropathy, which is usually 
characterized by numbness, tingling, and/or pain in the feet or hands. Peripheral neuropathy is a 
common AE of ddI and d4T.
Treatment of the peripheral neuropathy is at the discretion of the investigator, but generally begins 
with nonopioid analgesics, including nonsteroidal anti-inflammatory agents and acetaminophen 
(paracetamol), and the use of tricyclic antidepressants and other agents when more severe pain is 
present. Some of these medications should be introduced with caution.
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10.3
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current International Conference on Harmonisation (ICH) guidelines on Good Clinical 
Practice (GCP), and applicable regulatory and country-specific requirements.
The investigator will be responsible for reporting cases of suspected child abuse and/or neglect 
according to local medical association (eg, American Academy of Pediatrics) or health department 
guidelines.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the participants, in which case the amendment must 
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
listed in the Contact Information page(s), which will be provided as a separate document. Except 
in emergency situations, this contact should be made before implementing any departure from the 
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the 
situation and agree on an appropriate course of action. The data recorded in the CRF and source 
documents will reflect any departure from the protocol, and the source documents will describe 
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
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Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention 
to the study site:
!
Protocol and amendment(s), if any, signed and dated by the principal investigator.
!
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, participant compensation programs. This approval must clearly identify the 
specific protocol by title and number and must be signed (or sealed, where appropriate per 
local regulations) by the chairman or authorized designee.
!
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from 
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study.
!
Regulatory authority approval or notification, if applicable.
!
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable.
!
Documentation of investigator qualifications (eg, curriculum vitae).
!
Completed investigator financial disclosure form from the principal investigator, where 
required.
!
Signed and dated clinical trial agreement, which includes the financial agreement.
!
Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first 
participant:
!
Completed investigator financial disclosure forms from all subinvestigators.
!
Documentation of subinvestigator qualifications (eg, curriculum vitae).
!
Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests.
!
Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license).
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Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator will provide the IEC/IRB with current and complete 
copies of the following documents (as required by local regulations):
!
Final protocol and, if applicable, amendments.
!
Sponsor-approved ICF (and any other written materials to be provided to the participants).
!
IB (or equivalent information) and amendments/addenda.
!
Sponsor-approved participant recruiting materials.
!
Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable.
!
Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB).
!
Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants.
!
Any other documents that the IEC/IRB requests to fulfill its obligation.
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
participants, data, or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator will send the following documents and updates to the IEC/IRB 
for their review and approval, where appropriate:
!
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data, or study conduct).
!
Revision(s) to ICF and any other written materials to be provided to participants.
!
If applicable, new or revised participant recruiting materials approved by the sponsor.
!
Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable.
!
New edition(s) of the IB and its amendments/addenda.
!
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually).
!
Reports of AEs that are serious, unlisted/unexpected, and associated with the study 
intervention.
!
New information that may adversely affect the safety of the participants or the conduct of the 
study.
!
Deviations from or changes to the protocol to eliminate immediate hazards to the participants.
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!
Report of deaths of participants under the investigator's care.
!
Notification if a new investigator is responsible for the study at the site.
!
Development Safety Update Report and Line Listings, where applicable.
!
Any other requirements of the IEC/IRB.
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data, or study conduct), the amendment and applicable ICF 
revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator will notify the IEC/IRB about the study completion (if 
applicable, the notification will be submitted through the head of investigational institution).
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 4.2.1, Study-specific Ethical Design 
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
INFORMED CONSENT PROCESS AND ASSENT FORM
Before any study-related activity, each participant’s representative must give written consent 
according to local requirements after the nature of the study has been fully explained. Sufficient 
time will be given to read the ICF and to ask questions. A copy of the ICF must be provided.
Assent must be obtained from children (minors) capable of understanding the nature of the study, 
typically participants aged ≥7 years, depending on the institutional policies. Children will be asked 
whether or not they wish to participate in the research, after having been informed about the study 
in a manner that is appropriate to their intellectual and emotional capacities. They will be informed 
to the fullest extent possible in language and terms they are able to understand. Written assent 
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should be obtained from participants who are able to write. A copy of the assent form must be 
provided.
The assent form and ICF must be approved by both the sponsor and by the reviewing IEC/IRB,
and be in a language that the participant (if applicable) and his or her representative can read and 
understand. If the representative is unable to read or write, an impartial witness should be present 
for the entire informed consent process (which includes reading and explaining all written 
information) and should personally date and sign the ICF after the oral consent of the 
representative is obtained. The informed consent process should be in accordance with principles 
that originated in the Declaration of Helsinki, current ICH and GCP guidelines, applicable 
regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential participants and/or their representatives the aims, methods, 
reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail.
Participants and/or their representatives will be informed that participation is voluntary and that 
they may withdraw consent/assent to participate at any time. They will be informed that choosing 
not to participate will not affect the care the participant will receive. Finally, they will be told that 
the investigator will maintain a participant identification register for the purposes of long-term 
follow-up if needed and that the records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the participant, to the extent permitted 
by the applicable law(s) or regulations. By signing the ICF the representative is authorizing such 
access. It also denotes that the participants and/or their representatives agree to allow the 
participants’ study physician to recontact the participants and/or their representatives for the 
purpose of obtaining consent/assent for additional safety evaluations, if needed.
In case of rescreening, a new ICF and new assent form (if applicable) are to be obtained before 
rescreening.
The medical record must include a statement that consent and assent (if applicable and deemed 
appropriate by local ethics review) were obtained before the participant was enrolled in the study 
and must also include the date of written consent. The medical record should also describe how 
the investigator determined that the person signing the ICF was the participant’s representative. 
The authorized person obtaining informed consent must also sign the ICF.
Participants and their representatives must be reconsented/re-assented to the most current version 
of the ICF/assent form (if applicable) during their participation in the study. 
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
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These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential.
The informed consent obtained from the participant’s representative includes explicit consent for 
the processing of personal data and for the investigator/institution to allow direct access to the 
participant’s original medical records (source data/documents) for study-related monitoring, audit, 
IEC/IRB review, and regulatory inspection. This consent also addresses the transfer of the data to 
other entities and to other countries.
The participants and their representatives have the right to request through the investigator access 
to the participant’s personal data and the right to request rectification of any data that are not 
correct or complete. Reasonable steps will be taken to respond to such a request, taking into 
consideration the nature of the request, the conditions of the study, and the applicable laws and 
regulations.
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand RPV and to develop tests/assays 
related to RPV. The research may begin at any time during the study or the post-study storage 
period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants and their representatives may withdraw their 
consent/assent for their samples to be stored for research (refer to Section 7.2, Participant 
Discontinuation/Withdrawal From the Study).
COMMITTEES STRUCTURE
Independent Data Monitoring 
An IDMC will be established to monitor and review PK, safety, tolerability, and efficacy data 
(including individual growth and pubertal development as part of physical examination) on an 
ongoing basis and to ensure the continuing safety of the participants enrolled in this study. The 
IDMC will be the same committee as for the study C213 and will include at least 1 HIV specialist
and at least 1 statistician; committee membership responsibilities, authorities, and procedures will 
be documented in its charter. The committee will meet periodically to review interim data. After 
the review, the IDMC will make recommendations regarding the continuation of the study.
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding RPV or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
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clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including research data, generated as a result of this study, are
considered confidential and remain the sole property of the sponsor. The investigator agrees to 
maintain this information in confidence and use this information only to accomplish this study, 
and will not use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of RPV, and thus may be disclosed as 
required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of analyses 
performed after the Clinical Study Report has been issued will be reported in a separate report and 
will not require a revision of the Clinical Study Report.
Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from copyright 
protection (except any publication by the investigator) shall be the property of the sponsor as 
author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter) 
data and information without approval from the investigator. The investigator has the right to 
publish study site-specific data after the primary data are published. If an investigator wishes to 
publish information from the study, a copy of the manuscript must be provided to the sponsor for 
review at least 60 days before submission for publication or presentation. Expedited reviews will 
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. If issues arise regarding scientific integrity or regulatory compliance, 
the sponsor will review these issues with the investigator. The sponsor will not mandate 
modifications to scientific content and does not have the right to suppress information. For
multicenter study designs and substudy approaches, secondary results generally should not be 
published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 18 months after the study end date, or the sponsor confirms there 
will be no multicenter study publication. Authorship of publications resulting from this study will 
be based on the guidelines on authorship, such as those described in the International Committee 
of Medical Journal Editors (ICMJE) Recommendations for the Conduct, Reporting, Editing and 
Publication of Scholarly Work in Medical Journals, which state that the named authors must have 
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made a significant contribution to the conception or design of the work; or the acquisition, analysis, 
or interpretation of the data for the work; and drafted the work or revised it critically for important 
intellectual content; and given final approval of the version to be published; and agreed to be 
accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity 
of any part of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law.
DATA QUALITY ASSURANCE
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's database. 
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study.
The sponsor will review CRF for accuracy and completeness during on-site monitoring visits and 
after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources.
CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in CRF. All CRF entries, corrections, and 
alterations must be made by the investigator or authorized study-site personnel. The investigator 
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents into the
CRF. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the participant's source documents. Data must be entered into 
CRF in English. The CRF must be completed as soon as possible after a participant visit and the 
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, questionnaires) will be completed by the same individual who 
made the initial baseline determinations whenever possible.
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If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done in either of the following ways:
!
Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).
!
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention 
receipt/dispensing/return records; study intervention administration information; and date of study 
completion and reason for early discontinuation of study intervention or withdrawal from the 
study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring guidelines 
(or other equivalent document).
The following data will be recorded directly into the CRF and will be considered source data:
!
Race
!
Details of physical examination
!
Investigator-completed scales and assessments
!
Diaries
The minimum source document requirements for Section 5.1, Inclusion Criteria and 
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
!
Referral letter from treating physician or
!
Complete history of medical notes at the site
!
Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol-required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or 
clinic record to document medical care (eg, electronic source documents) as well as the clinical 
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study-specific data fields as determined by the protocol. This data is electronically extracted for 
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the 
eSource system but information collected through eSource may not be limited to that found in the 
CRF.
MONITORING
The sponsor will use a combination of monitoring techniques: remote and on-site monitoring.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study-site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the CRF with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
CRF are known to the sponsor and study-site personnel and are accessible for verification by the 
sponsor study-site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying 
that the recorded data are consistent with the original source data. Findings from this review will 
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the 
relevant study-site personnel will be available, the source documents will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor will 
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site.
ON-SITE AUDITS
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Participant privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and available 
for consultation during routinely scheduled study-site audit visits conducted by the sponsor or its 
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
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RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and 
all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study documents, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
documents.
STUDY AND SITE CLOSURE
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.
Reasons for the early closure of a study site by the sponsor may include, but are not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines.
!
Inadequate recruitment of participants by the investigator.
!
Discontinuation of further study intervention development.
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10.4
Appendix 4: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information 
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and in 
Section 10.8, Appendix 8 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.
Definitions
Girl of Childbearing Potential
A girl is considered fertile following menarche.
Girl not of Childbearing Potential
A girl in premenarchal state; in whom menarche has not yet occurred.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal girl
experiences menarche) or the risk of pregnancy changes (eg, a girl who is not heterosexually active 
becomes active), a girl must begin a highly effective method of contraception, as described 
throughout the inclusion criteria.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly effective methods that are user independent - failure rate of ≤1% per year when used 
consistently and correctly.
!
Implantable progestogen-only hormone contraception associated with inhibition of ovulation
!
Intrauterine device
!
Intrauterine hormone-releasing system
!
Bilateral tubal occlusion
!
Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is 
the sole sexual partner of the girl of childbearing potential and the absence of sperm has been 
confirmed. If not, additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.)
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USER DEPENDENT
Highly effective methods that are user dependent - failure rate of ≤1% per year when used 
consistently and correctly.
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
#
oral
#
intravaginal
#
transdermal
#
injectable
!
Progestogen-only hormone contraception associated with inhibition of ovulation
#
oral
#
injectable
!
Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY
(not considered to be highly effective - failure rate of >1% per year)
!
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action
!
Male or female condom b
!
Cap, diaphragm, or sponge 
!
A combination of male condom with either cap, diaphragm, or sponge (double barrier 
methods)b
!
Periodic abstinence (calendar, symptothermal, postovulation methods)
!
Withdrawal (coitus-interruptus)
!
Lactational amenorrhea method
a
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local
regulations regarding the use of contraceptive methods for participants in clinical studies.
b
Male condom and female condom should not be used together (due to risk of failure with friction).
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Pregnancy during the study
Any participant who becomes pregnant during the study must be promptly withdrawn from the 
study and discontinue further study intervention.
For a female participant who becomes pregnant, this information will be shared with the 
participant’s representative.
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10.5
Appendix 5: DAIDS Table
DIVISION OF AIDS (DAIDS) TABLE FOR GRADING THE SEVERITY OF ADULT AND 
PEDIATRIC ADVERSE EVENTS, CORRECTED VERSION 2.1, PUBLISH DATE: JULY, 2017
The DAIDS grading table is a descriptive terminology to be utilized for AE reporting in this study. 
A grading (severity) scale is provided for each AE term.
General Instructions
Grading Adult and Pediatric Adverse Events
When a single parameter is not appropriate for grading an AE in both adult and pediatric populations, 
separate parameters with specified age ranges are provided. If there is no distinction between adult and 
pediatric populations, the listed parameter should be used for grading an AE in both populations.
Determining Severity Grade for Parameters Between Grades
If the severity of an AE could fall under either 1 of 2 grades (eg, the severity of an AE could be either 
grade 2 or grade 3), sites should select the higher of the 2 grades.
Laboratory normal ranges should be taken into consideration to assign gradings to a laboratory value.
Definitions
Basic self-care functions
Adults: activities such as bathing, dressing, toileting, transfer/movement, 
continence, and feeding
Young children: activities that are age and culturally appropriate 
(eg, feeding self with culturally appropriate eating implements)
Usual social & functional 
activities
Activities which adults and children perform on a routine basis and those 
which are part of regular activities of daily living, for example:
Adults: adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, or pursuing a hobby
Young Children: activities that are age and culturally appropriate (eg, 
social interactions, play activities, learning tasks)
Intervention
Medical, surgical, or other procedures recommended or provided by a 
healthcare professional for the treatment of an AE.
Estimating Severity Grade for Parameters not Identified in the Grading Table
The functional table below should be used to grade the severity of an AE that is not specifically identified 
in the grading table. In addition, all deaths related to an AE are to be classified as grade 5.
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Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
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Status:Approved,  Date: 22 February 2021
10.6
Appendix 6: Established and Theoretical Drug Interactions With 
Commonly Used Comedications and RPV
Drug Class
Interaction Effect
Clinical Comment
● Medication with risk for TdP
- Bepridil
Data on interaction with RPV 
currently not available.
Disallowed.
- Cisapride
Data on interaction with RPV 
currently not available.
Disallowed.
- Pimozide
Data on interaction with RPV 
currently not available.
Disallowed.
- Arsenic trioxide
Data on interaction with RPV 
currently not available.
Use with caution. Additional safety 
monitoring is required if taken for >2 
daysa.
- Chloroquine, halofantrine
Data on interaction with RPV 
currently not available.
Use with caution. Additional safety 
monitoring is required if taken for >2 
daysa.
- Chlorpromazine, haloperidol, 
mesoridazine, thioridazine, 
droperidol
Data on interaction with RPV 
currently not available.
Use with caution. Additional safety 
monitoring is required if taken for >2 
daysa.
- Clarithromycin, erythromycin, 
telithromycin, troleandomycin, 
roxithromycin
Note: azithromycin is preferred 
option 
Data on interaction with RPV 
currently not available.
Use with caution. Plasma 
concentrations of RPV may be 
increased when coadministered. 
Additional safety monitoring is 
required if taken for >2 daysa. 
Azithromycin is expected to have no or 
minimal effect on RPV plasma 
concentrations and is therefore the 
preferred option for treatment with 
macrolide antibiotics; no additional 
monitoring is required for azithromycin 
coadministration.
- Dofetilide, ibutilide, 
procainamide, sotalol
Data on interaction with RPV 
currently not available.
Use with caution. Additional safety 
monitoring is required if taken for >2 
daysa
- Domperidone
Data on interaction with RPV 
currently not available.
Use with caution. Additional safety 
monitoring is required if taken for >2 
daysa.
- Flecainide, propafenone, 
systemic lidocaine, mexilitine
