Clinical trial NCT00799864
Conditions: HIV-1
Keywords: HIV Infection Antiretroviral HIV-1 AIDS Children Rilpivirine (TMC278) Pediatric
Sponsor: Janssen Sciences Ireland UC
Start date: 2011-01-01; Completion date: 2022-08-01
Enrollment: 54 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the pharmacokinetics, safety and antiviral activity of rilpivirine (TMC278) 25 milligram (mg) or adjusted dose once daily in combination with an investigator-selected background regimen containing 2 nucleoside/nucleotide reverse transcriptase inhibitors (N\[t\]RTIs) (zidovudine \[AZT\], abacavir \[ABC\], or tenofovir disoproxil fumarate \[TDF\] in combination with lamivudine \[3TC\] or emtricitabine \[FTC\] in antiretroviral (ARV) treatment-naïve adolescents and children aged greater than or equal to (\>=) 6 to less than (\<) 18 years.

Detailed description:
This is a Phase II, open-label (all people involved know the identity of the assigned drug) and single arm study. The study will consist of a screening period of maximum 8 weeks, an initial treatment period of 48 weeks, a post week 48 treatment extension period of 4 years (Cohort 1 only), and a 4 week follow-up (cohort 2 only) period. Participants who withdraw from the trial on or before the Week 48 visit or subjects with ongoing (serious) adverse events (\[S\]AEs), laboratory abnormalities, or viral load increase at the last on-treatment visit in the extension, will be seen for a follow-up visit 4 weeks later. The initial 48-week treatment period will be structured into 2 age Cohorts; Cohort 1 (Aged greater than or equal to \[\>=\] 12 to less than \[\<\] 18 years) and Cohort 2 (Children Aged \>= 6 to \< 12 years). The trial is designed to evaluate the steady-state pharmacokinetic (PK) profile (based on intensive PK analysis) and the short-term safety and antiviral activity of rilpivirine (RPV). Participants will receive RPV 25 milligram (mg), or weight-adjusted dose orally once daily for 240 weeks when administered in combination with 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). The trial will also evaluate long-term (48 weeks and 240 weeks \[Cohort 1\]) safety, efficacy, and pharmacokinetics of rilpivirine in combination with the background regimen of 2 NRTIs. Patients safety will be monitored throughout the study and during the follow up visits.

Arms: arm 1: The patients received rilpivirine with 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) as a background regimen in cohort 1 \[aged greater than or equal to (\> =) 12 to less than (\<) 18 years\] for up to 240 weeks which is already completed and recruitment closed and will receive this treatment in cohort 2 (children aged \> = 6 to \< 12 years) for up to 48 weeks. The NRTIs include zidovudine, abacavir, or tenofovir disoproxil fumarate in combination with lamivudine or emtricitabine.
Interventions: intervention 1: Rilpivirine intervention 2: Zidovudine intervention 3: Abacavir intervention 4: Tenofovir disoproxil fumarate intervention 5: Lamivudine intervention 6: Emtricitabine
Intervention descriptions: intervention 1: Patients will receive rilpivirine (RPV) tablet 25 milligram dose or an adjusted dose orally once daily in Cohort 1 (adolescents aged \>=12 to \<18 years) up to 240 weeks. Patients will receive RPV weight-adjusted dose orally once daily in Cohort 2 (children aged \>=6 to \<12 years) or 25 mg once daily for up to 48 weeks. intervention 2: Type=exact, form= appropriate pediatric formulation, unit=mg, route=oral. The patients may receive this selected NRTI together with another NRTI once daily for up to 48 weeks (Cohort 2) and 240 weeks (Cohort 1). intervention 3: Type=exact, form=appropriate pediatric formulation, unit=mg, route=oral. The patients may receive this selected NRTI together with another NRTI once daily for up to 48 weeks (Cohort 2) and 240 weeks (Cohort 1). intervention 4: Type=exact, form=appropriate pediatric formulation, unit=mg, route=oral. The patients may receive this selected NRTI together with another NRTI once daily for 240 weeks (Cohort 1). intervention 5: Type=exact, form=appropriate pediatric formulation, unit=mg, route=oral. The patients may receive this selected NRTI together with another NRTI once daily for up to 48 weeks (Cohort 2) and 240 weeks (Cohort 1). intervention 6: Type=exact, form=appropriate pediatric formulation, unit=mg, route=oral. The patients may receive this selected NRTI together with another NRTI once daily for up to 48 weeks (Cohort 2) and 240 weeks (Cohort 1).

Protocol documents:
Prot_000.pdf: 
TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
1
Approved, Issued Date: 03-FEB-2020
Clinical Trial Protocol Amendment 
GEN-X
Project no:
TMC278-TiDP38
Department:
Clinical R&D
Nonproprietary name:
rilpivirine hydrochloride
Status:
Approved
Issued Date:
03-FEB-2020
Protocol Title:
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
Trial no:
TMC278-TiDP38-C213
Clinical Phase:
II
Sponsor
Janssen Research & Development*
NCT00799864


TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
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Approved, Issued Date: 03-FEB-2020
Summary:
This is a Phase II, open label, single arm trial to evaluate the 
pharmacokinetics, safety, tolerability and efficacy of rilpivirine (RPV, 
previously known as TMC278) 25 mg once daily (q.d.) or an adjusted dose 
of RPV (q.d.) in combination with an investigator-selected background 
regimen containing 2 nucleoside/nucleotide reverse transcriptase inhibitors 
(N[t]RTIs) (zidovudine [AZT], abacavir [ABC], or tenofovir disoproxil 
fumarate [TDF] in combination with lamivudine [3TC] or emtricitabine 
[FTC], whichever is approved and marketed or considered local standard of 
care) in antiretroviral (ARV) treatment-naïve adolescents and children aged 
!6 to <18 years.
The trial will consist of a screening period of maximum 8 weeks, an initial 
treatment period of 48 weeks, and a post Week 48 treatment extension period 
of 4 years. As of Amendment 10, the post Week 48 treatment extension 
period of 4 years is removed for Cohort 2, children ≥6 to <12 years of age.
Subjects who withdraw from the trial on or before the Week 48 visit or 
subjects with ongoing (serious) adverse events ([S]AEs), laboratory 
abnormalities, or viral load increase at the last on-treatment visit in the 
extension, will be seen for a follow-up visit 4 weeks later. Additional 
unscheduled visits may be performed for safety/tolerability reasons and for 
confirmation of plasma viral load results.
Recruitment and analyses of the initial 48-week treatment period will be 
structured into 2 age cohorts: Cohort 1, adolescents ≥12 to <18 years of age; 
Cohort 2, children ≥6 to <12 years of age.
Cohort 1 (≥12 to <18 Years of Age):
As of Amendment 10, Cohort 1, adolescents ≥12 to <18 years of age, has 
been completed. Therefore, all sections related to Cohort 1 are removed from 
the summary and greyed out from the body of text for ease of reading.
Cohort 2 (!6 to <12 Years of Age): 
To accommodate regulatory requirements concerning the evaluation of RPV 
in the pediatric population, overall across studies C213 (Cohort 2; children 
aged ≥6 to <12 years) and TMC278HTX2002 (children aged ≥2 to <12 years 
with a body weight of ≥11 kg), approximately 40 subjects will be enrolled of 
which at least 12 subjects with a body weight of <25 kg, including at least 7 
subjects with a body weight of <20 kg. The PK data from Cohort 2 will be 
combined with the data from pediatric study TMC278HTX2002. 
The analysis of the first 10 subjects in Cohort 2, including PK modeling and 
simulation to further assess the RPV pediatric dose based on accumulating 
data, was discussed with and endorsed by the IDMC. With this, at the time 
NCT00799864


TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
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Approved, Issued Date: 03-FEB-2020
of Amendment 10, the following RPV dose recommendations will apply to 
newly enrolled subjects:
∀
RPV 25 mg q.d. for subjects with a body weight of ≥25 kg 
∀
RPV 15 mg q.d. for subjects with a body weight of <25 kg
All ongoing subjects in Cohort 2 (who are already in the post Week 48
treatment extension period at the time of Amendment 10) will remain on 
the RPV 25 mg q.d. dose + 2 N(t)RTIs (investigator-selected), until their 
roll-over to study TMC278IFD3004 has been completed (see addendum 
7.11). All newly recruited subjects will start treatment with the weight-
appropriate RPV dose stated above + 2 N(t)RTIs (investigator-selected), until 
they reach a total treatment duration of 48 weeks, or discontinue earlier. If 
newly recruited subjects, with a body weight of <25 kg, increase in weight 
such that they require a 25 mg RPV dose, they can change to the 25 mg tablet 
formulation.
To further evaluate and confirm the RPV dose for subjects with lower body 
weight, newly enrolled subjects with a body weight of <25 kg require 
intensive 
PK 
evaluation. 
An 
overall 
analysis 
of 
the 
intensive 
pharmacokinetic data and all available safety, tolerability and antiviral 
activity/efficacy data will be reviewed by the Sponsor and the IDMC to 
assess appropriateness of the dose (see section 6.1.1.2.1 for dose evaluation 
criteria).
∀
If the results are not deemed satisfactory, and no alternative RPV 
dose seems feasible, all subjects will be seen for a Withdrawal visit, 
treatment with RPV will be stopped, subjects will be switched to 
local standard of care, and Cohort 2 will be stopped. 
∀
If the results are not deemed satisfactory but concerns can be 
addressed by adjusting the RPV dose (doses of >25 mg q.d. are not 
allowed) for certain subjects (e.g. up to a certain body weight), those 
subjects will be switched to an adjusted dose, while those that don't 
need dose adjustment, will continue their treatment. For all subjects 
who require an RPV dose adjustment, a 24-hour intensive 
pharmacokinetic evaluation after 14 to 18 days on the adjusted dose 
will be performed. After the subjects have been treated with the 
adjusted RPV dose for at least 4 weeks or discontinued earlier, an 
analysis of the intensive pharmacokinetic data (after 14 to 18 days of 
RPV dosing), and all available safety, tolerability and antiviral 
activity/efficacy data will be reviewed. If, after review of the data, the 
RPV dose is still not acceptable, the process will be repeated until an 
acceptable RPV dose is found or it is deemed necessary to stop 
NCT00799864


TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
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Approved, Issued Date: 03-FEB-2020
Cohort 2.
Post Week 48 Treatment Extension  Cohort 2 (!6 to <12 Years of Age):
For subjects enrolling in Cohort 2 as of Amendment 10, the post Week 48 
treatment extension has been removed. 
Subjects who experience and are expected to continue experiencing clinical 
benefit from RPV and their background regimen comprising 2 investigator-
selected N(t)RTIs at the end of the initial 48-week treatment period, or 
ongoing subjects who are already in the post Week 48 treatment extension 
period at the time of Amendment 10, may continue treatment (i.e., RPV + 
2 N[t]RTIs)  in the roll-over study TMC278IFD3004 or 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.
Study Treatment (Cohort 2):
All ongoing subjects in Cohort 2 (who are already in the post Week 48
treatment extension period at the time of Amendment 10) will remain on 
the RPV 25 mg q.d. dose + 2 N(t)RTIs (investigator-selected), until their 
roll-over to study TMC278IFD3004 has been completed (see addendum 
7.11). For newly recruited subjects as of Amendment 10, the ART will 
consist of RPV
(weight-based dosing)
and an investigator-selected 
background regimen containing 2 N(t)RTIs. The investigator-selected 
N(t)RTIs will be AZT, ABC, or TDF in combination with 3TC or FTC, 
given as the co-formulation or as the separate components, whichever is 
approved and marketed or considered local standard of care for children aged 
!6 to <18 years in a particular country. Only branded versions of the 
N(t)RTIs, or generics with tentative US FDA approval and/or WHO 
prequalified drugs, are to be prescribed by the investigator. If not available,
generic drugs approved by the local Health Authorities or drugs procured by 
the UN international organizations (i.e., UNICEF) can be allowed upon 
approval by the sponsor.
Investigator:
See local Informed Consent Form
Site Address:
See local Informed Consent Form
Treatment: 
48 weeks + post Week 48 treatment extension of 192 weeks, if applicable
(excluding max. 8 weeks screening and 4 weeks follow-up).
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TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
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Protocol Historya
TMC278-TiDP38-C213
Document Type and
File Name
Issue Date
Amendement
Type
Comments
Initial Clinical Trial Protocol 
TMC278-C213-CTP
12-Aug-2008
-
-
Clinical Trial Protocol 
Amendment I
TMC278-C213-CTPA-GEN-I
05-Aug-2009
Substantial
Mainly: Change in withdrawal 
criteria related to virologic failure, 
withdrawal of consent and grade 3 
or 4 glucose elevations; change in 
inclusion 
criterion 
regarding 
minimum body weight necessary 
for 
inclusion; 
additional 
assessments 
of 
17-
hydroxyprogesterone, aldosterone, 
FSH, 
LH, 
progesterone, 
androstenedione, 
testosterone, 
DHEAS at Week 12 and 24; no 
ACTH test to be performed in case 
of withdrawal from trial because of 
pregnancy; reduce total volume of 
blood drawn over the entire trial; 
update 
of 
safety 
monitoring 
guidance 
in 
case 
of 
signs/symptoms 
of 
adrenal 
insufficiency; 
additional 
measurement of CD4+ cell count at 
Week 12; follow-up visit necessary 
in case of ongoing AEs at Week 48 
or early withdrawal from the trial; 
optional 4-year extension of RPV 
treatment after Week 48; height no 
longer determined at all visits; 
terminology of glomerular filtration 
rate to be used instead of creatinine 
clearance; 
correct 
mistake 
in 
NNRTI list in exclusion criterion; 
specification 
that 
the 
data 
monitoring committee will not 
include Sponsor representatives, 
only external experts; Other minor 
corrections 
for 
accuracy, 
consistency, clarification.
First Revised Clinical Trial 
Protocol
TMC278-C213-CTP-v2
05-Aug-2009
-
Integrates the Initial CTP and 
CTPA GEN I.
                                                          
a This overview lists general amendments to the protocol only. Site and country specific amendments to the protocol 
are not included.
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TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
Approved, Issued Date: 03-FEB-2020
Protocol Historya
TMC278-TiDP38-C213
Document Type and
File Name
Issue Date
Amendement
Type
Comments
Clinical Trial Protocol 
Amendment II
TMC278-C213-CTPA-GEN-II
20-May-2010
Substantial
This 
amendment 
implements 
following changes:
It allows subjects to switch to a 
weight-adjusted dose, if needed, it
allows
tenofovir 
disoproxil 
fumarate (TDF) and emtricitabine 
(FTC) 
as 
investigator-selected 
background regimen and it aligns 
changes with the latest EMA 
Decision 
on 
the 
Pediatric 
Investigational Plan (PIP).
Second Revised Clinical Trial 
Protocol
TMC278-C213-CTP-v3
10-Sep-2010
-
Integrates the First Revised CTP 
and CTPA GEN II.
Clinical Trial Protocol 
Amendment III
TMC278-TiDP38-C213-
CTPA-GEN-III
29-Jun-2011
Substantial
This amendment implements the 
following changes: 
a 4-year post Week 48 treatment 
extension provided through this 
trial; first part of this trial covers 
Part 1a and Part 1b to collect 
pharmacokinetic, 
safety, 
and 
efficacy data in a small cohort 
before proceeding with Part 2; 
change in inclusion criterion with 
regards to baseline viral load; 
update of Phase IIb and Phase III 
data in adults; option to prolong the 
screening period; clarification that 
N(t)RTI combinations other than 
ABC/3TC, 
AZT/3TC, 
and 
TDF/FTC are allowed; treatment 
adherence 
counseling 
(and 
checking 
of 
adherence 
if 
applicable) required at every visit; 
update of time points for statistical 
analyses; administrative and textual 
changes and corrections.
Third Revised Clinical Trial 
Protocol
TMC278-C213-CTP-v4
06-Jul-2011
-
Integrates the Second Revised CTP 
and CTPA GEN-III.
Clinical Trial Protocol 
Amendment IV
TMC278-C213-CTPA-GEN-IV
02-Feb-2012
Non-
Substantial
See Protocol Amendments Section
for details.
Clinical Trial Protocol 
Amendment V
TMC278-C213-CTPA-GEN-V
29-Aug-2013
Non-
Substantial
See Protocol Amendments Section 
for details.
Clinical Trial Protocol 
Amendment VI
TMC278-
C213_Protocol_Amend_6
08-Oct-2015
Substantial
See Protocol Amendments Section 
for details.
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TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
Approved, Issued Date: 03-FEB-2020
Protocol Historya
TMC278-TiDP38-C213
Document Type and
File Name
Issue Date
Amendement
Type
Comments
Clinical Trial Protocol 
Amendment VII
TMC278-
C213_Protocol_Amend_7
18-Dec-2015
Substantial
See Protocol Amendments Section 
for details.
Clinical Trial Protocol 
Amendment VIII
TMC278-
C213_Protocol_Amend_8
01-Dec-2016
Substantial
See Protocol Amendments Section 
for details.
Clinical Trial Protocol 
Amendment IX
TMC278-
C213_Protocol_Amend_9
20-Mar-2018
Substantial
See Protocol Amendments Section 
for details.
Clinical Trial Protocol 
Amendment X
TMC278-
C213_Protocol_Amend_10
This document
Substantial
See Protocol Amendments Section 
for details.
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TMC278-TiDP38-C213
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 8
PROTOCOL AMENDMENTS..................................................................................................................... 12
PART 1.
CLINICAL TRIAL PROTOCOL ................................................................................................33
1.
GLOSSARY....................................................................................................................................... 33
List of Abbreviations.................................................................................................................................... 33
2.
FLOWCHART.................................................................................................................................... 36
2.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years..............................................................................36
2.1.1.
Flowchart for All Assessments in Cohort 1 (Screening, Initial Treatment Period, Post 
Week 48 Treatment Extension, and Follow-up) ......................................................................... 36
2.1.1.1.
Flowchart for Assessments up to Week 4 in Cohort 1 (Screening and Initial 
Treatment Period up to Week 4) .............................................................................................36
2.1.1.2.
Flowchart for Switch to Weight-adjusted Dose in Cohort 1, Part 1 Only (If Applicable).......... 39
2.1.1.3.
Flowchart for Assessments From Week 8 Onwards in Cohort 1 (Initial Treatment 
Period From Week 8 Onwards, Post Week 48 Treatment Extension, and Follow-up) ........... 41
2.1.2.
Flowchart for Intensive Pharmacokinetic Sampling in Cohort 1, Part 1 Only............................. 44
2.2.
Cohort 2: Children Aged ≥6 to <12 Years......................................................................................45
2.2.1.
Flowchart for all Assessments in Cohort 2 (Screening, Initial Treatment Period, Post 
Week 48 Treatment Extension, and Follow-up) ......................................................................... 45
2.2.1.1.
Flowchart for Assessments up to Week 4 in Cohort 2 (Screening and Initial 
Treatment Period up to Week 4) .............................................................................................45
2.2.1.2.
Flowchart for Switch to Adjusted Dose in Cohort 2................................................................. 48
2.2.1.3.
Flowchart for Assessments From Week 8 Onwards in Cohort 2 (Initial Treatment 
Period From Week 8 Onwards, and Follow-up) ......................................................................50
2.2.2.
Flowchart for Intensive Pharmacokinetic Sampling in Cohort 2................................................. 52
3.
OVERVIEW OF TRIAL DESIGN ....................................................................................................... 53
3.1.
Cohort 1: Adolescent Subjects Aged ≥12 to <18 Years ................................................................53
3.2.
Cohort 2: Pediatric Subjects Aged ≥6 to <12 Years ......................................................................55
4.
INTRODUCTION................................................................................................................................ 60
5.
OBJECTIVES .................................................................................................................................... 64
6.
METHODS ......................................................................................................................................... 66
6.1.
Trial Design .................................................................................................................................... 66
6.1.1.
Overview of Trial......................................................................................................................... 66
6.1.1.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years ....................................................................... 66
6.1.1.2.
Cohort 2: Children Aged ≥6 to <12 Years ...............................................................................71
6.1.1.2.1.
Dose Evaluation Criteria for Cohort 2 .................................................................................. 73
6.1.2.
Discussion of Trial Design and Selection of Dose(s) in the Trial ............................................... 75
6.1.2.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years ....................................................................... 75
6.1.2.2.
Cohort 2: Children Aged ≥6 to <12 Years ...............................................................................79
6.2.
Trial Population .............................................................................................................................. 85
6.2.1.
Sample Size................................................................................................................................ 85
6.2.1.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years ....................................................................... 85
6.2.1.2.
Cohort 2: Children Aged ≥6 to <12 Years ...............................................................................85
6.2.2.
Inclusion Criteria......................................................................................................................... 85
6.2.3.
Exclusion Criteria........................................................................................................................ 86
6.2.4.
Precautions and Restrictions...................................................................................................... 90
6.2.4.1.
Precautions.............................................................................................................................. 90
6.2.4.2.
Restrictions.............................................................................................................................. 90
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6.2.5.
Removal of Subjects From Therapy or Assessment..................................................................91
6.3.
Treatment....................................................................................................................................... 96
6.3.1.
Identity of Investigational Product............................................................................................... 96
6.3.2.
Other Medication Administered in the Trial ................................................................................ 96
6.3.3.
Dosage and Treatment Overview Per Subject ........................................................................... 96
6.3.4.
Timing of Dosing......................................................................................................................... 97
6.3.5.
Individually Selected Background Regimen ............................................................................... 98
6.3.6.
Packaging and Labeling ........................................................................................................... 100
6.3.7.
Randomization.......................................................................................................................... 100
6.3.8.
Blinding and Unblinding............................................................................................................ 100
6.3.9.
Independent Data Monitoring Committee................................................................................. 100
6.3.10.
Drug Accountability................................................................................................................... 101
6.3.11.
Storage ..................................................................................................................................... 101
6.3.12.
Adherence ................................................................................................................................ 102
6.3.13.
Prior and Concomitant Therapy................................................................................................ 103
6.3.13.1.
Disallowed Concomitant Medication .....................................................................................104
6.3.13.2.
Disallowed Antiretroviral Medication ..................................................................................... 112
6.4.
Assessments................................................................................................................................ 113
6.4.1.
Timing of Assessments............................................................................................................. 113
6.4.2.
Time Windows .......................................................................................................................... 114
6.4.3.
Handling of Biological Samples ................................................................................................ 115
6.4.4.
Initial Subject and Disease Characteristics ..............................................................................115
6.4.5.
Antiviral Activity......................................................................................................................... 116
6.4.6.
Immunologic Change................................................................................................................ 116
6.4.7.
Resistance Determinations....................................................................................................... 116
6.4.8.
Pharmacokinetic Evaluations ................................................................................................... 117
6.4.8.1.
Sample Collection and Handling ........................................................................................... 117
6.4.8.2.
Bioanalysis............................................................................................................................. 118
6.4.9.
Safety Evaluations.................................................................................................................... 119
6.4.9.1.
Adverse Events/HIV-Related Events.....................................................................................119
6.4.9.2.
Clinical Laboratory Tests....................................................................................................... 119
6.4.9.2.1.
Hematology ........................................................................................................................ 119
6.4.9.2.2.
Biochemistry....................................................................................................................... 119
6.4.9.2.3.
Endocrine Assessments..................................................................................................... 120
6.4.9.2.3.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years...............................................................120
6.4.9.2.3.2.
Cohort 2: Children Aged ≥6 to <12 Years.......................................................................121
6.4.9.2.4.
Urinalysis............................................................................................................................ 122
6.4.9.2.5.
Hepatitis Serology/Viremia................................................................................................. 122
6.4.9.3.
Cardiovascular Safety ........................................................................................................... 123
6.4.9.3.1.
Vital Signs .......................................................................................................................... 123
6.4.9.3.2.
ECG.................................................................................................................................... 123
6.4.9.4.
Physical Examination ............................................................................................................ 123
6.4.10.
Adherence Questionnaire......................................................................................................... 124
6.4.11.
Evaluation for Depression......................................................................................................... 125
6.4.12.
Assessment of Palatability of RPV Formulation .......................................................................125
6.5.
Monitoring and Safety for Specific Toxicities ............................................................................... 125
6.5.1.
Cutaneous Event/Rash............................................................................................................. 126
6.5.2.
Acute Systemic Allergic Reaction............................................................................................. 130
6.5.3.
AST, ALT, and Total Bilirubin Elevation....................................................................................132
6.5.4.
Pancreatic Amylase or Lipase Elevations ................................................................................ 133
6.5.5.
Signs and Symptoms of Adrenal Insufficiency ......................................................................... 134
6.5.5.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years ..................................................................... 134
6.5.5.2.
Cohort 2: Children Aged ≥6 to <12 Years .............................................................................136
6.5.6.
Clinical Hepatitis ....................................................................................................................... 136
6.5.7.
Neuropsychological Symptoms ................................................................................................ 136
6.5.8.
Gastrointestinal Nausea (With or Without Vomiting) ................................................................137
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6.5.9.
Diarrhea .................................................................................................................................... 138
6.5.10.
Other Toxicities......................................................................................................................... 138
6.5.11.
Specific Toxicities With Concomitant ARVs ............................................................................. 139
6.5.11.1.
Hyperglycemia....................................................................................................................... 139
6.5.11.2.
Hypertriglyceridemia and Hypercholesterolemia................................................................... 140
6.5.11.3.
Hypersensitivity Reactions .................................................................................................... 140
6.5.11.4.
Lactic Acidosis....................................................................................................................... 143
6.5.11.5.
Renal Complications.............................................................................................................. 144
6.5.11.6.
Pancreatitis............................................................................................................................ 145
6.5.11.7.
Peripheral Neuropathy........................................................................................................... 146
6.6.
Statistical Methods Planned and Determination of the Sample Size........................................... 146
6.6.1.
Determination of Sample Size .................................................................................................. 148
6.6.1.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years ..................................................................... 148
6.6.1.2.
Cohort 2: Children Aged ≥6 to <12 Years .............................................................................148
6.6.2.
Statistical Analyses................................................................................................................... 150
6.6.2.1.
Initial Subject and Disease Characteristics ........................................................................... 150
6.6.2.2.
Efficacy .................................................................................................................................. 150
6.6.2.2.1.
Plasma viral load................................................................................................................ 150
6.6.2.2.1.1.
Analysis........................................................................................................................... 150
6.6.2.2.2.
Immunology........................................................................................................................ 150
6.6.2.3.
Resistance Determinations.................................................................................................... 151
6.6.2.4.
Pharmacokinetic Parameter Analyses .................................................................................. 151
6.6.2.5.
Safety..................................................................................................................................... 153
6.6.2.5.1.
Adverse Events/HIV-Related Events ................................................................................. 153
6.6.2.5.2.
Clinical Laboratory Tests.................................................................................................... 153
6.6.2.5.3.
Cardiovascular Safety........................................................................................................ 153
6.6.2.5.4.
Physical Examination ......................................................................................................... 154
6.6.2.6.
Diaries.................................................................................................................................... 154
6.6.2.7.
Questionnaires ...................................................................................................................... 154
6.7.
Data Quality Assurance ............................................................................................................... 154
7.
REFERENCES................................................................................................................................. 155
7.1.
Addendum 1: Trial Contact Persons ............................................................................................ 159
7.2.
Addendum 2: DAIDS Table.......................................................................................................... 160
7.3.
Addendum 3: Visit Schedule for Cutaneous Reaction/Rash Follow-up....................................... 179
7.4.
Addendum 4: Cardiovascular Safety – Abnormalities ................................................................. 181
7.5.
Addendum 5: HIV-Related Events or Outcomes in Adolescents and Adults (>13 Years 
Old)............................................................................................................................................... 183
7.5.1.
Clinical categories..................................................................................................................... 183
7.5.1.1.
Category A............................................................................................................................. 183
7.5.1.2.
Category B (Symptomatic Non-AIDS Conditions)................................................................. 183
7.5.1.3.
Category C (AIDS Indicator Conditions as Defined by Diagnostic or Presumptive 
Measures).............................................................................................................................. 184
7.6.
Addendum 6: HIV-Related Events or Outcomes in Children (<13 Years Old) ............................ 186
7.6.1.
Clinical Categories.................................................................................................................... 186
7.6.1.1.
Category N: Not Symptomatic............................................................................................... 186
7.6.1.2.
Category A: Mildly Symptomatic............................................................................................ 186
7.6.1.3.
Category B: Moderately Symptomatic...................................................................................186
7.6.1.4.
Category C: Severely Symptomatic ......................................................................................187
7.7.
Addendum 7: Study Adherence Questionnaire for Children and Teenagers .............................. 189
7.8.
Addendum 8: Study Adherence Questionnaire for Caregivers.................................................... 191
7.9.
Addendum 9: Tanner Scales ....................................................................................................... 193
7.10.
Addendum 10: Childhood Immunizations ....................................................................................195
7.11.
Addendum 11: Pharmacokinetic Modeling for Cohort 2 Dose Selection..................................... 196
7.12.
Addendum 12: Taste Assessment Form for Children.................................................................. 200
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PART 2.
PROCEDURES....................................................................................................................... 204
1.
ADVERSE EVENTS ........................................................................................................................ 204
1.1.
Definitions .................................................................................................................................... 204
1.2.
Attribution Definitions ................................................................................................................... 205
1.3.
HIV-Related Events or Outcomes................................................................................................ 206
1.4.
Reporting of AEs and HIV-Related Events ..................................................................................206
2.
TRIAL CLOSURE CONSIDERATIONS ..........................................................................................209
2.1.
Trial Completion........................................................................................................................... 209
2.2.
Trial Termination .......................................................................................................................... 209
3.
TRIAL MATERIALS ........................................................................................................................ 209
3.1.
Investigational Products............................................................................................................... 209
3.2.
Trial Documents........................................................................................................................... 210
3.3.
Participation Cards....................................................................................................................... 212
3.4.
Source Data ................................................................................................................................. 212
3.5.
Electronic Case Report Forms..................................................................................................... 213
3.6.
Subject Identification Code List & Subject Screening and Enrollment Log ................................. 214
3.7.
Archiving ...................................................................................................................................... 215
3.8.
Protocol Amendments.................................................................................................................. 215
3.9.
Monitoring .................................................................................................................................... 216
4.
CONFIDENTIALITY.........................................................................................................................216
5.
REPORTING AND PUBLICATION .................................................................................................217
5.1.
Reporting...................................................................................................................................... 217
5.2.
Use of Information and Publication.............................................................................................. 217
6.
AUTHORITIES/ETHICS .................................................................................................................. 218
6.1.
Regulatory Authorities.................................................................................................................. 218
6.2.
Independent Ethics Committee/Institutional Review Board.........................................................218
6.3.
ICH-GCP Guidelines.................................................................................................................... 220
6.4.
Subject Information and Informed Consent .................................................................................220
6.5.
Privacy of Personal Data.............................................................................................................. 222
6.6.
Country Selection......................................................................................................................... 222
7.
FINANCING AND INSURANCE......................................................................................................223
7.1.
Financial Disclosure..................................................................................................................... 223
7.2.
Indemnification............................................................................................................................. 223
7.3.
Insurance ..................................................................................................................................... 223
8.
DATA QUALITY CONTROL/ASSURANCE ................................................................................... 223
9.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................224
9.1.
Procedures................................................................................................................................... 224
9.2.
Contacting Sponsor Regarding Product Quality ..........................................................................224
SIGNATURE PAGE.................................................................................................................................. 225
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PROTOCOL AMENDMENTS
Amendment GEN-X (Issued Date: 12 December 2019)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The initial RPV dose selected for all subjects, including children aged ≥6 
to <12 years, was 25 mg q.d. Based on accumulating data a new dose has been selected for this subgroup. This 
amendment is created to include the recommended RPV dose of 15 mg q.d. for children aged ≥6 to <12 years
(Cohort 2) with a body weight of <25 kg. Subjects already enrolled before the implementation of this amendment 
will remain on their original RPV dose of 25 mg q.d. Other changes are described in the rationales below and are all 
applicable to Cohort 2 only, as Cohort 1 (adolescents) has already been completed.
Description of Change(s)
Rationale: Based on all the available PK data for RPV at the time of Amendment 10, it was determined through 
modeling and simulation that children with a body weight of <25 kg should be dosed with RPV 15 mg q.d. and 
children with a body weight of ≥25 kg should be dosed with RPV 25 mg q.d. The appropriateness of RPV 15 mg 
q.d. dose for children with body weight <25 kg will be evaluated through the current study in combination with data 
obtained in another ongoing pediatric RPV study TMC278HTX2002 (see further). For subjects with a body weight 
of ≥25 kg, sufficient intensive PK data have been gathered. Therefore, for new subjects with a body weight of 
≥25 kg no further intensive PK sampling is needed, and these subjects can follow the Cohort 2 visit schedule with 
sparse PK sampling only. For subjects on the RPV 15 mg q.d. dose, intensive PK data are needed for further dose 
evaluation and confirmation. Therefore, subjects with body weight <25 kg will undergo an intensive PK visit after 2 
weeks (Day 14-18) of treatment (see section 2.2.2) and, if the dose is appropriate and no further adjustment is 
needed according to the dose evaluation criteria described in section 6.1.1.2.1, they can continue the Cohort 2 visit 
schedule.
Summary
2.2.1.2. Flowchart for Switch to Adjusted Dose in Cohort 2
2.2.2. Flowchart for Intensive Pharmacokinetic Sampling in Cohort 2 
3.2. Cohort 2: Pediatric Subjects Aged ≥6 to <12 Years
4. Introduction
5. Objectives
6.1.1.2. Cohort 2: Children Aged ≥6 to <12 Years
6.1.1.2.1 Dose Evaluation Criteria for Cohort 2
6.1.2.2. Cohort 2: Children Aged ≥6 to <12 Years
6.3.1. Identity of Investigational Product
6.3.3. Dosage and Treatment Overview Per Subject
6.4.12. Assessment of Palatability of RPV Formulation
6.5 Monitoring and Safety for Specific Toxicities
6.6.2.4 Pharmacokinetic Parameter Analyses
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7.11. Addendum 11: Pharmacokinetic Modeling for Cohort 2 Dose 
Selection
Rationale: It is clarified that, to accommodate regulatory requirements concerning the evaluation of RPV in the 
pediatric population, overall across studies C213 (Cohort 2; children aged ≥6 to <12 years) and TMC278HTX2002 
(children aged ≥2 to <12 years with a body weight of ≥11 kg), approximately 40 subjects will be enrolled of which 
at least 12 subjects with a body weight of <25 kg, including at least 7 subjects with a body weight of <20 kg. The 
PK data from Cohort 2 will be combined with the data from pediatric study TMC278HTX2002.
Summary
6.1.2.2. Cohort 2: Children Aged ≥6 to <12 Years
6.3.9 Independent Data Monitoring Committee
6.6.1.2. Cohort 2: Children Aged ≥6 to <12 Years
Rationale: The requirement for a 4-year follow-up period in this study for subjects enrolled in Cohort 2, has been 
removed from the Pediatric Investigational Plan (PIP) by the Pediatric Committee (PIP Decision P/0322/2018, dated 
12 September 2018). Therefore the 4-year follow-up is removed from this C213 study and subjects are offered to 
continue treatment with RPV through a roll-over study or to switch to locally available medication.
Summary
2.2.1. Flowchart for all Assessments in Cohort 2 (Screening, Initial 
Treatment Period, Post Week 48 Treatment Extension, and Follow-up)
2.2.1.3. Flowchart for Assessments From Week 8 Onwards in Cohort 2
(Initial Treatment Period From Week 8 Onwards, and Follow-up)
3.2. Cohort 2: Pediatric Subjects Aged ≥6 to <12 Years
4. Introduction
5. Objectives
6.1.1.2. Cohort 2: Children Aged ≥6 to <12 Years
6.2.5. Removal of Subjects From Therapy or Assessment
6.3.2. Other Medication Administered in the Trial
6.4.1. Timing of Assessments
6.4.2. Time Windows
6.6 Statistical Methods Planned and Determination of the Sample Size
Rationale: The ACTH stimulation test at Day 1 and Week 24 has been removed because no clinically relevant 
suppression of cortisol secretion and of the adrenal function was observed in adults or adolescents aged ≥12 to <18 
years (Cohort 1) in the clinical studies with RPV. Additionally, in the first 9 children aged ≥6 to < 12 years in 
Cohort 2 of this study 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. 
2.1.1 Flowchart for All Assessments in Cohort 1 (Screening, Initial 
Treatment Period, Post Week 48 Treatment Extension, and Follow-up)
2.2.1.3. Flowchart for Assessments From Week 8 Onwards in Cohort 2
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(Initial Treatment Period From Week 8 Onwards, and Follow-up)
6.3.13.1. Disallowed Concomitant Medication
6.4.9.2.3.2. Cohort 2: Children Aged ≥6 to <12 Years
6.6.2.5.2 Clinical Laboratory Tests
Rationale: The section ‘Disallowed Concomitant Medication’ has been adjusted to clarify that the additional safety 
monitoring by ECG and the PK sample are only required for subjects receiving CYP3A4 inhibitory medications or 
medications associated with risk of Torsade de Pointes for >2 days, as no cardiovascular impact is expected with a 
period of administration of ≤2 days. Therefore, in order to limit the burden for subjects and reduce complexity of the 
study, the requirements for an ECG, and its associated PK sample, before the start of the medication have been 
removed for use of such medications ≤2 days, and are kept if these aformentioned medications are used >2 days.
6.3.13.1. Disallowed Concomitant Medication
6.5 Monitoring and Safety for Specific Toxicities
Rationale: The exclusion of “personal history of asymptomatic arrhythmia” and of “syncopal episodes” (exclusion 
criterion #19, Risk factors for QTc prolongation) is adapted. 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.60 Also 
syncopal episodes in children are not uncommon and are usually benign61 and not associated with cardiac pathology. 
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, and syncopal episodes are a 
reason for exclusion if repeated, unexplained, and unrelated to emotional distress.
6.2.3. Exclusion Criteria
6.3.1 Identity of Investigational Product
6.4.12 Assessment of Palatability of RPV Formulation
Rationale: The requirement for digital pictures has been removed. 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.
6.5.1. Cutaneous Event/Rash
7.3. Addendum 3: Visit Schedule for Cutaneous Reaction/Rash Follow-up
Rationale: Efficacy parameters TLOVR-based response rates and change in log10 plasma viral load have been 
removed as these endpoints are no longer reported in HIV clinical trials as they are superseded by the Snapshot 
approach.
6.6.2.2.1. Plasma viral load
Rationale: Some administrative and editorial adjustments were made.
“i.e., generics” corrected to “or 
generics”
Summary
6.2.5. Removal of Subjects from Therapy or Assessment #5
6.3.3.Dosage and Treatment Overview Per Subject
6.3.5. Individually Selected Background Regimen
6.5.11.3. Hypersensitivity Reactions
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Abbreviations ADR, HLA, PK and VL
added. Definition for ‘Suspected 
Virologic Failure’ added for alignment 
with PIP. Definition for ‘Virologic 
Response’ removed from Loss of 
Response description and added 
independently.
1. Glossary
Clarified that the retest of abnormal 
laboratory results or plasma 
VL/resistance testing should be 
captured in this C213 study if the 
participant rolls over to the 
TMC278IFD3004 study.
2.2.1.3 Flowchart for Assessments From Week 8 Onwards in Cohort 2
(Initial Treatment Period From Week 8 Onwards, and Follow-up)
3.2 Cohort 2: Pediatric Subjects Aged ≥6 to <12 Years
6.1.1.2 Cohort 2: Children Aged ≥6 to <12 Years
6.2.5 Removal of Subjects From Therapy or Assessment
Added ‘at least’ and ‘approximately’ 
to the blood volumes to be collecte as
each tube may draw up to 1.2 mL and
the total volume may add up to 9.6 mL
2.2.2.  Flowchart for Intensive Pharmacokinetic Sampling in Cohort 2 
Clarified that site staff provides 
support to the subject or their 
parent(s)/caregiver(s) in completing 
the questionnaires.
6.3.12. Adherence
Added a note to Table 1 clarifying that 
the list of disallowed concomitant 
medication and medication to be used 
with caution is not exhaustive.
6.3.13.1. Disallowed Concomitant Medication
Added Post Switch Visit time 
windows for completion.
6.4.2 Time Windows
Alignment with PIP: Adjusted 
‘Virologic Failure’ to ‘Suspected 
Virologic Failure’ and added the fact 
that deep sequencing may be 
performed.
6.4.7. Resistance Determinations
Editorial error corrected
6.4.8. Pharmacokinetic Evaluations
Removed ‘Subjects should be 
undressed (underwear is allowed) 
during these full physical 
examinations’, as the full physical 
examination is to be done as per local 
standard of care.
6.4.9.4. Physical Examination
248 nmol/L corrected to 500 nmol/L
6.5.5.2. Cohort 2: Children Aged ≥6 to <12 Years
The obligatory withdrawal from the 
study for renal complications is 
removed and ‘must be’ has been 
adjusted to ‘may be’. As these renal 
complications refer to specific 
toxicities with concomitant ARV 
N(t)RTIs used in the study, 
management of a decrease in eGFR is 
6.2.5 Removal of Subjects From Therapy or Assessment
6.5.11.5. Renal Complications
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Amendment GEN-IX (Issued Date: 20-Mar-2018)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: This amendment is created to update the in- and exclusion criteria to
facilitate patient recruitment since the study target population has become scarce. Through this amendment,
enrollment of subjects ≥6 to <12 years of age who have a history of receiving a single dose of nevirapine (sdNVP)
for prevention of mother-to-child transmission (PMTCT) in Cohort 2 of the study will be allowed. The evolution of 
proviral genotype will be assessed at screening and Week 48 and virologic response will be closely monitored 
during the treatment period.
Description of Change(s)
Rationale: In order to facilitate patient recruitment, the protocol in- and exclusion criteria are adjusted to allow 
enrollment in Cohort 2 of subjects ≥6 to <12 years of age who previously received a sdNVP for PMTCT. In 
Cohort 1 of the study, subjects who received sdNVP for PMTCT were enrolled. In Cohort 1, 8/36 subjects 
experienced virologic failure, however, data on PMTCT use at time of birth were either not available (13/30, 
43.3%) or it was reported that no PMTCT was used (17/30, 56.7%).a The emerging mutations observed in these 
subjects with virologic failure were previously identified in the RPV Phase 3 adult studies. Virologic failure was 
generally associated with the emergence of RPV resistance-associated mutations (RAMs), most commonly E138K, 
in combination with NRTI RAMs, most commonly M184V. Given the virologic failures observed in Cohort 1, 
subjects who previously received sdNVP for PMTCT were not allowed in Cohort 2 at the time of implementation of 
Amendment 6. The reason for the virologic failures observed in Cohort 1 is now considered most probably not 
related to the use of sdNVP for PMTCT because the observed resistance patterns were in line with those observed in 
Phase 3 in adults and because the data on PMTCT use at time of birth were either not available or no PMTCT was 
used. Moreover, most virologic failures (6/8) occurred in Uganda where PMTCT was not widely adopted at the time 
the Ugandan study participants were infected.
The main reasons for adapting the in- and exclusion criteria in terms of prior sdNVP use for PMTCT are: 
1.
Infeasibility of recruitment: 
Because of the successful global adoption of PMTCT regimensb, pediatric patients naïve to sdNVP or 
zidovudine (AZT) use for the PMTCT have become increasingly scarce. The Joint United Nations Program 
on human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (UNAIDS) 
reported that coverage of antiretroviral programs for PMTCT increased from 57% in 2011 to 73% in 2014 
among their 22 priority countries.
In June 2016, the World Health Organization (WHO) issued updated HIV-exposed infant prophylaxis
guidelines, stating that infants born to mothers with HIV who are at high risk of acquiring HIV should 
receive dual prophylaxis with AZT twice daily and NVP once daily for the first 6 weeks of life (whether 
they are breastfed or formula fed). Prior to 2012, the PMTCT treatment for infants consisted almost 
exclusively of sdNVP. As patients in the age range to be enrolled in Cohort 2 (≥6 to <12 years) would have 
                                                          
a Stevens M, Vanveggel S, Hoogstoel A et al. 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. Janssen Infectious Diseases – Diagnostics BVBA. TMC278-TiDP38-C213 
Clinical Study Report Week 48 Analysis. Issued date: 18 December 2014.
b Joint United Nations Programme on HIV/AIDS (UNAIDS). 2014 Progress report on the global plan towards the 
elimination of new HIV infections among children by 2015 and keeping their mothers alive. Geneva, 
Switzerland, 2014. Available at http://www.unaids.org/sites/default/files/documents/JC2681_2014-Global-Plan-
progress_en.pdf. Accessed 
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been born in 2012 or before, it is likely they received sdNVP, making recruitment impracticable. 
2.
Archived resistance: 
The strongest predictor for carrying NNRTI mutations after PMTCT exposure is young age.c The 
probability for otherwise treatment-naïve children to have resistance due to sdNVP use at birth decreases 
with age as resistance against NVP typically declines over time towards frequencies below the detection 
threshold of sequencing assays.c,d,e The decreased incidence of NNRTI resistance in individual infants has 
been confirmed by multiple studies, showing the fading of sdNVP-induced mutations over 12 months after 
infection. Studies with longer individual follow-up time are rare, but a recent study investigated the 
persistence of NNRTI resistance up to 32 months of age using deep sequencing and showed that certain 
NNRTI RAMs can persist without decay over a median of 13 months (interquartile range [IQR] 12-16) to a 
median of 21 months of age (IQR 17-32).f The persistence of NNRTI resistance is likely highest for infants 
and children <2 years of age and it is anticipated that prevalence will further decrease with age.
In subjects who have received sdNVP for PMTCT and who will be allowed to enroll in Cohort 2 after 
implementation of the current Amendment 9, the presence of archived NNRTI or NRTI resistance cannot 
be fully excluded. Archived resistance is difficult to assess with accuracy and the current methods are 
generally used for exploratory research. Nonetheless, the sponsor will collect peripheral blood 
mononuclear cells (PBMCs) at screening to retrospectively evaluate the presence of RAMs in children 
enrolled in Cohort 2 after the implementation of Amendment 9. To assess whether this could have had an 
impact on response to the study regimen, the evolution of proviral genotype will be assessed at screening 
and Week 48 and virologic response will be closely monitored during the treatment period. No human 
DNA analysis will be performed on these samples. Given the exploratory nature of the assessment and the 
large number of assessments and extensive blood sampling at the baseline visit, the reference PBMC 
sample will be taken at screening. 
1 Glossary
2.2.1.1 Flowchart for Assessments up to Week 4 in Cohort 2 (Screening 
and Initial Treatment Period up to Week 4)
2.2.1.3 Flowchart for Assessments From Week 8 Onwards in Cohort 2
(Initial Treatment Period From Week 8 Onwards, and Follow-up)
6.1.1.2 Cohort 2: Children Aged ≥6 to <12 Years
6.2.2 Inclusion Criteria
6.2.3 Exclusion Criteria
6.4.7 Resistance Determinations
6.6.2.3 Resistance Determinations
                                                          