Data on interaction with RPV 
currently not available. 
Use with caution. Additional safety 
monitoring is required if taken for >2 
daysa.
- Levomethadyl
Data on interaction with RPV 
currently not available.
Use with caution. Additional safety 
monitoring is required if taken for >2 
daysa.
- Methadone
RPV reduces the exposures 
(AUCs) of R-methadone and 
S-methadone by 16%.
Use with caution. Plasma 
concentrations of methadone may be 
decreased when coadministered with 
RPV. No dose adjustments are 
required. Monitor for signs and 
symptoms of methadone withdrawal; 
some participants may need an increase 
in the methadone dose.
Additional safety monitoring is 
required if taken for >2 daysa.
- Probucol
Data on interaction with RPV 
currently not available.
Use with caution. Additional safety 
monitoring is required if taken for >2 
daysa.
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Status:Approved,  Date: 22 February 2021
Drug Class
Interaction Effect
Clinical Comment
- Quinidine, disopyramide, 
amiodarone
Data on interaction with RPV 
currently not available.
Use with caution. Additional safety 
monitoring is required if taken for >2 
daysa.
- Sparfloxacin, pentamidine
Data on interaction with RPV 
currently not available.
Use with caution. Additional safety 
monitoring is required if taken for >2 
daysa.
●Anticonvulsants
- Phenobarbital, carbamazepine, 
oxcarbazepine, and phenytoin
Data on interaction with RPV 
currently not available.
Disallowed. Coadministration may 
result in reduced RPV plasma 
concentrations and in loss of 
therapeutic effect.
- Modafinil
Data on interaction with RPV 
currently not available. 
Disallowed. Coadministration may 
result in reduced RPV plasma 
concentrations and in loss of 
therapeutic effect.
● Antidiabetic agents
- Pioglitazone, troglitazone
Data on interaction with RPV 
currently not available.
Disallowed. Coadministration may 
result in reduced RPV plasma 
concentrations and in loss of 
therapeutic effect.
● Calcium channel blockers
- Verapamil, diltiazem
Data on interaction with RPV 
currently not available.
Use with caution. Plasma 
concentrations of RPV may be 
increased when coadministered. 
Additional safety monitoring is 
required if taken for >2 daysa.
● Azole antifungal agents
- Ketoconazole, itraconazole, 
voriconazole, fluconazole, 
posaconazole
Note: fluconazole is preferred 
option
Ketoconazole increased the 
exposure to RPV by 50% for 
AUC and by 30% for Cmax.
Use with caution. Plasma 
concentrations of RPV may be 
increased by coadministration of these 
medications. Additional safety 
monitoring is required if taken for >2 
daysa. Fluconazole in a dose of 
200 mg/day is expected to have no or 
minimal effect on RPV plasma 
concentrations and is therefore the 
preferred option for treatment with 
azole antifungal agents; additional 
safety monitoring is only required for 
fluconazole coadministration when 
used in doses of 400-800 mg/day.
● Antibiotics
- Rifabutin, rifampicin, rifapentine
Rifabutin reduced exposure 
(AUC) to RPV by 42%. 
Rifampicin reduced exposure 
(AUC) to RPV by 80%.
No data available on interaction 
with rifapentine.
Disallowed. Coadministration may 
result in reduced RPV plasma 
concentrations and in loss of 
therapeutic effect.
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Status:Approved,  Date: 22 February 2021
Drug Class
Interaction Effect
Clinical Comment
● Glucocorticoids 
- Dexamethasone (systemic and 
more than a single dose)
Data on interaction with RPV 
currently not available.
Disallowed (only topical and 
inhalation products allowed*). 
Coadministration may result in 
reduced RPV plasma concentrations 
and in loss of therapeutic effect. 
Could suppress adrenal gland 
function.
*use of both chronic inhaled and 
intranasal dexamethasone is 
disallowed within 30 days before
baseline and within 30 days before 
ACTH stimulation testing (only for 
participants aged ≥6 to <12 years, 
including participants who turn 
12 years old during the study). 
Occasional use of either inhaled or 
intranasal steroids is allowed.
- Other glucocorticoids
Data on interaction with RPV 
currently not available.
Disallowed if chronic (topical and 
inhalation products allowed*). Could 
suppress adrenal gland function.
*use of both chronic inhaled and 
intranasal steroids is disallowed 
within 30 days before baseline and 
within 30 days before ACTH 
stimulation testing (only for 
participants aged ≥6 to <12 years, 
including participants who turn 
12 years old during the study). 
Occasional use of either inhaled or 
intranasal steroids is allowed.
● Progestogens
- Megestrol acetate
Data on interaction with RPV 
currently not available.
Disallowed. Could suppress adrenal 
gland function.
● Proton pump inhibitors
- eg, omeprazole, lansoprazole, 
rabeprazole, pantoprazole, 
esomeprazole
Omeprazole reduced the steady-
state exposure (AUC) of RPV by 
40%.
Disallowed. Coadministration of 
proton pump inhibitors reduces the 
plasma concentrations of RPV, and 
may result in loss of therapeutic 
effect.
● H2-receptor antagonists and antacids
- H2-blockers (cimetidine, 
ranitidine, famotidine, nizatidine)
Famotidine taken 2 hours before 
RPV reduced the exposure 
(AUC) by 76%. There was no 
interaction after separate intake.
Use with caution. H2-blockers should 
be taken at least 12 hours before or 4 
hours after RPV intake.
- Antacids 
(eg, aluminium/magnesium 
hydroxide, calcium carbonate)
Data on interaction with RPV 
currently not available. 
Use with caution. Antacids should be 
taken at least 2 hours before or 
4 hours after RPV intake.
● St John’s wort
Data on interaction with RPV 
currently not available.
Disallowed. Coadministration may 
result in reduced RPV plasma 
concentrations and in loss of 
therapeutic effect.
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Status:Approved,  Date: 22 February 2021
● Antiemetics
- Aprepitant
Data on interaction with RPV 
currently not available.
Use with caution. Coadministration 
may result in increased plasma 
concentrations of RPV. Additional 
safety monitoring is required if taken 
for >2 daysa.
Drug Class
Interaction Effect
Clinical Comment
● Antidepressants
- Nefazodone
Data on interaction with RPV 
currently not available.
Use with caution. 
Coadministration may result in 
increased plasma concentrations 
of RPV. Additional safety 
monitoring is required if taken for 
>2 daysa.
a
The required additional safety monitoring consists of an unscheduled ECG taken 3 to 7 days after initiation 
of the comedication, taken at approximately 4 hours after RPV intake. Also, a PK sample needs to be drawn 
within 10 minutes after the ECG. The date and time of sampling and last RPV intake prior to PK sampling 
should be recorded on the CRF. If the participants experience a QTcF %480 ms that is confirmed by another 
ECG (repeat ECG should be performed within 48 hours after the site has received the abnormal result), the 
comedication should be stopped, if possible. Approximately 1 week after the comedication was stopped an 
ECG should be taken again to ensure normalization. If comedication treatment cannot be stopped, the 
participant should be withdrawn from the study. Approximately 1 week after withdrawal, another ECG 
should be performed during an unscheduled visit to ensure normalization.
Note: The list of disallowed concomitant medication and medication to be used with caution is not exhaustive; for 
products falling in one of the categories and not mentioned by name, the Sponsor should be contacted to determine 
whether the product can be allowed.
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Status:Approved,  Date: 22 February 2021
10.7
Appendix 7: Clinical Laboratory Tests
The following tests will be performed according to the Schedule of Activities by the central 
laboratory (unless indicated otherwise):
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC count
Hemoglobin
Hematocrit
RBC Indices:
MCV
MCH
MCH concentration
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Note: A WBC evaluation may include any abnormal cells, which will then be reported by the 
laboratory. A RBC evaluation may include abnormalities in the RBC count, RBC parameters, or 
RBC morphology, which will then be reported by the laboratory. In addition, any other abnormal 
cells in a blood smear will also be reported.
Clinical 
Chemistry
Sodium
Potassium
Chloride
Calcium
Calcium corrected for albumin
Magnesium
Phosphate
Bicarbonate
Blood urea nitrogen
Uric acid
Creatinine
Human serum albumin
Total protein
AST/Serum glutamic-oxaloacetic
ALT/Serum glutamic-oxaloacetic
GGT
Alkaline phosphatase
Total, direct, and indirect bilirubin
Pancreatic amylase
Lipase
Glucose (fasting)
Insulin
Cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
Note: Lactate will be assessed in case of suspicion of lactic acidosis syndrome (refer to
Section 10.2, Appendix 2, Monitoring and Safety for Specific Toxicities) and creatine 
phosphokinase will be assessed in case of suspicion of rhabdomyolysis. These assessments will 
be done at the local laboratory.
The central laboratory will calculate the eGFR according to the following formula32:
k = 0.55 in children aged 2-12 years, 0.55 in adolescent girls aged 13-21 years, and 0.70 in 
adolescent boys aged 13-21 years.
eGFR
=
k * L (cm)
Plasma creatinine (Pcr) (mg/dL)
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Status:Approved,  Date: 22 February 2021
Endocrine
Tests (only for 
participants 
aged ≥6 to 
<12 years,
including 
participants 
who turn 
12 years old 
during the 
study)
FSH, LH, androstenedione, testosterone, 17-hydroxyprogesterone and DHEAS, in conjunction 
with cortisol.
At the time of protocol Amendment 2 writing, 240-week results from C213 Cohort 1 
(adolescents aged ≥12 to <18 years) are available. The 4-year follow-up data in adolescents did 
not show an effect on pubertal development. No clinically relevant suppression of cortisol 
secretion is observed in adults27,29 or adolescents aged ≥12 to <18 years (C213 Cohort 1).34,35
Also, in the first 9 children aged ≥6 to <12 years in C213 Cohort 2 there were no emergent cortisol 
abnormalities and no signs or symptoms of adrenal insufficiency.24 Therefore an ACTH 
stimulation test, including measurements of cortisol and 17-hydroxyprogesterone, will be 
performed for all participants in the morning between 7h30 and 9h30 in case of confirmed 
abnormally low cortisol (<248 nmol/L [9 μg/dL] or signs or symptoms of adrenal insufficiency.
After a sample for the determination of these endocrine parameters has been drawn (T0), 250 μg 
of tetracosactide or cosyntropin will be injected IV over 2 minutes or intramuscularly and an 
additional blood sample will be collected 60 minutes (T60) after injection for the determination of 
cortisol and 17-hydroxyprogesterone. 
If the ACTH stimulation test results are abnormal (ie, the cortisol value after ACTH stimulation 
is <500 nmol/L [18.1 μg/dL]), a retest needs to be performed at the next scheduled visit or at least 
within the next 8 weeks, including during the follow-up period. If the repeat ACTH stimulation 
test results are normal, the participant should continue study treatment. If the test results are 
abnormal, but the participant is asymptomatic, the sponsor should be notified. If the test results 
are abnormal, and the participant has symptoms consistent with adrenal insufficiency (refer to 
Section 10.2, Appendix 2, Monitoring and Safety for Specific Toxicities), withdrawal of the 
participant should be discussed with the sponsor.
In case of clinical signs or symptoms or laboratory abnormalities (other than cortisol) indicative 
of adrenal insufficiency (refer to Section 10.2, Appendix 2, Monitoring and Safety for Specific 
Toxicities), an ACTH stimulation test should be done as soon as possible during an unscheduled 
visit. If the ACTH stimulation test is abnormal (ie, the cortisol value after ACTH stimulation is 
<500 nmol/L [18.1 μg/dL]), withdrawal of the participant should be discussed with the sponsor.
Routine 
Urinalysis
Dipstick
Glucose
Protein
Blood
Sediment (if dipstick result is abnormal)
RBCs
WBCs
Casts
If dipstick result is abnormal, microscopy will be used to measure sediment. In the microscopic 
examination, observations other than the presence of WBC, RBC, and casts may also be reported 
by the laboratory.
Other 
Screening 
Tests
Serum pregnancy testing at screening for girls of childbearing potential only.
Serology (hepatitis A antibody, hepatitis B surface antigen, and hepatitis C virus antibody) at 
baseline.
Additional 
Tests
In addition to the serum pregnancy test at screening (see above), a urine pregnancy test will be 
performed at the other time points indicated in the Schedule of Activities for girls of childbearing 
potential only.
Additional tests may be performed at the central laboratory, if needed. However, additional 
testing requires approval from the sponsor.
HDL=high-density lipoprotein, LDL=low-density lipoprotein, MCH=mean corpuscular hemoglobin, MCV=mean 
corpuscular volume
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Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
137
Status:Approved,  Date: 22 February 2021
10.8
Appendix 8: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that medicinal 
(investigational or non-investigational) product (definition per ICH).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose:
!
Results in death
!
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)
!
Requires inpatient hospitalization or prolongation of existing hospitalization
!
Results in persistent or significant disability/incapacity
!
Is a congenital anomaly/birth defect
!
Is a suspected transmission of any infectious agent via a medicinal product
!
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the participant or may 
require intervention to prevent 1 of the other outcomes listed in the definition above. These should 
usually be considered serious.
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Status:Approved,  Date: 22 February 2021
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product 
reference safety information. For RPV, the expectedness of an AE will be determined by whether 
or not it is listed in the IB. For ARVs allowed per protocol with a marketing authorization, the 
expectedness of an AE will be determined by whether or not it is listed in the package 
insert/summary of product characteristics.
Adverse Event Associated With the Use of the Intervention
An AE is considered associated with the use of the study intervention if the attribution is possible, 
probable, or very likely by the definitions listed below (see Attribution Definitions).
ATTRIBUTION DEFINITIONS
Not Related
An AE that is not related to the use of the study intervention.
Doubtful
An AE for which an alternative explanation, eg, concomitant treatment(s), concomitant disease(s), 
is more likely or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the study intervention. An alternative explanation, 
eg, concomitant treatment(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the study intervention. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation, eg, concomitant treatment(s), 
concomitant disease(s), is less likely.
Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, concomitant treatment(s), concomitant disease(s). The relationship in 
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
SEVERITY CRITERIA
An assessment of severity grade will be made using the general categorical descriptors outlined in 
the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (refer to 
Section 10.5, Appendix 5, DAIDS Table).
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities).
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TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status:Approved,  Date: 22 February 2021
SPECIAL REPORTING SITUATIONS
Safety events of interest on RPV that may require expedited reporting or safety evaluation include, 
but are not limited to:
!
RPV overdose
!
Suspected abuse/misuse of RPV
!
Accidental or occupational exposure to RPV
!
Unexpected therapeutic or clinical benefit from use of RPV
!
Medication error involving RPV (with or without participant exposure to RPV, eg, name 
confusion)
!
Exposure to RPV from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the CRF.
PROCEDURES
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must 
be recorded using medical terminology in the source documents and the CRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, 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 
AE to study therapy. All measures required for AE management must be recorded in the source 
documents and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must 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, in the local language(s), that the participant 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)
!
Site number
!
Participant number
For participants who do not roll over in the pediatric study TMC278IFD3004, all AEs still ongoing 
at the end of the treatment will be followed until satisfactory resolution (ie, value back to baseline 
value) or stabilization (to be agreed upon in collaboration with the sponsor).
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Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
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Status:Approved,  Date: 22 February 2021
New AEs reported during the follow-up period of the study will be followed as agreed between 
the sponsor and investigator. Certain long-term AEs of ART cannot be followed until resolution 
within the setting of this protocol; in these cases, follow-up will be the responsibility of the treating 
investigator. However, this has to be agreed upon with the sponsor.
Serious Adverse Events
The start date of the SAE documented on the SAE form should be the date the AE first fulfilled 
any serious criterion. If a change in severity is noted for the existing AE, it must be recorded as a 
new AE. If a worsened AE meets the criteria for an SAE, the start date of the SAE must be the 
same as the start date of the worsened AE.
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the participant's participation in the study, must be followed until any of the 
following occurs:
!
The event resolves
!
The event stabilizes
!
The event returns to baseline, if a baseline value/status is available
!
The event can be attributed to agents other than the study intervention or to factors unrelated 
to study conduct
!
It becomes unlikely that any additional information can be obtained (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant's participation in a study must be reported as an SAE, except 
hospitalizations for the following:
!
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending 
placement in long-term care facility)
!
Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.
The cause of death of a participant in a study, whether or not the event is expected or associated 
with the study intervention, is considered an SAE.
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
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Status:Approved,  Date: 22 February 2021
After termination of the clinical study (last participant last visit in the study), any unexpected safety 
issue that changes the benefit/risk analysis and is likely to have an impact on the participants who 
have participated in it, should be reported as soon as possible to the competent authority(ies) 
concerned together with proposed actions.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of participants, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates will 
be conducted in accordance with those procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with an SAE, the study-site personnel must report the PQC to the sponsor 
according to the SAE reporting timelines (refer to Section 8.3.1, Time Period and Frequency for 
Collecting Adverse Event and Serious Adverse Event Information). A sample of the suspected 
product should be maintained for further investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
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Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status:Approved,  Date: 22 February 2021
10.9
Appendix 9: Tanner Scales
The Five Stages of Female Breast and Pubic Hair Development
Breast and pubic hair development should be staged separately
Stage
Female breast
Pubic hair
1
Breasts during childhood. 
The breasts are flat and 
show no signs of 
development.
None
2
Breast bud stage. Milk ducts 
and fat tissue forms a small 
mound.
Sparse, lightly 
pigmented, straight, 
medial border of 
labia.
3
Breasts continue to grow. 
Breasts become rounder and 
fuller.
Darker, beginning to 
curl, increased 
amount.
4
Nipple and areola form 
separate small mound. Not 
all girls go through this 
stage. Some skip stage 4 and 
go directly to stage 5.
Coarse, curly, 
abundant, but amount 
less than in adult.
5
Breast growth enters final 
stage. Adult breast is full 
and round shaped.
Adult feminine 
triangle, spread to 
medial surface of 
thighs.
Copyright© 1998, 1999 VirtualKid All Rights Reserved.
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TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
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143
Status:Approved,  Date: 22 February 2021
The Five Stages of Male Genitalia and Pubic Hair Development
Genitalia and Pubic hair should be staged separately
Stage
Male Genitalie
Pubic hair
1
Penis and testicles of a 
child. Testicles between 
1 and 3 milliliters in 
volume.
No pubic hair.
2
First signs of penis and 
testicle growth. Testicles 
become larger. Testicles 
between 4 and 6 milliliters
in volume.
Pubic hair beginning 
to grow: appears 
sparse and downy 
straight.
3
Penis continues to grow 
getting wider and longer. 
Testicles continue to grow 
larger. Testicles between 
7 and 16 milliliters in 
volume.
Pubic hair appears 
curlier and coarser 
with increased 
pigmentation.
4
Penis continues to grow 
getting wider and longer. 
Testicles continue to grow 
larger. Penis gland or head 
is more developed. Testicles 
between 12 and 
24 milliliters in volume. 
Testicles are about 
1 ½ inches long.
Pubic hair becomes 
adult type, but less. 
5
Penis growth enters final 
stage. Average erect penis 
length 6 ¼ inches. 90% are 
5 to 7 inches. Glans penis or 
head is fully developed. 
Testicles 16-27 milliliters in 
volume. Testicles are about 
1 to 3/4 inches.
Pubic hair is thick,
spreading to medial 
thighs. 
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
144
Status:Approved,  Date: 22 February 2021
10.10
Appendix 10: Pediatric European Network for the Treatment of AIDS 
(PENTA) Adherence Questionnaire 
Note: This appendix provides a representative example of the questions that will be used in this 
study. The site should always use the most recently provided version of the questionnaire.
STUDY ADHERENCE QUESTIONNAIRE FOR CAREGIVERS
To the investigator/trial personnel: please complete the following table and write the names, color and type 
of medicines that the child has been taking in the tables in question 2 and 8.
Completed by Parent/carer alone?  
Yes     No  
If no, who else was involved? ______________
If not completed: 
Not enough time  Refusal 
Parent/carer not available 
Other  specify: ________________
To the carer:
We know that it can be difficult giving antiretroviral medicines to children every day. We are interested in 
finding out what it is like for you and your family. Please tick the answer which best describes your true
situation or feeling, as your answers may help others in the future. Thank you.
1) Do you give antiretroviral medicines to your child? __________________________
2) At what time do you usually give your child their antiretroviral medicines?
Name 
of 
medicine
Colour, Type
Timing of dosing
a.m./ p.m.
1. RPV
2.
3.
3) Which dose, if any, is the most difficult for you or your child?
None 
morning 
lunchtime/after school 
evening 
all 
4) How easily do you remember to give all the medicines to your child?
Easily 
quite easily 
with some difficulty 
with great difficulty 
5) What helps you give the medicines? (tick all that apply)
Labels  Medicine Chart 
Pill box 
MEM Caps 
Timer/alarm clock/beeper
Diary  Daily events (e.g., breakfast time) 
Other  Name them:
____________________________
6) How much does giving medicines to your child interfere with you/your child’s everyday life?
A lot 
quite a lot 
not much 
not at all 
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
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145
Status:Approved,  Date: 22 February 2021
How? __________________________________________________________________
7) How important do you think it is to administer the medicines in the way indicated by the doctor 
(e.g. remembering to take every dose?)
Extremely  Very 
Don’t know 
Not very 
Not at all 
8) Over the last 3 days, can you say how many times, your child has missed a dose:
No medicine missed 
Drug
Yesterday
Day before yesterday
3 days ago
1. RPV
.…. dose(s) missed
.…. dose(s) missed
….. dose(s) missed
2.
3.
9)
Since the last visit, when was the last time you missed a dose of any medication?
Never