c 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.
d 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.
e 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.
f Kanthula R, Beck I, Van Dyk G, et al. Persistance of HIV drug resistance in children exposed to nevirapine 
prophylaxis. CROI 2016. Poster 847.
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Rationale: The main PK analyses to characterize the RPV PK properties in children are conducted at the time of the 
Week 4, Week 24 and Week 48 analyses. Pharmacokinetic samples taken at a later time point are not anticipated to 
have a significant impact on the findings/conclusions of the Week 24/48 PK analyses. Therefore, for Cohort 2, no 
PK sample will be taken beyond Week 48 and the assessment at Week 240 is deleted from the flowchart.
2.2.1.3 Flowchart for Assessments From Week 8 Onwards in Cohort 2
(Initial Treatment Period From Week 8 Onwards, and Follow-up)
Rationale: The introduction was updated to indicate that, at the time of the Amendment 9 writing, rilpivirine (RPV) 
was approved in several countries, including USA and Europe, in adolescents ≥12 years of age. 
4 Introduction
Rationale: The definition of an abnormal ACTH stimulation test as defined for Cohort 2 was corrected: “the 
cortisol value after ACTH stimulation is <500 nmol/L” instead of "all cortisol values prior to and after ACTH 
stimulation are <500 nmol/L”.
2.2.1.3 Flowchart for Assessments From Week 8 Onwards in Cohort 2
(Initial Treatment Period From Week 8 Onwards, and Follow-up)
6.2.5 Removal of Subjects From Therapy or Assessment
6.4.9.2.3.2 Cohort 2: Children Aged ≥6 to <12 Years
Rationale: Section 6.4.1 Timing of Assessments of the protocol has been aligned with Section 6.4.8 
Pharmacokinetic evaluations regarding the planning of an unscheduled visit for repeat PK sampling. Moreover, the 
Time and Events schedule has been aligned with Section 6.4.1 Assessments: following the Week 240 study visit, 
unscheduled visits may be scheduled in order to follow-up on safety concerns ([S]AEs, laboratory abnormalities and 
increase in viral load) and to allow retesting of parameters as described in Section 6.4.1. 
Summary
2.2.1.3 Flowchart for Assessments From Week 8 Onwards in Cohort 2
(Initial Treatment Period From Week 8 Onwards, and Follow-up)
3.2 Cohort 2: Pediatric Subjects Aged ≥6 to <12 Years
6.2.5 Removal of Subjects From Therapy or Assessment
6.4.1 Timing of Assessments
Rationale: It is clarified in the protocol that study visits should be scheduled relative to the baseline visit (Day 1), 
eg, the Week 1 visit should be scheduled on Day 8 (Day 1 + 7 days) ± the allowed time windows as specified in 
Section 6.4.2.  
2.2.1.1 Flowchart for Assessments up to Week 4 in Cohort 2 (Screening 
and Initial Treatment Period up to Week 4)
2.2.1.3 Flowchart for Assessments From Week 8 Onwards in Cohort 2
(Initial Treatment Period From Week 8 Onwards, and Follow-up)
6.4.2 Time Windows
Rationale: Some clarifications were added and editorial errors and inconsistencies were corrected.
6.1.1.2 Cohort 2: Children Aged ≥6 to <12 Years
6.1.1.2.1 Dose Evaluation Criteria for Cohort 2
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Amendment GEN-VIII (Issued Date: 01-Dec-2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: Based on local practice and availability of antiretrovirals (ARVs) in 
certain countries, the protocol requires adjustments to allow the prescription of WHO prequalified drugs. If not 
available, the use of generic drugs approved by the local Health Authorities or drugs prescribed by the UN 
international organizations can be acceptable as nucleotide analog reverse transcriptase inhibitor (N(t)RTI) 
background medication. The inclusion criterion regarding the start of treatment is updated to reflect the new WHO
guideline on the start of ARV therapy. Additionally, the criterion for withdrawal after a total cumulative duration of 
treatment interruptions for suspected toxicities is further clarified per study period instead of over the entire study 
duration. Other minor changes are described in the rationales below.
Description of Change(s)
Rationale: The protocol requires adjustments to allow the prescription of WHO prequalified drugs, based on local 
practice and availability of ARVs. If not available, the use of generic drugs approved by the local Health Authorities
or drugs prescribed by the UN international organizations can be acceptable as N(t)RTI background medication.
6.1.1.1 Cohort 1: Adolescents Aged ≥12 to <18 Years
6.2.5 Removal of Subjects From Therapy or Assessment
6.3.3 Dosage and Treatment Overview Per Subject
6.3.5 Individually Selected Background Regimen
6.3.13.2 Disallowed Antiretroviral Medication
6.5.11.3 Hypersensitivity Reactions
Rationale: The criterion for withdrawal after a total cumulative duration of treatment interruptions for suspected 
toxicities was further clarified as applying cumulatively for a time frame of 48 weeks, and not cumulatively over the 
entire 240 weeks of the study.
6.1.1.1 Cohort 1: Adolescents Aged ≥12 to <18 Years
6.2.5 Removal of Subjects From Therapy or Assessment
6.3.5 Individually Selected Background Regimen
6.5 Monitoring and Safety for Specific Toxicities
Rationale: The minimum number of subjects in Part 2 of Cohort 2 was updated to 25, in line with the Pediatric 
Investigation Plan Decision P/0012/2016 dated 29 January 2016.
Summary
3.2 Cohort 2: Pediatric Subjects Aged ≥6 to <12 Years
6.1.1.2 Cohort 2: Children Aged ≥6 to <12 Years
6.2.1.2 Cohort 2: Children Aged ≥6 to <12 Years
Rationale: In 2016, WHO released "Consolidated Guidelines on The Use of Antiretroviral Drugs for Treating and 
Preventing HIV Infection”59. The guidelines recommend that antiretroviral therapy (ART) should be initiated in all 
children living with HIV, regardless of WHO clinical stage or at any CD4+ cell count. Therefore, the word "chronic" 
was removed in Inclusion criterion #3. Additionally, the Note in Inclusion criterion #8 became outdated and was
removed. Subjects with acute HIV infection are still excluded from the study.
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6.2.2 Inclusion Criteria
Rationale: The eGFR for subjects aged 22 years and older will be calculated by the MDRD equation as the 
currently used formula is validated up until 21 years of age.
6.4.9.2.2 Biochemistry
6.5.11.5 Renal Complications
6.3.1 Identity of Investigational Product
Rationale: The wording on final analysis of Cohort 1 and Cohort 2 was adjusted to clarify that there will be 2 final 
analyses, one for each cohort.
6.6 Statistical Methods Planned and Determination of the Sample Size
6.3.1 Identity of Investigational Product
Rationale: Minor corrections were made.
6.3.5 Individually Selected Background Regimen
6.3.9 Independent Data Monitoring Committee
Rationale: The Janssen Research & Development disclaimer on the frontpage was updated.
Frontpage
Amendment GEN-VII (Issued Date: 18-Dec-2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: Based on local practice in certain countries, children younger than 12 
years of age are not consistently informed of having HIV infection. Therefore inclusion criterion 3 will be updated 
to remove the requirement that children enrolled in the study are aware of their HIV status. Children that are 
unaware of their HIV status, but comply with all other inclusion and exclusion criteria are nevertheless allowed to 
participate in the study.
Description of Change(s)
Applicable Section(s)
Rationale: See above
6.2.2 Inclusion Criteria
Rationale: An ECG assessment after at least 4 weeks of treatment with RPV (initial dose or adjusted dose) is not 
necessary. An ECG is required after at least 2 weeks of treatment with RPV, when RPV plasma concentrations are 
at steady-state (steady-state plasma concentrations of RPV are usually reached within 11 days of dosing). This 
Week 2 ECG assessment is adequate to assess potential safety concerns. The ECG at the 4-weeks Post Switch Visit 
(in case of switch to a RPV adjusted dose) is therefore removed (in line with assessments for the initial RPV dose)
2.2.1.2 Flowchart for Switch to Adjusted Dose in Cohort 2, Part 1 Only 
(If Applicable)
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Approved, Issued Date: 03-FEB-2020
Amendment GEN-VI (Issued Date: 08-Oct-2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: The protocol which was originally designed to include adolescents of 
≥12 to <18 years of age has been amended to also include children of ≥6 to <12 years of age.
Description of Change(s)
Applicable Section(s)
Rationale: An additional cohort (Cohort 2) of children of ≥6 to <12 years of age has been added to the current 
study design in order to collect data on short-term and long-term pharmacokinetics, safety, tolerability, and antiviral 
activity/efficacy of rilpivirine (RPV) in this additional pediatric age group. In this cohort, treatment-naïve human 
immunodeficiency virus - type 1 (HIV-1) infected subjects with HIV RNA ≤100,000 copies/mL of ≥6 to <12 years 
of age will be allowed to enter. The subjects will be treated with RPV 25 mg once daily (q.d.) or an adjusted dose 
for a maximum of 240 weeks. The primary and final endpoints are Week 48 and Week 240, respectively.
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Additional section headings have been 
added for clarity
Title Page
Summary
2 Flowchart
3 Overview of Trial Design
4 Introduction
5 Objectives
6.1.1 Overview of Trial
6.1.2 Discussion of Trial Design and Selection of Dose(s) in the Trial
6.2.1 Sample Size
6.2.2 Inclusion Criteria
6.2.3 Exclusion Criteria
6.2.4.2 Restrictions
6.2.5 Removal of Subjects From Therapy or Assessment
6.3.1 Identity of Investigational Product
6.3.2 Other Medication Administered in the Trial
6.3.3 Dosage and Treatment Overview Per Subject
6.3.4 Timing of Dosing
6.3.5 Individually Selected Background Regimen
6.3.9 Independent Data Monitoring Committee
6.3.12 Adherence
6.3.13.1 Disallowed Concomitant Medication
6.4.1 Timing of Assessments
6.4.2 Time Windows
6.4.7 Resistance Determinations
6.4.8.1 Sample Collection and Handling
6.4.9.2.2 Biochemistry
6.4.9.2.3 Endocrine Assessments
6.4.12 Assessment of Palatability of RPV Formulation (Other Than 
Tablet Formulation)
6.5 Monitoring and Safety for Specific Toxicities
6.5.5 Signs and Symptoms of Adrenal Insufficiency
6.6 Statistical Methods Planned and Determination of the Sample Size
6.6.1 Determination of Sample Size
6.6.2.2.1 Plasma viral load
6.6.2.4 Pharmacokinetic Parameter Analyses
6.6.2.5.2 Clinical Laboratory Tests
7 References
7.11 Addendum 11: Pharmacokinetic Modeling for Cohort 2 Dose 
Selection
5.1 Reporting
Throughout the protocol
Rationale: The following clarification related to safety monitoring was added:
- evaluation of individual growth and pubertal development will also be done by the Independent Data 
Monitoring Committee (IDMC)
6.3.9 Independent Data Monitoring Committee
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Approved, Issued Date: 03-FEB-2020
Rationale: In the adolescent cohort (Cohort 1), corrections were made to the statistical analyses, a Week 240 
objective was added, and the wording regarding resistance determination was simplified. In addition, minor 
corrections were made to the description of the conduct of the trial.
Changes were made to the statistical 
analyses
An additional objective was added 
(240-week evaluation objective)
Wording 
regarding 
resistance 
determination was simplified
Minor corrections were made
6.6.2.2.1.1 Analysis
6.6.2.2.2 Immunology
6.6.2.5.1 Adverse Events/HIV-Related Events
6.6.2.5.3 Cardiovascular Safety
6.6.2.5.4 Physical Examination
5 Objectives
2.1.1.1 Flowchart for Assessments up to Week 4 in Cohort 1 (Screening 
and Initial Treatment Period up to Week 4)
2.1.1.2 Flowchart for Switch to Weight-adjusted Dose in Cohort 1, Part 1 
Only (if applicable)
2.1.1.3 Flowchart for Assessments from Week 8 onwards in Cohort 1 
(Initial Treatment Period from Week 8 onwards, Post Week 48 Treatment 
Extension, and Follow-up)
6.4.7 Resistance Determinations
Summary
2.1.2 Flowchart for Intensive Pharmacokinetic Sampling in Cohort 1, 
Part 1 Only
6.1.1.1 Cohort 1: Adolescents Aged ≥12 to <18 Years
Rationale: The most recent version of the IB has been referenced and all applicable text has been updated. 
Summary
4 Introduction
6.3.13.1 Disallowed Concomitant Medication
6.5.11.5 Renal Complications
7 References
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Approved, Issued Date: 03-FEB-2020
Additional section headings have been 
added for clarity
Title Page
Summary
2 Flowchart
3 Overview of Trial Design
4 Introduction
5 Objectives
6.1.1 Overview of Trial
6.1.2 Discussion of Trial Design and Selection of Dose(s) in the Trial
6.2.1 Sample Size
6.2.2 Inclusion Criteria
6.2.3 Exclusion Criteria
6.2.4.2 Restrictions
6.2.5 Removal of Subjects From Therapy or Assessment
6.3.1 Identity of Investigational Product
6.3.2 Other Medication Administered in the Trial
6.3.3 Dosage and Treatment Overview Per Subject
6.3.4 Timing of Dosing
6.3.5 Individually Selected Background Regimen
6.3.9 Independent Data Monitoring Committee
6.3.12 Adherence
6.3.13.1 Disallowed Concomitant Medication
6.4.1 Timing of Assessments
6.4.2 Time Windows
6.4.7 Resistance Determinations
6.4.8.1 Sample Collection and Handling
6.4.9.2.2 Biochemistry
6.4.9.2.3 Endocrine Assessments
6.4.12 Assessment of Palatability of RPV Formulation (Other Than 
Tablet Formulation)
6.5 Monitoring and Safety for Specific Toxicities
6.5.5 Signs and Symptoms of Adrenal Insufficiency
6.6 Statistical Methods Planned and Determination of the Sample Size
6.6.1 Determination of Sample Size
6.6.2.2.1 Plasma viral load
6.6.2.4 Pharmacokinetic Parameter Analyses
6.6.2.5.2 Clinical Laboratory Tests
7 References
7.11 Addendum 11: Pharmacokinetic Modeling for Cohort 2 Dose 
Selection
5.1 Reporting
Throughout the protocol
Rationale: Wording from the most recent protocol template has been incorporated in this document.
Note: Some of the changes may have an effect on study procedures of both cohorts while other changes may not be 
applicable to Cohort 1 (currently already beyond Week 48) because they are related to e.g., study start-up 
procedures.
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Text related to the following has been 
revised: 
-
Labeling of sample tubes
-
Collection of questionnaires
-
Definition of (serious) adverse events 
[(S)AEs]
-
Reporting of (S)AEs.
-
Trial closure considerations
-
Source data
-
Reporting and publication details
-
Privacy of personal data
Information regarding the following has 
been added:
-
A 
clinical 
status 
check 
before 
administration of the first dose
-
Questions about inclusion/exclusion 
criteria
-
Precautions and restrictions
-
Withdrawn subjects or subjects who 
are lost to follow-up
-
Reporting of prohibited therapies
-
Recording of sample collection
-
Description of statistical methods
-
Destruction of used and unused 
medication
-
List of trial documents to be provided 
to the Sponsor by the site
-
Participation cards
-
Electronic case report forms (eCRFs)
-
Subject Identification Code List & 
Subject Screening and Enrollment Log
-
Trial record transfer of custody
-
Administrative requirements related to 
protocol amendments
-
On-site monitoring
-
Reporting obligations towards the 
Independent 
Ethics 
Committee 
(IEC)/Institutional 
Review 
Board 
(IRB)
-
Subject Information and Informed 
Consent
-
Country selection
-
The data quality control/assurance 
information
-
Product quality complaint handling
6.4.3 Handling of Biological Samples
6.3.12 Adherence
6.4.10 Adherence Questionnaire
1.1 Definitions
1.4 Reporting of AEs and HIV-Related Events
2 Trial Closure Considerations
3.4 Source Data
5.2 Use of Information and Publication
6.5 Privacy of Personal Data
2.1.1.1 Flowchart for Assessments up to Week 4 in Cohort 1 
(Screening and Initial Treatment Period up to Week 4)
6.2.2 Inclusion Criteria
6.2.3 Exclusion Criteria
6.2.4 Precautions and Restrictions
6.2.5 Removal of Subjects From Therapy or Assessment
6.3.13 Prior and Concomitant Therapy
6.4.3 Handling of Biological Samples
6.6 Statistical Methods Planned and Determination of the Sample Size
3.1 Investigational Products
3.2 Trial Documents
3.3 Participation Cards
3.5 Electronic Case Report Forms
3.6 Subject Identification Code List & Subject Screening and 
Enrollment Log
3.7 Archiving
3.8 Protocol Amendments
3.9 Monitoring
6.2 Independent Ethics Committee/Institutional Review Board
6.4 Subject Information and Informed Consent
6.6 Country Selection
8 Data Quality Control/Assurance
9 PRODUCT QUALITY COMPLAINT HANDLING
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Approved, Issued Date: 03-FEB-2020
Additional section headings have been 
added for clarity
Title Page
Summary
2 Flowchart
3 Overview of Trial Design
4 Introduction
5 Objectives
6.1.1 Overview of Trial
6.1.2 Discussion of Trial Design and Selection of Dose(s) in the Trial
6.2.1 Sample Size
6.2.2 Inclusion Criteria
6.2.3 Exclusion Criteria
6.2.4.2 Restrictions
6.2.5 Removal of Subjects From Therapy or Assessment
6.3.1 Identity of Investigational Product
6.3.2 Other Medication Administered in the Trial
6.3.3 Dosage and Treatment Overview Per Subject
6.3.4 Timing of Dosing
6.3.5 Individually Selected Background Regimen
6.3.9 Independent Data Monitoring Committee
6.3.12 Adherence
6.3.13.1 Disallowed Concomitant Medication
6.4.1 Timing of Assessments
6.4.2 Time Windows
6.4.7 Resistance Determinations
6.4.8.1 Sample Collection and Handling
6.4.9.2.2 Biochemistry
6.4.9.2.3 Endocrine Assessments
6.4.12 Assessment of Palatability of RPV Formulation (Other Than 
Tablet Formulation)
6.5 Monitoring and Safety for Specific Toxicities
6.5.5 Signs and Symptoms of Adrenal Insufficiency
6.6 Statistical Methods Planned and Determination of the Sample Size
6.6.1 Determination of Sample Size
6.6.2.2.1 Plasma viral load
6.6.2.4 Pharmacokinetic Parameter Analyses
6.6.2.5.2 Clinical Laboratory Tests
7 References
7.11 Addendum 11: Pharmacokinetic Modeling for Cohort 2 Dose 
Selection
5.1 Reporting
Throughout the protocol
Rationale: Minor corrections and administrative and textual changes were made.
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Approved, Issued Date: 03-FEB-2020
Due to a change in legal entities in 
Ireland, the sponsorship statement has 
been updated.
Other corrections, administrative and 
textual changes have been made.
Title Page
Summary
Protocol History
1 Glossary
2.1.1.1 Flowchart for Assessments up to Week 4 in Cohort 1 (Screening 
and Initial Treatment Period up to Week 4)
2.1.1.2 Flowchart for Switch to Weight-adjusted Dose in Cohort 1, Part 1 
Only (if applicable)
2.1.1.3 Flowchart for Assessments from Week 8 onwards in Cohort 1 
(Initial Treatment Period from Week 8 onwards, Post Week 48 Treatment 
Extension, and Follow-up)
3.1 Cohort 1: Adolescent Subjects Aged ≥12 to <18 Years
4 Introduction
5 Objectives
6.1.1 Overview of Trial
6.1.1.1 Cohort 1: Adolescents Aged ≥12 to <18 Years
6.1.2.1 Cohort 1: Adolescents Aged ≥12 to <18 Years
6.2.1.1 Cohort 1: Adolescents Aged ≥12 to <18 Years
6.2.2 Inclusion Criteria
6.2.3 Exclusion Criteria
6.2.4.1 Precautions
6.2.5 Removal of Subjects From Therapy or Assessment
6.3.1 Identity of Investigational Product
6.3.2 Other Medication Administered in the Trial
6.3.4 Timing of Dosing
6.3.5 Individually Selected Background Regimen
6.3.6 Packaging and Labeling
6.3.10 Drug Accountability
6.3.11 Storage
6.4.1 Timing of Assessments
6.4.7 Resistance Determinations
6.4.9.2.3 Endocrine Assessments
6.4.9.2.3.1 Cohort 1: Adolescents Aged ≥12 to <18 Years
6.4.9.3.2 ECG
6.4.10 Adherence Questionnaire
6.5.1 Cutaneous Event/Rash
6.5.3 AST, ALT, and Total Bilirubin Elevation
6.5.5.1 Cohort 1: Adolescents Aged ≥12 to <18 Years
6.5.11.4 Lactic Acidosis
6.5.11.5Renal Complications
6.6 Statistical Methods Planned and Determination of the Sample Size
6.6.1.1 Cohort 1: Adolescents Aged ≥12 to <18 Years
6.6.2.2.1 Plasma viral load
6.6.2.2.1.1 Analysis
6.6.2.3 Resistance 
6.6.2.4 Pharmacokinetic Parameter Analyses
6.6.2.5.2 Clinical Laboratory Tests
6.6.2.6 Diaries
6.6.2.7 Questionnaires
7.3 Addendum 3: Visit Schedule for Cutaneous Reaction/Rash Follow-up
7.12 Addendum 12: Taste Assessment Form for Children
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Approved, Issued Date: 03-FEB-2020
TMC278 
has 
been 
changed 
to
rilpivirine or RPV
1.4 Reporting of AEs and HIV-Related Events
3.1 Investigational Products
Throughout the protocol
Amendment GEN-V (Issued Date: 29-Aug-2013)
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: As part of its portfolio review, Janssen Diagnostics has decided to 
discontinue virco®TYPE HIV-1 by end 2013 in clinical practice. In addition, Janssen Diagnostics discontinued 
routine use of Antivirogram® in 2012 and will cease to provide this service also for clinical trials. Therefore, for 
genotypic and phenotypic resistance testing in this protocol, another geno- and phenotyping assay will be 
implemented. 
Description of Change(s)
Applicable Section(s)
Rationale: As part of its portfolio review, Janssen Diagnostics has decided to discontinue virco®TYPE HIV-1 by 
end 2013 in clinical practice. In addition, Janssen Diagnostics discontinued routine use of Antivirogram® in 2012 
and will cease to provide this service also for clinical trials. Therefore, for genotypic and phenotypic resistance 
testing in this protocol, another geno- and phenotyping assay will be implemented. Any reference to virco®TYPE 
HIV-1 or Antivirogram® in the protocol is through this amendment being replaced by a more generic term for 
geno-/phenotypic testing.
2.1.1.1 Flowchart for Assessments up to Week 4 (Screening and Initial 
Treatment Period up to Week 4)
2.1.1.2 Flowchart for Switch to Weight-adjusted Dose (if applicable)
2.1.1.3
Flowchart for Assessments from Week 8 onwards (Initial 
Treatment Period from Week 8 onwards, Post Week 48 Treatment 
Extension, and Follow-up)
3 Overview of Trial Design
6.1.1 Overview of Trial
6.1.2 Discussion of Trial Design and Selection of Dose(s) in the Trial
6.2.2 Inclusion Criteria
6.2.5 Removal of Subjects From Therapy or Assessment
6.3.5 Individually Selected Background Regimen
6.4.7 Resistance Determinations
6.5.11.3 Hypersensitivity Reactions
6.6.2.3 Resistance determinations
Rationale: Update to reflect the status of the study and the results of Part 1, and addition of an Independent Data 
Monitoring Committee analysis for Part 1 and Part 2, at Week 12, to bring in line with the actual performed and 
planned analysis.
Summary
3 Overview of Trial Design
6.1.1 Overview of Trial
6.1.2 Discussion of Trial Design and Selection of Dose(s) in the Trial
6.6 Statistical Methods Planned and Determination of the Sample Size
Rationale: Exploratory analyses on virologic response and change in CD4+ cell count were removed from the 
statistical methods, as the study size will not be sufficiently large to make valuable conclusions.
6.6.2.2.1.1 Analysis
6.6.2.2.2 Immunology
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Approved, Issued Date: 03-FEB-2020
Rationale: Following the implementation of the ICH E2F guideline, the Annual Safety Report has been replaced 
with the Development Safety Update Report. Until 2011, the data lock of the Development Safety Update report 
was 23 August. From 2012 onward, the data lock was aligned with the International Birth Date of 20 May 2011 
(after approval of RPV in the United States).
1 Glossary
Part 2, 5.1 Reporting
Part 2, 6.2 Independent Ethics Committee/Institutional Review Board
Rationale: Per the revised template wording, a clarification was added with regards to the reporting by the 
laboratory of certain laboratory data in addition to those required per protocol. 
6.4.9.2.4 Urinalysis
Rationale: The sponsor has decided to harmonize the procedures for emergency medical questions and product 
complaints. Therefore, the telephone number mentioned on the title page has been removed. Appropriate 
information about who should be contacted regarding safety issues or questions regarding the study is provided in 
Section 8.1, Addendum 1, Trial Contact Persons
Removal of the emergency phone 
number.
Title Page
Rationale: Timing of the completion of the adherence questionnaire in the Flowchart did not match the timing 
mentioned in the questionnaire itself. The assessment at Week 240 is removed from the Flowchart. It is specified 
that questionnaires appended in this protocol are sample questionnaires, and that sites should always use the most 
recently provided version of the questionnaire. 
2.1.1.3
Flowchart for Assessments from Week 8 onwards (Initial 
Treatment Period from Week 8 onwards, Post Week 48 Treatment 
Extension, and Follow-up)
6.4.10 Adherence Questionnaire
8.7 Addendum 7: Study Adherence Questionnaire for Children and 
Teenagers
8.8 Addendum 8: Study Adherence Questionnaire for Caregivers
Rationale: Some administrative and textual changes were made.
Per revised template, addition of a 
footnote in the Flowchart, to clarify 
that 
informed 
consent 
must 
be 
obtained prior to any study related 
activity.
Deletion of duplicated information.
Minor typographic error
Other textual changes, to improve 
consistency in the document.
2.1.1.1 Flowchart for Assessments up to Week 4 (Screening and Initial 
Treatment Period up to Week 4)
Title Pages
6.1.1 Overview of Trial
2.1.1.1 Flowchart for Assessments up to Week 4 (Screening and Initial 
Treatment Period up to Week 4)
2.1.1.3
Flowchart for Assessments from Week 8 onwards (Initial 
Treatment Period from Week 8 onwards, Post Week 48 Treatment 
Extension, and Follow-up)
6.1.1 Overview of Trial
6.2.3 Exclusion Criteria
6.4.10 Adherence Questionnaire
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Amendment GEN-IV (Issued Date: 02-Feb-2012)
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: Based on correspondence exchange with the Food and Drug 
Administration (FDA), Snapshot analysis was added, as a secondary efficacy analysis. At the request of the 
Pediatric Committee (PDCO), the timing of the Week 12 interim analysis was changed.
Description of Change(s)
Applicable Section(s)
Rationale: Addition of snapshot analysis, as a secondary efficacy analysis, as requested by the FDA.
Addition of Snapshot analysis.
6.6.2.2.1.1 Analysis
Rationale: At the request of the PDCO, the timing of Week 12 interim analysis changed from ‘when all subjects 
have reached 12 weeks of treatment or discontinued earlier’ to ‘when all Part 1a and Part 1b subjects have reached 
12 weeks of treatment or discontinued earlier’.
Week 12 interim analysis will be 
performed when all Part 1 subjects 
have reached Week 12 or discontinued 
earlier.
6.1.1 Overview of Trial
6.3.9 Independent Data Monitoring Committee
6.6 Statistical Methods Planned and Determination of the Sample Size
Rationale: Changes of Protocol Amendment III were not made consistently/correctly throughout the protocol.
Flowchart for switch to weight-
adjusted dose was updated through 
Amendment III. However, footnote i
was inadvertently left in while it 
should have been deleted.
2.1.1.2 Flowchart for Switch to Weight-adjusted Dose (if applicable)
4-week follow-up visit should take 
place regardless of the presence of 
(S)AEs if subjects withdraw early (i.e., 
before Week 48) or if subjects do not 
participate in the extension after 
Week 48. After Week 48, a 4-week 
follow-up visit is only required in case 
of ongoing (S)AEs at the final on-
treatment visit.
Summary
2.1.1.3
Flowchart for Assessments from Week 8 onwards (Initial 
Treatment Period from Week 8 onwards, Post Week 48 Treatment 
Extension, and Follow-up)
3 Overview of Trial Design
6.1.1 Overview of Trial
6.2.5 Removal of Subjects From Therapy or Assessment
In the post Week 48
treatment 
extension period, the time window for 
study visits is +/-1 week.
6.4.2 Time Windows
Pharmacokinetic parameter analyses 
applicable for Part 1 should take place 
on Day 14 for Part 1a and on Day 28 
for Part 1b.
6.6.2.4 Pharmacokinetic Parameter Analyses
Since Week 48 and Week 96 Phase III 
data are now available, AUC are and 
will be compared with these Phase III 
data.
6.6.2.4 Pharmacokinetic Parameter Analyses
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Approved, Issued Date: 03-FEB-2020
Rationale: The name of the sponsor of the trial changed from Tibotec Pharmaceuticals to Janssen R&D Ireland 
because of the transition of the Johnson & Johnson Research & Development companies to a unified Janssen 
identity.
The name of the sponsor of the trial 
changed.
Title Page
Summary
6.3.1 Identity of Investigational Product
6.5.1 Cutaneous Event/Rash
8.2 Addendum 2: DAIDS Table
Rationale: Some administrative and textual changes were made.
Administrative and textual changes
Title Page
List of Abbreviations
2.1.1.1 Flowchart for Assessments up to Week 4 (Screening and Initial 
Treatment Period up to Week 4)
2.1.1.2 Flowchart for Switch to Weight-adjusted Dose (if applicable)
2.1.1.3
Flowchart for Assessments from Week 8 onwards (Initial 
Treatment Period from Week 8 onwards, Post Week 48 Treatment 
Extension, and Follow-up)
3 Overview of Trial Design
4 Introduction
5 Objectives
6.1.2 Discussion of Trial Design and Selection of Dose(s) in the Trial
6.2.4.1 Precautions
6.2.5 Removal of Subjects From Therapy or Assessment
6.3.3 Dosage and Treatment Overview Per Subject
6.3.13.1 Disallowed Concomitant Medication
6.4.7 Resistance Determinations
6.4.10 Adherence Questionnaire
6.5.5 Signs and Symptoms of Adrenal Insufficiency
6.5.9 Diarrhea
6.5.10 Other Toxicities
6.5.11.3 Hypersensitivity Reactions
6.6.1 Determination of Sample Size
6.6.2.2.1 Plasma viral load
6.6.2.3 Resistance determinations
6.6.2.4 Pharmacokinetic Parameter Analyses
1.4 Reporting of AEs and HIV-Related Events
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PART 1.
CLINICAL TRIAL PROTOCOL
1.
GLOSSARY
List of Abbreviations
ABC
abacavir
ACTH
adrenocorticotropic hormone
ADR
adverse drug reaction
AE
adverse event
AIDS
Acquired Immunodeficiency Syndrome
ALP
alkaline phosphatase
ALT/SGPT
alanine aminotransferase
ART
antiretroviral therapy
ARV
antiretroviral
AST/SGOT
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC24h
AUC from time of administration up to 24 hours post dosing
AZT
zidovudine
BMD
bone mineral density
BMI
body mass index
BP
blood pressure
CDC
Centers for Disease Control and Prevention
CDER
Center for Drug Evaluation and Research
CI
confidence interval
CL/F
total apparent plasma clearance at steady-state
C0h
predose (trough) plasma concentration
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration between 0 hour and τ (τ = dosing interval)
CPMP
Committee for Proprietary Medicinal Products
ClCr
creatinine clearance
Css,av
average steady-state plasma concentration
%CV
percentage of coefficient of variation
CV
coefficient of variation
CYP3A4
cytochrome P450, isoenzyme 3A4
d4T
stavudine
DAIDS
Division of AIDS
DBP
diastolic blood pressure
ddI
didanosine
DHEAS
dehydroepiandrosterone sulfate
DHHS
Department of Health and Human Services
DSUR
Development Safety Update Report
EC50
50% effective concentration
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EFV
efavirenz
ENF
enfuvirtide
ETR
etravirine
FDA
Food and Drug Administration
FSH
folllicle stimulating hormone
FTC
emtricitabine
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyltransferase
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HAART
highly active antiretroviral therapy
HCV
hepatitis C virus
HDL
high-density lipoprotein
HIV-1(2)
human immunodeficiency virus - type 1 (type 2)
HLA
Haman Leukocyte Antigen
HMG-CoA
3-hydroxy-3-methylglutaryl coenzyme A
IAS-USA
International Antiviral Society United State of America
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
ITT
intent-to-treat
IRB
Institutional Review Board
IUD
intra-uterine device
LDL
low density lipoprotein
LH
luteinizing hormone
LOCF
last observation carried forward
LS
least square
MCH
mean corpuscular hemoglobin
M = F
missing = failure
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MTCT
mother-to-child transmission
n
number of observations
NA
not applicable
NC = F
non-completer = failure
NNRTI
non-nucleoside reverse transcriptase inhibitor
N(t)RTI
nucleoside/nucleotide analogue reverse transcriptase inhibitor
NVP
nevirapine
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PI
protease inhibitor
PK
pharmacokinetic
PMTCT
prevention of mother-to-child transmission
PoP
proof-of-principle 
PR
pulse rate
PQC
product quality complaint
QA
Quality Assurance
QC
Quality Control
q.d.
quaque die; once daily
RAM
resistance-associated mutation
RBC
red blood cell
RNA
ribonucleic acid
RPV
rilpivirine
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
sdNVP
single dose of nevirapine
SJS
Stevens-Johnson Syndrome
SUSAR
suspected unexpected serious adverse reaction
3TC
lamivudine
TDF
tenofovir disoproxyl fumarate
TEN
toxic epidermal necrolysis
TLOVR
time to loss of virologic response
tmax
time to reach the maximum plasma concentration
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TMC
Tibotec Medicinal Compound
t1/2,term
terminal elimination half-life
ULN
upper limit of laboratory normal range
USA
United States of America
VL
viral load
WBC
white blood cell
Definition of terms
BMI
Weight in kg divided by the square of the height in meters
QTcB
QT interval corrected for heart rate using Bazzet’s formula
QTc = QT x (1000/RR)b where b = 1/2
QTcF
QT interval corrected for heart rate using Fridericia’s formula
QTc = QT x (1000/RR)b where b = 1/3
Study drug
the medication under investigation (RPV in this trial)
Background regimen
the 2 investigator-selected N(t)RTIs
ARV medication
all ARV medication administered in this trial, i.e., RPV and the background 
regimen
Virologic Response
2 consecutive measurements of <400 HIV-1 RNA copies/mL
Virologic Failure
Lack or loss of virologic response
Suspected Virologic Failure
HIV-1 RNA ≥ 200 copies/mL after confirmed HIV-1 RNA of <50 
copies/mL
Lack of response
Confirmed decrease in plasma viral load of <1.0 log10 at Week 12 from the 
baseline viral load (i.e., 2 consecutive measurements at least 2 weeks apart)
Loss of response
Two consecutive measurements of >400 HIV-1 RNA copies/mL at least 
2 weeks apart after having been confirmed virologic responder 
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2.
FLOWCHART
2.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years
2.1.1.
Flowchart for All Assessments in Cohort 1 (Screening, Initial Treatment Period, Post Week 48 
Treatment Extension, and Follow-up)
2.1.1.1.
Flowchart for Assessments up to Week 4 in Cohort 1 (Screening and Initial Treatment Period up to 
Week 4)
Type of Visit
Screening*
Baseline
Initial Treatment Period**
Time of Visit
W-6
D 1
W 1
W 2***
W 4***
Informed consentbb, demographic data, medical and surgical history, concomitant diseases
#
Inclusion/exclusion criteria
#
#
HLA-B*5701 testinga
X
Determination of plasma viral load
#*
#
#
#
Immunology
#
#
#
#
Samples for viral phenotype/genotype determinationsb,c
#
#
#
#d
Hematology & biochemistrye
#*
#f
X
#
#
Electrocardiogram (ECG)g
X
Xh
Xi
Vital signs (Pulse, blood pressure [BP])
#
#
#
#
Physical examination
#
#
X
#j
#k
Height/weightl
#
#
Xm
#m
#m
Check occurrence of first mensesn
X
X
X
X
X
Evaluation of pubertal development (Tanner scale)
#
Contraceptive counsellingo
X
Pregnancy testp
#
#
#
Urinalysis
#
#
X
#
#
Sampling for pharmacokineticsq
Xr
#s
Cortisol (and adrenocorticotropic hormone [ACTH] stimulation testing if applicable)t
X
X
Endocrine assessmentsu
X
Cortisol, 17-hydroxyprogesterone, aldosterone assessments, and ACTH stimulation testingv
X
Treatment adherence counseling and checking of adherencew
X
X
X
X
X
Study Adherence Questionnaire for Children and Teenagers and/or Carersx
X
X
#
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Type of Visit
Screening*
Baseline
Initial Treatment Period**
Time of Visit
W-6
D 1
W 1
W 2***
W 4***
Evaluation for depressiony
X
X
X
Dispensation of antiretroviral (ARV) medication
#
X
#
#
Drug accountability
#
#
Completion of diaryz
X
X
X
X
Concomitant therapyaa
#
#
X
#
#
Observe/Interview for adverse events (AEs), including HIV-related eventsaa
#
X
#
#
*
During the screening period it is allowed to assess the viral load and CD4+ cell count before continuing with the other screening assessments. After obtaining informed consent, 
samples will be taken for determination of plasma viral load and CD4+ cell count. If plasma viral load results meet the inclusion criteria and the investigator considers initiation 
of ART appropriate (taking into account current treatment guidelines, including CD4+ cell count and the subject’s clinical situation), the subject 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 subject 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 assessment, if these were 
assessed separately before continuing with the other screening assessments), but in case of unforeseeable circumstances, this period can be prolonged by 2 weeks maximum.
**
Unscheduled visits may be performed for safety/tolerability reasons and for confirmation of plasma viral load results (see Section 6.4.1).
*** If the short-term Part 1 results show a safety concern, that potentially could be avoided by lower exposure to RPV, as deemed by the IDMC, subjects up to a certain body 
weight (determined based on the intensive pharmacokinetic results) will be switched to a lower, weight-adjusted dose of RPV. Please refer to the flowchart in Section 2.1.1.2
for further details. If the Week 2 results are not deemed satisfactory by the IDMC, all subjects will be seen for a Withdrawal visit, treatment with RPV will be stopped, subjects 
will be switched to a locally available ARV regimen, and the trial will be stopped. For more details on the trial design and stopping rules, please refer to Section 6.1.1.
a
HLA-B*5701 testing is only required for subjects for whom the investigator considers ABC in the background regimen and is not required for subjects with prior documented 
HLA-B*5701 negative results. The test involves a cheek swab. No eating or drinking is allowed for 30 minutes before the swab. In those subjects where HLA-B*5701 is 
positive, ABC cannot be administered, but instead, the investigator should select another N(t)RTI in the background regimen.
b
Samples collected at screening will be tested in real time for the determination of the HIV-1 genotype. These HIV-1 genotyping results will be provided to the investigator as 
soon as they are available. Samples collected at baseline and at the first visit after confirmed loss of response (see Section 6.2.5) will be tested for the determination of the 
HIV-1 genotype, as long as the viral load is sufficiently high to allow HIV-1 genotyping. 
Phenotyping will be done at baseline. Samples will be analyzed as long as the viral load is sufficiently high to allow phenotyping. Samples collected at other intervals may be 
selected for the determination of HIV-1 genotype and/or phenotype by the Protocol Virologist based on plasma viral load. 
c
In case Cohort 1 is stopped after Part 1, a sample will be analyzed in real time for the determination of HIV-1 genotype (as long as the viral load is sufficiently high to allow 
HIV-1 genotyping), in order to assist in the selection of a new ARV regimen. When determination of HIV-1 genotype on this sample is not possible due to a too low viral load, 
the new ARV regimen will be based on the screening HIV-1 genotyping result. 
d
Samples for viral phenotype/genotype will only be taken if the plasma viral load at the previous visit was >50 HIV-1 RNA copies/mL. If at a certain visit the plasma viral load, 
after having been < 50 HIV-1 RNA copies/mL at a previous visit, has increased to >50 HIV-1 RNA copies/mL, samples for viral phenotype/genotype should be taken at an 
unscheduled visit.
e
Sample should be taken fasted (overnight).
Footnotes continue on the next page
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f
A hepatitis A, B, and C test will be performed at baseline, and whenever clinically relevant, extra tests can be done at other visits. The hepatitis C test will be a hepatitis C virus 
(HCV)-antibody test. Only in case the CD4+ cell count at screening was <100 cells/mm3 or in case the HCV-antibody test at baseline was positive, a qualitative HCV RNA 
sample should be drawn at Week 1.
g
Whenever possible, the ECG should be taken at expected Cmax (i.e., 4 hours after intake of RPV). Additional ECGs must be performed in case of start of certain concomitant 
medication (see Section 6.3.13.1).
h
For Part 1a subjects only.
i
For Part 1b and Part 2 subjects only.
j
Only skin examination.
k
A brief physical examination only.
l
Growth will be followed using the standardized charts (see Section 6.4.9.4).
m
Height does not need to be measured.
n
At screening, it will be assessed whether girls already have had their first menses. As part of the evaluation of pubertal development, for girls who have not yet had their first 
menses at screening, it will be checked at every visit whether they have had their first menses and the date of first menses will be recorded. 
o
It is the investigator’s responsibility to ensure that the subjects receive appropriate counseling about precautions to reduce the risk of transmitting HIV and birth control 
methods (see Section 6.2.4.1). Girls having their first menses during the trial should receive counseling again.
p
Serum test at screening and urine test at other visits, for girls of childbearing potential.
q
A pharmacokinetic sample will be taken at any time during the visit. The date and time of sampling and the date and time of the RPV intake prior to that sample should be 
recorded on the electronic Case Report Form (eCRF). Where possible (i.e., if that RPV intake occurs during the visit), at least on one occasion, the sample will be taken just 
prior to RPV intake.
r
For Part 1a subjects only: intensive pharmacokinetic sampling took place at the Week 2 visit. See Section 2.1.2 for details.
For Part 1b and Part 2 subjects only: sparse pharmacokinetic sampling will take place at the Week 2 visit.
s
For Part 1b subjects only: intensive pharmacokinetic sampling will take place at the Week 4 visit. See Section 2.1.2 for details. 
t
Basal cortisol will be measured in the morning at the indicated visits, between 7h30 and 9h30. If at any visit, as of the baseline visit, basal cortisol value is <248 nmol/L 
(9 μg/dL) a retest will be done at the subsequent visit or at least within the next 8 weeks. If 2 consecutive basal cortisol values are <248 nmol/L (9 μg/dL), an ACTH 
stimulation test will be done at the next scheduled visit with measurements of cortisol, 17-hydroxyprogesterone, and aldosterone before (T0), 30 (T30) and 60 (T60) minutes 
after ACTH stimulation (see Section 6.4.9.2.3). In case of clinical signs or symptoms or laboratory abnormalities (other than cortisol) indicative of adrenal insufficiency (see 
Section 6.5.5), an ACTH stimulation test should be done as soon as possible during an unscheduled visit. If an unscheduled ACTH stimulation test is performed at a visit with 
a scheduled basal cortisol assessment, only one sample needs to be collected for the determination of basal (T0) cortisol.
u
Assessment of follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, androstenedione, testosterone, dehydroepiandrosterone sulfate (DHEAS) in 
conjunction with the basal (T0) cortisol assessment.
v
ACTH stimulation test including measurements of cortisol, 17-hydroxyprogesterone and aldosterone, measured before (T0), 30 (T30) and 60 (T60) minutes after ACTH 
stimulation, at baseline (see Section 6.4.9.2.3). If the ACTH stimulation test is abnormal (i.e., all cortisol values [before and after ACTH stimulation] are <500 nmol/L [18.1 
∃g/dL]), a retest needs to be performed at the next scheduled visit. In case of withdrawal due to pregnancy, no ACTH stimulation test needs to be performed, but basal 
assessments need to be performed.
w
Treatment adherence counseling should be performed at screening and baseline; treatment adherence should be checked and counseling repeated at every visit thereafter (see 
Section 6.3.12).
x
Questionnaires will only be administered if a certified translation is available in the local language.
y
Evaluation should be done according to local standard of care at the site (see Section 6.4.11 for details).
z
For Part 1a and Part 1b subjects only: subjects, their parent(s), or caregiver(s) will have to complete a diary documenting the intake of RPV from the start of treatment until the 
day of intensive pharmacokinetic sampling. 
aa
Adverse events (including HIV-related events and the occurrence of AIDS-defining illnesses) and the intake of concomitant medication will be monitored throughout the trial 
from signing of the informed consent form (ICF) onwards until the last trial-related activity.
bb
Informed consent must be obtained prior to any trial-related activity.
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2.1.1.2.
Flowchart for Switch to Weight-adjusted Dose in Cohort 1, Part 1 
Only (If Applicable)
Note: The following flowchart was also applicable for subjects in Part 1a in case of switch to 
weight-adjusted dose. However, after review of Part 1a Week 2 data the IDMC did not warrant 
the need for a switch to weight-adjusted dose. Recruitment for Part 1a has been closed in the 
meantime.
Type of Visit
Initial Treatment Period*
Time of Visit
Dose Switch Visit**
Post Switch Visit***
Determination of plasma viral load 
#
Immunology
#
Samples for viral phenotype/genotype determinationsa,b
#
Hematology & biochemistryc
#
Electrocardiogram (ECG)d
X
Vital signs (Pulse, blood pressure [BP])
#
Physical examination 
#e
Height/weightf
#g
Check occurrence of first mensesh
X
Urinalysis
#
Sampling for pharmacokinetics
Xj
Treatment adherence counseling and checking of 
adherence
X
X
Study Adherence Questionnaire for Children and 
Teenagers, if applicablek
X
Evaluation for depressionl
X
Dispensation of antiretroviral (ARV) medication
X
#
Drug accountability
#
Completion of diarym
X
Concomitant therapyn
#
#
Observe/Interview for adverse events (AEs), including 
HIV-related eventsn
#
#
*
Unscheduled visits may be performed for safety/tolerability reasons, for confirmation of plasma viral load results, and for the 
dose switch visit and/or post switch visit (see Section 6.4.1).
**
As soon as the recommended pediatric dose is communicated, subjects from Part 1 will have to attend a dose switch visit 
(unscheduled visit) in order to be provided with RPV at the recommended weight-adjusted dose, if applicable. If the dose 
switch visit is done within 1 week of the next scheduled visit as indicated in the flowchart, this next planned visit can be 
cancelled but assessments of that visit will have to be performed at the dose switch visit.
*** A re-evaluation of subjects who have been treated with the weight-adjusted dose for 4 weeks (+/-1 week) will be done 
(unscheduled visit). If the post switch visit is done within 1 week of the next planned visit as indicated in the flowchart, this 
next planned visit can be cancelled but assessments of that visit that are not planned at the post switch visit will have to be 
added to the planned assessments at the post switch visit.
a
Samples collected at the first visit after confirmed loss of response (see Section 6.2.5) will be tested for the determination of 
the HIV-1 genotype, as long as the viral load is sufficiently high to allow HIV-1 genotyping. 
Samples collected at other intervals may be selected for determination of the HIV-1 genotype and/or phenotype by the 
Protocol Virologist based on plasma viral load.
b
In case the Cohort 1 is stopped after Part 1, a sample will be analyzed in real time for the determination of HIV-1 genotype 
(as long as the viral load is sufficiently high to allow HIV-1 genotyping), in order to assist in the selection of a new ARV 
regimen. When determination of HIV-1 genotype on this sample is not possible due to a too low viral load, the new ARV 
regimen will be based on the screening HIV-1 genotype result.
c
Sample should be taken fasted (overnight).
Footnotes continue on the next page
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TMC278-TiDP38-C213
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d
Whenever possible, the ECG should be taken at expected Cmax (i.e., 4 hours after intake of RPV). Additional ECGs must be 
performed in case of start of certain concomitant medication (see Section 6.3.13.1).
e
Only skin examination.
f
Growth will be followed using the standardized charts (see Section 6.4.9.4).
g
Height does not need to be measured.
h
As part of the evaluation of pubertal development, for girls who have not yet had their first menses at screening, it will be 
checked at every visit whether they have had their first menses and the date of first menses will be noted. 
j
For Part 1a subjects only: intensive pharmacokinetic sampling was to take place at the post switch visit (at least 2 weeks after 
the dose switch visit). See Section 2.1.2 for details.
For Part 1b subjects only: intensive pharmacokinetic sampling will take place at the post switch visit (4 weeks [+/-1 week] 
after the dose switch visit). See Section 2.1.2 for details.
k
Questionnaires will only be administered if a certified translation is available in the local language.
l
Evaluation should be done according to local standard of care at the site (see Section 6.4.11 for details).
m
For Part 1a and Part 1b subjects only: subjects, their parent(s), or caregiver(s), will have to complete a diary documenting the 
intake of RPV from the start of treatment with the weight-adjusted dose until the day of intensive pharmacokinetic sampling.
n
Adverse events (including HIV-related events and the occurrence of AIDS-defining illnesses) and the intake of concomitant 
medication will be monitored throughout the trial from signing of the informed consent form (ICF) onwards until the last 
trial-related activity.
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2.1.1.3.
Flowchart for Assessments From Week 8 Onwards in Cohort 1 (Initial Treatment Period From 
Week 8 Onwards, Post Week 48 Treatment Extension, and Follow-up)
Type of Visit
Initial Treatment Period*
Final/ 
Withdrawal 
Visit**
Post Week 48 
Treatment 
Extension*
Final/ Post 
Week 48
Withdrawal 
Visit***
Post-treatment 
Follow-up 
Period****
Time of Visit
W 8
W 12
W 16
W 24
W 32
W 40
W 48
Every 3 
Months
Every 6 
Months
W 240
4 Weeks After 
Final/Withdra
wal Visit
Informed consenta
X
Determination of plasma viral load
X
X
X
X
X
X
X
X
X
X
X
Immunology
X
X
X
X
X
X
X
X
Samples for viral phenotype/genotype determinationsb
Xc
Xc
Xc
Xc
Xc
Xc
X
X
X
X
X
Hematology & Biochemistryd,e
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (ECG)f
X
X
X
X
Vital signs (Pulse, blood pressure [BP])
X
X
X
X
X
X
X
X
X
X
X
Physical examination
Xg
X
Xg
X
Xg
Xg
X
Xg
X
X
Xg
Height/weighth
X
Xi
X
X
X
X
X
X
X
X
Check occurrence of first mensesj
X
X
X
X
X
X
X
X
X
X
X
Evaluation of pubertal development (Tanner scale)
X
X
X
X
X
X
X
Pregnancy testk
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
Sampling for pharmacokineticsl
X
X
X
X
X
Cortisol (and adrenocorticotropic hormone [ACTH] stimulation 
testing if applicable)m
X
X
X
X
X
Endocrine assessmentsn
X
X
X
X
Cortisol, 17-hydroxyprogesterone, aldosterone assessments, and 
ACTH stimulation testingo
X
X
X
X
Treatment adherence counseling and checking of adherence
X
X
X
X
X
X
X
X
X
X
X
Study Adherence Questionnaire for Children and Teenagers and/or
Carersp
X
X
X
X
X
X
X
Evaluation for depressionq
X
X
X
X
X
X
X
X
X
X
X
Dispensation of antiretroviral (ARV) medication
X
X
X
X
X
X
Xr
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
Concomitant therapys
X
X
X
X
X
X
X
X
X
X
X
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Type of Visit
Initial Treatment Period*
Final/ 
Withdrawal 
Visit**
Post Week 48 
Treatment 
Extension*
Final/ Post 
Week 48
Withdrawal 
Visit***
Post-treatment 
Follow-up 
Period****
Time of Visit
W 8
W 12
W 16
W 24
W 32
W 40
W 48
Every 3 
Months
Every 6 
Months
W 240
4 Weeks After 
Final/Withdra
wal Visit
Observe/interview for adverse events (AEs), including HIV-
related eventss
X
X
X
X
X
X
X
X
X
X
X
*
Unscheduled visits may be performed for safety/tolerability reasons and for confirmation of plasma viral load results (see Section 6.4.1).
**
For subjects who discontinue the trial before Week 48, this is the Withdrawal visit; otherwise this is the Final visit.
***
For subjects who discontinue the trial after Week 48 but before Week 240, this the Withdrawal visit; otherwise this is the Final visit.
**** In the initial treatment period, the 4-week Follow-up visit is only performed for subjects who withdraw early from the trial (i.e., before Week 48) (unless consent is 
withdrawn) or who do not participate in the extension after Week 48. In the extension period the 4-week Follow-up visit is only performed if there is an ongoing (S)AE at the 
last on-treatment visit. 
a
Informed consent to the post Week 48 treatment extension must be given prior to the start of this treatment extension.
b
Samples collected at the first visit after confirmed loss of response (see Section 6.2.5), at the Week 48 visit, and at the Final/Withdrawal visit will be tested for the 
determination of the HIV-1 genotype, as long as the viral load is sufficiently high to allow HIV-1 genotyping. 
Phenotype will be done at the Week 48 visit and at the Final/Withdrawal visit. Samples will be analyzed as long as the viral load is sufficiently high to allow phenotyping. 
Samples collected at other intervals may be selected for determination of the HIV-1 genotype and/or phenotype by the Protocol Virologist based on plasma viral load. 
c
Samples for viral phenotype/genotype will only be taken if the plasma viral load at the previous visit was >50 HIV-1 RNA copies/mL. If at a certain visit the plasma viral load, 
after having been <50 HIV-1 RNA copies/mL at a previous visit, has increased to >50 HIV-1 RNA copies/mL, samples for viral phenotype/genotype should be taken at an 
unscheduled visit.
d
Sample should be taken fasted (overnight).
e
Tests can be performed whenever clinically relevant. The hepatitis C test will be a hepatitis C virus (HCV)-antibody test. 
f
Whenever possible, the ECG should be taken at expected Cmax (i.e., 4 hours after intake of RPV). Additional ECGs must be performed in case of start of certain concomitant 
medication (see Section 6.3.13.1).
g
A brief physical examination only.
h
Growth will be followed using the standardized charts (see Section 6.4.9.4).
i
Height does not need to be measured.
j
As part of the evaluation of pubertal development, for girls who have not yet had their first menses at screening, it will be checked at every visit whether they have had their 
first menses and the date of first menses will be noted. 
k
Urine test for girls of childbearing potential.
l
A pharmacokinetic sample will be taken at any time during the visit. The date and time of sampling and the date and time of the RPV intake prior to that sample should be 
recorded on the electronic Case Report Form (eCRF). Where possible (i.e., if that RPV intake occurs during the visit), at least on one occasion, the sample will be taken just 
prior to RPV intake.
m
Basal cortisol will be measured in the morning at the indicated visits, between 7h30 and 9h30. If at any visit, as of the baseline visit, basal cortisol value is <248 nmol/L (9 
μg/dL) a retest will be done at the subsequent visit or at least within the next 8 weeks. If 2 consecutive basal cortisol values are <248 nmol/L (9 μg/dL), an ACTH stimulation 
test will be done at the next scheduled visit with measurements of cortisol, 17-hydroxyprogesterone, and aldosterone before (T0), 30 (T30) and 60 (T60) minutes after ACTH 
stimulation (see Section 6.4.9.2.3). In case of clinical signs or symptoms or laboratory abnormalities (other than cortisol) indicative of adrenal insufficiency (see Section 6.5.5), 
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Approved, Issued Date: 03-FEB-2020
an ACTH stimulation test should be done as soon as possible during an unscheduled visit. If an unscheduled ACTH stimulation test is performed at a visit with a scheduled 
basal (T0) cortisol assessment, only one sample needs to be collected for the determination of basal cortisol.
n
Assessment of follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, androstenedione, testosterone, dehydroepiandrosterone sulfate (DHEAS) in 
conjunction with the basal (T0) cortisol assessment.
o
ACTH stimulation test including measurements of cortisol, 17-hydroxyprogesterone and aldosterone, measured before (T0), 30 (T30) and 60 (T60) minutes after ACTH 
stimulation, needs to be performed at Week 48 (see Section 6.4.9.2.3). If the ACTH stimulation test is abnormal (i.e., all cortisol values [before and after ACTH stimulation] 
are <500 nmol/L [18.1 ∃g/dL]), a retest needs to be performed at the next scheduled visit. At Week 12 and 24, no ACTH stimulation test needs to be performed, only basal 
assessments of cortisol, 17-hydroxyprogesterone and aldosterone. In case of withdrawal due to pregnancy, no ACTH stimulation test needs to be performed, but basal 
assessments need to be performed.
p
Questionnaires will only be administered if a certified translation is available in the local language.
q
Evaluation should be done according to local standard of care at the site (see Section 6.4.11 for details).
r
Only for subjects who enter the post Week 48 treatment extension.
s
Adverse events (including HIV-related events and the occurrence of AIDS-defining illnesses) and the intake of concomitant medication will be monitored throughout the trial 
from signing of the informed consent form (ICF) onwards until the last trial-related activity.
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Clinical Trial Protocol Amendment X
Approved, Issued Date: 03-FEB-2020
2.1.2.
Flowchart for Intensive Pharmacokinetic Sampling in Cohort 1, 
Part 1 Only
Note: For Part 1a subjects, intensive pharmacokinetic sampling was to take place after at least 
2 weeks of treatment with rilpivirine (RPV) 25 mg q.d. or a weight-adjusted dose q.d. For
Part 1b subjects, intensive pharmacokinetic sampling will take place after 4 weeks (+/-1 week) of 
treatment with RPV 25 mg q.d. or a weight-adjusted dose q.d.
Time
Blood Samplea
ECG, Pulse Rate (PR), BP
Other
Admission to unit 
Predose
Xb
Xc,d
Standardized breakfast in unit 
0 h
Intake RPV 25 mg 
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 unite
a
At each time point, 4 mL of blood should be collected (total volume of blood drawn during the 24-hour 
period is 32 mL).
b
Within 1 hour before dosing.
c
Within 2 hours before dosing.
d
ECG and vital signs measurements should be performed preferably before blood sampling.
e
In case it is not feasible for subjects to stay overnight, the subject can be discharged after the 12-hour sample. 
In this case, the subject should return to the unit for the 24-hour sample.
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Clinical Trial Protocol Amendment X
45
Approved, Issued Date: 03-FEB-2020
2.2.
Cohort 2: Children Aged ≥6 to <12 Years
2.2.1.
Flowchart for all Assessments in Cohort 2 (Screening, Initial Treatment Period, Post Week 48 
Treatment Extension, and Follow-up)
2.2.1.1.
Flowchart for Assessments up to Week 4 in Cohort 2 (Screening and Initial Treatment Period up to 
Week 4)
Type of Visit
Screening*
Baseline
Initial Treatment Period**
Time of Visitaa
W-6
D 1
W 1
W 2***,†,††
W 4***
Informed consenta, demographic data, medical and surgical history, concomitant diseases
#
Check clinical statusb
X
Inclusion/exclusion criteria
#
X
HLA-B*5701 testingc
X
Determination of plasma viral loadd
#*
#
#
#
Immunology
#*
#
#
#
Samples for viral phenotype/genotype determinationse
#
X
X
PBMC samplez
X
Hematology & biochemistryf,g
#
#
X
#
#
Electrocardiogram (ECG)h
X
X
Vital signs (Pulse, blood pressure [BP])
#
#
X
#
#
Physical examination
#
#
X
#i
#j
Height/weightk
#
#
Xl
#l
#l
Check occurrence of first mensesm
X
X
X
X
X
Evaluation of pubertal development (Tanner scale)
#
Contraceptive counsellingn
X
Pregnancy testo
#
#
#
Urinalysis
#
#
#
Sampling for pharmacokineticsd
X††,p
#q
Endocrine assessmentsr
X
ACTH stimulation testing (cortisol, 17-hydroxyprogesterone assessments)s
Reflex Test
Treatment adherence counseling and checking of adherencet
X
X
X
X
X
Study Adherence Questionnaire for Children and Teenagers and/or Carersu
X
X
#
NCT00799864


TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
46
Approved, Issued Date: 03-FEB-2020
Type of visit
Screening*
Baseline
Initial Treatment period**
Time of Visit
W-6
D 1
W 1
W 2***,†,††
W 4***
Palatability assessmentv
X
X
Evaluation of depressionw
X
X
X
Dispensation of antiretroviral (ARV) medication
#
#
Drug accountability
X
#
#
Completion of diaryx
X
X
X
Concomitant therapyy
#
#
X
#
#
Observe/Interview for AEs, including HIV-related eventsy
#
X
#
#
*
During the screening period it is allowed to assess the viral load and CD4+ cell count before continuing with the other screening assessments. In such case, after obtaining 
informed consent, samples will be taken for determination of plasma viral load and CD4+ cell count. If plasma viral load results meet the inclusion criteria and the investigator 
considers initiation of ART appropriate (taking into account current treatment guidelines, including CD4+ cell count and the subject’s clinical situation), the subject 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 subject 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 assessment, if these were 
assessed separately before continuing with the other screening assessments), but in case of unforeseeable circumstances, the screening period can be prolonged by 2 weeks 
resulting in a maximum screening period duration of 8 weeks.
**
Unscheduled visits may be performed for safety/tolerability reasons, for reflex ACTH stimulation test in case basal cortisol is <248 nmol/L on initial and repeat testing, and for 
confirmation of plasma viral load results (see Section 6.4.1).
*** If the intensive PK results show a safety concern that potentially could be addressed by lower exposure to RPV, subjects will be switched to a lower dose. Please refer to the 
flowchart in Section 2.2.1.2 for further details. If the results after at least 4 weeks of treatment are not deemed satisfactory, all subjects will be seen for a Withdrawal visit, 
treatment with RPV will be stopped, subjects will be switched to local standard of care, and Cohort 2 will be stopped. For more details on the trial design and dose evaluation 
criteria, please refer to Section 6.1.1.2 and Section 6.1.1.2.1, respectively.
†
The Week 2 visit should only be scheduled for subjects with body weight of <25 kg at baseline.
††
Subjects with body weight of <25 kg or their parent(s)/caregiver(s) should be contacted via telephone or email to assess adherence (to study drug and other ARVs) and to 
reinforce trial instructions every day for 3 days prior to the intensive pharmacokinetic visit. If potential AEs are detected during these telephone/email contacts then the subject 
will be required to have an additional visit at the clinic and evaluations done as specified in Section 6.5. If the subject has missed a dose of RPV within 10 days prior to the 
intensive pharmacokinetic visit, the visit should be rescheduled to allow for steady-state of RPV to be reached.
a
Informed consent must be obtained prior to any trial-related activity.
b
If a subject's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study drug is 
given such that he or she no longer meets all eligibility criteria, then the subject should be excluded from participation in the trial.
c
HLA-B*5701 testing is only required for subjects for whom the investigator considers ABC in the background regimen and is not required for subjects with prior documented 
HLA-B*5701 negative results. The test involves a cheek swab. No eating or drinking is allowed for 30 minutes before the swab. In those subjects where HLA-B*5701 is 
positive, ABC cannot be administered, but instead, the investigator should select another N(t)RTI in the background regimen.
d
In case of suspected virologic failure (unconfirmed loss/lack of response, see Section 1) a sample for confirmation of plasma viral load and pharmacokinetics should be taken 
at an unscheduled visit (see Section 6.4.1). 
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Clinical Trial Protocol Amendment X
47
Approved, Issued Date: 03-FEB-2020
Footnotes continue on the next page
e
Samples collected at screening will be tested in real time for the determination of the HIV-1 genotype. Samples collected at baseline, at virologic failure (see Section 6.2.5), at 
Week 48, and at the Final/Withdrawal visit will be tested for the determination of the HIV-1 genotype and phenotype, as long as the viral load is sufficiently high. Samples 
collected at other intervals may be selected for the determination of HIV-1 genotype and phenotype by the Protocol Virologist based on plasma viral load.
f
Sample should be taken fasted (overnight).
g
A hepatitis A, B, and C test will be performed at baseline, and whenever clinically relevant, extra tests can be done at other visits. The hepatitis C test will be a HCV-antibody 
test. Only in case the CD4+ cell count at screening was <100 cells/mm3 or in case the HCV-antibody test at baseline was positive, a qualitative HCV RNA sample should be 
drawn at Week 1.
h
Whenever possible, the ECG should be taken at expected Cmax (i.e., 4 hours after intake of RPV).
i
Only skin examination.
j
A brief physical examination only.
k
Growth will be followed using the standardized charts (see Section 6.4.9.4).
l
Height does not need to be measured.
m
At screening, it will be assessed whether girls already have had their first menses. As part of the evaluation of pubertal development, for girls who have not yet had their first 
menses at screening, it will be checked at every visit whether they have had their first menses and the date of first menses will be recorded. 
n
It is the investigator’s responsibility to ensure that the subjects receive appropriate counseling about precautions to reduce the risk of transmitting HIV and birth control 
methods (see Section 6.2.4.1). Girls having their first menses during the trial should receive counseling again.
o
Serum test at screening and urine test at other visits, for girls of childbearing potential.
p
Intensive pharmacokinetic sampling will take place at the Week 2 visit (Day 14-18). See Section 2.2.2 for details. Intensive pharmacokinetic sampling will only take place in 
subjects with a body weight of <25 kg
q
A pharmacokinetic sample will be taken at any time during the visit. The date and time of sampling and the date and time of the RPV intake prior to that sample should be 
recorded on the eCRF. Where possible (i.e., if RPV intake occurs during the visit), at least on one occasion, the sample will be taken just prior to RPV intake. 
r
Assessment of FSH, LH, androstenedione, testosterone, DHEAS, in conjunction with basal cortisol and 17-hydroxyprogesterone.
sAs of Amendment 10 this ACTH stimulation test is not scheduled at baseline, but needs to be performed in case of confirmed abnormally low cortisol (<248 nmol/L [9 μg/dL]) 
or signs or symptoms of adrenal insufficiency (see Section 6.4.9.2.3.2).
t
Treatment adherence counseling should be performed at screening and baseline; treatment adherence should be checked and counseling repeated at every visit thereafter (see 
Section 6.3.12).
u
Questionnaires will only be administered if a certified translation is available in the local language. 
v
Assessment should only be done if a formulation other than the adult tablet formulation is being used.
w
Evaluation should be done according to local standard of care at the site (see Section 6.4.11 for details).
x
For subjects undergoing intensive PK sampling only. Subjects, their parent(s), or caregiver(s) will have to complete a diary documenting the intake of RPV from the start of 
treatment until the day of intensive pharmacokinetic sampling. 
y
AEs (including HIV-related events and the occurrence of AIDS-defining illnesses) and the intake of concomitant medication will be monitored throughout the trial from 
signing of the ICF onwards until the last trial-related activity.
z
A peripheral blood mononuclear cell (PBMC) sample will be taken to retrospectively characterize archived viral resistance.
aa
All study visits should be scheduled relative to the baseline visit date (eg, Day 1 + 7 days for Week 1) ± the allowed time window.
NCT00799864


TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
Approved, Issued Date: 03-FEB-2020
2.2.1.2.
Flowchart for Switch to Adjusted Dose in Cohort 2
Note: As of Amendment 10 the following flowchart is applicable for subjects with a body 
weight of <25 kg as determined at baseline. 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). Dose change is 
not allowed between baseline (when weight is defined) and Week 2 (start of intensive PK 
sampling).
Type of Visit
Initial Treatment Period*
Time of Visit
Dose Switch Visit**
2-weeks Post Switch 
Visit (After at Least 
2 Weeks of Treatment 
With the Adjusted 
Dose)***
4-weeks Post Switch 
Visit (After at Least 
4 weeks of Treatment 
With the Adjusted 
Dose)***
Determination of plasma viral load 
#
X
Immunology
#
X
Samples for viral phenotype/genotype 
determinationsa
X
Hematology & biochemistryb
#
X
ECGc
X
Vital signs (Pulse, BP)
#
X
Physical examination 
#d
Xe
Height/weightf
#g
Xg
Check occurrence of first mensesh
X
X
Urinalysis
#
Sampling for pharmacokinetics
Xi
Xj
Treatment adherence counseling and 
checking of adherence
X
X
X
Study Adherence Questionnaire for 
Children and Teenagers, if applicablek
X
Evaluation for depressionl
X
Palatability assessment
X
Dispensation of ARV medication
X
#
X
Drug accountability
#
X
Completion of diarym
X
Concomitant therapyn
#
#
X
Observe/Interview for AEs, including 
HIV-related eventsn
#
#
X
*
Unscheduled visits may be performed for safety/tolerability reasons, for confirmation of plasma viral load results, and for the 
dose switch visit and/or post switch visits (see Section 6.4.1).
**
As soon as the recommended pediatric dose is communicated, subjects with a body weight of <25 kg will have to attend a 
dose switch visit (unscheduled visit) in order to be provided with RPV at the recommended adjusted dose, if applicable. If the 
dose switch visit is done within 1 week of the next scheduled visit as indicated in the flowchart, this next planned visit can be 
cancelled but assessments of that visit will have to be performed at the dose switch visit.
*** A re-evaluation of subjects who have been treated with the adjusted dose for at least 2 weeks (between 14 and 18 days) and at 
least 4 weeks will be done (captured as unscheduled visits in the eCRF). If the post switch visits are done within 1 week of 
the next planned visit as indicated in the flowchart (see Section 2.2.1.3), this next planned visit can be cancelled but 
assessments of that visit that are not planned at the post switch visit will have to be added to the planned assessments at the 
post switch visit.
Footnotes continue on the next page
NCT00799864


TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
Approved, Issued Date: 03-FEB-2020
a
Samples collected at baseline, at virologic failure (see Section 6.2.5), Week 48 and at the Final/Withdrawal visit will be 
tested for the determination of the HIV-1 genotype and phenotype, as long as the viral load is sufficiently high. Samples 
collected at other intervals may be selected for the determination of HIV-1 genotype and phenotype by the Protocol 
Virologist based on plasma viral load.
b
Sample should be taken fasted (overnight).
c
Whenever possible, the ECG should be taken at expected Cmax (i.e., 4 hours after intake of RPV).
d
Only skin examination.
e
A brief physical examination only.
f
Growth will be followed using the standardized charts (see Section 6.4.9.4).
g
Height does not need to be measured.
h
As part of the evaluation of pubertal development, for girls who have not yet had their first menses at screening, it will be 
checked at every visit whether they have had their first menses and the date of first menses will be noted. 
i
Intensive pharmacokinetic sampling will take place at the 2-weeks Post Switch visit i.e., between 14 and 18 days after the 
Dose Switch visit. See Section 2.2.2 for details.
j
A pharmacokinetic sample will be taken at any time during the visit. The date and time of sampling and the date and time of 
the RPV intake prior to that sample should be recorded on the eCRF.
k
Questionnaires will only be administered if a certified translation is available in the local language.
l
Evaluation should be done according to local standard of care at the site (see Section 6.4.11 for details).
m
For subjects undergoing intensive PK sampling only: subjects, their parent(s), or caregiver(s), will have to complete a diary 
documenting the intake of RPV from the start of treatment with the adjusted dose until the day of intensive pharmacokinetic 
sampling.
n
AEs (including HIV-related events and the occurrence of AIDS-defining illnesses) and the intake of concomitant medication 
will be monitored throughout the trial from signing of the informed consent form (ICF) onwards until the last trial-related 
activity.
NCT00799864


TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
50
Approved, Issued Date: 03-FEB-2020
2.2.1.3.
Flowchart for Assessments From Week 8 Onwards in Cohort 2 (Initial Treatment Period From 
Week 8 Onwards, and Follow-up)
Type of Visit
Initial Treatment Period*
Post Week 48 
Treatment 
Extension*
Post-
treatment 
Follow-up 
Period****
Time of Visitu
W 8
W 12
W 16
W 24
W 32
W 40
W 48**
/Final 
Visit*
Every 3 
Months
Every 6 
Months
4 weeks After 
Final/Withdra
wal Visit
Determination of plasma viral loada
X
X
X
X
X
X
X
X
X
X
Immunology
X
X
X
X
X
X
X
X
X
Samples for viral phenotype/genotype determinationsb
X
X
X
X
X
X
X
X
X
X
PBMC samplet
Xv
Hematology & Biochemistryc
X
X
X
X
X
X
X
X
Xd
ECGe
X
X
Xf
Vital signs (Pulse, BP)
X
X
X
X
X
X
X
X
X
X
Physical examination
Xg
X
Xg
X
Xg
Xg
X
Xg
X
Xg
Height/weighth
X
Xi
X
X
X
X
X
X
X
Check occurrence of first mensesj
X
X
X
X
X
X
X
X
X
Evaluation of pubertal development (Tanner scale)
X
X
X
X
X
Pregnancy testk
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Xf
X
Sampling for pharmacokineticsa,l
X
X
X
Xv
Endocrine assessmentsn
X
Xf, v
ACTH stimulation testing (Cortisol, 17-hydroxyprogesterone
assessments)o
Reflex Test
Treatment adherence counseling and checking of adherence
X
X
X
X
X
X
X
X
X
Study Adherence Questionnaire for Children and Teenagers and/or 
Carersp
X
X
X
X
X
X
Xv
Evaluation for depressionq
X
X
X
X
X
X
X
X
X
X
Dispensation of ARV medication
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
Concomitant therapys
X
X
X
X
X
X
X
X
X
X
Observe/interview for AEs, including HIV-related eventss
X
X
X
X
X
X
X
X
X
X
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Clinical Trial Protocol Amendment X
51
Approved, Issued Date: 03-FEB-2020
*
For subjects enrolling as of Amendment 10, the post Week 48 treatment extension has been removed. Subjects may continue treatment (i.e., RPV + 2 N[t]RTIs) in the roll-over study 
TMC278IFD3004 or 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. Subjects from Cohort 2 already in the post Week 48 treatment extension period will have to stop participation in C213 and 
will have the same options for continuing treatment. Visits will continue every 3 and 6 months until roll over to study TMC278IFD3004 is completed. Subjects should transition to 
TMC278IFD3004 at the next planned Post Week 48 treatment extension visit after Amendment 10 is approved. Any retest, of abnormal laboratory results or plasma viral load/resistance 
testing, should be captured in this C213 study if the subjects roll over to the TMC278IFD3004 study.
Unscheduled visits may be performed for safety/tolerability reasons, for reflex ACTH stimulation test in case basal cortisol is <248 nmol/L (<9 μg/dL) on initial and repeat testing, and 
for confirmation of plasma viral load results (see Section 6.4.1).
**
For subjects who discontinue the trial before Week 48, this is the Withdrawal visit.
****
In the initial treatment period, the 4-week Follow-up visit is performed for subjects who withdraw early from the trial (i.e., before Week 48) (unless consent is withdrawn) or who do not 
participate in the extension after Week 48. In the extension period the 4-week Follow-up visit is only performed if there is an ongoing (S)AE, laboratory abnormality, or an increase in 
viral load at the last on-treatment visit. Additional unscheduled visits may be performed for safety/tolerability reasons, for reflex ACTH stimulation test in case basal cortisol is <248 
nmol/L (9 μg/dL) on initial and repeat testing, and for confirmation of plasma viral load results.
a
In case of suspected virologic failure (unconfirmed loss/lack of response, see Section 1) a sample for confirmation of plasma viral load and pharmacokinetics should be taken at an 
unscheduled visit (see Section 6.4.1). 
b
Samples collected at baseline, at virologic failure (see Section 6.2.5), at Week 48 and at the Final/Withdrawal visit will be tested for the determination of the HIV-1 genotype and 
phenotype, as long as the viral load is sufficiently high. Samples collected at other intervals may be selected for the determination of HIV-1 genotype and phenotype by the Protocol 
Virologist based on plasma viral load.
c
Sample should be taken fasted (overnight).
d
Any previously abnormal chemistry or hematology test should be repeated at this visit.
e
Whenever possible, the ECG should be taken at expected Cmax (i.e., 4 hours after intake of RPV). 
f
Assessment does not need to be performed at the withdrawal visit.
g
A brief physical examination only.
h
Growth will be followed using the standardized charts (see Section 6.4.9.4).
i
Height does not need to be measured.
j
As part of the evaluation of pubertal development, for girls who have not yet had their first menses at screening, it will be checked at every visit whether they have had their first menses 
and the date of first menses will be noted. 
k
Urine test for girls of childbearing potential.
l
A pharmacokinetic sample will be taken at any time during the visit. The date and time of sampling and the date and time of the RPV intake prior to that sample should be recorded on 
the eCRF. Where possible (i.e., if RPV intake occurs during the visit), at least on one occasion, the sample will be taken just prior to RPV intake.
n
Assessment of FSH, LH, androstenedione, testosterone, DHEAS, in conjunction with basal cortisol.
o
As of Amendment 10 this ACTH stimulation test is not scheduled at Week 24, but needs to be performed in case of confirmed abnormally low cortisol (<248 nmol/L [9 μg/dL]) or 
signs or symptoms of adrenal insufficiency (see Section 6.4.9.2.3.2). 
ACTH stimulation test including measurements of cortisol and 17-hydroxyprogesterone, measured before (T0) and 60 minutes (T60) after ACTH stimulation, needs to be performed 
(see Section 6.4.9.2.3.2). The ACTH stimulation test needs to be conducted in the morning at the indicated visits, between 7h30 and 9h30. If ACTH stimulation test is abnormal (i.e., 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 (see Section 
6.4.9.2.3.2). In case of withdrawal due to pregnancy, no ACTH stimulation test needs to be performed, but basal assessments need to be performed.
p
Questionnaires will only be administered if a certified translation is available in the local language.
q
Evaluation should be done according to local standard of care at the site (see Section 6.4.11 for details).
s
AEs (including HIV-related events and the occurrence of AIDS-defining illnesses) and the intake of concomitant medication will be monitored throughout the trial from signing of the 
ICF onwards until the last trial-related activity.
t
A PBMC sample will be taken to retrospectively characterize archived viral resistance.
u
All study visits should be scheduled relative to the baseline visit date (eg, Day 1 + 56 days for Week 8) ± the allowed time window.
v
Assessments not required for ongoing Cohort 2 subjects who are already in the post Week 48 treatment extension period at the time of Amendment 10.
NCT00799864


TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
52
Approved, Issued Date: 03-FEB-2020
2.2.2.
Flowchart for Intensive Pharmacokinetic Sampling in Cohort 2 
Note: As of Amendment 10 intensive pharmacokinetic sampling will take place for subjects 
with body weight <25 kg, after at least 2 weeks (between Day 14 and 18) of treatment with RPV 
and if a dose adjustment is required, after 14 to 18 days on the adjusted dose. 
Subjects or their parent(s)/caregiver(s) should be contacted by telephone or email to assess 
adherence (to study drug and other ARVs) and to reinforce trial instructions every day for 3 days 
prior to the intensive pharmacokinetic visit. If the subject has missed a dose of RPV within 
10 days prior to the intensive pharmacokinetic visit, the visit should be rescheduled so as to 
allow steady-state of RPV to be reached.
Subjects, their parent(s), or caregiver(s) will have to complete a diary documenting the intake of 
RPV from the start of treatment until the day of intensive pharmacokinetic sampling.
Time
Blood Samplea
ECG, Pulse Rate (PR), BP
Other
Admission to unit 
Predose
Xb
Xc
Age-appropriate standardized breakfast in unit 
0 h
Intake RPV dosee
2 h
X
Resume usual diet
4 h
X
Xd
5 h
X
6 h
X
9 hf
X
12 hf
X
24 hf
X
Discharge from unitg
a
At each time point, at least 1 mL of blood should be collected (total volume of blood drawn during the 
24-hour period is approximately 10 mL).
b
Within 1 hour before dosing.
c
Within 2 hours before dosing.
d
Only ECG should be performed at this time point (not PR and BP).
e
RPV dose should be taken within 40 minutes following the start of the meal. For subjects who vomit within 
30 minutes after dosing, the dose should be re-administered. Re-dosing is not allowed if the subject vomits 
more than 30 minutes after study drug intake. In the event that the subject vomits more than 30 minutes after 
the study drug intake on the day of pharmacokinetic evaluation, that assessment must be rescheduled.
f
To allow for some flexibility, the 9-hour sample can be collected with a window of 8-10 hours postdose, the 
12-hour sample within a window of 11-13 hours and the 24-hour sample with a window of 22-26 hours. The 
24-hour sample must be collected prior to the next dose of RPV.
g
In case it is not feasible for subjects to stay overnight, the subject can be discharged after the 12-hour sample. 
In this case, the subject should return to the unit for the 24-hour sample.
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TMC278-TiDP38-C213
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3.
OVERVIEW OF TRIAL DESIGN
3.1.
Cohort 1: Adolescent Subjects Aged ≥12 to <18 Years
Part 1a
Part 1b
Screeninga
Maximum 
6 weeks
Screeninga Maximum 
8 weeksj
N = 11 
Subjectsb
RPV 25 mg q.d. 
+ 2 N(t)RTIsc
Week 2 analysis
(pharmacokinetic, safety, and 
efficacy results reviewed by the 
IDMCd)
For more details on stopping rules 
after intensive pharmacokinetic 
sampling, see Section 6.1.1.
N = 14 Subjectsb
RPV 25 mg q.d. + 
2 N(t)RTIsc
Part 1 data analysis
(pharmacokinetic, safety, and 
efficacy results reviewed by the 
IDMCd) For more details on 
stopping rules after intensive 
pharmacokinetic sampling, see 
Section 6.1.1.
Stop 
recruitment
Stop recruitment
Results not deemed 
satisfactory by IDMC
Results deemed conditionally
satisfactoryf by IDMC
Results deemed satisfactory 
by IDMC
N =  Part 1 subjectsg
RPV weight-adjusted dose + 2 N(t)RTIsc
Additional analysish
(pharmacokinetic, safety, and efficacy 
results reviewed by the IDMCd)
Results deemed satisfactory by 
IDMC
Screening 
Maximum 
8 weeksj
Withdrawal visit + 
Subjects switched to 
locally available ARVe
N = all subjects 
included in 
Part 1
New subjects
Part 2i
N ≥35 Subjects
RPV 25 mg q.d. or weight-adjusted RPV 
dose + 2 N(t)RTIs
Up to 48 weeks
Primary analysis at Week 24
Interim analysis at Week 48
4 weeks follow-up visit
Treatment extension of 192 weeks
Final analysis at Week 240
Footnotes for this figure are provided on the next page
4 weeks follow-up visit for subjects who 
withdraw from the trial on or before the Week 
48 visit or for subjects with ongoing (S)AEs at 
the last on-treatment visit in the extension
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a
To ensure that the duration between baseline and the review by the IDMC for subjects in Part 1a of Cohort 1 was 
kept as short as possible, investigators were to identify eligible subjects in advance. Recruitment was to be 
started when the majority of the sites had the necessary documentation and approvals in place and were therefore 
considered activated for enrollment. Recruitment of subjects for Part 1a has already been closed and the enrolled 
subjects can continue in the trial as judged by the IDMC. 
For Part 1b, recruitment could start at the individual sites as soon as the necessary documentation and approvals 
were in place, and was closed once the required number of subjects was recruited. Trial sites were to be informed 
in advance regarding stop of recruitment.
b
For Part 1a, at least 5 subjects in the age group !12 to <15 years and at least 5 subjects in the age group !15 to 
<18 years were to be recruited (simultaneously). Part 1a included 11 subjects, 4 subjects in the age group !12 to 
<15 years and 7 subjects in the age group !15 to <18 years. In Part 1b, approximately 12 subjects (in order to 
have at least 10 evaluable subjects at Week 4) were to be enrolled, aiming at an equal distribution of subjects 
between the two age groups (i.e., subjects !12 to <15 years of age and subjects !15 to <18 years of age). Part 1b 
included 14 subjects, 8 subjects in the age group !12 to <15 years and 6 subjects in the age group !15 to 
<18 years.
c
Investigator-selected with a choice limited to AZT, ABC, or TDF in combination with 3TC or FTC, given as the 
co-formulation or as the separate components.
d
Subjects included in the first part (Part 1) will continue their ARV regimen during this review period.
e
In case Cohort 1 is stopped after Part 1, a sample will be analyzed in real time for the determination of HIV-1 
genotype (as long as the viral load is sufficiently high to allow HIV-1 genotyping), in order to assist in the 
selection of a new ARV regimen. When determination of HIV-1 genotype on this sample is not possible due to a 
too low viral load, the new ARV regimen will be based on the screening HIV-1 genotyping result.
f
Short-term Part 1 results show a safety concern that could potentially be avoided by lower exposure to RPV, as 
deemed by the IDMC.
g
If applicable, RPV dose switch to weight-adjusted dose will be done for all Part 1 subjects up to a certain body 
weight.
h
Analysis will be done when these subjects have been treated for 4 weeks (+/-1 week) with the weight-adjusted 
dose.
i
In case a dose switch is not required, Part 2 will start immediately after the positive IDMC evaluation of the 
short-term Part 1 results. In case a dose switch is required, Part 2 will start after re-evaluation by the IDMC of 
the analysis when subjects have been treated for 4 weeks (+/-1 week) with the weight-adjusted dose.
j
The screening period can be prolonged to maximum 8 weeks in order to allow plasma viral load and CD4+ cell 
count to be assessed before continuing with the other screening assessments. After obtaining informed consent, 
samples will be taken for determination of plasma viral load and CD4+ cell count. If plasma viral load results 
meet the inclusion criteria and the investigator considers initiation of ART appropriate (taking into account 
current treatment guidelines, including CD4+ cell count and the subject’s clinical situation), the subject 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 subject will be considered a screen failure.
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3.2.
Cohort 2: Pediatric Subjects Aged ≥6 to <12 Years
Prior to Amendment 10 Flow 1, as depicted below, was followed. All subjects enrolled in Cohort 
2 at the time were treated with 25 mg RPV q.d., and since results of the Week 4 analysis were
deemed satisfactory, no dose adjustments were required. These subjects are currently on 25 mg 
RPV q.d. as originally planned (no dose adjustments). Only limited data (i.e. 5 subjects) were 
available for subjects with body weight <25 kg.
Based on accumulating data and PK modeling and simulation, at the time of Amendment 10, 
the following RPV dose recommendations were determined and endorsed by the IDMC for 
further enrolled subjects (aimed at achieving similar exposures as in adults): 
∀
RPV 25 mg q.d. for subjects with a body weight of ≥25 kg 
∀
RPV 15 mg q.d. for subjects with a body weight of <25 kg
Appropriateness of these doses will be further evaluated in this study in combination with data 
generated from pediatric study TMC278HTX2002. To this end, as depicted in Flow 2 below, 
newly enrolled subjects with a body weight of <25 kg will require intensive pharmacokinetic 
evaluation. 
Note that as of Amendment 10 the requirement for the 4-year follow-up period in this study for 
subjects enrolled in Cohort 2, has been removed.
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a
During the screening period it is allowed to assess the viral load and CD4+ cell count before continuing with the 
other screening assessments. In such case, after obtaining informed consent, samples will be taken for 
determination of plasma viral load and CD4+ cell count. If plasma viral load results meet the inclusion criteria 
and the investigator considers initiation of ART appropriate (taking into account current treatment guidelines, 
including CD4+ cell count and the subject’s clinical situation), the subject will return within 2 weeks after 
availability of these results, for the remainder of the screening procedures. In case of unforeseeable 
circumstances, the screening period can be prolonged by 2 weeks resulting in a maximum screening period 
duration of 8 weeks, see Section 6.4.1.
b
Investigator-selected with a choice limited to AZT, ABC, or TDF in combination with 3TC or FTC, given as a
co-formulation or as separate components.
c
Subjects will continue their ART during this review period.
d
For details on dose evaluation criteria, see Section 6.1.1.2.1.
e
In case Cohort 2 is stopped after Part 1, a sample will be analyzed in real time for the determination of HIV-1 
genotype (as long as the viral load is sufficiently high to allow HIV-1 genotyping), in order to assist in the 
selection of a new ART. When determination of HIV-1 genotype on this sample is not possible due to a too low 
viral load, the new ART will be based on the screening HIV-1 genotyping result.
f
All subjects who received the RPV dose which was not deemed satisfactory will receive an adjusted dose and 
undergo an intensive pharmacokinetic evaluation between 14 to 18 days after starting the adjusted dose. The 
results may indicate that only subjects up to e.g., a certain age or body weight would need a lower RPV dose in 
which case the subjects that do not need an RPV dose change will continue treatment with their current dose.
g
Analysis will be done when all subjects in Part 1 have been treated for at least 4 weeks, or discontinued earlier 
with their current RPV dose (original and/or adjusted dose[s]).
h
Additional subjects will be recruited to aim for at least 10 subjects with intensive PK data (including the subjects 
of the mini-cohort).
i
Subjects in Part 2 will remain on the RPV dose established in Part 1 with no changes allowed in dosing except 
for adjustments due to age or body weight changes, if applicable.
j
Additional unscheduled visits may be performed for safety/tolerability reasons and for confirmation of plasma 
viral load results.
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Footnotes for this figure are 
provided on the next page
Flow 2: Flow applicable as of Amendment 10.
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a
During the screening period it is allowed to assess the viral load and CD4+ cell count before continuing with the 
other screening assessments. In such case, after obtaining informed consent, samples will be taken for 
determination of plasma viral load and CD4+ cell count. If plasma viral load results meet the inclusion criteria 
and the investigator considers initiation of ART appropriate (taking into account current treatment guidelines, 
including CD4+ cell count and the subject’s clinical situation), the subject will return within 2 weeks after 
availability of these results, for the remainder of the screening procedures. In case of unforeseeable 
circumstances, the screening period can be prolonged by 2 weeks after screening tests have been performed,
resulting in a maximum screening period duration of 8 weeks, see Section 6.4.1.
b
Investigator-selected with a choice limited to AZT, ABC, or TDF in combination with 3TC or FTC, given as a 
co-formulation or as separate components. 
c
Subjects will continue their ART during this review period.
d
For details on dose evaluation criteria, see Section 6.1.1.2.1.
e
In case Cohort 2 is stopped, a sample will be analyzed in real time for the determination of HIV-1 genotype (as 
long as the viral load is sufficiently high to allow HIV-1 genotyping), in order to assist in the selection of a new 
ART. When determination of HIV-1 genotype on this sample is not possible due to a too low viral load, the new 
ART will be based on the screening HIV-1 genotyping result.
f
All subjects who received an RPV dose which was deemed conditionally satisfactory (e.g. up to a certain body 
weight) will receive an adjusted dose and undergo an intensive pharmacokinetic evaluation between 14 to 18 
days after starting the adjusted dose. Those that don't need dose adjustment, will continue their treatment.
g
Analysis will be done combined with applicable data from the TMC278HTX2002 study, when all subjects have 
been treated for at least 4 weeks or discontinued earlier with their current RPV dose (original and/or adjusted 
dose[s]).
h
Approximately 40 subjects will be enrolled in Cohort 2 and in pediatric study TMC278HTX2002 combined: at 
least 12 subjects with a body weight of <25 kg, including at least 7 subjects with a body weight of <20 kg.
i
Subjects will remain on the RPV dose established with no changes allowed in dosing except for adjustments due 
to body weight changes, if applicable.
j
Additional unscheduled visits may be performed for safety/tolerability reasons and for confirmation of plasma 
viral load results.
k 
Any retest of abnormal laboratory results or plasma viral load/resistance testing, should be captured in this C213 
study if the subjects roll over to the TMC278IFD3004 study.
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4.
INTRODUCTION
Antiretroviral therapy in ARV-naïve children provides evidence that the combination of 2 NRTIs 
and a non-nucleoside reverse transcriptase inhibitor (NNRTI) may reduce HIV RNA to 
undetectable levels in a substantial proportion of children1,2. 
Human immunodeficiency virus type 1 (HIV-1)-infected subjects are routinely being treated 
with combinations of 3 or 4 drugs (highly active ARV therapy [HAART]), including N(t)RTIs, 
NNRTIs, and protease inhibitors (PIs), to reduce the risk of viral resistance development. 
Development of new potent ARV compounds is urgently needed to prolong suppression of viral 
replication in subjects infected with HIV-11,2,3,51,52.
Approved NNRTIs in the United States of America (USA) and/or Europe are nevirapine (NVP; 
Viramune®), delavirdine (Rescriptor®), and efavirenz (EFV, Sustiva®, Stocrin®). These drugs 
show cross-resistance and are associated with safety problems (mainly hepatotoxicity, central 
nervous system symptoms, and/or rash)3. Etravirine (ETR, Intelence®), a NNRTI with a higher 
genetic barrier to the development of resistance, is approved for the use in treatment-experienced 
adults.
At the time of Amendment 6 writing, RPV (formerly known as TMC278 or R278474) has been 
approved for the treatment of HIV-1 infection in ARV treatment-naïve adult patients in multiple 
countries including the USA and European Union as EDURANT®. In most countries, including 
the USA and EU, this indication is further restricted to patients with a HIV-1 viral load ≤100,000 
copies/mL. 
Nevirapine is labelled for use in young children (aged 15 days and older) but has been shown to 
be inferior to lopinavir/ritonavir (LPV/r, Kaletra®)49. Efavirenz is approved for use in children 
from 3 months of age, but there are concerns about the approved dose such as risks to the fetus in 
females of childbearing age50. Etravirine is approved for ARV treatment-experienced children 
down to 6 years of age. A medical need still exists for development of new potent ARV 
compounds and age-appropriate formulations, particularly in adolescents and children. At the 
time of Amendment 9 writing, in several countries, including the USA and Europe, the 
indication of RPV has been extended to include adolescent patients aged ≥12 to <18 years of 
age, based on Week 48 data from Cohort 1 of the current study (see Section 6.1.2.2). Per the 
indication, RPV is approved for the treatment of HIV-1 infection in ARV treatment-naïve 
patients 12 years of age and older with a viral load ≤100,000 copies/mL. At the time of 
Amendment 9 writing, RPV was not approved in children <12 years of age.
RPV, a diarylpyrimidine derivative, is a potent NNRTI with in vitro activity against wild-type 
HIV-1 (50% effective concentration [EC50] ranging from 0.30 to 0.73 nM for HIV-1/IIIb4) and 
NNRTI-resistant mutants. RPV is able to combine the convenience of once daily (q.d.) dosing 
with good antiviral effects and a good safety and tolerability profile as compared to most 
currently licensed NNRTIs (with the exception of ETR).
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Non-clinical safety and toxicology studies demonstrated that RPV is safe for use in clinical 
testing4. In non-clinical studies in rats and dogs, changes in adrenal hormones and histopathology 
have been observed. In those studies, RPV appears to interfere with steroid biosynthesis, leading 
to decreases in cortisol and increases in progesterone and 17α-hydroxyprogesterone and as a 
result to increases in serum adrenocorticotropic hormone (ACTH). Preclinical work with RPV
also identified changes in the thyroid glands in rats. Endocrine monitoring was included in the 
safety monitoring of all RPV clinical trials conducted thus far. However, to date, no clinically 
relevant effects on adrenal or thyroid function were observed in clinical studies with RPV in 
adults or adolescents. 
The effects of RPV on adrenal glands of rats, dogs and cynomolgus monkeys on the estrous 
cycle of dogs are not expected to be clinically relevant for adolescents and children. However, in 
theory, some concerns in adolescents and children could be raised by these non-clinical findings: 
the possibility of partial adrenal insufficiency, virilization in girls and/or growth retardation due 
to 21-hydroxylase inhibition and precocious puberty due to ovarian stimulation in girls. In case 
significant inhibition of cortisol synthesis (partial adrenal insufficiency) would occur, androgen 
production might increase. In girls, this could result in masculinization and blunted growth. In 
boys, due to increased levels of testosterone, growth might also be impaired. Since the time of 
initial protocol writing, additional non-clinical information has become available in cynomolgus 
monkeys, which did not show evidence of induction of premature ovulation in juvenile animals. 
Refer to Section 6.1.2.2 for a brief summary of the non-clinical data on effects of RPV on 
adrenal and gonadal hormone biosynthesis. Therefore, in this trial, growth will be followed 
regularly and evaluated consistently using standardized growth charts. Sexual maturation will be 
evaluated according to Tanner stages. Finally, hormone testing will be performed, including 
measurements of testosterone, FSH, LH, cortisol, progesterone (only in the adolescent cohort), 
androstenedione, 
aldosterone
(only 
in 
the 
adolescent
cohort), 
DHEAS,
and 
17-hydroxyprogesterone.
Rilpivirine did not show a potential for genotoxicity, teratogenicity, phototoxicity, skin or 
mucous membrane irritation, or delayed-type sensitization. Fertility, early embryonic 
development, pre- and postnatal development, and the immune system were not affected by RPV
at oral doses ranging from 160 to 1600 mg base eq./kg.
Results from previous pooled Phase I trials, in which 404 healthy adult subjects and 15 HIV-1 
infected adults have been dosed with RPV, provided an understanding of the compound’s short-
term safety and efficacy profile, and its pharmacokinetic characteristics4. Two exploratory proof-
of-principle (PoP) Phase IIa trials in 83 adults (47 ARV-naïve and 36 ARV-experienced) were 
performed to evaluate the short-term antiviral and immunologic activity during a 7-day once
daily treatment up to 150 mg RPV5,6. One Phase IIb trial (i.e., TMC278-C204) in which 368 
ARV-naïve HIV-1 infected adults were included, has been completed and was set up to evaluate 
the dose-response relationship of efficacy over 96 weeks of treatment with 3 different dose 
regimens (25 mg q.d., 75 mg q.d., and 150 mg q.d.) of RPV. The trial has been extended to a 
total treatment duration of 240 weeks in order to collect long-term efficacy and safety data from 
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subjects who continue to benefit from their treatment. After 240 weeks of treatment, continued 
access to RPV is foreseen in another trial or program, until RPV becomes commercially 
available, is reimbursed, or can be accessed through another source. All RPV-treated subjects 
were switched to RPV 25 mg q.d. (the dose selected for further development) at approximately 
Week 144, but no later than Week 157, and continued on this dose for the remainder of the trial. 
Data from the primary analysis at 48 weeks and the analyses at 96, 144, 192, and 240 weeks of 
treatment in this trial are available7,8. These data showed that RPV was generally safe and well 
tolerated after long-term treatment. This was confirmed by final data of two completed Phase III 
trials in ARV treatment-naïve HIV-1 infected adults. These trials were set up to evaluate long-
term efficacy, safety, and tolerability of RPV 25 mg q.d. versus efavirenz 600 mg q.d. (each in 
combination with 2 N[t]RTIs).
Rilpivirine, formulated as a tablet, was well absorbed after oral administration in humans. The 
time to reach the maximum plasma concentration (tmax) was consistently around 4 hours in all 
trials. The terminal elimination half-life (t1/2,term) was approximately 45 hours across trials, 
supporting q.d. administration. Renal clearance is only a minor route for the elimination of 
RPV4.
The relative oral bioavailability of RPV formulated as a tablet increased approximately 1.5-fold 
when administered with food as compared to administration under fasted conditions. RPV, 
administered as the Phase II tablet formulation, exhibited linear pharmacokinetics for maximum 
plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in 
healthy subjects after single- and multiple-dose administration up to a dose of 150 mg q.d.4
The relative oral bioavailability of RPV as the Phase III tablet formulation was shown to be 
comparable to that of the Phase II tablet. These results support the use of the Phase III tablet 
formulation for the further clinical development of RPV9. 
The safety data from the pooled Phase I studies showed that RPV was generally safe and well 
tolerated after multiple dosing in adults up to 150 mg q.d. for 14 days4. The 2 PoP Phase IIa 
trials5,6 demonstrated the safety and efficacy of RPV in HIV-1 infected subjects who were ARV-
naïve as well as in HIV-1 infected subjects who were failing either an NNRTI- or PI-containing 
(with evidence of resistance to the current NNRTIs) therapy. 
The primary analysis of the Phase III, randomized, double-blind, double dummy, 
active-controlled trials in adults with RPV (i.e., TMC278-TiDP6-C209 and TMC278-TiDP6-
C215) was conducted when all subjects had reached Week 48 or discontinued earlier. In total, 
1,368 subjects who were randomized and received at least one dose of study drug were included 
in this analysis: 686 subjects in the RPV group and 682 subjects in the control group on 
efavirenz41,42. The primary analysis (pooled) of these trials at 48 weeks showed non-inferiority of 
RPV versus control with response rates of 84.3% and 82.3% in the RPV and the control group, 
respectively, for the primary efficacy parameter (confirmed and sustained plasma viral load 
<50 HIV-1 RNA copies/mL according to the time to loss of virologic response [TLOVR] 
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algorithm)43. The rate of virologic failure was shown to be dependent on the baseline viral load, 
with a higher rate of virologic failure in the >100,000 copies/mL category (15.1% in the RPV
group and 6.3% in the control group) than in the ≤100,000 copies/mL category (3.8% in the RPV
group and 3.3% in the control group). The effect of baseline viral load was more pronounced in 
the RPV group than in the control group (i.e., 2- to 3-fold higher rate of virologic failure in the 
>100,000 copies/mL category in the RPV group compared to control)45. RPV was generally safe 
and well tolerated up to Week 48. The most common adverse events (AEs) in the RPV group 
according to the pooled Phase III Week 48 analysis were headache (13.8%), nausea (13.4%), 
diarrhea (11.4%), and nasopharyngitis (10.1%).44
At the time of protocol amendment 6 writing, both Phase III trials had been completed. The data 
of these trials show that RPV was efficacious, generally safe and well tolerated after 96-weeks of
treatment. No new safety signals were observed between the first 48-weeks of treatment (primary 
analysis) and the end of the trial. A brief summary of the final Phase III results in adults is
presented in Section 6.1.2.2.
In accordance to the International Conference on Harmonization (ICH) E14 guideline10, a 
thorough QT trial in adults (TMC278-TiDP6-C131) was carried out11. At a dose of RPV
75 mg q.d., a clinically relevant increase of the QTc interval by up to 10.4 ms (90% confidence 
interval [CI]: 7.7 ms; 13.1 ms) as compared to reference (i.e., baseline) was observed and the 
effect was dose- and concentration-dependent, with a higher increase at higher exposures 
obtained with a dose of 300 mg q.d. (i.e., up to 23.8 ms [19.8 ms; 27.8 ms] compared to 
reference). Besides these recent findings in the thorough QT trial, all single dose as well as 
multiple-dose trials with RPV in healthy subjects showed no consistent or clinically relevant 
changes in any particular ECG parameter, including the QTc interval. Also in HIV-1 infected 
subjects in short-term PoP trials and the Phase IIb trial, the observed changes in ECG parameters 
are not clinically relevant. In the Phase IIb trial, up to Week 96, 3 female subjects were 
discontinued from the trial because of QTcF prolongation (grade 2-3, all considered related to 
RPV), but without clinical symptoms7. No clinically relevant findings in ECG parameters have 
been seen up to now, but, besides the thorough QT trial, these trials were not specifically 
designed to study the effect on cardiac electrophysiology in healthy or HIV-1 infected subjects. 
No sudden deaths or life-threatening dysrhythmias such as Torsade de Pointes have been 
observed in any of the trials. Based on pharmacokinetic/pharmacodynamic modeling it was 
predicted that RPV 25 mg q.d. would not have a clinically relevant effect on QTc. This 
assumption was confirmed in a pilot QT trial12 and a thorough QT trial20, specifically designed to 
explore the effect of steady-state concentrations of RPV 25 mg q.d. on the QT/QTc interval: the 
25 mg q.d. dose used in these trials did not cause a clinically relevant QT prolongation, hence the 
25 mg q.d. dose of RPV is suitable for further development.
RPV 25 mg q.d. was the dose used in the Phase III trials and therefore also the reference dose for 
the pediatric development. For the most current information and additional details on 
characteristics, non-clinical or clinical data, please consult the Investigator’s Brochure4. A 
summary of new clinical data, relevant to this trial, can also be found in Section 6.1.2.2.
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The current trial is the first to be conducted with RPV in the adolescent population (Cohort 1). 
The purpose of the present trial is first to compare the short-term steady-state RPV
pharmacokinetics in a small group of ARV treatment-naïve subjects aged !12 to <18 years with 
that in the adult population (in trials TMC278-C204, TMC278-TiDP6-C209, and TMC278-
TiDP6-C215), as well as to evaluate short-term safety and antiviral activity of RPV in the 
adolescent population (Part 1). If the short-term results of Part 1 are deemed satisfactory by the 
Independent Data Monitoring Committee (IDMC), long-term treatment will be evaluated in a 
larger group of subjects aged !12 to <18 years in the second part of this cohort (Part 2). At the 
time of protocol amendment 6 writing, 48-week results from this adolescent cohort are available.
The 48-week results demonstrated that treatment with RPV 25 mg q.d., in combination with an 
investigator-selected background regimen, is efficacious, generally safe and well tolerated in 
adolescents of ≥12 to <18 years of age. For more details about the 48-week results see 
Section 6.1.2.2, the clinical study report of Cohort 153 or the abstract54. These 48-week treatment
results are considered adequate to start treatment in children <12 years of age and therefore the 
protocol has been amended. 
In addition to adolescents (Cohort 1), the trial was extended to include children ≥6 to <12 years 
of age (Cohort 2). In Part 1 of this cohort, the short-term steady-state RPV pharmacokinetics in a 
group of ARV treatment-naïve subjects aged ≥6 to <12 years were compared with that in the 
adult population, and an evaluation of safety, tolerability and antiviral activity/efficacy of RPV
in these children was done.
At the time of Amendment 10, the following RPV dose recommendations were determined 
based on accumulating data and were endorsed by the IDMC, in order to achieve similar 
exposure to RPV compared to adults: RPV 25 mg q.d. for subjects with a body weight of ≥25 kg, 
and RPV 15 mg q.d. for subjects with a body weight of <25 kg. Appropriateness of these doses
will be further evaluated in this study. 
It is recognized that the pediatric age group deserves specific attention, both towards more 
intense compliance counseling and, especially for the adolescents, towards sexual behavior and 
risk of HIV transmission. Specific sections in the protocol will address these.
5.
OBJECTIVES
The objectives are:
%
To evaluate the steady-state pharmacokinetics (based on intensive PK analysis) of RPV
25 mg q.d. or adjusted dose of RPV (q.d.) in subjects aged !12 to <18 years and !6 to 
<12 years;
%
to evaluate short-term safety, tolerability and antiviral activity/efficacy of RPV in these 
age groups.
%
To evaluate safety, tolerability and efficacy of RPV over a 24-week (Cohort 1 only) 
and 48-week (Cohort 1 and 2) treatment period;
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%
to evaluate immunologic changes (as measured by CD4+ cell parameters) over 24 weeks 
(Cohort 1 only) and 48 weeks (Cohort 1 and 2) of treatment with RPV;
%
to assess the evolution of viral genotype and phenotype over 24 weeks (Cohort 1 only)
and 48 weeks (Cohort 1 and 2) of treatment with RPV;
%
to evaluate pharmacokinetics (by means of population pharmacokinetics) and 
pharmacokinetic-pharmacodynamic relationships for safety and efficacy of RPV;
%
to evaluate treatment adherence as measured by the Study Adherence Questionnaire for 
Children and Teenagers (see Addendum 7: Study Adherence Questionnaire for Children 
and Teenagers).
%
To evaluate the safety, tolerability and efficacy of RPV for up to 240 weeks of
treatment (Cohort 1 only).
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6.
METHODS
Details on the treatment and assessments are given in the flowchart (see Section 2).
6.1.
Trial Design
6.1.1.
Overview of Trial
This is a Phase II, open label, single arm trial to evaluate the pharmacokinetics, safety, 
tolerability and efficacy of RPV 25 mg q.d. or adjusted dose of RPV (q.d.) in combination with 
an investigator-selected background regimen containing 2 N(t)RTIs (AZT, ABC, or TDF in 
combination with 3TC or FTC, age-appropriate formulations are to be used), in ARV treatment-
naïve adolescents and children aged !6 to <18 years.
6.1.1.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years
ARV treatment-naïve HIV-1 infected subjects, aged !12 to <18 years, with a plasma viral load 
!5,000 HIV-1 RNA copies/mL could be included in Part 1a of Cohort 1. However, in Part 1b 
and Part 2, recruitment was limited to subjects with a plasma viral load ≥500 HIV-1 RNA 
copies/mL but ≤100,000 HIV-1 RNA copies/mL. Any previous use of ARVs, with the exception 
of a single dose of NVP at birth to prevent mother-to-child transmission (MTCT), is not allowed. 
Subjects who were infected by MTCT are allowed to enter, provided the mother was ARV 
treatment-naïve at the time of delivery with the exception of NVP monotherapy for no more than 
3 days. Subjects should have no NNRTI resistance-associated mutations (RAMs) on their 
screening HIV-1 genotyping result (exclusion based on the list of NNRTI RAMs detailed in 
Section 6.2.3). ABC has been associated with severe hypersensitivity reactions, and the risk for 
developing such reactions has been linked to the presence of the HLA-B*5701 allele. Therefore, 
subjects without prior documented HLA-B*5701 negative results for whom the investigator 
considers to use ABC/3TC as background regimen should test negative for HLA-B*5701 at 
screening, to avoid hypersensitivity reactions (see Section 6.5.11.3 for details).
Subjects willing and able to give consent (in case the subject’s age is below the cut-off age for 
consent [according to local regulations], their parent/caregiver should be able and willing to give 
consent, and the subject will be informed about the trial and asked to give positive assent) and 
found eligible for the trial at screening, will be required to discontinue specified disallowed 
medication to allow a washout period of at least 4 weeks prior to baseline. Assessments at 
screening will be performed as indicated in the flowchart (see Section 2).
The trial will consist of a screening period of maximum 8 weeks (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 assessment, if these were assessed separately before continuing with the other 
screening assessments, but in case of unforeseeable circumstances, this period can be prolonged 
by 2 weeks maximum), an initial treatment period of 48 weeks, and a post Week 48 treatment 
extension period of 4 years. Subjects who withdraw from the trial on or before the Week 48 visit 
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or subjects with ongoing (S)AEs at the last on-treatment visit in the extension, will be seen for a 
follow-up visit 4 weeks later. 
Recruitment and analyses of the initial 48-week treatment period will be structured into 2 parts 
(for a flowchart of the trial visits, see Section 2).
The first part of Cohort 1 (Part 1, consisting of Part 1a and Part 1b) is designed to evaluate the 
steady-state pharmacokinetic profile and the short-term safety and antiviral activity of RPV
25 mg q.d. when administered in combination with 2 N(t)RTIs, in adolescents. In Part 1a, a
group of at least 10 subjects, i.e., at least 5 subjects in the age group !12 to <15 years and at least 
5 subjects in the age group !15 to <18 years, were to be enrolled and to receive treatment. 
Eventually, 11 subjects were enrolled, 4 subjects in the age group ≥12 to <15 years and 
7 subjects in the age group ≥15 to <18 years, and enrollment was paused at that time. At Week 2, 
an analysis for pharmacokinetics together with short-term safety and antiviral activity was 
reviewed by an IDMC (for more information on this IDMC, see Section 6.3.9). Based on these 
Week 2 data the IDMC agreed for these subjects to continue treatment with RPV 25 mg q.d. and 
their background regimen. Following the review of the 2-week interim results in adolescents and 
the available Phase III results in adults, the Sponsor decided to collect more short-term data in 
adolescents before proceeding with the second part of Cohort 1 (Part 2). Therefore, Part 1 was
expanded by enrolling approximately 12 additional subjects (in order to have at least 
10 evaluable subjects at Week 4) in Part 1b, aiming at an equal distribution of subjects between 
the two age groups (i.e., subjects ≥12 to <15 years of age and subjects ≥15 to <18 years of age). 
Eventually, 14 subjects were enrolled in Part 1b, 8 subjects in the age group !12 to <15 years 
and 6 subjects in the age group !15 to <18 years, to a total of 25 subjects enrolled in Part 1. In 
Part 1b, only subjects with a screening viral load ≥500 HIV-1 RNA copies/mL but ≤100,000 
HIV-1 RNA copies/mL were to be enrolled. The 4-week interim analysis of Part 1b was
evaluated by the IDMC before the start of Part 2. The results indicated that no RPV dose 
adjustment was needed.
When reviewing the Part 1 results, the IDMC took into account the guidelines and stopping rules 
mentioned below.
∀
If the mean steady-state exposure of RPV in Part 1 subjects is comparable to that of the 
adult population (i.e., is within 80-125% of the mean exposure of the 25 mg q.d. dose 
group in available trials in HIV-infected adults) and the short-term safety and antiviral 
activity results have been reviewed and deemed satisfactory by the IDMC, the second 
part of Cohort 1 will start. 
∀
However, if the mean exposure in adolescents is <80% of the mean exposure in adults or 
the Week 2/Week 4 results are not deemed satisfactory, all subjects will be seen for a 
Withdrawal visit, treatment with RPV will be stopped, subjects will be switched to a 
locally available ARV regimen, and the trial will be stopped. In this case, a sample will 
be analyzed in real time for the determination of HIV-1 genotype (as long as the viral 
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load is sufficiently high to allow HIV-1 genotyping), in order to assist in the selection of 
a new ARV regimen. When determination of HIV-1 genotype on this sample is not 
possible due to a too low viral load, the new ARV regimen will be based on the screening 
HIV-1 genotyping result. 
∀
If the mean exposure in adolescents is >125% of the mean exposure in adults, but 
antiviral activity results are satisfactory and there are no safety concerns, as judged by the 
IDMC, the second part of Cohort 1 will start. 
∀
If the mean exposure in adolescents is >125% of the mean exposure in adults, the 
antiviral activity is satisfactory, but there are safety concerns that could potentially be 
avoided by a lower exposure to RPV, as judged by the IDMC, subjects up to a certain 
body weight (determined based on the intensive pharmacokinetic results) will be 
switched to a lower, weight-adjusted dose; subjects who do not require a dose switch will 
continue treatment with RPV 25 mg q.d. A new analysis will be performed when all 
subjects on the weight-adjusted dose have been treated for 4 weeks (+/-1 week). When 
these results are deemed satisfactory by the IDMC, these subjects will continue treatment 
with RPV at the weight-adjusted dose and the second part of Cohort 1 will start.
All subjects in Part 1 were to continue their ART (RPV plus an investigator-selected background 
regimen of 2 N[t]RTIs) during the review period by the IDMC. For more information, see 
Section 6.1.2.
To ensure that the duration between baseline and the review by the IDMC for subjects in Part 1a
was kept as short as possible, investigators were to identify eligible subjects in advance.
Recruitment was to be started when the majority of the sites had the necessary documentation 
and approvals in place and were therefore considered activated for enrollment. Recruitment of 
subjects for Part 1a has already been closed and the enrolled subjects can continue in the trial as 
judged by the IDMC. For Part 1b, recruitment could start at the individual sites as soon as the 
necessary documentation and approvals were in place, and was completed once the required 
number of subjects was recruited. Trial sites were informed in advance regarding stop of 
recruitment.
In case of inadequate exposure, dose adjustments of RPV cannot be allowed in order to avoid 
exposing children to a daily dose exceeding the total adult daily dose (i.e., 25 mg q.d.). 
The second part of Cohort 1 will evaluate long-term safety, efficacy, and pharmacokinetics of 
RPV in combination with a background regimen of 2 N(t)RTIs, in a total of at least 
35 adolescents (approximately 12 female subjects will be targetted). All subjects initially 
enrolled in Part 1 were to continue the initial treatment period until they reach a treatment 
duration of 48 weeks. Additional subjects were recruited with a screening viral load ≥500 HIV-1 
RNA copies/mL but ≤100,000 HIV-1 RNA copies/mL, so that at least 35 subjects were enrolled 
and also received initial treatment for 48 weeks. The additional subjects were only be recruited 
after the IDMC had decided that this second part of Cohort 1 could start. 
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Subjects who experience and are expected to continue experiencing clinical benefit from RPV
and the background regimen comprising 2 N(t)RTIs at the end of the initial 48-week treatment 
period, will have the option to continue treatment (i.e., RPV 25 mg q.d. + 2 N[t]RTIs) through 
this trial for an additional 4 years in a post Week 48 treatment extension period. During this 
treatment extension, trial visits will occur approximately every 3 months.
Formal analyses (with formal database lock) will be performed when all subjects have reached 
Week 24 (or discontinued earlier) (primary analysis time point), when all subjects have reached 
Week 48 (or discontinued earlier), and when all subjects have completed the trial (after 240 
weeks of treatment) (or discontinued earlier). Furthermore, data monitoring for risk-benefit 
assessment was to be performed when all Part 1 (i.e., Part 1a and Part 1b) subjects had reached 
Week 12 (or discontinued earlier) and will be performed when all Part 1 and Part 2 subjects have 
reached Week 12 of treatment (or discontinued earlier). These analyses will be run based on the 
accumulated data at that point. The results of all analyses up to Week 48 will be shared and 
discussed with the IDMC.
The design of the trial is illustrated in Section 3.
For eligible subjects, the trial will be initiated on Day 1. In both Part 1 and Part 2, as well as in 
the post Week 48 treatment extension, the ARV regimen will consist of RPV 25 mg q.d. or 
weight-adjusted dose, and an investigator-selected background regimen containing 2 N(t)RTIs. 
The investigator-selected N(t)RTIs will be AZT, ABC, or TDF in combination with 3TC or FTC, 
whichever is approved and marketed or considered local standard of care for children aged !12 
to <18 years in a particular country. The background regimen will be given as the co-formulation 
or as the separate components, according to local availability and use in the country (e.g., 
Combivir® or AZT/3TC, Epzicom®/Kivexa® or ABC/3TC, Truvada® or TDF/FTC). For those 
subjects who do not tolerate the selected N(t)RTIs, switching to alternative N(t)RTIs (brand 
name versions, US FDA tentatively approved generics, WHO prequalified drugs and if not 
available, exceptionally generic drugs approved by local Health Authorities or drugs procured by 
UN international organizations upon approval by the sponsor) is allowed for some predefined 
toxicities (see Section 6.3.5). At all times, the background regimen should consist of 2 N(t)RTIs 
and the subject’s HIV-1 genotype at screening should show sensitivity to the alternative 
N(t)RTIs. Also in case of switch to ABC, the subject should test negative for HLA-B*5701, to 
limit the risk of hypersensitivity reactions (in case no prior documented HLA-B*5701 negative 
results are available) (see Section 6.5.11.3). The symptoms of intolerance to the N(t)RTI(s) 
should be reported as AE(s) and should be clearly documented as leading to the change in 
N(t)RTIs. If the tolerability issue is related to only 1 of the 2 N(t)RTIs, it is only needed to 
switch that one. The use of PIs, NNRTIs (other than RPV), enfuvirtide (ENF), integrase 
inhibitors, and investigational ARVs during the trial is not allowed.
In the second part of Cohort 1 temporary interruption of all ARVs during the treatment period 
will be allowed in the event of suspected toxicity, as long as the temporary interruption is 
associated with and can be linked to an AE or a serious AE (SAE) and this is not one of the cases 
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listed in Section 6.2.5 or Section 6.5. The maximum allowed duration of a single treatment 
interruption for toxicity reasons will be 4 weeks and the maximum allowed cumulative duration 
of the treatment interruptions for toxicity reasons will be 8 weeks (interruptions are counted 
cumulatively within a time frame of 48 weeks). Subjects should maintain the regular visit 
schedule during the treatment interruptions. Additional unscheduled visits may be performed for 
safety or tolerability reasons. Re-initiation of therapy including the background regimen will 
only be allowed once the event has resolved or decreased to a grade 2 or below. A subject must 
be withdrawn from the trial in case the total cumulative duration of treatment interruptions for 
suspected toxicities is more than 8 weeks (interruptions are counted cumulatively within a time 
frame of 48 weeks) or the duration of a single treatment interruption for a suspected toxicity is 
more than 4 weeks (see Section 6.2.5). Special considerations may be warranted for the 
discontinuation of certain ARV agents (see Section 6.3.5).
During the treatment period, the subject will have regular visits as stated in the flowchart 
(Section 2) during which the investigator will assess the subject’s medical condition, virologic 
and immunologic response, any AEs, safety and tolerability issues (including blood and urine 
tests) and study drug compliance, and during which pharmacokinetic samples will be taken. The 
subject and/or their parent(s) or caregiver(s) will also complete a compliance questionnaire 
(Study Adherence Questionnaire for Children and Teenagers, Addendum 7; and Study 
Adherence Questionnaire for Caregivers, Addendum 8). Subjects included in Part 1, or their 
parent(s) or caregiver(s), additionally were to complete a diary documenting the intakes of RPV
from the start of treatment with RPV 25 mg q.d. or weight-adjusted dose until the day of 
intensive pharmacokinetic sampling.
Details on the timing of the treatments and assessments are given in the flowchart (Section 2) 
and in Section 6.4.
Subjects who withdraw from the trial early (i.e., before the Week 48 visit) or subjects who do not 
participate in the extension after Week 48, will be seen for a follow-up visit. In the extension 
period, the 4-week follow-up visit is only performed if there is an ongoing (S)AE at the last on-
treatment visit.
After 240 weeks of treatment, continued access to RPV is foreseen in an open label roll-over trial 
until RPV becomes commercially available, is reimbursed or can be accessed through another 
program. Provision of study drug will be stopped in case subjects cease to benefit from the 
treatment or when development of RPV is discontinued.
Note: At the time of protocol amendment 6 writing, 48-week results from the adolescent cohort 
were available and a summary of these results has been provided in Section 6.1.2.2. For 
more details refer to the clinical study report of Cohort 153 or the abstract54.
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6.1.1.2.
Cohort 2: Children Aged ≥6 to <12 Years
In Cohort 2 of the trial, ARV treatment-naïve HIV-1 infected subjects aged ≥6 to <12 years with 
a plasma viral load ≥500 HIV-1 RNA copies/mL but ≤100,000 HIV-1 RNA copies/mL will be 
included. Any previous use of ARVs, with the exception of a single dose of NVP at birth or up to 
6 weeks of AZT use to prevent MTCT, is not allowed. The same exclusion criterion related to 
NNRTI RAMs (see Section 6.2.3) and precautions related to ABC use applies as in adolescents
in Cohort 1 (see Section 6.5.11.3). For a list of all inclusion and exclusion criteria see 
Section 6.2.2 and 6.2.3. For a list of specific guidelines regarding use of prior and concomitant 
therapy (see Section 6.3.13). For more information about the visit schedule of Cohort 2 see the 
flowcharts in Section 2.2.
To accommodate regulatory requirements concerning the evaluation of RPV in the pediatric 
population, overall across studies C213 (Cohort 2; children aged ≥6 to <12 years) and 
TMC278HTX2002 (children aged ≥2 to <12 years with a body weight of ≥11 kg), approximately 
40 subjects will be enrolled of which at least 12 subjects with a body weight of <25 kg, including 
at least 7 subjects with a body weight of <20 kg. The PK data from Cohort 2 will be combined 
with the data from pediatric study TMC278HTX2002. 
The analysis of the first 10 subjects in Cohort 2, including PK modeling and simulation to further 
assess the RPV pediatric dose based on accumulating data, was discussed with and endorsed by 
the IDMC. With this, at the time of Amendment 10, the following RPV dose recommendations 
will apply to newly enrolled subjects:
∀
RPV 25 mg q.d. for subjects with a body weight of ≥25 kg 
∀
RPV 15 mg q.d. for subjects with a body weight of <25 kg
All ongoing subjects in Cohort 2 (who are already in the post Week 48 treatment extension 
period at the time of Amendment 10) will remain on the RPV 25 mg q.d. dose + 2 N(t)RTIs 
(investigator-selected), until their roll-over to study TMC278IFD3004 has been completed (see 
addendum 7.11). All newly recruited subjects will start treatment with the weight-appropriate 
RPV dose stated above + 2 N(t)RTIs (investigator-selected), until they reach a total treatment 
duration of 48 weeks or discontinue earlier. If newly recruited subjects with a body weight of
<25 kg, increase in weight such that they require a 25 mg RPV dose, they can change to the 25 
mg tablet formulation.
To further evaluate and confirm the RPV dose for subjects with lower body weight, newly 
enrolled subjects with a body weight of <25 kg require intensive PK evaluation. An overall 
analysis of the intensive pharmacokinetic data and all available safety, tolerability and antiviral 
activity/efficacy data will be reviewed by the Sponsor and the IDMC to assess appropriateness of 
the dose (see section 6.1.1.2.1 for dose evaluation criteria).
∀
If the results are not deemed satisfactory, and no alternative RPV dose seems feasible, all 
subjects will be seen for a Withdrawal visit, treatment with RPV will be stopped, subjects 
will be switched to local standard of care, and Cohort 2 will be stopped. 
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∀
If the results are not deemed satisfactory but concerns can be addressed by adjusting the 
RPV dose (doses of >25 mg q.d. are not allowed) for certain subjects (e.g. up to a certain 
body weight), those subjects will be switched to an adjusted dose, while those that don't 
need dose adjustment, will continue their treatment. For all subjects who require an RPV 
dose adjustment, a 24-hour intensive pharmacokinetic evaluation after 14 to 18 days on 
the adjusted dose will be performed. After the subjects have been treated with the 
adjusted RPV dose for at least 4 weeks or discontinued earlier, an analysis of the 
intensive pharmacokinetic data (after 14 to 18 days of RPV dosing), and all available 
safety, tolerability and antiviral activity/efficacy data will be reviewed. If, after review of 
the data, the RPV dose is still not acceptable, the process will be repeated until an 
acceptable RPV dose is found or it is deemed necessary to stop Cohort 2.
Note: If in the mini-cohort, subjects discontinue the trial before receiving their first dose of 
study drug, additional subjects can be recruited to have 5 subjects with a body weight of 
<25 kg starting treatment in the mini-cohort. If subjects discontinue the trial after starting 
treatment for reasons other than drug tolerability/safety, additional subjects can be 
recruited to have at least 12 subjects with a body weight of <25 kg with intensive 
pharmacokinetic data. Additional subjects may also be recruited if the Sponsor and the 
IDMC deem it necessary to have additional subjects with intensive pharmacokinetic data 
because interpretation of the data is hampered by e.g., study drug adherence issues prior 
to the intensive pharmacokinetic sampling time point.
Subjects who experience and are expected to continue experiencing clinical benefit from RPV 
and their background regimen comprising 2 investigator-selected N(t)RTIs at the end of the 
initial 48-week treatment period, may continue treatment (i.e., RPV + 2 N[t]RTIs) in the roll-
over study TMC278IFD3004 or 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. Any retest, of abnormal laboratory 
results or plasma viral load/resistance testing, should be captured in this C213 study if the 
subjects roll over to the TMC278IFD3004 study.
Formal analyses (with formal database lock) will be performed when all subjects have reached 
Week 48, or discontinued earlier (primary analysis). Furthermore, data monitoring for risk-
benefit assessment (no formal database lock) will be performed when all subjects in this C213 
study reach Week 12 and Week 24, or discontinued earlier. These analyses will be based on the 
accumulated data at that point. The results of all analyses up to Week 48 will be shared and 
discussed with the IDMC. Analyses (no formal database lock) will also be performed for 
subjects with body weight <25 kg (mini-cohort and full group of subjects with body weight <25 
kg) for dose finding purposes when the subjects have been treated for at least 4 weeks, or 
discontinued earlier, with the original and/or adjusted dose. These analyses for dose finding 
purposes will be based on the intensive pharmacokinetic data after 14 to 18 days of treatment 
with the original and/or adjusted RPV dose and all available safety, tolerability and antiviral 
activity/efficacy data. Results of these intensive pharnacokinetic analyses, and if applicable, 
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analyses after RPV dose adjustments will be shared and discussed with the IDMC. For more 
details about the analyses, see Section 6.6.
The design of the trial is illustrated in Section 3.2.
Information on the study drug and investigator-selected background regimen can be found in 
Sections 6.3.1 and 6.3.2. Guidance on temporary interruptions and switching to alternative 
N(t)RTIs in case of toxicities can be found in Sections 6.3.5 and 6.5.11.3, and information on 
study drug discontinuation or removal of the subject from the trial can be found in Section 6.2.5.
Details about the treatment duration and assessments to be performed during the trial are 
provided in the flowcharts in Section 2 and in Section 6.4.
The total blood volume to be collected in this pediatric study has been optimized as much as 
possible, considering the safety assessments required in this clinical study, and the 
pharmacokinetic analysis necessary for establishing the appropriate dose. The sponsor considers 
the total blood quantity drawn clinically acceptable, in view of the age span of the children 
included in the study i.e., between ≥6 to <12 years old57.
After 48 weeks of treatment, continued access to RPV is foreseen in the roll-over study 
TMC278IFD3004 or by switching 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. Provision of study drug will be 
stopped in case subjects cease to benefit from the treatment or when development of RPV is 
discontinued.
6.1.1.2.1.
Dose Evaluation Criteria for Cohort 2
AUC24h of a selected RPV dose under fed and steady-state conditions will be the primary
pharmacokinetic parameter for determination of the acceptability of the RPV dose. The target 
geometric mean RPV AUC24h is between 80% and 150% of the observed geometric mean 
AUC24h for RPV in HIV-1 infected adults from the Phase III pharmacokinetic substudies of 
TMC278-TiDP6-C209 and TMC278-TiDP6-C215 (i.e., between 1426 and 2673 ng•h/mL). 
While the RPV AUC24h will be the primary pharmacokinetic parameter for acceptability of dose 
determination, the Sponsor will also consider the Cmax and C0h/C24h of RPV in its determination 
of the acceptability of the RPV dose. 
The analysis of the first 10 subjects in Cohort 2, including PK modeling and simulation to further 
assess the RPV pediatric dose based on accumulating data, was discussed with and endorsed by 
the IDMC. With this, at the time of Amendment 10, the following RPV dose recommendations 
will apply:
∀
RPV 25 mg q.d. for subjects with a body weight of ≥25 kg
∀
RPV 15 mg q.d. for subjects with a body weight of <25 kg
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Mini-cohort data review by the Sponsor after 4 weeks of treatment on the original or 
adjusted dose:
If the safety and pharmacokinetic data of the first 5 subjects (mini-cohort) are acceptable i.e., the 
data indicate that it is likely that the desired pharmacokinetic and safety criteria for the full group 
of subjects with a body weight of <25 kg will be achieved (see below), then additional subjects 
will be enrolled to
N≥12
subjects.
Failure with respect to safety/tolerability and/or 
pharmacokinetics will result in an evaluation whether it is safe to continue the attempt to find an 
optimal RPV dose in children of ≥6 to <12 years of age, and if considered safe, may result in a 
dose adjustment.
∀
If none of the 5 subjects in the mini-cohort has experienced a life-threatening AE
(including death) or a grade 4 AE that is at least probably related to RPV and ≤1 of the 
subjects has terminated the study drug due to a ≥grade 3 at least possibly related AE, the
mini-cohort has passed the safety review.
∀
If ≤1 of the 5 subjects 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 subjects under e.g., a certain body 
weight is warranted. 
Overall data review of subjects with body weight <25 kg by the Sponsor and IDMC after 4 
weeks of treatment on the original or adjusted dose:
When reviewing the overall results, the following guidelines and stopping rules will be taken 
into account:
∀
If none of the subjects 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 
subjects on this dose terminated study drug due to ≥grade 3 at least possibly related AE, 
then this dose will be considered safe. If the dose is not considered safe, all relevant 
safety and pharmacokinetic data will be reviewed to determine whether it is safe to 
continue the attempt to find an optimal RPV dose in children of ≥6 to <12 years of age.
∀
The RPV dose will be deemed acceptable if the dose is tolerated and appears to be safe
and the geometric mean RPV AUC24h is between 80% and 150% of the observed 
geometric mean AUC24h in HIV-1 infected adults from the Phase III pharmacokinetic 
substudies of TMC278-TiDP6-C209 and TMC278-TiDP6-C215 (i.e., between 1,426 and 
2,673 ng•h/mL). For safety reasons, the individual Cmax should be ≤440 ng/mL (1.85-fold 
the mean Cmax of RPV 25 mg q.d. in healthy adults and evaluated as not posing an 
increased risk for QT prolongation). If an individual Cmax is >440 ng/mL, an overall 
assessment of the subject’s safety will be performed (including additional ECG with 
optional PK sample) and the RPV dose can be continued for that subject if there are no 
safety findings. Failure with respect to the safety and/or PK guidelines will result in an 
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assessment by the sponsor study team to determine whether or not a dose adjustment for 
the cohort may be warranted.
∀
If the geometric mean RPV AUC24h is >150% of the observed geometric mean AUC24h in 
adults, dose adjustment for all subjects or subjects below a certain body weight will be 
considered. For this, available antiviral activity/efficacy and safety results will also be 
taken into account. 
∀
If the geometric mean RPV AUC24h is <80% of the observed geometric mean AUC24h in 
adults, results are not deemed satisfactory, all subjects will be seen for a Withdrawal 
visit, treatment with RPV will be stopped, subjects will be switched to local standard of 
care, and Cohort 2 will be stopped. 
If an adjusted RPV dose is needed, modeling and simulation will be used, incorporating all 
available pharmacokinetic data at that time, to propose an adjusted dose for RPV 
 