During the previous 2 weeks

During the last month

Over a month ago

Don’t remember

10) If your child has missed any doses during the last two weeks, please indicate the reason(s) and 
say which medicine(s) :
No medicine missed 
Because:
Name of medicine
You had run out of medicine?

Your child has problems taking some of the medicine?

You had forgotten?

You think the medicines are toxic or harmful?

Taking the medicine is difficult with school hours, meals, sleep etc

Your child refused to take them

Your child was being looked after by someone else?

You did not want other people to know your child was taking medicine?

Your child was unwell?

Your routine, or your child’s routine, was different from normal (e.g., 
holidays, weekends etc)?

Further details or any other reason (please specify): ________________________________________
_
Thank you for taking the time to fill out this form, please add any comments you have:
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
146
Status:Approved,  Date: 22 February 2021
STUDY ADHERENCE QUESTIONNAIRE FOR CHILDREN
Note: This questionnaire is a sample questionnaire. The site should always use the most recently 
provided version of the questionnaire.
Study Adherence Questionnaire for Children
To the investigator/study-site personnel: please complete the following table and write the names, color and 
type of the medicines that the child has been taking in the tables in question 1 and 8.
To be completed by the investigator/trial personnel:
Completed by patient alone?  
Yes     No  
If no, who else was involved? 
________________________
If not completed: 
Not enough time  Refusal  Other 
specify: _________
To be completed by the patient (for children 6 years of age and older)
We know that it can be difficult taking medicines every day. We are interested in finding out what it is like 
for you and your family. Please tick the answer which best describes your true situation or feeling, as your 
answers may help others in the future. Thank you.
1) At what time do you usually take your medicines?
Name of 
medicine 
Color, Type
Time of dosing
a.m./p.m.
1. RPV
2.
3.
2) Which dose, if any, is the most difficult? 
None 
morning 
lunchtime/after school 
evening 
all 
3) Does anyone remind you when to take your medicine? Yes        No 
If someone reminds you, who is it? ___________________________
4) How easily do you remember to take all your medicines?
Easily 
quite easily 
with some difficulty 
with great difficulty 
5) What helps you take the medicine? (Tick all that apply)
Labels 
Medicine chart 
Pill box 
MEM Caps 
Alarm clock/Timer/beeper 
Diary 
Daily events (e.g., breakfast time) 
Text messages 
Support from Mum/Dad/Carer 
Knowing my blood results 
Knowing why I need to take medicines 
Other  Namely:___________________________
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
147
Status:Approved,  Date: 22 February 2021
6) How much does taking medicines interfere with your life?
A lot 
quite a lot 
not much 
not at all 
How? __________________________________________________________________
7) How important do you think it is to take the medicines in the way your doctor told you (e.g. 
remembering to take every dose?)
Extremely 
Very 
Don’t know 
Not very 
Not at all 
8) Over the last 3 days, can you say how many times, you have missed a dose:
No doses missed 
Drug
Yesterday
Day before yesterday
3 days ago
1. RPV
.…. dose(s) missed
.…. dose(s) missed
….. dose(s) missed
2. 
3.
9)
Since the last visit, when was the last time you missed a dose of any medication?
Never

During the previous 2 weeks

During the last month

Over a month ago

Don’t remember

10) If you have missed any doses during the last two weeks, please tick the reason(s) why and say 
which medicine:
No doses missed 
Because :
Name of medicine
You had run out of medicine ?

You had forgotten?

You think the medicine is toxic or harmful?

Taking medicine is difficult with school hours, meals, sleep etc

You didn’t want to take it?

You did not want other people to know you were taking medicine?

You were unwell?

Your routine was different from normal (e.g., holidays, weekends 
etc)?

You are fed up taking medicine?

Further details or any other reason (please specify): ____________________________
________________________________________________________________________
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
148
Status:Approved,  Date: 22 February 2021
Thank you for taking the time to fill out this form, please add any comments you have:
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
149
Status:Approved,  Date: 22 February 2021
10.11
Appendix 11: Palatability Questionnaire
Note: This appendix provides a representative example of the questions that will be used in this 
study. The site should always use the most recently provided version of the questionnaire.
PALATABILITY QUESTIONNAIRE FOR CHILDREN
CHILDREN’S RILPIVIRINE TASTE TEST
Today we are asking children like you about how you like the taste of the study medication 
rilpivirine when mixed in water 
You do not have to take this test if you wish so.
--------------------------------------------------------------------------
ASK CHILD:
1.
How does this study medication taste to you, when you drink it after mixing it with 
water? 
(Please look at the pictures and check  ONLY one box for your answer).
READ SCALE AND POINT TO THE PICTURES 
(If the child cannot convey their taste perception, parents can help the child)
Really Good
Pretty Good
Okay
Not good
Terrible
□
□
□
□
□
Comments: ___________________________________________________________________________
____________________________________________________________________________________
Thank you for participating in this taste evaluation process; you have been very helpful.
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
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Status:Approved,  Date: 22 February 2021
10.12
Appendix 12: Swallowability Questionnaire
Note: This appendix provides a representative example of the questions that will be used in this 
study. The site should always use the most recently provided version of the questionnaire.
QUESTIONS FOR THE CHILD:
Please answer the questions below. There is no right or wrong answer. We just want to know 
how you have been feeling about swallowing the study pill.
1. Please tell us how easy or hard it was to swallow the tablet?
(Please check  ONLY one box for your answer)
hard
neither hard 
nor easy
easy
□
□
□
2. If you would have to take the tablet once daily for a longer period, how would you describe 
it?
(Please check  ONLY one box for your answer)
Comments: _________________________________________________________________
__________________________________________________________________________
__________________________________________________________________________
Thank you for taking the time to fill out this form.
Not acceptable
Acceptable
Good to take
□
□
□
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
151
Status:Approved,  Date: 22 February 2021
To the investigator/trial personnel: please answer the questions below.
QUESTIONS FOR THE OBSERVER:
1. Indicate how the tablet was taken
□swallowed with water
□mixed with tablespoon of semi-solid food and drinking water afterwards
2a. Did the patient have problems swallowing the tablet?
□ No □ Yes
If no, go to Question 3
If yes, continue here:
Indicate which problems
□Refusing (could not take it)
□Vomiting/spitting up
□Gagging
□Other, specify _______________________________________
2b.
Did the patient need a second attempt?
□ No □ Yes
If no, go to Question 3
If yes, continue here
Did the patient have problems swallowing the tablet at the second attempt?
□ No □ Yes
If no, go to Question 3
If yes, continue here
Indicate which problems
□Refusing (could not take it)
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
152
Status:Approved,  Date: 22 February 2021
□Vomiting/spitting up
□Gagging
□Other, specify _______________________________________
3. Are there any other comments related to the intake of the tablet? 
□ No
□ Yes
If no, STOP
If yes, please specify the comments
_________________________________________________________
_________________________________________________________
_________________________________________________________
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
153
Status:Approved,  Date: 22 February 2021
10.13
Appendix 13: Cardiovascular Safety - Abnormalities
ECG
QTc intervala:
!
Grade 1: ≥450 to ≤470 ms
!
Grade 2: >470 to ≤500 ms
!
Grade 3: >500 ms 
QTc change from baseline: 
!
≥30 to <60 ms 
!
≥60 ms
Vital Signs
Pulse:
!
abnormally high: ≥120 bpm
!
abnormally low: ≤50 bpm
Systolic and diastolic blood pressurea,b:
!
Grade 1: >120/80 mmHg
!
Grade 2: ≥95th to <99th percentile +5 mmHg adjusted for age, height, and gender (systolic 
and/or diastolic)
!
Grade 3: ≥99th percentile +5 mmHg adjusted for age, height, and gender (systolic and/or 
diastolic)
a
Refer to the DAIDS version 2017
b
Blood pressure norms for children <18 years of age can be found in: Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally 
published online November 14, 2011; DOI: 10.1542/peds.2009-2107C. 
NCT04012931


NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
155
Status:Approved,  Date: 22 February 2021
Section Number
and Name
Description of Change
Brief Rationale
1.3.1 General Schedule of 
Activities
2.3.5 Overall Benefit/Risk 
Assessment
6.5.3 Disallowed Concomitant 
Therapy
9.4.3 Safety Analyses
10.2 Appendix 2: Monitoring 
and Safety for Specific 
Toxicities
10.6 Appendix 6: Established 
and Theoretical Drug 
Interactions With Commonly 
Used Comedications and RPV
10.7 Appendix 7: Clinical 
Laboratory Tests
The ACTH stimulation test on
Day 1 and at Week 24 has been 
removed.
There was no clinically relevant suppression 
of cortisol secretion and of the adrenal 
function observed in adults or adolescents 
aged ≥12 to <18 years in the clinical studies 
with RPV. Additionally, in the first 9 
children aged ≥6 to < 12 years in study C213 
treated with RPV +2 N(t)RTIs, there were 
no AEs related to cortisol abnormalities or 
signs or symptoms related to clinical 
manifestations of adrenal insufficiency 
reported, and no abnormalities in the ACTH 
stimulation test observed during treatment. 
Therefore, the performance of the ACTH 
stimulation test will be limited to cases of 
confirmed abnormally low cortisol or when 
signs or symptoms of adrenal insufficiency 
are observed.
5.2 Exclusion Criteria
11 REFERENCES
The exclusion of ‘personal 
history of asymptomatic 
arrhythmia’ in exclusion 
criterion #18i), is adapted and 
the following exclusion criterion 
is added: Syncopal episodes if 
repeated, unexplained, and 
unrelated to emotional distress.
Extrasystoles are common in children (20% 
to 30% in younger children and up to 40% in 
teenage boys) and occasionally ventricular 
bigeminy can be seen.40 Therefore, it is 
added that personal history of asymptomatic 
arrhythmias is a reason for exclusion if the 
asymptomatic arrhythmia is clinically 
significant in the opinion of the investigator.
Syncopal episodes as a risk factor for QTc 
prolongation (Exclusion criterion #18) was 
deleted in Amendment 1. This exclusion 
criterion is now added in a clarified form. 
6.5.1 Background Regimen
Added a statement explaining 
that no dual combination of 
ARVs are allowed in this study.
Use of DTG as part of a dual combination 
regimen with RPV is currently under 
investigation in children and not yet 
approved. Investigator selected ARVs can 
only be administered according to the 
indication approved in the country. Dual 
combination of ARVs is not allowed in this 
study.
6.5.2 Allowed Concomitant 
Therapy
10.6 Appendix 6: Established 
and Theoretical Drug 
Interactions With Commonly 
Used Comedications and RPV
Updated to clarify that the 
additional safety monitoring by 
ECG and the PK sample are 
only required for participants 
receiving CYP3A4 inhibitory 
medications or concomitant 
medications associated with risk 
of Torsade de Pointes for >2 
days. The requirements for an 
ECG, and its associated PK 
sample, before the start of the 
medication have been removed 
for use of such disallowed 
medications ≤2 days and are 
kept if these medications are 
going to be used >2 days.
To limit the burden for participants and 
reduce complexity of the study. No 
cardiovascular impact is expected with a 
short period of administration (≤2 days).
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
156
Status:Approved,  Date: 22 February 2021
Section Number
and Name
Description of Change
Brief Rationale
1.1 Synopsis
1.3.1 General Schedule of 
Activities
1.3.3 Schedule of Activities 
for Switch to Adjusted RPV 
Dose (if Applicable)
2.1 Study Rationale
2.2 Background
3 OBJECTIVES AND 
ENDPOINTS
4.3 Justification for Dose
6.1 Study Interventions 
Administered
8.10.3 Questionnaires
Replaced the term ‘dispersible 
tablet’ with ‘2.5-mg tablet’
To align with the more appropriate technical 
terminology for this formulation.  The tablet 
composition and intended use have not 
changed and hence safety and efficacy are 
not impacted.  Tablets still need to be 
dispersed prior to use.
1.3.1 General Schedule of 
Activities
Adjusted footnotes for PENTA 
Adherence Questionnaires in 
flowchart 1.3.1.:
Removed footnote ff and added 
new footnote ll. 
The PENTA Adherence Questionnaires are 
translated in each local language requested.
The PENTA adherence Questionnaire is for 
children above 6 years of age and for 
caregivers 
1.1 Synopsis
3 OBJECTIVES AND 
ENDPOINTS
Added secondary endpoint: 
Proportion of participants with 
HIV-1 RNA <400 and ≥400
copies/mL using the FDA 
Snapshot approach through
24 and 48 weeks of study 
treatment
For completeness
1.2. Schema
1.3.1 General Schedule of 
Activities
4.1 Overall Design
Added that the retest of 
abnormal laboratory results or 
plasma VL/resistance testing, 
should be captured in this 
TMC278HTX2002 study if the 
participants roll over to the 
TMC278IFD3004 study.
Clarification
1.3.2 Schedule of Activities 
for Intensive Pharmacokinetic 
Sampling
Added that the body weight for 
inclusion in intensive PK 
sampling is determined at 
baseline
Clarification
1.3.2 Schedule of Activities 
for Intensive Pharmacokinetic 
Sampling
8 STUDY ASSESSMENTS 
AND PROCEDURES
Adjusted ‘approximately 8 mL’ 
to ‘approximately 10 mL’ total 
volume intensive PK sampling. 
As each tube may draw up to 1.2 mL, the 
total volume may add up to 9.6 mL
5.1 Inclusion Criteria
Added ‘or at least 6 months 
prior to screening’ to inclusion 
criterion #4
Alignment with section 4.1 Overall Design
5.3 Lifestyle Considerations
Adjusted the lifestyle 
considerations.
To limit dietary restrictions for HIV infected 
children and align with other pediatric RPV 
studies
6.5.1 Background Regimen
‘i.e., generics’ is corrected to ‘or 
generics’
Correction
6.5.3 Disallowed Concomitant 
Therapy
Added the exception for the 
ARVs efavirenz and nevirapine
Clarification
6.6.1 Dose Evaluation Criteria
Added Mini-Cohort Dose 
Evaluation Criterion 
Alignment with study C213
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
157
Status:Approved,  Date: 22 February 2021
Section Number
and Name
Description of Change
Brief Rationale
6.7 Intervention After the End 
of the Study
Added treatment options after 
the end of the study: locally 
available RPV (once 
commercially available AND 
reimbursed, OR accessible 
through another source [e.g. 
access program or government 
program]), or other locally 
available RPV-based regimens.
Alignment with study C213
8.10.3 Questionnaires
Added that site staff provides 
support to the participant or 
their parent(s)/caregiver(s) in 
completing the questionnaires.
Clarification
8.2.1 Physical Examination
Removed ‘Subjects should be 
undressed (underwear is 
allowed) during these full 
physical examinations.’
Full physical examination is to be done as 
per local standard of care
8 STUDY ASSESSMENTS 
AND PROCEDURES
Adjusted blood volumes
Update to current schedule
8 STUDY ASSESSMENTS 
AND PROCEDURES
Added Post-Switch Visit time 
windows
For completeness
8 STUDY ASSESSMENTS 
AND PROCEDURES
Added ‘participants’’ before 
‘representative’
Clarification
1.1 Synopsis
9.4.2 Efficacy Analyses
Removed ‘Time-to-event data 
(ie, time to loss of virologic 
response) will be graphically 
presented by means of 
Kaplan-Meier curves’.
Correction
10.1 Appendix 1: 
Abbreviations and 
Trademarks
Definitions for Virologic 
Response, Virologic Failure, 
Suspected Virologic Failure and 
Confirmed Virologic Failure 
added. 
Clarification
10.2 Appendix 2: Monitoring 
and Safety for Specific 
Toxicities
Removed the sentence on the 
investigator manual.
An investigator manual is not being used in 
this study. The management of rash is 
described throughout this section in the 
protocol.
10.2 Appendix 2: Monitoring 
and Safety for Specific 
Toxicities
Changed ‘%248 nmol/L 
(9 &g/dL)’ to ‘%500 nmol/L 
(18.1 &g/dL)’
Correction
10.6 Appendix 6: Established 
and Theoretical Drug 
Interactions With Commonly 
Used Comedications and RPV
Moved telithromycin and 
troleandomycin up to be 
included with clarithromycin 
and erythromycin
To present all macrolide antibiotics together
10.6 Appendix 6: Established 
and Theoretical Drug 
Interactions With Commonly 
Used Comedications and RPV
Added the note to Appendix 6 
that the list of disallowed 
concomitant medication and 
medication to be used with
caution is not exhaustive.
Clarification
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
158
Status:Approved,  Date: 22 February 2021
Section Number
and Name
Description of Change
Brief Rationale
10.15 Appendix 15: CDC 
Growth Charts
The CDC growth charts for 
Boys and Girls 2-20 years were 
included in the protocol as an 
Appendix.
For completeness
Throughout entire document
Including ‘approximately’
12 participants with a body 
weight of <25 kg at baseline
was adjusted to ‘at least’ 
12 participants.
Correction
Throughout entire document
Substituted ‘subjects’ with 
‘participants’
Current standard language
1.1 Synopsis
8.10.1 Resistance
9.4.2 Efficacy Analyses
Some administrative and 
editorial adjustments were made
Clarification
Amendment 1 (24 April 2019)
Overall Rationale for the Amendment: Based on local practice in certain countries, children younger 
than 12 years of age are not consistently informed of their HIV-1 diagnosis. Therefore, inclusion criterion 
5 will be removed. Other additional updates are listed below.
Section Number
and Name
Description of Change
Brief Rationale
5.1 Inclusion Criteria
Inclusion criterion 5 stating that 
participants need to be aware of 
their HIV-1 diagnosis was 
removed.
Based on local practice in certain countries, 
children younger than 12 years of age are 
not consistently informed of their HIV-1 
diagnosis.
5.1 Inclusion Criteria
Inclusion criterion 4 was 
modified requiring viral load 
testing within 2-12 months prior 
to screening and at screening 
and allowing ‘blips’ (single 
viral load ≥50 HIV-1 RNA 
copies/mL) during this period.
Not all investigators perform viral load 
testing every 6 months and blips occur quite 
regularly (eg due to other illnesses) which is 
anticipated to limit recruitment.
5.2 Exclusion Criteria
Exclusion criterion 10 was 
modified to allow treatment 
with placebo within 90 days 
prior to screening.
Participants who received placebo treatment 
in another clinical trial within 90 days prior 
to screening and who meet all eligibility 
criteria will be allowed to enter the study 
immediately.
5.2 Exclusion Criteria
Syncopal episodes were 
removed from exclusion 
criterion 18.
Syncopal episodes in children are usually 
benign.12 Additionally, in the current study 
an ECG is performed at Screening and 
Baseline, and children with clinically 
significant ECG findings (exclusion 
criterion 11) and risk factors for QT 
prolongation (exclusion criterion 18) are 
excluded from participation in the study.
1.3.1 General Schedule of 
Activities, 4.1 Overall Design
The requirement to record 
historical HIV-1 genotyping 
results in the CRF at screening 
was added.
Per inclusion criterion 12, sensitivity to RPV 
and the selected background ARVs should 
be demonstrated by historical HIV-1 
genotyping results at screening for children 
aged ≥2 to <6 years. It was clarified that the 
availability of the results and the subtype
will be recorded in the CRF. If a historical 
NCT04012931


TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
159
Status:Approved,  Date: 22 February 2021
Section Number
and Name
Description of Change
Brief Rationale
HIV-1 genotyping result (ie, subtype) is 
available for children aged ≥6 to <12 years,
this should be recorded in the CRF as well
and provided to the sponsor.
1.3.1 General Schedule of 
Activities
The requirement for collecting 
plasma for genotyping at 
screening was removed.
Participants need to be virologically 
suppressed on a stable ARV regimen for at 
least 6 months at screening.
1.3.1 General Schedule of 
Activities
The requirement for PK sample 
collection at W2 was added.
An extra pre-dose sample for PK, 2 weeks 
after switch to RPV, is considered relevant 
information.
1.1 Synopsis
4.1 Overall Design
6.7 Intervention After the End 
of the Study
The requirement for 
participation to rollover study 
TMC278IFD3004 was clarified.
Participants will only enroll in the pediatric 
rollover study TMC278IFD3004 if there is a 
clinical benefit from treatment with RPV 
after 48 weeks of treatment in 
TMC278HTX2002.
10.1 Appendix 1: 
Abbreviations and 
Trademarks, 10.7 Appendix 7: 
Clinical Laboratory Tests
GFR correction factor for 
children 12 years of age was 
added
As children <12 years of age are allowed in 
this study and they will be treated for 48 
weeks (potentially becoming ≥12 years 
during the study), GFR may need to be 
calculated for children >12 years of age. 
Therefore, the GFR correction factor for 
children >12 years of age was added.
10.10 Appendix 10: Pediatric 
European Network for the 
Treatment of AIDS (PENTA) 
Adherence Questionnaire, 
10.11 Appendix 11: 
Palatability Questionnaire, 
10.12 Appendix 12: 
Swallowability Questionnaire
The questionnaires were 
replaced with updated ones.
Updated questionnaires are available and 
were included.
The PENTA Adherence Questionnaire 
(Appendix 10) for patients is to be 
completed by children 6 years of age and 
older, as younger children are not expected 
to be able to complete it.
8.10.2 Diaries
An inconsistency/unclarity was 
corrected.
It was made clear that diary completion is 
also required in case of dose adjustment.
10.2 Appendix 2: Monitoring 
and Safety for Specific 
Toxicities
Removal of requirement for 
digital pictures.
Rash is a known ADR for RPV. In case of a 
grade 3-4 rash, urgent clinical evaluation by 
a dermatologist is required per protocol. The 
collection of digital pictures for rash in this 
study is therefore not considered to add 
relevant information. 
10.2 Appendix 2: Monitoring 
and Safety for Specific 
Toxicities
An error was corrected.
Minor error was noted.
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10.15
Appendix 15: CDC Growth Charts
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CDC. Morbidity and Mortality Weekly Report. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6303a1.htm. 
Published 11 April 2014. Accessed 21 November 2018.
2.
CDC, National Center for Health Statistics. CDC Growth Charts. 
https://www.cdc.gov/growthcharts/cdc_charts.htm. Published 07 December 2016. Accessed 21 November 
2018.
3.
Clinical Protocol Amendment TMC278-TiDP38-C213. A phase II, open label, single arm trial to evaluate the 
pharmacokinetics, safety, tolerability, and antiviral activity of rilpivirine (TMC278) in antiretroviral-naïve 
HIV-1 infected adolescents and children aged ≥6 to <18 years. Janssen Research & Development (24 Apr 
2018).
4.
Clinical Study Report TMC278-TiDP38-C213. A phase II, open-label, single-arm trial to evaluate the 
pharmacokinetics, safety, tolerability, and antiviral activity of rilpivirine (TMC278) in antiretroviral-naïve 
HIV-1 infected adolescents and children aged ≥6 to <18 years (Week 240 analysis of Cohort 1 in adolescents 
aged ≥12 to <18 years). Janssen Research & Development (28 Sep 2018).
5.
Clinical Study Report TMC278-TiDP38-C213. A phase II, open-label, single arm trial to evaluate the 
pharmacokinetics, safety, tolerability, and antiviral activity of TMC278 in antiretroviral-naïve HIV-1 infected 
adolescents aged 12 to <18 years (Week 48 analysis). Janssen Research & Development (18 Dec 2014).
6.
Cohen C, Wohl D, Arribas JR, et al. Week 48 results from a randomized clinical trial of 
rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate 
in treatment-naive HIV-1-infected adults. AIDS. 2014;28(7):989-997.
7.
Coovadia A, Abrams EJ, Strehlau R, et al. Efavirenz-based antiretroviral therapy among nevirapine-exposed 
HIV-infected children in South Africa: a randomized clinical trial. JAMA. 2015;314(17):1808-1817.
8.
CPMP/EPW/633:02. Committee for Proprietary Medicinal Products (CPMP) note for guidance on the clinical 
development of medicinal products for treatment of HIV Infection. 19 March 2003. 
9.
DeJesus E, Ramgopal M, Crofoot G, et al. Switching from efavirenz, emtricitabine, and tenofovir disoproxil 
fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults 
with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study. Lancet HIV. 
2017;4(5):e205-e213. 
10.
Department of Health and Human Services, panel on antiretroviral guidelines for adults and adolescents. 
Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. 
http://www.aidsinfo nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Published 25 October 2018. Accessed 
21 November 2018.
11.
Development Safety Update Report No.8. TMC278. Janssen Research & Development (5 July 2018).
12.
Driscoll DJ, Jacobsen SJ, Porter CJ, Wollan PC. Syncope in children and adolescents. Cardiology, 1997. 
29(5):1039-1045. Available at https://www.sciencedirect.com/science/article/pii/S073510979700020X.
13.
Edurant [prescribing information]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products; 2018.
14.
EMA. Ethical considerations for clinical trials on medicinal products with the paediatric population. 
http://ec.europa.eu/health/files/eudralex/vol-10/ethical_considerations_en.pdf. Published 2008. Accessed 
21 November 2018.
15.
EMA. Guideline on the clinical development of medicinal products for the treatment of HIV infection. 
https://www.ema.europa.eu/documents/scientific-guideline/guideline-clinical-development-medicinal-
products-treatment-hiv-infection_en.pdf. Published 28 April 2016. Accessed 15 November 2018.
16.
Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants 
receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET012). AIDS. 2011;15(15):1951-1957.
17.
Fisher M, Palella F, Tebas P, et al. SPIRIT: switching to emtricitabine/rilpivirine/tenofovir DF single-tablet 
regimen from boosted protease inhibitor maintains HIV suppression at week 48. Abstracts of the Eleventh 
International Congress on Drug Therapy in HIV Infection. J Int AIDS Soc. 2012;15(Suppl 4):18275.
18.
Tanner JM. Growth at adolescence. Blackwell, 1962.
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Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
163
Status:Approved,  Date: 22 February 2021
19.
Howie SRC. Blood sample volumes in child health research: review of safe limits. Bull World Health Organ.
2011;89:46-53.
20.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use. ICH Harmonized Tripartite Guideline E14: Clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs. ICH 12 May 2005.
21.
Investigator’s Brochure: TMC278 (rilpivirine, oral [EDURANT] and parenteral), Edition 11. Janssen Research 
& Development (24 July 2018).
22.
Kanthula R, Beck I, Van Dyk G, et al. Persistence of HIV drug resistance in children exposed to nevirapine 
prophylaxis. CROI 2016. Poster 847.
23.
Kuhn L, Hunt G, Technau KG, et al. Drug resistance among newly-diagnosed HIV-infected children in the era 
of more efficacious antiretroviral prophylaxis. AIDS. 2014;28(11):1673-1678.
24.
Leen Gilles, Rodica Van Solingen-Ristea, Herta Crauwels, Simon Vanveggel, Veerle Van Eygen; TMC278-
TiDP38, iDMC Report Cohort 2: Intermediate Week 4 analysis: A Phase II, open label, single arm trial to 
evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of TMC278 in antiviral-naïve HIV-1 
infected adolescents and children aged 6 to < 18 years.
25.
Loubster S, Balfe P, Sherman G, et al. Decay of K103N mutants in cellular DNA and plasma RNA after 
single-dose nevirapine to reduce mother-to-child HIV transmission. AIDS. 2006;20(7):995-1002.
26.
Mackie NE, Fidler S, Tamm N, et al. Clinical implications of stopping nevirapine-based antiretroviral therapy: 
relative pharmacokinetics and avoidance of drug resistance. HIV Med. 2004;5(3):180-184.
27.
Molina JM, Clumeck N, Orkin C, Rimsky LT, Vanveggel S, Stevens M; ECHO and THRIVE Study Groups. 
Week 96 analysis of rilpivirine or efavirenz in HIV-1-infected patients with baseline viral load ≤ 100 000 
copies/mL in the pooled ECHO and THRIVE phase 3, randomized, double-blind trials. HIV Med. 2014 
Jan;15(1):57-62.
28.
Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S. Prospective genetic screening decreases the 
incidence of abacavir hypersensitivity reactions in the western Australian HIV cohort study. Clin Infect Dis. 
2006;43(1):99-102.
29.
Rimsky L, Vingerhoets J, et al. Genotypic and phenotypic characterization of HIV-1 isolates obtained from 
patients on rilpivirine therapy experiencing virologic failure in the phase 3 ECHO and THRIVE studies: 48 
week analysis. J Acquir Immune Defic Syndr. 2012; 59(1):39-46.
30.
Sabin CA, Worm S, Weber R, et al. Recent use of abacavir and didanosine, but not of thymidine analogeus, is 
associated with risk of mycocardial infarction. [Poster # 957c]. 15th Conference on Retroviruses and 
Opportunistic Infections, Boston, February 2008.
31.
Sadiq ST, Fredericks S, Khoo SH, Rice P, Holt DW. Efavirenz detectable in plasma 8 weeks after stopping 
therapy and subsequent development of non-nucleoside reverse transcriptase inhibitor-associated resistance. 
AIDS. 2005;19(15):1716-1717.
32.
Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular 
filtration rate in infants, children and adolescents. Pediatr Clin North Am. 1987; 34(3):571-590.
33.
Shet A, Mehta S, Rajagopalan N, et al. Anemia and growth failure among HIV-infected children in India: a 
retrospective analysis. BMC Pediatr. 2009;9(37).
34.
TMC278-C213_W240_Cohort 1_CSR_Full: A Phase II, open-label, single-arm trial to evaluate the 
pharmacokinetics, safety, tolerability, and antiviral activity of rilpivirine (TMC278) in antiretroviral-naïve 
HIV-1 infected adolescents and children aged ≥6 to <18 years. v1.0, 03 October 2018
35.
TMC278-C213_Wk48_CSR_Full: A Phase II, open-label, single arm trial to evaluate the pharmacokinetics, 
safety, tolerability, and antiviral activity of TMC278 in antiretroviral-naïve HIV-1 infected adolescents aged 12 
to <18 years. v1.0, 06 February 2015
36.
Van Dyke RB, Lee S, Johnson GM, et al. Reported adherence as a determinant of response to highly active 
antiretroviral therapy in children who have HIV infection. Pediatrics. 2002;109(4):e61.
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TMC278 (rilpivirine)
Clinical Protocol TMC278HTX2002 AMENDMENT 3 Clean
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
164
Status:Approved,  Date: 22 February 2021
37.
Veal GJ. Blood volumes in pediatric clinical trials: a review of current regulations and guidance for research 
studies. Clin Invest (Lond). 2014;4(11):1005-1011.
38.
Wang Y, Jadhav PR, Lala M, and Gobburu JV. Clarification on precision criteria to derive sample size when 
designing pediatric pharmacokinetic studies. J Clin Pharmacol. 2012;52:1601-1606.
39.
Wensing AM, Calvez V, Günthard HF, et al. 2017 update of the drug resistance mutations in HIV-1. Top 
Antivir Med. 2017;24(4):132-133.
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The Normal ECG in Childhood and Adolescence, Heart 2005;91:1626-1630.
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SAP_001.pdf: 
1
Approved, Date: 27 March 2023
Janssen Research & Development*
Statistical Analysis Plan
Week 24 (Primary) and Week 48 (Final) Analysis
A Phase 2, Open-label, Single-arm, Multicenter Study to Evaluate the Pharmacokinetics,
Safety, Tolerability, and Efficacy of Switching to RPV Plus Other ARVs in HIV-1-infected
Children (Aged 2 to <12 years) who are Virologically Suppressed
Protocol TMC278HTX2002; Phase 2
Edurant®/TMC278(rilpivirine)
Status: 
Approved
Date: 
27 March 2023
Prepared by: 
Janssen Research & Development, a division of Janssen Pharmaceutica NV
Document No.: EDMS-ERI-196339540
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP).
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or
confidential.
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Edurant®/TMC278(rilpivirine)
                                                                          Statistical Analysis Plan TMC278HTX2002 (W24 &W48 Analysis)
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Approved, Date: 27 March 2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY............................................................................................................................ 4
ABBREVIATIONS ........................................................................................................................................ 4
1. 
INTRODUCTION ................................................................................................................................ 6
1.1. 
Trial Objectives.................................................................................................................................. 6
1.2. 
Trial Endpoints................................................................................................................................... 6
1.3. 
Trial Design ....................................................................................................................................... 7
1.4. 
Statistical Hypotheses for Trial Objectives............................................................................................ 7
1.5. 
Sample Size Justification..................................................................................................................... 7
1.6. 
Randomization and Blinding................................................................................................................ 7
1.7. 
Changes to planned analyses................................................................................................................ 8
2. 
GENERAL ANALYSIS DEFINITIONS ............................................................................................... 8
2.1. 
Analysis Phases.................................................................................................................................. 8
2.2. 
Visit Windows.................................................................................................................................... 8
2.3. 
Pooling Algorithm for Analysis Centers ............................................................................................... 9
2.4. 
Analysis Sets...................................................................................................................................... 9
2.4.1. 
All Enrolled Analysis Set................................................................................................................. 9
2.4.2. 
Full Analysis Set (FAS) ................................................................................................................... 9
2.5. 
Definition of Subgroups ...................................................................................................................... 9
2.6. 
Study Day and Relative Day.............................................................................................................. 10
2.7. 
Baseline........................................................................................................................................... 10
2.8. 
Imputation Rules for Missing AE Date/Time of Onset/Resolution ........................................................ 10
3. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW.................................. 11
4. 
SUBJECT INFORMATION ............................................................................................................... 11
4.1. 
Demographics and Baseline Characteristics ........................................................................................ 11
4.2. 
Disposition Information .................................................................................................................... 12
4.3. 
Treatment Adherence........................................................................................................................ 13
4.4. 
Extent of Exposure ........................................................................................................................... 14
4.4.1. 
Diaries.......................................................................................................................................... 15
4.5. 
Protocol Deviations........................................................................................................................... 15
4.6. 
Prior and Concomitant Medications.................................................................................................... 15
5. 
EFFICACY......................................................................................................................................... 16
5.1. 
Analysis Specifications ..................................................................................................................... 16
5.1.1. 
Level of Significance..................................................................................................................... 16
5.1.2. 
Data Handling Rules...................................................................................................................... 16
5.2. 
Efficacy Endpoints............................................................................................................................ 16
5.2.1. 
Definition..................................................................................................................................... 17
5.2.2. 
Analysis Methods.......................................................................................................................... 18
5.3. 
Other Efficacy Variables ................................................................................................................... 18
5.3.1. 
Resistance..................................................................................................................................... 18
6. 
SAFETY............................................................................................................................................. 20
6.1. 
Adverse Events (AE) ........................................................................................................................ 20
6.2. 
Clinical Laboratory Tests .................................................................................................................. 22
6.3. 
Vital Signs and Physical Examination Findings................................................................................... 23
6.4. 
Electrocardiogram ............................................................................................................................ 25
7. 
PHARMACOLOGY........................................................................................................................... 26
7.1. 
Population Pharmacokinetics ............................................................................................................. 26
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                                                                          Statistical Analysis Plan TMC278HTX2002 (W24 &W48 Analysis)
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Pharmacokinetic/Pharmacodynamic Relationships ........................................................................................... 26
7.2. 
Other Pharmacology Endpoints.......................................................................................................... 27
REFERENCES ............................................................................................................................................ 28
ATTACHMENTS........................................................................................................................................ 29
ATTACHMENT 1: DAIDS GRADING TABLE .......................................................................................... 29
ATTACHMENT 2: BLOOD PRESSURE LEVELS BY AGE AND HEIGHT PERCENTILES.................... 34
ATTACHMENT 3: STAGE-3-DEFINING OPPORTUNISTIC ILLNESSES IN HIV INFECTION............. 38
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AMENDMENT HISTORY
NA
ABBREVIATIONS
17-OH  
17-hydroxyprogesteron
3TC  
lamivudine
ABC  
abacavir
ACTH  
adrenocorticotropic hormone
ADaM  
Analysis Data Model
AE 
Adverse Events
AESI 
Adverse Events of Special Interest
ALT  
alanine transaminase
ART  
antiretroviral therapy
ARV 
antiretroviral
AST  
aspartate transaminase
ATC  
Anatomic and Therapeutic Chemical
AUC  
area under the curve
AZT  
zidovudine
BMI 
Body Mass Index
CD4 
cluster of differentiation 4
CDC  
Centers for Disease Control and Prevention
CI 
Confidence Interval
cm 
centimeter
CRF  
Case Report Form
DAIDS  
Division of AIDS
DHEAS  
dehydroepiandrosterone-sulfate
DPS  
Data Presentation Specifications
ECG  
electrocardiogram
eGFR  
estimated glomerular filtration rate
EOI 
event of interest
FAS  
Full Analysis Set
FC 
Fold Change
FDA 
Food and Drug Administration
FPI 
First Patient In
FSH  
Follicle-stimulating hormone
FTC  
Emtricitabine
FU 
Follow Up
HIV-RNA  
Human immunodeficiency virus Ribonucleic Acid
HR  
Heart Rate
IDMC  
Independent Data Monitoring Committee
ICH  
International Conference on Harmonization
IVRS  
interactive voice response system
kg 
Kilogram
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Edurant®/TMC278(rilpivirine)
                                                                          Statistical Analysis Plan TMC278HTX2002 (W24 &W48 Analysis)
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LH  
luteinizing hormone
LOCF  
Last Observation Carried Forward
NC  
Non Completer
MedDRA  
Medical Dictionary for Regulatory Activities
mL 
millilitre
MTCT  
Mother to Child Transmission
NAP  
Not Applicable
N(t)RTI 
nucleoside/nucleotide reverse transcriptase inhibitors
nmol 
nanomol
PBMC  
peripheral blood mononuclear cell
PD 
Pharmacodynamic
PK 
Pharmacokinetic(s)
q.d. 
quaque die (one a day)
QTc 
corrected QT interval
QTcB  
Bazett’s square-root corrected QT
QTcF  
Fridericia’s square-root corrected QT
RPV 
Rilpivirine
SAE 
Serious Adverse Events
SAP  
Statistical Analysis Plan
SD 
Standard Deviation
SDTM  
Study Data Tabulation Model
SE 
Standard Error
SI 
International System of Units
TLF 
Tables, Listings and Figures
TLOVR  
Time to Loss of Virologic Response
WHO-DD 
World Health Organization-Drug Dictionary
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Edurant®/TMC278(rilpivirine)
                                                                          Statistical Analysis Plan TMC278HTX2002 (W24 &W48 Analysis)
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Approved, Date: 27 March 2023
1. 
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and statistical
methods for the Week 24 (primary) and Week 48 (final) analysis of safety and efficacy (antiviral activity)
of the study TMC278HTX2002 based on the protocol version 16.0 dated 22 February 2021 (Amendment
3).
1.1. 
Trial Objectives
Primary Objectives:
- 
To evaluate the steady-state Pharmacokinetic (PK) of rilpivirine (RPV) and determine the
appropriate dose of RPV in combination with other antiretrovirals (ARVs) in participants aged ≥2
to <12 years with a body weight of <25kg.
- 
To evaluate the safety and tolerability of RPV in combination with other ARVs in participants aged
≥2 to <12 years over a 24-week treatment period.
Secondary Objectives:
- 
To evaluate the safety and tolerability of RPV in combination with other ARVs over a 48-week
treatment period.
- 
To evaluate the efficacy of RPV in combination with other ARVs over a 24- and 48-week treatment
period.
- 
To evaluate population PK and PK/pharmacodynamic (PD) relationships for safety and efficacy of
RPVin combination with other ARVs.
- 
To assess resistance in case of loss of virologic response to RPV in combination with other ARVs.
- 
To evaluate treatment adherence to RPV in combination with other ARVs over a 24- and 48-week
treatment period.
Exploratory Objectives:
- 
To assess the palatability of the 2.5-mg tablet formulation of RPV, if applicable.
- 
To assess the swallowability ofthe 25-mg tablet formulation of RPV, if applicable.
- 
To assess archived viral resistance, if feasible depending on available blood volume.
1.2. 
Trial Endpoints
Primary Endpoints:
- 
Area under the plasma concentration-time curve from time of administration up to 24 hours post-
dose of RPV, as derived from the intensive PK assessments.
- 
Incidence of grade 3/4 adverse events (AEs), serious adverse events (SAEs), Human
Immunodeficiency Virus (HIV)-related events (including acquired immune deficiency syndrome
[AIDS]-defining illnesses and Stage-3-defining Opportunistic Illnesses in HIV Infection), and AEs
leading to discontinuation of study intervention through 24 weeks of study treatment.
Secondary Endpoints:
- 
Incidence and severity of AEs/HIV-related events and their relatedness to RPV through 24 and 48
weeks of study treatment.
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                                                                          Statistical Analysis Plan TMC278HTX2002 (W24 &W48 Analysis)
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- 
Change from baseline over time and shift in toxicity grades/abnormalities versus reference for
clinical laboratory parameters, electrocardiogram (ECG) parameters, vital signs, and physical
examination through 24 and 48 weeks of study treatment.
- 
Proportion of participants with HIV-1 RNA <50/400 and ≥50/400 copies/mL using the Food and
Drug Administration (FDA) Snapshot approach through 24 and 48 weeks of study treatment.
- 
Immunologic changes, measured by CD4+ cell count (absolute and percentage relative to total
lymphocytes), through 24 and 48 weeks of study treatment.
- 
Pharmacokinetic parameters of RPV (other than area under the plasma concentration-time curve
[AUC]), as derived from the intensive PK assessments.
- 
Pharmacokinetic parameters of RPV, as derived by population PK modeling, through 24  and 48
weeks of study treatment.
- 
Viral genotype at the time of virologic failure through 24 and 48 weeks of study treatment.
- 
Treatment adherence, as assessed by the Pediatric European Network for the Treatment of AIDS
(PENTA) adherence questionnaire and by study intervention accountability, through 24 and 48
weeks of study treatment.
Exploratory Endpoints:
- 
Responses to the palatability questionnaire after 2 weeks of study treatment.
- 
Responses to the swallowability questionnaire after 2 weeks of study treatment.
- 
Mutations in HIV-1 DNA or in HIV-1 RNA, as assessed by retrospective peripheral blood
mononuclear cell (PBMC)- or plasma-based analyses, through 24 and 48 weeks of study treatment.
1.3. 
Trial Design
This is a Phase 2, open-label, single-arm, multicenter, interventional study in HIV-1-infected participants
(boys and girls) aged ≥2 to <12 years with a body weight of at least 10kg to evaluate the PK, safety,
tolerability, and efficacy of switching to RPV once daily in combination with other, investigator-selected
ARVs.
For more details refer section 4 of the study protocol.
1.4. 
Statistical Hypotheses for Trial Objectives
No formal hypothesis will be tested.
1.5. 
Sample Size Justification
No formal sample size calculation was performed.
The sample size is based on overall regulatory requirements and the number of participants enrolled in
Cohort 2 in study TMC278-C213: approximately 25 to 30 participants aged ≥2 to <12 years will be recruited
in the current study.
For more details refer section 9.2 of the study protocol.
1.6. 
Randomization and Blinding
Randomization
As this was a single arm trial, no randomization procedures were applicable.
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Edurant®/TMC278(rilpivirine)
                                                                          Statistical Analysis Plan TMC278HTX2002 (W24 &W48 Analysis)
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Approved, Date: 27 March 2023
Blinding
Since this was an open label trial, blinding procedures were not applicable.
1.7. 
Changes to planned analyses
NAP
2. 
GENERAL ANALYSIS DEFINITIONS
2.1. 
Analysis Phases.
Table 1 –Trial Phases
Trial phase 
Start date 
End date
Screening 
Date of signing the informed 
consent
Start date of Treatment phase - 1 day
Treatment 
Date of the first intake of RPV 
If the participant died during the study
intervention phase: min (date of last RPV+ 7
days; date of death)
If the participant permanently stopped the
trial medication: minimum of:
 