 
 For this, available doses of RPV (based on weight-
appropriate formulation which can be dosed in steps of 2.5 mg RPV) between 2.5 mg q.d. and 25 
mg q.d., in increments of 2.5 mg, will be considered. The new dose scheme and clear instructions 
on how to handle dosing in subjects will be provided to all participating sites by the Sponsor via 
a written notification.
6.1.2.
Discussion of Trial Design and Selection of Dose(s) in the Trial
6.1.2.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years
Antiretroviral therapy in ARV-naïve children provides evidence that the combination of 2 NRTIs 
and an NNRTI may reduce HIV RNA to undetectable levels in a substantial proportion of 
children1. 
Because this is the first trial with RPV (an NNRTI) to be conducted in adolescents aged !12 to 
<18 years, recruitment and analyses in this trial will be structured into 2 parts. In Part 1 
(consisting of Part 1a and Part 1b), the pharmacokinetics and short-term safety and antiviral 
activity were to be assessed in a subgroup of adolescent patients, in order to determine the 
appropriateness of the RPV dose for the remainder of the adolescents. In Part 1a, an analysis was 
performed when the first 11 subjects (i.e., 4 subjects aged !12 to <15 years and 7 subjects aged 
!15 to <18 years) had been treated for 2 weeks, or discontinued earlier. These Week 2 data 
showed that the mean exposure in adolescents (following intensive pharmacokinetic sampling) 
was within 80-125% of that in adults (with mean C0h ratio = 105% and mean 
AUC24h ratio = 83%) and safety and short-term antiviral activity were satisfactory. Based on 
these data the IDMC agreed for these subjects to continue treatment with RPV 25 mg q.d. and 
their background regimen. Given the fact that the AUC ratio was at the lower end, the Sponsor 
decided to enroll the additional subjects in smaller cohorts and gather more intensive 
pharmacokinetic data in order to increase the precision of the pharmacokinetic parameter ratios, 
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an approach which was agreed upon with the IDMC46. Therefore, Part 1 of Cohort 1 was to be 
expanded by enrolling approximately 12 additional subjects (in order to have at least 
10 evaluable subjects at Week 4) in Part 1b, aiming at an equal distribution of subjects between 
the two age groups (i.e., subjects ≥12 to <15 years of age and subjects ≥15 to <18 years of age). 
Part 1b included 14 subjects, 8 subjects in the age group !12 to <15 years and 6 subjects in the 
age group !15 to <18 years. This provided sufficient data on the pharmacokinetics, and short-
term safety, tolerability, and antiviral effect of RPV in adolescents to assess whether continued 
treatment with RPV 25 mg q.d. was acceptable. The IDMC deemed the results satisfactory and 
hence, long-term safety, efficacy, and pharmacokinetics will be evaluated in a larger group of 
subjects (Part 2). It could have been that the short-term results indicated the need for a switch to 
a lower dose for all Part 1 subjects up to a certain body weight. In this case, prior to the start of 
Part 2, there could have been an additional analysis (pharmacokinetics, safety and tolerability, 
antiviral activity) when these subjects had been treated with the weight-adjusted dose for 
4 weeks (+/-1 week). The appropriate dose for subjects entering Part 2 was assessed based on the 
data obtained in Part 1. The results indicated that no RPV dose adjustment was needed, as 
confirmed by the IDMC. For more details on the trial design, please refer to Section 2.2 and 
Section 6.1.1.
In Part 1a of Cohort 1, subjects with a screening viral load ≥5,000 HIV-1 RNA copies/mL could 
be included, an inclusion criterion which also applied in the Phase III trials. Data from these 
Phase III trials showed a higher virologic failure rate at Week 48 in the RPV-treated subjects 
with a baseline viral load >100,000 HIV-1 RNA copies/mL compared to subjects with a baseline 
viral load ≤100,000 HIV-1 RNA copies/mL, a trend which was also seen in the control group but 
to a lesser extent. Therefore, in line with the anticipated indication in adults in the European 
Economic Area47, the Sponsor has decided to limit the recruitment of the adolescent population 
in Part 1b and Part 2 to subjects with a screening viral load ≤100,000 HIV-1 RNA copies/mL.
The lower limit for screening viral load was changed as well, from 5,000 to 500 HIV-1 RNA 
copies/mL, as current treatment guidelines in adolescents48 indicate that treatment initiation 
should primarily depend on CD4+ cell count and other clinical factors, but not on viral load. So 
in Part 1b and Part 2, only subjects with a screening viral load ≥500 HIV-1 RNA copies/mL but 
≤100,000 HIV-1 RNA copies/mL will be enrolled. The 4-week interim analysis of Part 1b was to 
be evaluated by the IDMC before the start of Part 2.
At the time of protocol amendment 6 writing, all subjects have been enrolled in Part 1 and Part 2 
of this cohort. A summary of the 48-week results is provided in Section 6.1.2.2. For more details 
refer to the clinical study report of Cohort 153 or the abstract54.
All subjects in Part 1 will continue their ART (RPV plus an investigator-selected background 
regimen of 2 N[t]RTIs) during the review period by the IDMC.
To ensure that the duration between baseline and the review by the IDMC for subjects in Part 1a
was kept as short as possible, investigators were to identify eligible subjects in advance. 
Recruitment was to be started when the majority of the sites had the necessary documentation 
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and approvals in place and were therefore considered activated for enrollment. Recruitment for 
Part 1a has already been closed and the enrolled subjects can continue in the trial as judged by 
the IDMC. For Part 1b, recruitment could start at the individual sites as soon as the necessary 
documentation and approvals were in place, and was closed once the required number of subjects 
was recruited. Trial sites were informed in advance regarding stop of recruitment.
The 25 mg q.d. dose of RPV is the selected dose for further development in adults, based on its 
substantial and sustained efficacy up to 96 weeks in the Phase IIb dose-finding trial TMC278-
C204, regardless of baseline viral load, and its beneficial safety profile compared to higher 
dosages13, including a lack of effect on the QTc interval20.
In adolescents, the processes that can impact the drug disposition have typically matured to 
adult-like activity
and the pharmacokinetics in adolescents are often similar to the 
pharmacokinetics in adults15. The hepatic metabolism of RPV involves mainly CYP3A4, the 
activity of which has largely matured by the age of 2 years36,37. The adult dose of RPV (i.e. 25 
mg q.d.) is therefore anticipated to result in similar exposures in adolescents as compared to 
adults, and to be a generally safe and efficacious dose for the adolescent population as well. This 
is currently confirmed in the Week 48 results of the adolescent cohort (Cohort 1).
Children with HIV infection are known to often present with a stunted growth and a low body
weight compared to healthy children, even more so if additional risk factors for growth 
impairment are present38. In order to ensure that a representative fraction of the HIV-infected 
adolescent population can be studied in the trial, adolescents with a body weight as of 32 kg are 
allowed to enter the trial in Cohort 1 (i.e., the 10th percentile of the growth curve for body weight 
for healthy adolescents aged 12 years)31.
In trial TMC278-C204, adult ARV treatment-naïve HIV-infected subjects weighing between 
38.2 and 121.1 kg were exposed to RPV doses of 25, 75, or 150 mg q.d., and RPV was found to 
be generally safe and well tolerated at all doses. Furthermore, the effect of body weight on RPV
exposure was found to be not significant within this population, as assessed using the population 
pharmacokinetic model39. Based on this, it is anticipated that the RPV exposure with the 25 mg 
q.d. dose would not be significantly different between subjects weighing 32 kg or 40 kg (40 kg 
being approximately the lower body weight limit observed in trial TMC278-C204). However, as 
the effects of body weight on exposure could become more important in the lower body weight 
range, the theoretical potential increase in exposure was estimated by adding body weight as a 
covariate function in the population pharmacokinetic model, with a widely used scaling factor 
for pediatrics of 0.7514. The RPV exposure for subjects with a body weight of 32 kg is estimated 
to be 16% higher for mean AUC24h and 20% higher for mean Cmax, as compared to these 
parameters for subjects of 40 kg. An increase in exposure of this magnitude is not expected to 
result in any safety issues.
A standard linear mixed model was fitted to the pooled data of the 2 thorough QT trials 
(TMC278-TiDP6-C13111 and TMC278-TiDP6-C15220) and the pilot QT trial (TMC278-TiDP6-
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C15112), in order to better characterize the relationship between RPV plasma concentrations and 
change in QTcF over a wide plasma concentration range. This indicated that at plasma 
concentrations of 420 ng/mL (i.e., double the Cmax observed in HIV-infected adults on RPV 25 
mg q.d.), the mean (90% CI) time-matched change from baseline in QTcF is estimated to be 4.6 
ms (2.8–6.4 ms), indicating that RPV at these plasma concentrations does not cause a clinically 
relevant prolongation of the QTc interval.
In addition to the above, there was no pharmacokinetic/pharmacodynamic relationship for any 
other safety parameters in trial TMC278-C204.
Taking into account all of the above, the 25 mg q.d. dose is therefore expected to be a safe and 
efficacious dose for the adolescent population studied in the current trial (≥12 to <18 years with a 
body weight of at least 32 kg).
Also for the backbone medications ABC and 3TC used in the current trial the adult dose is 
recommended for children ≥30 kg, for efavirenz (approved NNRTI for pediatric use) the adult 
dose is recommended for children >40 kg, for AZT the adult dose is recommended for children 
>12 years, for FTC the adult dose is recommended for children ≥33 kg, and for TDF the adult 
dose is recommended for children ≥12 years and ≥35 kg.
In case of inadequate exposure, dose adjustments of RPV cannot be allowed at this stage in order 
to avoid exposing children to a daily dose exceeding the total adult daily dose (i.e., 25 mg q.d.). 
The combined use of at least 3 active ARV drugs in ARV treatment-naïve HIV-1 infected 
subjects is currently recommended due to the inherent high mutation rate of HIV1,16. One 
recommended treatment regimen for ARV treatment-naïve subjects is 2 N(t)RTIs and an 
NNRTI. Therefore, all subjects in this trial will receive, in addition to the NNRTI RPV, an 
investigator-selected background regimen of 2 N(t)RTIs (AZT, ABC, or TDF in combination 
with 3TC or FTC). Consistent with the treatment guidelines for ART, sensitivity to the chosen 
N(t)RTIs should be established. In this trial, the subject’s sensitivity at screening will be 
established using HIV-1 genotyping 1.
The combination of ABC with 3TC and AZT with 3TC are recommended and approved N(t)RTI 
regimens for first line use in adults and adolescents1,16.
When looking at the subset of subjects who used AZT/3TC as background regimen in the RPV
dose finding trial in adults (TMC278-C204), it was shown that there were no safety or 
tolerability concerns with coadministration of these NRTIs and RPV8. Based on the metabolic 
profiles and elimination, clinically relevant interactions between the other NRTI in the 
background regimen and RPV are unlikely4.
For safety and efficacy information from studies using AZT, ABC, TDF, FTC, and/or 3TC or the 
combination products Combivir®, Truvada®, or Epzicom®/Kivexa® in combination with other 
ARV agents, please consult the package insert for these products.
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Data from a recent clinical trial indicated that combination therapy including ABC/3TC is less 
effective in ARV treatment-naïve adult subjects with a high viral load at screening 
(≥100,000 HIV-1 RNA copies/mL) compared to regimens containing TDF/ FTC. Moreover, it 
was found that among adult subjects with a high viral load at screening, those subjects receiving 
ABC/3TC developed non-specific side effects, such as body aches, and laboratory test 
abnormalities, such as elevated cholesterol and triglyceride levels, faster compared to those 
receiving TDF/FTC17. Recent use of ABC was also reported to be associated with increased risk 
of myocardial infarction, especially in adult subjects with a high underlying cardiovascular 
risk18, but this has not been confirmed by other clinical trials. Fatal hypersensitivity reactions 
have been associated with ART including ABC (see Section 6.5.11.3). In clinical trials, 
hypersensitivity reactions have been reported in approximately 5% of adult and pediatric subjects 
receiving ABC18. Since the risk for developing such reactions has been linked to the presence of 
the HLA-B*5701 allele19, subjects without prior documented HLA-B*5701 negative results for 
whom the investigator considers ABC/3TC as background regimen should test negative for 
HLA-B*5701 at screening to limit the risk of hypersensitivity reactions (see Section 6.5.11.3 for 
details). If a subject is planned to be switched to an ABC-containing background regimen during 
the trial (due to intolerance, see Section 6.3.5), an HLA-B*5701 test has to be performed to 
determine eligibility to start ABC treatment (unless prior documented negative results are 
available).
There have been reports of delusions and inappropriate behavior in subjects receiving licensed 
NNRTIs, predominantly in subjects with a history of mental illness or substance abuse. Severe 
acute depression (including suicidal ideation/attempts) has also been reported in subjects 
receiving NVP or EFV (package insert). In trial TMC278-C204, 6.5% of subjects receiving 
RPV 25 mg b.i.d. were reported with depression8. Therefore, in order to proactively assess the 
risk of depression in these adolescents and children treated with RPV, at every visit indicated in 
the flowchart, an evaluation will be done using questionnaires or other means, as in use at the 
site as part of local standard of care for this population, to determine who needs to be referred for 
a complete mental health assessment by a mental health professional (see Section 6.4.11 for 
details).
Pharmacokinetic evaluations have shown that RPV is better absorbed following oral 
administration with food. Therefore intake should occur with a meal. For details, see 
Section 6.3.4. Whenever possible, RPV should be taken around the same time each day, with 
approximately 24 hours between the doses. Intake of the N(t)RTIs in the background regimen 
will be according to the locally applicable procedures and package inserts. 
A trial duration of minimally 48 weeks is mandatory for providing long-term safety and efficacy 
data16.
6.1.2.2.
Cohort 2: Children Aged ≥6 to <12 Years
At the time of Amendment 10, 240-week results from 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 
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development. No clinically relevant suppression of cortisol secretion is observed in adults62,63 or 
adolescents aged ≥12 to <18 years (Cohort 1)64,65. Also, in the first 9 children aged ≥6 to <12 
years in Cohort 2 of this study there were no emergent cortisol abnormalities and no signs or 
symptoms of adrenal insufficiency66. The following RPV dose recommendations were 
determined based on accumulating data and were endorsed by the IDMC, in order to achieve
similar exposure to RPV compared to adults: RPV 25 mg q.d. for subjects with a body weight of 
≥25 kg, and RPV 15 mg q.d. for subjects with a body weight of <25 kg. Appropriateness of these 
doses will be further evaluated in this study. 
At the time of protocol amendment 6 writing, new clinical information has become available. For 
the discussion of the trial design in children (Cohort 2), a summary of relevant new and existing
information has been provided below.
In mice, rats, dogs, and cynomolgus monkeys RPV affects adrenal hormone biosynthesis by 
direct inhibition of 21-hydroxylase and 17-hydroxylase (the latter in cynomolgus monkey only). 
Studies in dogs indicate that this effect does not occur after a single dose but that repeated dosing 
is needed to alter adrenal hormone levels in the circulation. There is potential concern for RPV to 
cause partial adrenal insufficiency, virilization in girls and/or growth retardation due to 21-
hydroxylase inhibition. Studies in juvenile female cynomolgus monkeys, a more relevant species 
than dogs, did not show evidence of induction of premature ovulation, therefore the effects on 
the estrous cycle in dogs is not considered relevant for pre-pubertal children. In case significant 
inhibition of cortisol synthesis would occur (partial adrenal insufficiency), androgen production 
might increase. In girls, this could result in masculinization and blunted growth. In boys, due to 
increased levels of testosterone, growth might also be impaired. No clinically relevant mean 
change from baseline in serum cortisol levels or 17-hydroxyprogesterone levels over time have 
been observed in the clinical Phase IIb or III studies in adult men and women or in the Week 48 
data of adolescents, neither for basal nor for ACTH stimulated values. In addition, growth and 
sexual maturation was not affected in adolescents and no clinically relevant effect was observed 
for gonadal laboratory parameters in adults or adolescents. As a precaution, endocrine testing 
will be conducted in this trial to verify whether any clinically relevant adrenal and/or gonadal 
effects of RPV are observed in pre-pubertal children.
Results of the Phase III studies in adults show that virologic response (<50 copies/mL, TLOVR) 
rates at Week 96 and in the extension after Week 96 were high and consistent between the 
Phase III studies. In the Week 96 pooled Phase III analysis a virologic response of <50 
copies/mL (ITT, TLOVR) was achieved in 77.6% of subjects in both the RPV and control group
(EFV). The proportion of virologic responders was higher in subjects with a baseline plasma 
viral 
load
≤100,000 
copies/mL 
compared 
to
subjects 
with 
baseline 
viral 
load 
>100,000 copies/mL. RPV was non inferior to control. In the Week 96 pooled Phase III analysis, 
beyond 48 weeks there were a limited number of additional virologic failures with fewer 
virologic failures in subjects with baseline viral load ≤100,000 copies/mL compared to subjects 
with baseline viral load >100,000 copies/mL.
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In the Week 96 pooled Phase III analysis, RPV provided clear immunologic benefits. The CD4+
cell count increased from Week 2 to Week 48, with a slower rate thereafter to Week 96.
In the Week 96 pooled Phase III analysis, in adult subjects treated with RPV the E138K RAM 
emerged most frequently and was commonly seen in combination with the M184I RAM. The 
FTC and 3TC RAMs M184I/V emerged more frequently in subjects experiencing virologic 
failure treated with RPV compared with subjects experiencing virologic failure treated with 
control (EFV).
In the Week 96 pooled Phase III and post Week 96 analyses, most AEs emerged in the first 48 
weeks of the trial and no new safety signals were observed thereafter. Overall RPV administered 
at 25 mg q.d. in combination with 2N(t)RTIs was generally safe and well tolerated. The most 
commonly reported AEs in the RPV group were headache (15.5%), nausea (14.6%), diarrhea 
(13.7%), upper respiratory tract infection (12.8%), and nasopharyngitis (12.8%), with similar 
incidences in the control group. Dizziness and rash (preferred term) were reported statistically 
significantly less on RPV than on control. A lower incidence on RPV than on control was 
observed for treatment-related AEs (≥grade 2), skin events of interest (including rash [grouped 
term]), neurologic events of interest, psychiatric events of interest, and grade 3 or 4 lipid-related 
laboratory abnormalities in the Week 96 pooled Phase III analysis. Small mean variations from 
baseline over the 96-week treatment period in adrenal and gonadal parameters indicate that 
neither RPV nor control had a clinically relevant inhibitory effect on 21-hydroxylase or 
17-hydroxylase. There were no clinical signs or symptoms suggestive of adrenal or gonadal 
dysfunction. In the Week 48 and Week 96 pooled Phase III analyses, there was a gradual mean 
increase (from baseline) in QTcF, similar in both treatment groups at all time points. No gender 
difference was observed. This mean increase from baseline was less pronounced in the TDF/FTC 
subgroup than in the AZT/3TC subgroup. The incidence of prolonged QTcF (>480 ms) was low 
in both treatment groups (0.3%). There were no QTcF >500 ms, a typical pro-arrhythmic 
threshold. No AEs suggestive of ventricular tachyarrhythmia were reported. There was no 
relationship between exposure to RPV (AUC24h) and the maximum mean change from baseline 
in QTcF across the exposure range in Phase III. No apparent relationship was observed between 
the pharmacokinetic parameters of RPV 25 mg q.d. and the occurrence of AEs or changes in 
laboratory or ECG parameters. Although it seems that RPV at the recommended dose has 
minimal effects on adults’ ECG and no ECG-related AEs or clinically relevant ECG 
abnormalities were reported in the adolescent cohort of this trial (see below), its effect on the 
ECG parameters of children <12 years of age needs to be established and will therefore be 
monitored in this trial.
The Week 48 efficacy analysis results of the adolescent cohort (!12 to <18 years of age) of this 
trial, demonstrated that RPV 25 mg q.d., in combination with an investigator-selected 
background regimen, is efficacious in adolescents of ≥12 to <18 years. A virologic response of 
<50 copies/mL (ITT, TLOVR) was achieved in 26/36 (72.2%) subjects at Week 48. At Week 48, 
the proportion of virologic responders was higher in subjects with a baseline plasma viral load 
≤100,000 copies/mL (78.6%) than in the limited number of subjects with a baseline plasma viral 
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load >100,000 copies/mL (50%). At Week 48, 5/28 (17.9%) subjects with a baseline plasma viral 
load ≤100,000 copies/mL and 3/8 (37.5%) subjects with a baseline plasma viral load >100,000 
copies/mL, were considered virologic failures.
RPV provided clear immunologic benefit in adolescents, as shown by an increase in CD4+ cell 
counts over the 48-week treatment period.
Among the 5 virologic failures with baseline plasma viral load ≤100,000 copies/mL at Week 48, 
3/5 (60.0%) developed RPV RAMs, which was associated with phenotypic resistance to RPV in 
2/3 (66.7%) cases. These 2 subjects also carried 1 treatment-emergent NRTI RAM at the last 
available visit with genotypic data. The 2 other virologic failures with baseline plasma viral load 
≤100,000 copies/mL did not carry treatment-emergent RPV RAMs (1 with V90I) or NRTI 
RAMs. Of the 3 virologic failures with baseline plasma viral load >100,000 copies/mL at Week 
48, 2/3 (66.7%) developed RPV RAMs, which was associated with phenotypic resistance to RPV 
in both (2/2, 100.0%) cases. These 2 subjects also carried at least 1 treatment-emergent NRTI 
RAM at the last available visit with genotypic data. In addition, 1 virologic failure with baseline 
viral load >100,000 copies/mL transiently carried an RPV RAM (E138K) in the absence of 
NRTI RAMs, returning to wild type at trial withdrawal. The observed treatment-emergent RPV 
and NRTI RAMs were previously identified in the Phase III studies conducted in adults.
To date and based on all in vitro and in vivo data, 16 NNRTI RAMs when present at baseline 
have been identified as potential determinants of decreased antiviral activity of RPV. These 
NNRTI RAMs are: K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, 
Y181I, Y181V, Y188L, H221Y, F227C, M230I, and M230L.
The 25 mg q.d. dose in adolescents resulted in similar RPV exposure as observed in adults. No 
apparent relationships were observed between the RPV pharmacokinetics and efficacy or safety 
parameters at Week 48.
The safety data up to Week 48 demonstrated that RPV, administered at 25 mg q.d., in 
combination with an investigator-selected background regimen of 2 N(t)RTIs, was generally safe 
and well tolerated in adolescents. RPV did not appear to affect pubertal development or growth
in these adolescents nor did it appear to have an effect on ECG parameters. The RPV safety 
profile as established in HIV-1 infected ARV treatment-naïve adults was confirmed in 
adolescents.
For further information on the above mentioned non-clinical and clinical data, see the 
Investigator’s Brochure4. For more details about the final 48-week- and 240-week results, see the 
clinical study report of Cohort 153 or the abstract54.
The results from the non-clinical studies and clinical trials in adults and adolescents are 
considered adequate to start treatment in children <12 years of age.
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In the adult trials, using RPV doses of 25 mg q.d. (~0.36 mg/kg/day for a 70-kg adult), no clear 
effect of body weight on the RPV exposure was seen4. Similarly, data in adolescents between 12 
and 18 years of age weighing approximately 33 to 93 kg also showed no effect of body weight 
on the RPV exposure53. While at some point, smaller body weight/size is expected to become 
more important and may start to have an effect on the RPV pharmacokinetics; it is at present not 
clear as of what age/body weight this would be. 
 
 
 
 
 