date of last RPV intake + 7 days, if
missing, max (early withdrawal visit date;
discontinuation date) + 7 days
 
date of last contact
[For W24 analysis only] If the participant is
still in the trial: cut-off date for the analysis,
ie. LPW24 visit date
Follow-up (not 
defined when 
derived End 
date is before
Start date of this
phase)
End date of the Treatment phase + 
1 day  
If the participant died: date of death
Otherwise: date of last contact (or cut-off date
for the analysis, if still in follow-up period)
If the date of first intake of the study medication is missing, this should be substituted by the baseline visit
date.
2.2. 
Visit Windows
As participants do not always adhere to the protocol visit schedule, the following rules are applied to assign
actual visits to analysis visits. Listed below are the visit windows and the target days for each visit. The
reference day is Study Day 1. If a participant has 2 or more actual visits in one visit window, the visit closest
to the target day will be used as the protocol visit for that visit window. The other additional visit(s) will
not be used in the summaries or analyses, but they can be used for determination of clinically important
endpoints. If 2 actual visits are equidistant from the target day within a visit window, the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit window, it will
no longer be used for a later time point except for the endpoint. Listed below (Table 2) are the visit windows
and the target days for each visit defined in the protocol.
Table 2 –Visit Windows
Parameter 
Analysis 
Period 
Scheduled 
Visit Number 
Time Interval 
(label on output) 
Time Interval 
(Day)** 
Target Time
Point (Day)
Vital Signs* 
Screening 
1 
Screening 
<0 
-∞
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Edurant®/TMC278(rilpivirine)
                                                                          Statistical Analysis Plan TMC278HTX2002 (W24 &W48 Analysis)
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Approved, Date: 27 March 2023
Parameter 
Analysis 
Period 
Scheduled 
Visit Number 
Time Interval 
(label on output) 
Time Interval 
(Day)** 
Target Time
Point (Day)
Baseline § 
2 
Baseline 
[-∞, 1] 
≤1
Treatment
3 
Week 2 
[2,21] 
15
4 
Week 4 
[22, 42] 
29
5 
Week 8 
[43, 70] 
57
6 
Week 12 
[71, 98] 
85
7 
Week 16 
[99, 140] 
113
8 
Week 24 
[141, 196] 
169
9 
Week 32 
[197, 252] 
225
10 
Week 40 
[253, 308] 
281
11 
Week 48 
[309, 378] 
337
Follow-up  
12 
Post-treatment 
Follow-up  
[Start FU phase, 
∞] 
(3x7) +1=22
after Start FU
phase
*Vital Signs used as an example refer parameter which data collected on each protocol schedule visit
**Relative to Study Day 1
§ Only the record prior to the first dose closest to target day 1 will be allocated to analysis time point ‘Baseline’; all
records prior to Day 1 that were not allocated to Baseline are assigned to ‘Screening’.
2.3. 
Pooling Algorithm for Analysis Centers
NAP.
2.4. 
Analysis Sets
2.4.1. 
All Enrolled Analysis Set
The all enrolled analysis set includes all participants who were not screen failures.
2.4.2. 
Full Analysis Set(FAS)
The FAS includes all participants who have taken at least 1 dose of RPV, regardless of their compliance
with the protocol and adherence to the dosing regimen.
The FAS will be used as primary and only population for all analyses.
2.5. 
Definition of Subgroups
All results will be presented by age group (2-<6 years; 6-<12 years) as well as overall across whole
study population.
In addition, the following subgroups defined:
Efficacy:
 
CD4+ count at baseline (< 350, 350 - < 500, 500 - < 750, ≥750 cells/μL) [Note: last 2 categories
may be combined into 1]
 
Background regimen (ie. ABACAVIR/LAMIVUDINE, Other)
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 
Adherence based on drug accountability (<80%, 80 - <95%, >=95%) cumulative up to Week 24/
Week 48
Safety:
 
Baseline body weight: <15 kg; 15 kg - <20 kg; 20 - <25 kg; at least 25 kg
 
RPV dose (12.5mg, 15mg, 25mg)
 
CD4+ count at baseline (< 350, 350 - < 500, 500 - < 750, ≥750 cells/μL) [Note: last 2 categories
may be combined into 1]
 
Background regimen (ie. ABACAVIR/LAMIVUDINE, Other)
2.6. 
Study Day and Relative Day
Study Day 1 or Day 1 refers to the start of the first study agent administration (date of first intake). All
efficacy and safety assessments at all visits will be assigned a day relative to this date.
Study day or relative day for a visit is defined as:
Study Day = visit date - date of Day 1 + 1; if visit date ≥ date of Day 1 (date of first study
treatment (RPV) administration).
Study Day = visit date –date of Day 1; if visit date < date of Day 1 (date of first study treatment
(RPV) administration).
There is no 'Day 0'
2.7. 
Baseline
A baseline (or reference) value will be defined as the value of the last available assessment prior to the first
study treatment (RPV) on Day 1.
If the baseline value is missing the last available screening value will be taken.
2.8. 
Imputation Rules for Missing AE Date/Time of Onset/Resolution
Partial AE onset dates will be imputed as follows:
 
If the onset date of an adverse event is missing day only, it will be set to:
 
First day of the month that the AE occurred, ifmonth/year of the onset of AE is different than the
month/year of the study agent start
 
The day of study agent start, if the month/year of the onset of AE is the same as month/year ofthe
study agent start date and month/year of the AE resolution date is different
 
The day of study agent start or day of AE resolution date, whichever is earliest, if month/year of
the onset of AE and month/year of the study agent start date and month/year of the AE resolution
date are same
 
If the onset date of an adverse event is missing both day and month, it will be set to the earliest of:
 
January 1 of the year of onset, as long as this date is on or after the study agent start date
 
Month and day of the study agent start date, if this date is the same year that the AE occurred
 
Last day of the year if the year of the AE onset is prior to the year of the study agent start date,
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The AE resolution date.
 
Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:
 
If the resolution date of an adverse event is missing day only, it will be set to the earliest of the last
day of the month of occurrence of resolution or the day of the date of death, if the death occurred in
that month.
 
If the resolution date of an adverse event is missing both day and month, it will be set to the earliest of
December 31 of the year or the day and month of the date of death, if the death occurred in that year.
 
Completely missing resolution dates will not be imputed.
AE onset/resolution dates with missing times will be imputed as follows:
 
A missing time of onset of an adverse event will be set to the earlier of:
 
00:01 as long as the onset date is after the study agent start date
 
The time of the study agent start if this is the same day the AE occurred.
 
The missing time of resolution of an adverse event will be set to 23:59.
If a missing time is associated with a partial or missing date, the date will be imputed first prior to imputing
the time.
3. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
An Independent Data Monitoring Committee (IDMC) was installed to monitor pharmacokinetic, efficacy,
and safety data, and to safeguard the participants in this trial.
Interim analyses were performed and presented to the IDMC at Week 4, at Week 12 when all participants
reached Week 12 (or discontinued earlier) and primary analysis at Week 24 when all participants reached
Week 24 (or discontinued earlier). The details of these analyses are described in the corresponding IDMC
SAPs. The Week 48 (final) analysis when all participants have completed the trial up to Week 48 (or
discontinued earlier) will be shared and discussed with the IDMC.
Further details are described in the IDMC charter.
4. 
SUBJECT INFORMATION
The number of participants in FAS will be summarized and listed by age group (2-<6 years; 6-<12
years) and overall.
4.1. 
Demographics and Baseline Characteristics
Table 3 presents a list of the demographic variables that will be summarized.
Table 3: Demographic Variables
Continuous Variables: 
Summary Type
Age (years) 
Descriptive statistics (N, mean,
standard deviation [SD], median,
and range [minimum and
maximum]).
Weight (kg) 
Height (cm) 
Body Mass Index (BMI) (kg/m2) 
Categorical Variables
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Age (≥2 - < 6years; ≥6 - < 9years; ≥9 - < 12years) 
Frequency distribution with the
number and percentage of
participants in each category.
Weight (<25kg, ≥25kg) 
Sex (male, female) 
Childbearing Potential (Yes, No)
Racea (American Indian or Alaska Native, Asian, Black or African
American, Native Hawaiian or other Pacific Islander, White, Not allowed
to ask per local regulations, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not allowed to ask
per local regulations)
Countryb
a If multiple race categories are indicated, Race is recorded as 'Multiple'
b Summary will be detailed for sites in each country
Table 4 presents a list of the baseline disease characteristic variables that will be summarized.
Table 4: Baseline Disease Characteristic Variables
Continuous Variables: 
Summary Type
CD4+ count (cells/μL) at Baseline
Descriptive statistics (N, mean,
standard deviation [SD], median, and
range [minimum and maximum]).
CD4+ count (%) at Baseline
HIV-1 viral load (copies/ml / log10 copies/ml) at Baseline
Duration ofknown HIVInfection (years):
[date of first confirmed positive HIV-1 test –date of Day 1]/365.25 
Note: provide duration in years; in case of incomplete date of first 
confirmed positive HIV test, impute with the 1st day of the month 
and/or 1st month of the year in order to derive the duration.
Categorical Variables
HIV –1 subtype (from historical report or PBMC)
Hepatitis B/C co-infection status (Yes, No, NAV)
Mode of HIV infection (Blood transfusion, Hemophilia-associated
injections, Mother to Child transmission, Other)
Frequency distribution with the
number and percentage of participants
in each category.
Clinical stage of HIV infection at screening based on CD4+ count OR
percentage of total lymphocytes
CD4+ count at Baseline (< 350, 350 - < 500, 500 - <750, ≥750 cells/μL)
HIV-1 viral load at Baseline (<50 copies/ml and ≥50 copies/ml)
4.2. 
Disposition Information
Screened participants and reason for screen failures will be summarized overall.
The number of participants in the following disposition categories will be summarized throughout the study
by age group (2-<6 years; 6-<12 years) and overall.
For the All Enrolled Analysis Set:
 
Participants enrolled
 
Participants enrolled but not treated
 
Participants treated with study treatment (FAS)
and for FAS:
 
Participants completing the study
 
Participants who terminated study participation prematurely
 
Reasons for termination of study
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4.3. 
Treatment Adherence
Treatment adherence is defined based on drug accountability and based on the Study Adherence
Questionnaire for Children and Teenagers / the Study Adherence Questionnaire for Caregivers (see
Appendix 10 of the Clinical Trial Protocol).
The following parameters are derived cumulatively up to week 24 or week 48/last intake for discontinued
participants as well as using all available data (Week 24 analysis only).
Treatment adherence will be summarized descriptively by age group  (2-<6 years; 6-<12 years) and
overall for the entire 24-Week and 48-Week treatment period.
Drug Accountability:
Drug accountability (DA) can only be calculated at time points when all kits that have been dispensed
before that time point have been returned –if DA cannot be derived (eg. cumulative up to week 24):
 
impute with value based on next available time point for which a DA calculation can be done,
eg. if cumulative DA up to week 24 cannot be derived, derive DA up to week 32; if not
calculable, derive DA up to week 40 etc.;
 
otherwise, use value based on closest preceding time point
Total Amount to be taken (in mg) =
∑
(numberofdayson same RPVdose x strengthin mg ofRPVdose)
  !" #$
Number of days on same RPVdose is based on:
- 
first and last RPV study medication intake date (if available) of the prescribed RPV dose
or, in case participant discontinued and last RPV study medication intake date is missing,
discontinuation date
Actual Total amount taken (in mg) =
∑
((numberoftabletsdispensed – numberoftabletsreturned)xstrengthin mg ofRPVtablet)
  !" #$
Level of adherence = (actual Total amount taken / Total amount to be taken) x 100%
Treatment adherence is defined as:
- 
adherent: the level of adherence is > 95%
- 
non-adherent: the level of adherence is ≤ 95%
Additionally, following categories of level of adherence will be defined: -
- 
> 95%
- 
]80%; 95%]
- 
]65%; 80%]
- 
]50%; 65%]
- 
≤ 50%
The numbers and percentages of participants by adherence category will be tabulated and descriptive
statistics of adherence (%) will be shown.
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Interruptions (for AEs) are not to be considered for the calculation of adherence, i.e. they will not be
subtracted from the Total amount to be taken.
PENTA Questionnaires:
Source for this adherence measure is the Study Adherence Questionnaire for Children and Teenagers (or,
when completed by the caregiver, the Study Adherence Questionnaire for Caregivers), more specifically
the following 2 questions:
i. 
Report of missed doses in last 3 days (Question 8).
ii. 
Report of missed doses over the last 2 weeks (Question 9).
If both child and a caregiver completed the questionnaire, the Child Questionnaire will be given
precedence.
Results will be summarized for RPVand for the background regimen separately (regardless which ARVs
are used) –in case questionnaire results for >1 ARV are reported concurrently, the worst outcome (eg.
higher # doses missed for Q8) across these ARVs will be used in the analysis, and further as follows:
i. Missed doses in last 3 days (Q8):
 
on a by visit basis (0, 1, 2, or 3 doses missed)
 
cumulatively, with the following categories and subcategories:
1. never missed a dose
2. missed not more than 1 dose
a. at most once
b. more than once
3. missed 2 or more doses
a. at most once
b. more than once
ii. Missed doses (Y/N) in last 2 weeks (Q9):
 
on a by visit basis (Y/N)
 
cumulatively, with the following categories and subcategories:
1. never missed doses
2. missed doses,
a. at most once
b. more than once
Treatment adherence, for both RPVand background regimen, is defined as:
- 
adherent: cumulatively, did not miss (2 or more) doses more than once (i.1., i.2.(a&b), i.3.a, ii.1,
and ii.2.a)
- 
non-adherent: cumulatively, missed (2 or more) doses more than once (i.3.b or ii.2.b)
4.4. 
Extent of Exposure
The number and percentage of participants who receive RPV will be summarized by age group (2-<6 years;
6-<12 years) and overall.
Exposure is defined as the duration of RPV treatment. The duration is calculated as follows:
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(date of last dose of RPV –date of first dose of RPV) + 1.
Note that this definition implies that drug interruptions are ignored in calculating exposure.
Descriptive statistics for RPV duration in weeks: ie, duration in days / 7; (N, mean, SD, median, and range
(minimum, maximum)) will be presented by age group (2-<6 years; 6-<12 years) and overall.
In addition, duration of exposure will be summarized by age group (2-<6 years; 6-<12 years) and overall
for the FAS in the following duration categories: <1 week, 1-<2 weeks, 2-<4 weeks, 4-<8 weeks, 8-<12
weeks, 12-<16 weeks, 16-<24 weeks, 24-<32 weeks, 32-<40 weeks and 40-48 weeks.
Total subject years of exposure is calculated as [sum of (days of exposure)/365.25]. Total subject years of
exposure will be presented by age group (2-<6 years; 6-<12 years) and overall.
4.4.1. 
Diaries
A listing will be created for all participants who underwent intensive PK sampling, comprising of the date
and time of RPV intake from the start of study treatment (or start of an adjusted RPV-dose, if applicable)
until the day of intensive PK sampling, based on the information entered in the participant diary.
4.5. 
Protocol Deviations
The major protocol deviations may have the potential to impact participants’ rights, safety or well-being,
or the integrity and/or result of the clinical study. Participants with major protocol deviations will be
identified prior to database lock and major protocol deviations (including a category for COVID-19 related
protocol deviations) will be summarized by category.
4.6. 
Prior and Concomitant Medications
Prior medications are defined as any therapy used before the day of first dose (partial or complete) of RPV.
Concomitant medications are defined as any therapy used on or after the same day as the first dose of RPV,
including those that started before and continue after the first dose of study agent. Follow-up medications
are defined as any therapy that started after the date of the last dose of RPV.
For non-ARV therapies, summaries of concomitant medications will be presented by Anatomic and
Therapeutic Chemical (ATC) class level using the World Health Organization-Drug Dictionary (WHO-
DD), and by age group (2-<6 years; 6-<12 years) and overall. The proportion of participants who receive
each concomitant medication will be summarized as well as the proportion of participants who receive at
least 1 concomitant medication.
For ARV therapies, summaries of prior and concomitant (ie, background regimen) medications will be
presented by individual ARVs and combination ARVs as collected in the electronic Case Report Form
(eCRF) by dose and weight group and overall. The proportion of participants for each category of
medication will be summarized.
Prior as well as concomitant ARVand concomitant non-ARV therapies will be tabulated. Participants who
switched ARV therapy during treatment will be listed.
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5. 
EFFICACY
5.1. 
Analysis Specifications
5.1.1. 
Level of Significance
No statistical testing will be done as this is a single arm trial.
5.1.2. 
Data Handling Rules
Viral Load:
Viral load testing will be measured at a central laboratory using standardized HIV-1 viral load assays as the
concentration of HIV-1 RNA in plasma. Reanalyzed samples will not be used in any of the calculations or
summary statistics.
Imputation of left-censored values: values below the detection limit  (ie, 20 copies/ml) will be scored as 1
less than the detection limit in the analysis  (ie, 20-1=19 copies/ml), unless explicitly specified differently.
Imputation of right-censored values: in case viral loads were above the upper limit of quantitation,
i.e.10,000,000 HIV-1 RNA copies/mL, the viral load will be scored as 1 more than the detection limit in
the analysis, unless explicitly specified differently.
If no observation is available at baseline the last available screening value will be taken.
Immunology:
For cases where no observation is available at the baseline date, the last available screening value will be
taken.
In case multiple observations (different sampling dates) are available within a single visit window, only the
one closest to the target day will be selected for the displays to select unique observations per time point
(visit window).
Rounding:
For point estimates (means or percentages), the following rounding rules are applied:
- 
CD4 count: 1 decimal
- 
all other parameters (including viral load in case not log-transformed, and Fold Change (FC)): 1
decimal
For confidence intervals (CIs), median, interquartile range, min and max: number of decimals for according
point estimate.
For SDs and SEs: number ofdecimals for according point estimate + 1 decimal.
5.2. 
Efficacy Endpoints
The following efficacy parameters will be analyzed:
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-
Virologic outcome (virologic response and virologic failure) applying HIV-1 RNA thresholds 50
and 400 copies/mL using the FDA Snapshot approach, at Week 24/Week 48.
-
Change in CD4 cell count (absolute and percentage) from baseline up to Week 24/Week 48.
5.2.1. 
Definition
Virologic response is defined as follows:
0 = non-responder: the viral load test result is above some threshold value
1 = responder: the viral load test result is below some threshold value
Virologic failure
Loss of response: two consecutive measurements of ≥200 HIV-1 RNA copies/mL at least 2 weeks apart
after having been confirmed virologic responder.
Suspected Virologic Failure: HIV-1 RNA ≥200 copies/mL.
FDA Snapshot approach:
The following outcome subcategories are defined (giving priority in the order as presented below, such that
each participant is categorized into a single subcategory)
1) Participant’s background regimen was switched as not permitted by the protocol; participants who
experienced a switch in their background regimen composition that lasted more than one week and
not permitted by the protocol (identify these from protocol deviations [ADDV]) and that occurred
before the earliest onset of AEs leading to permanent stop, and, if the participant is ongoing, that
occurred up to and including the end day of the 24/48 week window, are assigned outcome
subcategory = 'Virologic failure –switch in background regimen not permitted by the protocol'.
2) Participant discontinued trial for virologic failure during treatment phase – if reason for
discontinuation is 'SUBJECT REACHED A VIROLOGIC ENDPOINT' and HIV-1 RNA is
missing at Week 24/48 then outcome subcategory = ' Virologic failure - leading to discontinuation';
3) Viral load data in the Week 24/48 window
-
if last available HIV RNA in the time window is <50/400 copies/mL then
outcome='Virologic success: HIV RNA < 50/400 copies/mL at Week 24/48';
-
if last available HIV RNA in the time window is ≥50/400 copies/mL then
outcome='Virologic failure: HIV RNA ≥50/400 copies/mL at Week 24/48;
4) No HIV RNA data in Week 24/48 window;
-
if the participant completed Week 24/48 but HIV RNA data at Week 24/48 is missing then
outcome='Missing data during window but on study';
-
if the reason for discontinuation='ADVERSE EVENT/HIV RELATED EVENT' and the
earliest AE leading to permanent stop was not preceded by a switch in the background
regimen that was not permitted by the protocol (see point 1) above), then
outcome='Discontinued due to AE/death';
-
if the reason for discontinuation is 'OTHER', ‘SPONSORS DECISION’, 'SUBJECT DID
NOT FULFILL ALL INCLUSION/EXCLUSION CRITERIA', 'SUBJECT INELIGIBLE
TO CONTINUE THE TRIAL', 'SUBJECT LOST TO FOLLOW-UP', 'SUBJECT
NONCOMPLIANT' or 'SUBJECT WITHDREW CONSENT': if the last available HIV
RNA is <50/400 copies/mL (or no post baseline HIV RNA data available), outcome
subcategory = 'Discontinued due to other reason and the last available HIV RNA < 50/400
copies/mL (or missing)', and (ii) if the last available HIV RNA ≥50/400 copies/mL,
outcome subcategory = ‘Virologic failure - discontinued due to other reason and last
available HIV RNA ≥50/400 copies/mL’;
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Week 24: The snapshot analysis is based on the last observed viral load data within the Week 24 window
(day 141 up to and including day 196, Window 20-28 weeks, baseline = day 1).
Week 48: The snapshot analysis is based on the last observed viral load data within the Week 48 window
(day 309 up to and including day 378, Window 44-54 weeks, baseline = day 1).
Changes from baseline in CD4+ count:
The change from baseline in CD4+ count and CD4% at a given time point is defined as: (CD4+/CD4% at
a given time point - baseline CD4+/CD4%).
Participants who discontinued will have their CD4+ values after discontinuation imputed with their baseline
value, thus resulting in a 0 change; For timepoints with intermittently missing data, last observation carried
forward approach is applied (Non-Completer=Failure imputation). Analysis results based on observed data
only will also be presented.
For cases where no observation is available at the baseline date, the last available screening value will be
taken.
In case multiple observations (different sampling dates) are available within a single visit window, only the
one closest to the target day will be selected for the displays to select unique observations per time point
(visit window).
The table shell for snapshot analysis will be presented in the DPS.
5.2.2. 
Analysis Methods
Tabulations (numbers and proportions) per time point by age group (2-<6 years; 6-<12 years) and overall
for the categorical parameters (virologic response, virologic failures); 95% CIs (Clopper-Pearson) for the
virologic response rates over time will be calculated.
Descriptive statistics (n, mean (se), median, and range (minimum and maximum) per time point and
graphical display for the continuous parameters CD4+ cell count and CD4+ (%) (change from baseline) will
be presented. Both observed value as well as imputed values using the NC=F imputation method will be
displayed.
Patient profiles will be provided for viral load and CD4+ counts over time.
5.3. 
Other Efficacy Variables
5.3.1. 
Resistance
HIV-1 Viral Genotyping:
Inclusion of participants for resistance analysis will solely be based on the availability of post-baseline
genotypic data within the treatment phase.
The first and the last post-baseline time point within the treatment phase for which genotypic data are
available will be analyzed and presented.
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Sequencing of HIV-1 protease, reverse transcriptase and integrase will be performed in real time on
plasma for participants with (suspected) virologic failure.
Reverse Transcriptase (RT) resistance associated mutations
- 
IAS-USA NRTI RAMs (n=22)2
M41L, A62V, K65E/N/R, D67N, 69ins, K70E/R, L74V, V75I, F77L, Y115F, F116Y, Q151M, M184I/V,
L210W, T215F/Y, K219E/Q.
- 
Extended NNRTI RAMs (n=53) 2
V90I, A98G, L100I, K101E/H/P/Q, K103H/N/S/T, V106A/I/M/T, V108I, E138A/G/K/Q/R,
V179D/E/F/G/I/L/T, Y181C/I/V, Y188C/H/L, V189I, G190A/C/E/Q/S/T, H221Y, P225H, F227C/L/R,
M230I/L, P236L, K238N/T, L243I, Y318F
- 
RPV RAMs (n=16)
K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L,
H221Y, F227C, M230I, M230L
Protease resistance associated mutations
- 
IAS-USA primary PI RAMs (n=24) 2
D30N, V32I, M46I/L, I47A/V, G48V, I50L/V, I54L/M/V, Q58E, T74P, L76V, V82A/F/L/S/T, N83D,
I84V, N88S, L90M
- 
IAS-USA PI RAMs (n = 75) 2
L10C/F/I/R/V, V11I,  G16E, K20I/M/R/T/V, L24I, D30N, V32I, L33I/F/V, E34Q, M36I/L/V, K43T,
M46I/L, I47A/V, G48V, I50L/V, F53L/Y, I54A/L/M/S/T/V, Q58E, D60E, I62V, L63P, I64L/M/V,
H69K/R, A71I/L/T/V, G73A/C/S/T, T74P, L76V, V77I, V82A/F/I/L/S/T, N83D, I84V, I85V, N88D/S,
L89I/M/V, L90M, I93L/M
Integrase resistance associated mutations (n=27):
- 
T66A/I/K, L74M, E92G/Q, T97A, G118R, F121Y, E138A/K/T, G140A/C/R/S, Y143C/H/R, S147G,
Q148H/K/R, S153F/Y, N155H, R263K
Concordance/discordance with “Virologic Failure” as per FDA Snapshot approach (see section 5.2.1) will
be assessed.
Results will be shown in different columns, unless explicitly specified differently in the DPS:
- 
Non-VF: responder
- 
Non-VF: discontinued due to AE or other reason
- 
VF
- 
Overall
Results from viral genotyping in plasma will be tabulated and described, particularly for participants with
virologic failure.
Individual mutations identified via viral genotyping will be reported relative to the HIV-1 WT reference
sequence.
Retrospective evaluation of RAMs in PBMCs:
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Peripheral Blood Mononuclear Cell (PBMC) sample will be taken to allow retrospective characterization
of archived viral resistance, if needed. Inclusion of participants for archived resistance analysis is based
on the availability of results obtained at screening, Week 24 or Week 48.
Results from archival viral resistance from PBMC sample will be tabulated and described, particularly for
participants with virologic failure.
6. 
SAFETY
All safety analyses will be based on the FAS. Selected outputs will be generated separately for the first 4
weeks of treatment.
For all continuous safety variables, descriptive statistics will include the N, mean, standard deviation,
median,  minimum, and maximum. Categorical variables will be summarized using frequency counts and
percentages. For laboratory, ECG and vital sign results, an abnormality is considered treatment-emergent
if it is worse than baseline. If baseline is missing, the abnormality is always considered treatment-emergent.
For pulse, a shift from ‘abnormally low’at baseline to ‘abnormally high’ post-baseline (or vice versa) is
also treatment-emergent.
Safety data will be presented by age group (2-<6 years; 6-<12 years) and overall, unless explicitly specified
differently in the DPS.
6.1. 
Adverse Events (AE)
Adverse Event (AE): An AE is any untoward medical occurrence in a clinical study participant administered
a medicinal (investigational or non-investigational) product
The verbatim terms used in the Case Report Form (CRF) by investigators to identify adverse events will be
coded using the Medical Dictionary for Regulatory Activities (MedDRA 24.1 or latest).
Any AE occurring at or after the initial administration of RPVthrough the day of last dose is considered to
be treatment emergent. If the event occurs on the day of the initial administration of RPV, and either event
time or time of administration are missing, then the event will be assumed to be treatment emergent. If the
event date is recorded as partial or completely missing, then the event will be considered to be treatment
emergent unless it is known to be prior to the first administration of RPV based on partial onset date or
resolution date.
All reported treatment-emergent adverse events will be included in the analysis. For each adverse event,
the number and percentage of participants who experience at least 1 occurrence of the given event will be
summarized by age group (2-<6 years; 6-<12 years) and overall.
Summary tables will be provided for all treatment-emergent:
 
AEs
 
SAEs
 
AEs leading to discontinuation of RPV
 
AEs leading to dose interruption of RPV
 
AEs by severity
 
AEs by relationship to RPV
In addition to the summary tables, listings will be provided for participants who had:
 
SAEs
 
AEs leading to discontinuation of RPV
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 
HIV-related AEs
 
Stage 3-defining Opportunistic Illnesses in HIV infection  (see Attachment 3: STAGE-3-
DEFINING OPPORTUNISTIC ILLNESSES IN HIV INFECTION)
A listing of participants who died during the study will be provided.
Overall AE summary tables by preferred term/SOC for SAEs and pregnancies, AEs leading to
discontinuation, AEs at least grade 3, HIV-related AEs, stage 3-defining Opportunistic Illnesses in HIV
infection and AEs at least possibly related to RPV will be presented throughout the treatment phase only;
any AEs in the Follow-up phase will be listed only.
Number of occurrences of an AE:
Number of recorded events of the same preferred term, during the trial phase. Combined events (i.e.
within the same phase) will be counted only once.
AE grading:
Reported AEs parameters and grades are based on the Division of AIDS Table for Grading the Severity of
Adult and Pediatric Adverse Events (ATTACHMENT 1: DAIDS GRADING TABLE).
AE duration.
For the calculation of duration of AEs, only AEs are considered with complete start and end date or for
which the end date is imputed (see STEP 1 for imputation of end date).
Duration is calculated as End date –Start date +1
Onset day of AE:
- 
after start of investigational medication = first start date of the AE –first intake date of
investigational medication + 1 day. In case of combined events, the onset day will be computed only
once, and relative to the start date of the first event.
- 
in the phase = first start date of the AE –start date of the phase in which the AE emerges + 1 day. In
case of combined events, the onset day will be computed only once, and relative to the start date of
the first event.
Adverse Events of Interest (EOI):
Different events of interest will be investigated separately.  A list of Events of Interest (EOI) is
maintained at Janssen Infectious Diseases which is updated (if necessary) based on accumulating AE data
from both RPV Adult Phase III studies. A list of EOI for analysis purposes will be provided prior to the
database lock.  The different classes of events of interest that should be investigated are the following:
- 
Skin events of interest: The skin events of interest will be defined based on the adverse event
preferred terms and will be summarized using alternative groupings: ‘Dermatitis Contact’,
‘Dermatitis / Eczema’, ‘Oedema’, ‘Rash’, ‘Rash Vesicular’, ‘Other’.
- 
Neuropsychiatric events ofinterest: Neuropsychiatric events of interest will be defined based on
the adverse event preferred terms and will be summarized using alternative groupings: ‘Nervous
System Disorders’, ‘Psychiatric Disorders’. Under the ‘Psychiatric Disorders’ an extra row will
be included, namely the combination of “ABNORMAL DREAMS” or “NIGHTMARES”.
- 
Potential QT prolongation-related events: selection of preferred terms is based on a MedDRA
standardized query for “Torsade de pointes/QT prolongation”
- 
Hepatic events of interest: Hepatic events of interest will be defined based on the adverse event
preferred terms.
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- 
Endocrinology events of interest: These are defined as all endocrinology events categorized under
the system organ class ‘ENDOCRINE DISORDERS’ or all AEs categorized under the system
organ class ‘INVESTIGATIONS’ related to any of the endocrine analytes measures (cortisol, 17-
OH progesterone, aldosterone, dehydroepiandrosterone (DHEAS), androstenedione, testosterone)
in the trial.
- 
AIDS defining Illnesses and Stage-3-defining Opportunistic Illnesses in HIV Infection: All
adverse events classified as CDC Stage 3 and Stage-3-defining Opportunistic Illnesses.
6.2. 
Clinical Laboratory Tests
All clinical laboratory tests will be displayed for the participants included in the FAS. Results from central
laboratory testing (Covance/Labcorp) will be included in the analysis; results from local laboratories will
not be included in the analysis, only listed.
Observed and change from baseline to each scheduled time point will be summarized descriptively for
laboratory tests and displayed by age group (2-<6 years; 6-<12 years) and overall.
The laboratory tests will be grouped as follows:
1) General biochemistry (albumin, blood urea nitrogen, calcium, calcium adjusted for albumin, chloride,
phosphate, creatinine, potassium, sodium, uric acid, creatinine phosphokinase, …)
2) Pancreatic Parameters (pancreatic amylase, lipase)
3) Renal Parameters (serum creatinine, eGFR (creatinine), …)
4) Hepatic parameters (ALT, AST, gamma-GT, alkaline phosphatase, LDH, bilirubin (all types), total
protein…)
5) Lipids and glucose (cholesterol, HDL cholesterol (HDL-C) (all types), LDL cholesterol (LDL-C) (all
types), TC/HDL-C, insulin, glucose, triglycerides, …)
6) General hematology (Hematocrit, hemoglobin, red blood cell count, mean corpuscular volume (MCV),
mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC),
platelet count, white blood cell count)
7) Hematology differential counts (Basophils, eosinophils, lymphocytes, monocytes, neutrophils (counts
and %), …)
8) Endocrinology 
(Cortisol, 
17-hydroxyprogesterone, 
dehydroepiandrosterone 
(DHEAS),
androstenedione, testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH))
Toxicity grades:
Toxicity grades are determined according to the DAIDS grading list (ATTACHMENT 1: DAIDS
GRADING TABLE). In case no toxicity grades are defined for a test, the abnormalities (above/below
normal range) are used. In determining toxicity grades, the following rules are applied:
- 
Laboratory values are rounded to the same number of decimals as the DAIDS grading, and the
rounded value is used to allocate a grading to the value.
- 
There is no overruling of the DAIDS grades when the value is between the normal limits
- 
In case no numeric value is available, but only a verbatim term (e.g. PTT>120) then the numeric
value will be derived by determining the closest value to the cut-off value, taking into account the
usual number of decimals for the particular parameter, in order to be able to allocate a grade to
these observations.
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- 
Note: as the grading scale for some parameters in the DAIDS grading table has some gaps (zones
where no toxicity grade definition exists), laboratory results falling in these zones are allocated to
the immediate worst-case grade.
Cross-tabulations for the worst toxicity grades versus reference per laboratory test will be reported.
Endocrine safety: Adrenocorticotropic hormone (ACTH) stimulation testing
Abnormal ACTH response:
The ACTH test result will be categorized into the following categories:
1) Maximum cortisol measurement (time points T0 and T60) ≥ 500 nmol/L
2) Maximum cortisol measurement (time points T0 and T60) [450; 500[ nmol/L
3) Maximum cortisol measurement (time points T0 and T60) < 450 nmol/L
Cross-tabulations for on-treatment ACTH stimulation test abnormalities (defined as cortisol after ACTH
stimulation < 500 nmol/L) will be reported for following time points: last on-treatment measurement, worst
on-treatment measurement.
Endocrine safety (cortisol and 17-hydroxyprogesterone) will be summarized per analysis time point for
following measurements: T0, T60. In addition, abnormal basal cortisol (defined as <248 nmol/L) will be
tabulated per analysis time point.
6.3. 
Vital Signs and Physical Examination Findings
Continuous vital sign parameters including height, weight, pulse, blood pressure (systolic and diastolic),
and BMI will be summarized at each assessment time point. BMI will be calculated as weight (kg)/(height
(m))2, at each time point that body weight is measured.
Observed and change from baseline will be summarized by age group (2-<6 years; 6-<12 years) and overall.
Descriptive statistics (mean, standard deviation, median, minimum and maximum) will be presented.
Incidence of markedly abnormal vital signs while on treatment, as defined in Table 5, will be summarized
for participants who had a baseline assessment and at least 1 postbaseline assessment for that vital sign.
Table 5: Markedly Abnormal Vital Signs
Vital Sign 
Criteria
Pulse 
≥ 120 bpm for higher limit
≤ 50 bpm for lower limit
Systolic blood pressure 
Grade 1:  >120 mmHg
Grade 2:  ≥95th  to <99th  percentile +5 mmHg adjusted for age, height, and
gender (systolic and/or diastolic)
Grade 3: ≥99th percentile +5 mmHg adjusted for age, height, and gender
(systolic and/or diastolic)
Diastolic blood pressure 
Grade 1:  >80 mmHg
Grade 2:  ≥95th  to <99th  percentile +5 mmHg adjusted for age, height, and
gender (systolic and/or diastolic)
Grade 3: ≥99th percentile +5 mmHg adjusted for age, height, and gender
(systolic and/or diastolic)
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To classify vital sign measurements into abnormality codes, the following approach is used:
An absolute blood pressure measurement is translated into a blood pressure percentile (cf table provided
in Attachment 2: BLOOD PRESSURE LEVELS BY AGE AND HEIGHT PERCENTILES)
based on the participant's age and height percentile (= height-for-age percentiles at the time of the blood
pressure measurement).
For calculation of height-for-age percentiles, see SAS programs available from
http://www.who.int/childgrowth/software/en/ (up to 5 years of age) and
http://www.who.int/growthref/tools/en/ (from 5 to 19 years of age).
Last-Observation-Carried-Forward (LOCF) imputation will be used for missing height percentiles. In case
a participant's height percentile does not exactly match a value reported in attachment 2, calculated
height-for-age percentiles are translated into values available in attachment 2 as follows:
Calculated height-for-age percentile Height Percentile
1 - 7 
5
8 - 17 
10
18 - 37 
25
38 - 62 
50
63 - 82 
75
83 - 92 
90
93 - 100 
95
Also, occurrence of orthostatic hypotension will be summarized, defined as:
supine SBP –standing SBP ≥ 20 mmHg OR
supine DBP –standing DBP ≥ 10 mmHg
Physical Examination:
Physical examination findings will be summarized at each scheduled time point with full physical
examination per body system by age group (2-<6 and 6-<12 years) and overall.
Physical examination abnormalities will be listed.
Growth Examination:
Growth will be followed regularly and evaluated consistently using WHO standardized growth charts, using
age at visit.
 
Height (cm)
 
Height-for-age (z-score and percentile)
 
Weight (kg)
 
Weight-for-age (z-score and percentile)
 
BMI = weight (kg)/ (height (m))2
 
BMI-for-age (z-score and percentile)
Observed and change from baseline will be summarized for by age group (2-<6 and 6-<12 years) and
overall. Descriptive statistics (mean, standard deviation, median, minimum and maximum) will be
presented.
Tanner Stage:
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Tanner stage (for pubic hair and genitalia/breasts) will be cross-tabulated versus baseline by age. In
addition, in girls, the occurrence of first menses during treatment will also be cross-tabulated versus
baseline, and the date of menarche will be listed.
6.4. 
Electrocardiogram
All ECG parameters will be displayed for the participants included in the FAS. No statistical testing will
be performed. In addition, for QTcB/F at pre-dose and post-dose at Week 4, 24, and 48 will be analyzed as
separate time points.
The ECG parameters that will be analyzed are heart rate, PR interval, RR interval, QRS interval, QT
interval, QTcB and QTcF using the following correction methods: Bazett’s formula (QTcB), Fridericia’s
formula (QTcF).
Bazett’s formula: QTcB (ms) =
1000
/
)
(
)
(
ms
RR
ms
QT
Fridericia’s formula: QTcF (ms) =
3 
1000
/
)
(
)
(
ms
RR
ms
QT
* If RR is missing, it will be derived from HR (see formula below) if this is parameter is available from
the same ECG reading as the QT. HR from the Vital Signs dataset will not be used to calculate the
corrected QT parameters.
)
(
60
*
1000
) 
(
bpm
HR
ms
RR
QT corrections will be re-computed even if they are provided.
Observed and change from baseline to each scheduled time point will be descriptively summarized by dose
and weight group and overall for the above ECG parameters.
A listing of clinically relevant ECG results will also be provided.
The number and percentage of participants within each of the categories defined below will be presented
for the maximum postbaseline value (ie: the maximum ECG result over the study period) by dose and
weight group, and overall.
Categories to assess QT prolongation:
QTc Interval: QTcB criteria are based on DAIDS 2017 (see the study protocol Addendum 2: DAIDS Table)
and QTcF criteria are from MOCHA/CRAYON protocol:
 
Normal:
QTcF: <460 ms
QTcB: <450 ms
 
Grade 1:
QTcF: ≥460 to <480 ms
QTcB: >450 to <470 ms
 
Grade 2:
QTcF: ≥480 to < 500 ms
QTcB: >470 to < 500 ms
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 
Grade 3:
QTcF: ≥500 ms OR QTcF ≥480 ms AND QTcF > 60 ms greater than baseline
QTcB: > 500 ms OR QTcB ≥60 ms greater than baseline
 
Grade 4:
QTcF/B: Life-threatening consequences: eg, Torsades de pointes, other serious ventricular
dysrhythmias.
QTcF change from baseline:
 
normal: <30 ms
 
borderline: ≥30 to ≤60 ms
 
abnormal high: >60 ms
QTcB change from baseline:
 
normal: <30 ms
 
borderline: ≥30 to ≤60 ms
 
abnormal high: >60 ms
7. 
PHARMACOLOGY
7.1. 
Population Pharmacokinetics
Population pharmacokinetic parameters (AUC24h  and C0h; based on sparse sampling) will be available for
all participants.
Pharmacokinetic/Pharmacodynamic Relationships
PK and Efficacy
Scatterplot of individual PK parameters (AUC24h and C0h) by virologic response (plasma viral load <50/400
copies/mL) as well as virologic failure (HIV RNA ≥50/400 copies/mL) using FDA Snapshot (yes/no) at
Week 24/Week 48, will be created.
PK and Safety
Relationship between RPVpharmacokinetics (AUC24h  only) and the following AE groups / abnormalities
will be explored graphically by the means of scatterplots.
 
Rash (yes/no) (The skin event of interest alternative grouping of ‘Rash’ will be used.)
 
All neuropsychiatric events of interest combined (yes/no)
 
Combined AEs in the Nervous System Disorders alternative grouping (yes/no)
 
Combined AEs in the ‘Psychiatric Disorders’ SOC (yes/no)
 
Combined AEs in the ‘Gastrointestinal Disorders’ SOC (yes/no)
 
Combined AEs in the ‘Blood and Lymphatic Disorders’ SOC (yes/no)
 
Combined AEs with preferred terms ‘abnormal dreams’, ‘vivid dreams’, ‘nightmare’ (yes/no)
 
Dizziness (yes/no)
 
Headache (yes/no)
 
QTcF abnormalities (yes/no), both based on absolute values and changes from baseline (section
6.4)
Scatterplots of individual PK parameter values (AUC24h  only) by specific laboratory/ECG parameters
(change from baseline), presented in the following table, will be shown.
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Biochemistry  
Lipids 
Hematology  
Glucose 
metabolism
ECG
ALT ([max]) 
HDL ([min]) 
Hemoglobin ([min]) 
Glucose ([max]) 
QTcF
([max])
AST ([max]) 
LDL ([max]) 
Hematocrit ([min]) 
Insulin ([min])
Total bilirubin  
([max]) 
Triglycerides 
([max])
HOMA-IR ([max])
Alkaline phosphatase 
([max]) 
Total cholesterol
([max])
Pancreatic amylase 
([max]) 
Total cholesterol /
HDL ([min])
Lipase ([max])
Creatinine ([max])
eGFR (creatinine)
([min])
Endocrine (Cortisol, 17-OH Progesterone)
Cortisol 
17-OH Progesterone 
Aldosterone
morning/T0 (non-ACTH) 
([min]) 
morning/T0 (non-ACTH) 
([max])
morning/T0 (non-ACTH) ([min])
[min] or [max] indicates which value to use, i.e. either the smallest or largest value respectively
7.2. 
Other Pharmacology Endpoints
Palatability:
The palatability of the 2.5 mg RPV tablet formulation will be assessed in a palatability questionnaire after
a 2-week treatment period by documenting the participant’s perception using a 5-point hedonic scale.
The number and percentage of participants within each of the categories, as well as cumulatively (from best
to worst) will be presented by age group (2-<6 years; 6-<12 years) and overall.
Swallowability:
The swallowability of the RPV 25-mg tablet formulation will be assessed in a swallowability questionnaire
after a 2-week treatment period by documenting the participant’s reaction when he or she is given the 25 mg
tablet formulation of RPV medication.
The number and percentage of participants within each of the response to two questions (ease of
swallowing, acceptability longer term) will be presented by age group (2-<6 years; 6-<12 years) and overall.
Similarly, responses by the observer (how tablet was taken, reported problems, whether second attempt was
needed) will be tabulated.
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REFERENCES
1. 
http://www.cdc.gov/growthcharts
2. 
Wensing AM, Calvez V, Ceccherine-Silberstein, et al. 2019 update of the drug resistance mutations in HIV-1.
Top Antivir Med Sep/Oct 2019; 27(3):111-121
3. 
NPR-20060022-VRR v7.0
4. 
Bennett DE, Camacho RJ, Otelea D, Kuritzkes DR, Fleury H, et al. 2009 Drug Resistance Mutations for
Surveillance of Transmitted HIV-1 Drug-Resistance: 2009 Update. PLoS ONE 4(3): e4724.
doi:10.1371/journal.pone.000472
5. 
H C Bazett: An analysis of the time-relations of electrocardiogram; Heart 1920; 7: 353 –370.
6. 
L S Fridericia: Die systolendauer im elektrokardiogramm bei normalen menchen und bei herzkranken; Acta
Med Scand 1920; 15: 335 –642.
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ATTACHMENTS
ATTACHMENT 1: DAIDS GRADING TABLE
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC
ADVERSE EVENTS, CORRECTED VERSION 2.1, PUBLISH DATE: JULY 2017
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ATTACHMENT 2: BLOOD PRESSURE LEVELS BY AGE AND HEIGHT
PERCENTILES
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ATTACHMENT 3: STAGE-3-DEFINING OPPORTUNISTIC ILLNESSES IN HIV
INFECTION
Bacterial infections, multiple or recurrent*
Candidiasis of bronchi, trachea, or lungs
Candidiasis of esophagus
Cervical cancer, invasive†
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (>1 month's duration)
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy attributed to HIV§
Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or esophagitis (onset
at age >1 month)
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1 month's duration)
Kaposi sarcoma
Lymphoma, Burkitt (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary
Mycobacterium tuberculosis of any site, pulmonary†, disseminated, or extrapulmonary
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
Pneumocystis jirovecii (previously known as "Pneumocystis carinii") pneumonia
Pneumonia, recurrent†
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain, onset at age >1 month
Wasting syndrome attributed to HIV§
* Only among children aged <6 years.
† Only among adults, adolescents, and children aged ≥6 years.
§ Suggested diagnostic criteria for these illnesses, which might be particularly important for HIV
encephalopathy and HIV wasting syndrome, are described in the following references:
CDC. 1994 Revised classification system for human immunodeficiency virus infection in children less
than 13 years of age. MMWR 1994;43(No. RR-12).
CDC. 1993 Revised classification system for HIV infection and expanded surveillance case definition
for AIDS among adolescents and adults. MMWR 1992;41(No. RR-17).
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