 Therefore, the 25 mg qd dose is considered adequate 
as a starting dose for children 6 to 12 years of age. However, the pharmacokinetic data will be 
evaluated in real-time every time a child has completed its intensive pharmacokinetic visit, and 
in the event the pharmacokinetic guidelines (see Section 6.1.1.2.1) cannot be met for the mini-
cohort or full group of subjects with a body weight of <25 kg, an alternative dose will be 
determined for evaluation. The background regimen selection will be similar as in Cohort 1
(adolescents ≥12 to <18 years of age): a regimen of 2 N(t)RTIs will be selected by the 
investigator. For details about timing of dosing, see Section 6.3.4.
In Cohort 2, children with a body weight as of 17 kg are allowed to enter the trial in this cohort 
(i.e., the 10th percentile of the growth curve for body weight for healthy children aged 6 years)31.
Similar as in Cohort 1, the risk of depression in subjects in Cohort 2 will be assessed at every 
visit indicated in the flowchart (see Section 6.4.11 for details). 
To accommodate regulatory requirements concerning the evaluation of RPV in the pediatric 
population, overall across studies C213 (Cohort 2; children aged ≥6 to <12 years) and 
TMC278HTX2002 (children aged ≥2 to <12 years with a body weight of ≥11 kg), approximately 
40 subjects will be enrolled of which at least 12 subjects with a body weight of <25 kg, including 
at least 7 subjects with a body weight of <20 kg. The PK data from Cohort 2 will be combined 
with the data from pediatric study TMC278HTX2002. 
The analysis of the first 10 subjects in Cohort 2, including PK modeling and simulation to further 
assess the RPV pediatric dose based on accumulating data, was discussed with and endorsed by 
the IDMC. With this, at the time of Amendment 10, the following RPV dose recommendations 
will apply to newly enrolled subjects:
∀
RPV 25 mg q.d. for subjects with a body weight of ≥25 kg
∀
RPV 15 mg q.d. for subjects with a body weight of <25 kg
All ongoing subjects in Cohort 2 (who are already in the post Week 48 treatment extension 
period at the time of Amendment 10) will remain on the RPV 25 mg q.d. dose + 2 N(t)RTIs 
(investigator-selected), until their roll-over to study TMC278IFD3004 has been completed (see 
addendum 7.11). All newly recruited subjects will start treatment with the weight-appropriate 
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RPV dose stated above + 2 N(t)RTIs (investigator-selected), until they reach a total treatment 
duration of 48 weeks or discontinue earlier. If newly recruited subjects with a body weight of 
<25 kg, increase in weight such that they require a 25 mg RPV dose, they can change to the 25 
mg tablet formulation.
To further evaluate and confirm the RPV dose for subjects with lower body weight, newly 
enrolled subjects with a body weight of <25 kg require intensive PK evaluation. An overall 
analysis of the intensive pharmacokinetic data and all available safety, tolerability and antiviral 
activity/efficacy data will be reviewed by the Sponsor and the IDMC to assess appropriateness of 
the dose (see section 6.1.1.2.1 for dose evaluation criteria).
∀
If the results are not deemed satisfactory, and no alternative RPV dose seems feasible, all 
subjects will be seen for a Withdrawal visit, treatment with RPV will be stopped, subjects 
will be switched to local standard of care, and Cohort 2 will be stopped. 
∀
If the results are not deemed satisfactory but concerns can be addressed by adjusting the 
RPV dose (doses of >25 mg q.d. are not allowed) for certain subjects (e.g. up to a certain 
body weight), those subjects will be switched to an adjusted dose, while those that don't 
need dose adjustment, will continue their treatment. For all subjects who require an RPV 
dose adjustment, a 24-hour intensive pharmacokinetic evaluation after 14 to 18 days on 
the adjusted dose will be performed. After the subjects have been treated with the 
adjusted RPV dose for at least 4 weeks or discontinued earlier, an analysis of the 
intensive pharmacokinetic data (after 14 to 18 days of RPV dosing), and all available 
safety, tolerability and antiviral activity/efficacy data will be reviewed. If, after review of 
the data, the RPV dose is still not acceptable, the process will be repeated until an 
acceptable RPV dose is found or it is deemed necessary to stop Cohort 2.
Once an appropriate RPV dose has been selected, Part 1 of Cohort 2 will be considered complete 
and Part 2 in which long-term safety, efficacy, and pharmacokinetics of RPV will be evaluated,
will start. For more details on the trial design, please refer to Section 2.2 and Section 6.1.1.
As in Cohort 1, a trial duration of minimally 48 weeks is mandatory for providing long-term 
safety, tolerability and efficacy data in this age group16.
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6.2.
Trial Population
6.2.1.
Sample Size
6.2.1.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years
Part 1a: N = 11 subjects (actual) and 
Part 1b: N =14 subjects (actual)
If in Part 1, subjects discontinued the trial before receiving their first dose of study drug, 
additional subjects could have been recruited to have at least 10 subjects starting treatment
each in Part 1a and Part 1b. If subjects were prematurely withdrawn from the trial after 
starting treatment for reasons other than drug tolerability/safety, additional subjects could 
have been recruited to aim for at least 10 evaluable subjects in each Part 1a and Part 1b at 
the time of intensive pharmacokinetic sampling.
Part 2: N ≥35 subjects (including all subjects already included in Part 1), regardless of dose 
switch.
For more details concerning the sample size, see Section 6.6.1.
6.2.1.2.
Cohort 2: Children Aged ≥6 to <12 Years
As of Amendment 10 approximately 40 subjects will be enrolled in this Cohort 2 and in 
pediatric study TMC278HTX2002 combined: at least 12 with a body weight of <25 kg, 
including at least 7 with a body weight of <20 kg.
For more details concerning the sample size, see Section 6.6.1.
6.2.2.
Inclusion Criteria
If there is a question about the inclusion criteria below, the investigator should consult with the 
appropriate Sponsor representative before enrolling a subject in the trial.
Subjects who meet all of the following criteria are eligible for this trial:
1.
Cohort 1: Boys or girls, aged ≥12 to <18 years.
Cohort 2: Boys or girls, aged ≥6 to <12 years.
2.
Cohort 1: Subject’s weight is ≥32 kg.
Cohort 2: Subject’s weight is ≥17 kg.
3.
Subject with documented HIV-1 infection.
4.
Subject willing and able to give consent. In case the subject’s age is below the cut-off age 
for consent (according to local regulations), their parent/caregiver should be able and willing 
to give consent, and the subject will be informed about the trial and asked to give positive 
assent.
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5.
Subject can comply with the protocol requirements.
6.
Subject has, prior to screening, never been treated with a therapeutic HIV vaccine or an HIV 
drug with the exception of a single dose of NVP (Cohort 1 and Cohort 2) or up to 6 weeks of 
AZT use (Cohort 2 only) to prevent MTCT.
7.
HIV-1 plasma viral load at screening !500 HIV-1 RNA copies/mL but ≤100,000 HIV-1 
RNA copies/mL (assayed by RNA polymerase chain reaction [PCR] standard specimen 
procedure).
Note: For Cohort 1 Part 1a, subjects with a screening viral load ≥5,000 HIV-1 RNA 
copies/mL were allowed.
Note: To reassess eligibility, retesting of a screening value that leads to exclusion will be 
allowed only once during the screening period using an unscheduled visit.
8.
In the judgment of the investigator, it is appropriate to initiate ART based on the subject’s 
medical condition and taking into account guidelines for the treatment of HIV-1 infection in 
children of this age group.
9.
Results from the screening HIV-1 genotype demonstrate sensitivity to the selected N(t)RTIs.
10. Subject is able to swallow the RPV tablet as a whole (since the tablet cannot be chewed, 
broken, or crushed), except when the appropriate RPV dose for the subjects is determined to 
be <25 mg (only applicable for subjects enrolled after it has been decided that a lower RPV 
dose is appropriate for subjects up to a certain e.g., age or body weight). In this case an age-
appropriate formulation other than the tablet formulation will be provided.
11. The subject agrees (or their parents/caregivers agree, in case the subject's age is below the 
cut-off age for consent according to local regulations, in which case the subject is informed 
and asked to give positive assent) not to start ART before the baseline visit.
12. General medical condition, in the investigator’s opinion, does not interfere with the 
assessments and the completion of the trial.
6.2.3.
Exclusion Criteria
If there is a question about the exclusion criteria below, the investigator should consult with the 
appropriate Sponsor representative before enrolling a subject in the trial.
Subjects meeting one or more of the following criteria cannot be selected:
1.
Any previous use of ARVs, with the exception of a single dose of NVP (Cohort 1 and Cohort 
2) or up to 6 weeks of AZT use (Cohort 2 only) to prevent MTCT.
Note: Cohort 1: Subjects who were infected by MTCT are allowed to enter, provided the 
mother was ARV treatment-naïve at the time of delivery with the exception of NVP 
for no more than 3 days.
2.
Having documented genotypic evidence of NNRTI resistance at screening or from historical 
data available in the source documents, i.e., !1 NNRTI RAM from the following list (the list 
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was compiled on the basis of the list of IAS-USA NNRTI RAMs21 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
3.
Previously documented HIV-2 infection.
4.
Subject has 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 N(t)RTI in the background regimen. HLA-
B*5701 testing is not required for subjects with prior documented negative results.
5.
Use of disallowed concomitant therapy from 4 weeks prior to the baseline visit.
6.
Any condition (including but not limited to alcohol and drug use), which, in the opinion of 
the investigator, could compromise the subject’s safety or adherence to the protocol.
7.
Life expectancy less than 6 months.
8.
Subject has any currently active Acquired Immunodeficiency Syndrome (AIDS) defining 
illness (Category C conditions according to the Centers for Disease Control and Prevention
[CDC] Classification System for HIV Infection 1993).
Note: An AIDS-defining illness not clinically stabilized for at least 30 days will be 
considered as clinically active.
Note: Primary or secondary prophylaxis for an AIDS-defining illness is allowed in case the 
medication used is not part of the disallowed medication.
9.
Any active clinically significant disease (e.g., pancreatitis, cardiac dysfunction, active and 
significant psychiatric disorders, clinical suspicion of adrenal insufficiency, hepatic 
impairment) or findings during screening or medical history that, in the investigator’s 
opinion, would compromise the outcome of the trial.
10. Subject has a known or suspected acute (primary) HIV-1 infection.
11. Any current or history of adrenal disorder.
12. Previously demonstrated clinically significant allergy or hypersensitivity to any of the 
components of the study drug (RPV) or the selected NRTIs. In this last case, the other 
N(t)RTI may be selected.
13. Receipt of any investigational drug or investigational vaccine within 90 days prior to the 
first administration of RPV.
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14. Pregnant or breastfeeding girl.
15. Heterosexually active girls of childbearing potential without the use of effective birth control 
methods or not willing to continue practicing these birth control methods from screening 
onwards until at least 30 days after last intake of RPV.
Note: RPV 25 mg q.d. did not change the pharmacokinetics of the oral contraceptives 
ethinylestradiol plus norethindrone, nor did it alter the pharmacodynamics40.
However, to be eligible for this trial, girls of childbearing potential must agree to use one of the 
following birth control methods:
%
A diaphragm or cervical cap and the male partner should use a condom;
%
A hormonal contraceptive or an intra-uterine device (IUD) in combination with a barrier 
contraceptive (i.e., male condom, diaphragm, cervical cap, or female condom);
or
%
Be non-heterosexually active, practice sexual abstinence or have a vasectomized 
partner.
Note: A female condom and a male condom should not be used together as friction 
between the two can result in failing of either product.
Note: Spermicides should not be used as this can potentially increase the rate of HIV-1 
transmission22.
Note: A cervical cap has been shown to be less effective in parous women. Therefore, the 
combination of a cervical cap with oral contraceptives is preferably not used in 
parous girls in this trial.
16. Heterosexually active boys without the use of effective birth control methods or not willing 
to continue practicing these birth control methods from screening onwards until 30 days 
after last intake of RPV.
Note: All HIV-infected boys are advised to use a condom to reduce the risk of transmitting 
HIV.
17. Any grade 3 or 4 laboratory toxicity according to the Division of AIDS (DAIDS) grading 
table (see Section 7.2, Addendum 2), except for:
%
Grade 3 absolute neutrophil count
%
Grade 3 platelets
%
Grade 3 glucose elevation in diabetics
%
Asymptomatic grade 3 pancreatic amylase elevation
%
Asymptomatic grade 3 triglyceride / cholesterol / glucose elevation
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%
Asymptomatic grade 4 triglyceride elevation
18. Subject has active tuberculosis and/or is being treated for tuberculosis at screening.
19. Subject has one or more of the following risk factors for QTc prolongation:
%
A confirmed prolongation of QT/QTc interval, e.g., repeated demonstration of QTcF 
(Fridericia correction) interval >450 ms in the screening ECG
%
Pathological Q-waves (defined as Q-wave >40 ms or depth >0.4-0.5 mV)
%
Evidence of ventricular pre-excitation
%
Electrocardiographic evidence of complete or incomplete left bundle branch block or 
complete or clinically significant incomplete right bundle branch block
%
Evidence of second or third degree heart block
%
Intraventricular conduction delay with QRS duration >120 ms (>90 ms for subjects <12 
years of age).
%
Bradycardia as defined by sinus rate <50 bpm
%
Personal or family history of long QT syndrome
%
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.
%
Syncopal episodes if repeated, unexplained, and unrelated to emotional distress.
%
Risk factors for Torsade de Pointes (e.g., heart failure, hypokalemia, hypomagnesemia)
20. Subject enrolled in other clinical trials that include any blood sampling with a volume higher 
than 50 mL taken over the course of 6 months, specimen collection, or other interventional 
procedure. Concurrent participation in non-interventional observational trials is allowed as 
long as there is no impact on the objectives of this trial. Data collected in this trial can be 
reported in the observational trial (see also Section 6.2.4.2).
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 period (to 
reassess eligibility). 
Note: Investigators should ensure that all trial enrollment criteria have been met at screening. If 
a subject's status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given 
such that he or she no longer meets all eligibility criteria, then the subject should be 
excluded from participation in the trial. Section 3.4, Source Data, describes the required 
documentation to support meeting the enrollment criteria.
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6.2.4.
Precautions and Restrictions
Potential subjects must be willing and able to adhere to the following precaution measures and 
restrictions during the course of the trial to be eligible for participation.
6.2.4.1.
Precautions
It is the investigator’s responsibility to provide appropriate counseling about precautions to avoid 
the risk of transmitting HIV.
Since the effects of RPV on gestation are unknown, heterosexually active boys and girls of 
childbearing potential should receive counseling about birth control methods23.
Boys and girls of childbearing potential having heterosexual intercourse must agree to use 
2 contraceptive methods in conjunction with their sex partner, i.e., use a condom in 
combination with hormonal contraceptives, an IUD, diaphragm, or cervical cap.
Note: A female condom and a male condom should not be used together as friction between the 
two can result in failing of either product.
Note: Spermicide should not be used as this can potentially increase the rate of HIV-1 
transmission22.
Note: A cervical cap has been shown to be less effective in parous women. Therefore, the 
combination of a cervical cap with oral contraceptives is preferably not used in parous 
girls in this trial.
All HIV-infected boys are advised to use a condom to reduce the risk of transmitting HIV.
These precautions apply from screening onwards until one month after the last study drug 
administration, i.e., until 30 days after the end of the treatment period or one month after 
discontinuation of RPV in case of premature discontinuation.
For details on the existing data with regard to the reproductive toxicity of RPV, please see the 
current Investigator’s Brochure4.
Girls should not breastfeed when taking RPV, as the effects to their newborn child are unknown. 
Girls who have a newborn child should talk to their investigator about the best way to feed their 
child. They should be aware that HIV could be transmitted through breastfeeding.
For the N(t)RTI background regimen, the package insert should be consulted with regard to 
directions concerning birth control and breastfeeding.
6.2.4.2.
Restrictions 
During the conduct of the trial, subjects are not allowed to participate in any other clinical trials 
that include any blood sampling with a volume higher than 50 mL taken over the course of 6 
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months, specimen collection, or other interventional procedure. Concurrent participation in non-
interventional observational trials is allowed as long as there is no impact on the objectives of 
this trial. Data collected in this trial can be reported in the observational trial.
No treatment interruptions are allowed prior to intensive PK in either cohort of the trial.
The consumption of grapefruit juice is not allowed during the trial. In addition, the subjects 
included prior to intensive PK in either cohort of the trial, may not consume beverages 
containing quinine (e.g., tonic, bitter lemon, bitter alcoholic beverages containing quinine), until 
after the pharmacokinetic sampling day at Week 2. Refer to Section 6.3.13.1 for more 
information on disallowed medication.
6.2.5.
Removal of Subjects From Therapy or Assessment
Severe acute exacerbations of hepatitis have been reported after discontinuation of 3TC in 
subjects with chronic hepatitis B infection who are using this agent in their ARV regimen. 
Discontinuation of this agent for any reason in subjects with hepatitis B infection should be 
undertaken with caution. Careful clinical and laboratory assessment of the hepatic status should 
be undertaken for at least several months in such subjects. Initiation of specific anti-hepatitis B 
therapy may be required.
Subjects may be withdrawn from the trial if:
1.
An SAE occurs.
2.
They fail to comply with the protocol requirements or to cooperate with the trial staff.
3.
They do not respect the washout period of disallowed medication (i.e., a period of at least 
4 weeks prior to first intake of RPV), or start treatment with one of the medications reported 
on the list of disallowed medications (see Section 6.3.13).
4.
The subject experiences a grade 3 AE or confirmed grade 3 laboratory abnormality, 
according to DAIDS grading table (see the DAIDS grading table in Addendum 2, 
Section 7.2). Exceptions are (unless clinical assessment foresees an immediate health risk to 
the subject):
%
Glucose elevations of grade 3 in subjects with pre-existing diabetes (see 
Section 6.5.11.1)
%
Asymptomatic glucose, triglyceride, or cholesterol elevations of grade 3 (see 
Sections 6.5.11.1 and 6.5.11.2)
%
Asymptomatic pancreatic amylase elevations of grade 3 in subjects with no history or 
concomitant disease of pancreatitis (see Section 6.5.4)
%
A grade 3 AE that is considered not related or doubtfully related to RPV
For grade 3 cutaneous reaction/rash, allergic reaction, or neurological events, persistent 
grade 3 glucose elevations despite appropriate antidiabetic medication/treatment, 
grade 3 
elevation 
in 
lipase, 
aspartate 
aminotransferase 
(AST) 
or 
alanine 
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aminotransferase (ALT), grade 4 elevation in pancreatic amylase, grade 3 or 4 
hypomagnesemia, and grade 3 nausea and diarrhea, see must be withdrawn criteria.
Note: For grade 3 or 4 laboratory abnormalities, subjects should have a confirmatory 
measurement preferably within 48 hours after the laboratory results become available 
to the site.
5.
The subject experiences an ABC hypersensitivity reaction (see Section 6.5.11.3); ABC 
treatment must be discontinued immediately. N(t)RTI background regimen will be replaced 
by an alternative regimen consisting of 2 N(t)RTIs (Brand name versions or generics with 
tentative US FDA approval and/or WHO prequalified drugs. If not available; generic drugs 
approved by the local Health Authorities or drugs procured by the UN international 
organizations can be allowed upon approval by the sponsor.). At all times the background 
regimen should consist of 2 N(t)RTIs and the subject’s HIV-1 genotype at screening should 
show sensitivity to the alternative N(t)RTIs. The subject must never be rechallenged with 
any medicinal product that contains ABC (Ziagen®, Trizivir®, or Epzicom®/Kivexa®).
6.
The subject demonstrates:
%
Loss of virologic response (i.e., 2 consecutive measurements of >400 HIV-1 
RNA copies/mL at least 2 weeks apart after having been confirmed virologic responder 
[defined as having had 2 consecutive measurements of <400 HIV-1 RNA copies/mL]). 
Withdrawal of the subject should be based on clinical judgment and preferably be 
discussed with the Sponsor.
Subjects must be withdrawn from the trial if:
1.
The pharmacokinetics or safety and antiviral activity/efficacy of RPV in the first part of 
either cohort of the trial are not satisfactory (as judged by the IDMC), the subjects included 
in this first part will be seen for a Withdrawal visit, treatment with RPV will be stopped, 
subjects will be switched to a locally available ARV regimen or local standard of care, and 
the cohort will be stopped (see also Section 6.1.1). Until the review by the IDMC has taken 
place, subjects will continue the intake of RPV and the background regimen. 
In case a cohort is stopped after the intensive pharmacokinetic sampling, a sample of the 
subjects participating in this cohort will be analyzed in real time for the determination of 
HIV-1 genotype (as long as the viral load is sufficiently high to allow HIV-1 genotyping), in 
order to assist in the selection of a new ARV regimen. When determination of HIV-1 
genotype on this sample is not possible due to a too low viral load, the new ARV regimen 
will be based on the screening HIV-1 genotyping result.
2.
The subject or parent/caregiver withdraws consent.
3.
The investigator considers, for safety reasons, it is in the best interest of the subject that 
he/she be withdrawn.
4.
Pregnancy has been determined.
5.
The subject demonstrates:
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%
Lack of virologic response, defined as confirmed decrease in plasma viral load 
<1.0 log10 at Week 12 from the baseline viral load (i.e., 2 consecutive measurements at 
least 2 weeks apart).
or
%
Resistance development to study treatment, defined as an increase in plasma viral load 
of at least 0.5 log10 HIV-1 RNA copies/mL above the nadir and the detection of at least 
one NNRTI or NRTI RAM that was not present at screening and/or baseline.
Confirmation may be obtained by performing an unscheduled visit.
Note: In order to assist in the selection of a new ARV regimen after withdrawal from either 
cohort of the trial, HIV-1 genotyping reports from the sample at the first visit after 
confirmed loss of response, as long as the viral load is sufficiently high to allow HIV-
1 genotyping, and from the Withdrawal visit will be provided to the investigator upon 
request.
Note:Subjects undergoing a controlled treatment interruption for tolerability reasons are 
exempted from the withdrawal criteria for virological failure up to 12 weeks after the 
end of the treatment interruption. 
6.
The subject develops tuberculosis during the trial. He/she will be withdrawn from the trial to 
allow appropriate tuberculosis therapy to be installed.
7.
The subject experiences a grade 3 or 4 cutaneous reaction/rash (see Section 6.5.1), allergic 
reaction (see Section 6.5.2), or neuropsychological event (see Section 6.5.7), according to 
the DAIDS grading table (see Addendum 2, Section 7.2).
8.
The subject experiences, after ARV medication interruption because of a confirmed grade 3 
increase in ALT or AST, a confirmed recurrence of grade 3 or 4 increase in ALT or AST 
after restarting ARV medication (see Section 6.5.3).
9.
The subject experiences a confirmed grade 3 increase in ALT or AST with a confirmed 
grade 3 or 4 increase in total bilirubin (see Section 6.5.3).
10. The subject experiences, after ARV medication interruption because of confirmed grade 3 or 
4 elevation in lipase, a confirmed recurrence of grade 3 or 4 elevation of lipase after 
restarting ARV medication (see Section 6.5.4).
11. The subject experiences, after ARV medication interruption because of confirmed grade 4 
elevation in pancreatic amylase, a confirmed recurrence of grade 4 elevation in pancreatic 
amylase after restarting ARV medication (see Section 6.5.4).
12. The subject experiences, after ARV medication interruption because of grade 3 nausea or 
diarrhea, a recurrence of grade 3 nausea or diarrhea, after restarting ARV medication, 
despite the use of antiemetics or appropriate medication, respectively (see Section 6.5.8 and 
6.5.9, respectively).
13. The subject, without pre-existing diabetes, has persistent grade 3 or 4 glucose elevations 
despite appropriate antidiabetic medication/treatment (see Section 6.5.11.1).
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14. The subject experiences a grade 4 AE or confirmed grade 4 laboratory abnormality,
according to DAIDS grading table (see the DAIDS grading table in Addendum 2, 
Section 7.2). Exceptions are, unless clinical assessment foresees an immediate health risk to 
the subject:
%
Glucose elevation of grade 4 in subjects with pre-existing diabetes (see 
Section 6.5.11.1)
%
Asymptomatic glucose or triglyceride elevations of grade 4 (see Sections 6.5.11.1
and 6.5.11.2)
%
Confirmed pancreatic amylase and lipase elevations of grade 4 (see criterion 9) (see 
Section 6.5.4)
%
A grade 4 AE (except cutaneous reaction/rash, allergic reaction, or neuropsychological 
event) that is considered not related or doubtfully related to RPV
Note: For grade 3 or 4 laboratory abnormalities, subjects should have a confirmatory 
measurement preferably within 48 hours after the laboratory results become available 
at the site. This management scheme is for confirmed laboratory abnormalities and 
not for isolated events.
15. The subject is diagnosed with acute hepatitis A, B, or C infection after baseline.
16. The subject experiences treatment-limiting clinical hepatitis (see Section 6.5.5.2), or 
pancreatitis (see Section 6.5.11.6), that is judged at least possibly related to RPV.
17. The subject experiences confirmed hyperlactatemia (>2x upper limit of laboratory normal 
range [ULN]) that is considered at least possibly related to RPV (see Section 6.5.11.4).
18. The subject experiences a confirmed QTc prolongation:
%
QTcF !500 ms or a confirmed increase in QTcF from screening of !60 ms (if the 
subject is >16 years old) (see the DAIDS grading table in Addendum 2, Section 7.2);
%
QTcF !480 ms (if the subject is &16 years old) (see the DAIDS grading table in 
Addendum 2, Section 7.2).
19. Cohort 1: If the subject does not achieve a cortisol value of ≥500 nmol/L (18,1 μg/dL) on at 
least one of the 3 time points of cortisol measurement during the ACTH stimulation test 
(i.e., morning cortisol, 30 or 60 minutes after ACTH stimulation) at a trial visit where 
ACTH stimulation testing is done (as a result of 2 consecutive cortisol values being 
<248 nmol/L [9 μg/dL] or as a result of an abnormal ACTH test at baseline or Week 48) and 
if this subject shows clinical signs and symptoms of adrenal insufficiency (see 
Section 6.5.5), which are evaluated in conjunction with other possible confounding factors 
(e.g., concomitant medication, AEs,…), withdrawal of the subject should be discussed with 
the Sponsor. Appropriate clinical follow-up, including further endocrine evaluations, should 
be installed24.
Note: An unscheduled ACTH test should only be performed if the morning cortisol level is 
<248 nmol (9 μg/dL) at 2 consecutive measurements or if the scheduled ACTH test 
at baseline or Week 48 is abnormal (i.e., all cortisol values [prior to and after ACTH 
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stimulation] are <500 nmol/L [18.1 μg/dL]). This ACTH test can be done at the next 
scheduled visit as long as there are no clinical signs or symptoms or laboratory 
abnormalities (other than cortisol) that could indicate hypoadrenalism. The procedure 
of testing and confirming abnormal cortisol and measuring the ACTH-stimulated 
cortisol value should not exceed 16 weeks.
Cohort 2: If, after the abnormal ACTH stimulation test (i.e., the cortisol value after ACTH 
stimulation is <500 nmol/L [18.1 μg/dL]) at Week 24 (if applicable), the repeat ACTH 
stimulation test results are abnormal and if the subject shows clinical signs and symptoms of 
adrenal insufficiency, withdrawal of the subject should be discussed with the Sponsor. Also, 
if a subject shows clinical signs and symptoms of adrenal insufficiency and the unscheduled 
ACTH stimulation test is abnormal, withdrawal of the subject should be discussed with the 
Sponsor. For more details see Section 6.4.9.2.3 and 6.5.5. Appropriate clinical follow-up, 
including further endocrine evaluations, should be installed24.
As of Amendment 10 the ACTH stimulation test is not scheduled on Day 1 and Week 24 
but needs to be performed in case of confirmed abnormally low cortisol (<248 nmol/L [9 
μg/dL]) or signs or symptoms of adrenal insufficiency (see Section 6.4.9.2.3.2). If the 
ACTH stimulation test is abnormal (i.e., the cortisol value after ACTH stimulation is <500 
nmol/L [18.1 μg/dL]), an  ACTH stimulation test must be performed at the next scheduled 
visit or at least within the next 8 weeks, with measurements of cortisol and 
17-hydroxyprogesterone (see Section 6.4.9.2.3.2).
20. The subject experiences a grade 3 or 4 decrease in serum magnesium (see Section 6.4.9.2.2).
21. In either Cohort of the trial, the total cumulative duration of treatment interruptions for 
suspected toxicities is more than 8 weeks (interruptions are counted cumulatively within a 
time frame of 48 weeks) or the duration of a single treatment interruption for a suspected 
toxicity is more than 4 weeks.
22. For toxicity management of subjects reporting specific toxicities, refer to Section 6.5.
When a subject withdraws before completing the trial, the reason for withdrawal is to be 
documented in the electronic Case Report Form (eCRF) and in the source document. Study drug 
assigned to the withdrawn subject may not be assigned to another subject.
All subjects prematurely discontinuing the trial (i.e., before Week 48), must be seen for a 
Withdrawal visit and a follow-up visit at 4 weeks post-treatment, except in the case of 
withdrawal of consent. All subjects who discontinue the trial and who have ongoing (S)AEs,
laboratory abnormalities, or viral load increase at the last on-treatment visit, will also be seen for 
a follow-up visit. Any retest of abnormal laboratory results or plasma viral load/resistance testing 
should be captured in this C213 study if the subjects roll over to the TMC278IFD3004 study. 
Additional unscheduled visits may be performed for safety/tolerability reasons and for 
confirmation of plasma viral load results. For these subjects, the date and reasons for 
discontinuation should be completed on the Trial Termination pages of the eCRF, on the date of 
discontinuation. Remaining data should be completed on the date of the last scheduled follow-up 
visit.
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If a subject is lost to follow-up, every reasonable effort must be made by the trial site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow-up must be documented.
6.3.
Treatment
6.3.1.
Identity of Investigational Product
The study drug, RPV, will be provided under the responsibility of the Sponsor.
RPV is formulated as an oral film-coated tablet 
 containing 
27.5 mg of RPV as the hydrochloric acid salt R314585, equivalent to 25 mg of RPV as the free 
base. The tablet contains lactose monohydrate.
For adjusted dosing, an age-appropriate formulation will be provided in the form of tablets
containing 2.5 mg of RPV as the free base. Tablets must be dispersed prior to use.
6.3.2.
Other Medication Administered in the Trial
The investigator-selected N(t)RTIs will be AZT, ABC, or TDF in combination with 3TC or FTC, 
whichever are approved and marketed or considered local standard of care for children aged !6 
to <18 years in a particular country. The background regimen will be given as the co-formulation 
or as the separate components according to local availability and use in the country (e.g., 
Combivir® or AZT/3TC, Epzicom®/Kivexa® or ABC/3TC, Truvada® or TDF/FTC).
N(t)RTIs will be prescribed by the investigator and reimbursed by the Sponsor during the first 48 
weeks of treatment. During the 4-year treatment extension period if applicable, it is not the 
Sponsor's intention to reimburse N(t)RTIs (Note: for countries where it is objectionable or 
impossible for N[t]RTIs to not be reimbursed during the extension period, the Sponsor will 
consider reimbursement of N[t]RTIs on a case by case basis).
6.3.3.
Dosage and Treatment Overview Per Subject
All subjects will receive RPV in combination with an investigator-selected background regimen 
consisting of 2 N(t)RTIs:
Screening period
(maximum 8 weeks)
No ARV treatment administration.
Initial Treatment period
(48 weeks)
Treatment extension, if 
applicable (192 weeks)
RPV 25 mg q.d., administered as 1 RPV tablet; or RPV adjusted dose 
q.d. administered as age-appropriate formulation other than the tablet 
formulation, if applicable; plus
An investigator-selected background regimen consisting of 2 N(t)RTIs.
Follow-up period
(4 weeks)
Investigator-selected regimen.
Subjects who started on the age-appropriate formulation, in case an adjusted RPV dose was 
required, will increase their RPV dose according to the final dosing schedule by weight/age
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bands as they grow. If subjects increase in weight and/or age such that they require a 25-mg RPV 
dose, they can change to the 25-mg tablet formulation.
The selected N(t)RTIs will be used in doses that are specified in the individual product labels or 
for which sufficient supporting data are available for use in this age group. Only branded 
versions of the N(t)RTIs, or generics with tentative US FDA approval and/or WHO prequalified 
drugs are to be prescribed by the investigator. If not available; generic drugs approved by the 
local Health Authorities or drugs procured by the UN international organizations (i.e., UNICEF) 
can be allowed upon approval by the sponsor. Applicable procedures and guidance based on 
package inserts should be respected.
For those subjects who do not tolerate the selected N(t)RTIs, switching to alternative N(t)RTIs 
(Brand name versions or generics with tentative US FDA approval and/or WHO prequalified 
drugs. If not available; generic drugs approved by the local Health Authorities or drugs procured 
by the UN international organizations can be allowed upon approval by the sponsor.) is allowed 
for some predefined toxicities (see Section 6.3.5 for details).
6.3.4.
Timing of Dosing
Pharmacokinetic evaluations have shown that RPV is better absorbed following oral 
administration with food. Therefore, RPV should always be administered with a meal.
Whenever possible, RPV should be taken around the same time each day (each dose should be 
separated by approximately 24 hours). The 25-mg tablets should be taken as a whole, and cannot 
be chewed, broken, or crushed.
Before the visit of the intensive pharmacokinetic sampling, subjects participating in the first part
of either cohort of the trial should take RPV with breakfast. This breakfast will be standardized 
in the morning of the intensive pharmacokinetic sampling. The standardized breakfast, provided 
at the site for Cohort 1, will consist of four slices of bread with ham or cheese, or cold cereal 
(1 serving size) and 2 pieces of toast, butter, jelly, and one or two cups of orange juice, coffee or 
tea, with milk and/or sugar, as desired. For subjects in Cohort 2 an age-appropriate meal will be 
provided. If more practical, subjects can switch the intake of RPV to another time of the day 
(always with a meal), after the visit of the intensive pharmacokinetic sampling.
Subjects in either cohort of the trial should take RPV with the main meal of the day throughout 
the trial.
The intake of the N(t)RTIs in the background regimen will be according to the locally applicable 
procedures and package inserts, but preferably at the same time as RPV for N(t)RTIs with a q.d. 
regimen. For N(t)RTIs with a b.i.d. regimen, one of the doses is preferably taken together with 
RPV; the other dose is taken according to the label.
Subjects will be instructed to start taking their ART, respecting the food requirements, on the day 
of the baseline visit (Day 1), or on the following day if for some reason it is not possible to start 
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RPV intake at baseline. The date of the first intake of RPV will be recorded on the eCRF. All 
ARVs (including the background N[t]RTIs) should be started on the same day, as instructed by 
the investigator.
In case a subject missed the intake of RPV, and this is noticed within 12 hours of the time of 
usual intake, the subject should take the missed dose as soon as possible, with food. The subject 
may then continue his/her usual dosing schedule. In case a subject missed the intake of RPV, and 
it is noticed more than 12 hours after the time of usual intake, the subject should not take that 
dose and simply resume the usual dosing schedule. The subject should not take a double dose to 
make up for a missed one.
For missed doses of N(t)RTIs in the background regimen, refer to the respective package inserts.
6.3.5.
Individually Selected Background Regimen
Once the screening resistance data (HIV-1 genotype) have become available, the investigator is 
to select a background regimen consisting of 2 N(t)RTIs, with a choice limited to AZT, ABC, or 
TDF in combination with 3TC or FTC, whichever is approved, marketed, or considered local 
standard of care for children aged !6 to <18 years in a particular country. The background 
regimen will be given as the co-formulation or as the separate components according to local 
availability and use in the country (e.g., Combivir® or AZT/3TC, Epzicom®/Kivexa® or 
ABC/3TC, Truvada® or TDF/FTC).
In clinical trials, hypersensitivity reactions have been reported in approximately 5% of adult and 
pediatric subjects receiving ABC18. Since the risk for developing such reactions has been linked 
to the presence of the HLA-B*5701 allele19, subjects without prior documented HLA-B*5701 
negative results in whom the investigator considers ABC/3TC as background regimen should test 
negative for HLA-B*5701 at screening to avoid hypersensitivity reactions (see Section 6.5.11.3
for details). If a subject is planned to be switched to an ABC-containing background regimen 
during the trial (due to intolerance, see paragraph below), an HLA-B*5701 test has to be 
performed to determine eligibility to start ABC treatment (unless prior documented specific 
negative results are available). 
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
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The symptoms of intolerance to the N(t)RTIs should be reported as AEs and should be clearly 
documented as leading to the change in N(t)RTIs. If the tolerability issue is related to only 1 of 
the 2 N(t)RTIs it is only needed to switch that one. At all times, the background regimen should 
consist of 2 N(t)RTIs (Brand name versions [or generics with tentative US FDA approval and/or 
WHO prequalified drugs]. If not available; generic drugs approved by the local Health 
Authorities or drugs procured by the UN international organizations can be allowed upon
approval by the sponsor.), and the subject’s HIV-1 genotype at screening should show sensitivity 
to the alternative N(t)RTIs.
Alternative N(t)RTIs will be used in doses that are specified in the individual product labels or 
for which sufficient supporting data are available. Only branded versions of the N(t)RTIs, or
generics with tentative US FDA approval and/or WHO prequalified drugs are to be prescribed by 
the investigator. If not available; generic drugs approved by the local Health Authorities or drugs
procured by the UN international organizations (i.e., UNICEF) can be allowed upon approval by 
the sponsor. Applicable procedures and treatment guidance based on package inserts of the 
selected N(t)RTIs should be respected. 
The use of PIs, NNRTIs (other than RPV), ENF, integrase inhibitors and investigational ARVs 
during the trial is not allowed.
In the second part of either cohort of the trial, temporary interruption of all ARVs during the 
treatment period will be allowed in the event of suspected toxicity, as long as the temporary 
interruption is associated with and can be linked to an AE or an SAE and this is not one of the 
cases listed in Section 6.2.5 or Section 6.5. The maximum allowed duration of a single treatment 
interruption for toxicity reasons will be 4 weeks and the maximum allowed cumulative duration 
of the treatment interruptions for toxicity reasons will be 8 weeks (interruptions are counted 
cumulatively within a time frame of 48 weeks). Subjects should maintain the regular visit 
schedule during the treatment interruptions. Additional unscheduled visits may be performed for 
safety or tolerability reasons. Re-initiation of therapy including the background regimen will 
only be allowed once the event has resolved or decreased to a grade 2 or below. A subject must 
be withdrawn from the trial in case the total cumulative duration of treatment interruptions for 
suspected toxicities is more than 8 weeks (interruptions are counted cumulatively within a time 
frame of 48 weeks) or the duration of a single treatment interruption for a suspected toxicity is 
more than 4 weeks (see Section 6.2.5). 
Special considerations may be warranted for the discontinuation of certain ARV agents:
%
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 resistance25,26. Some experts 
recommend stopping the NNRTI first, before the other ARVs (i.e., 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.
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Discontinuation of 3TC in subjects with hepatitis B co-infection: Severe acute exacerbations 
of hepatitis have been reported after discontinuation of 3TC in subjects with chronic 
hepatitis B infection who are using this agent in their ARV regimen. Discontinuation of this 
agent for any reason in subjects 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 subjects. Initiation of specific anti-hepatitis B therapy 
may be required (see Section 6.5.3).
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Subjects 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 (for more details, see 
Section 6.5.11.3).
6.3.6.
Packaging and Labeling
The study drug (RPV) will be packed under responsibility of the Sponsor.
Labels will be according to Good Manufacturing Practice (GMP)27 Annex 13 and local 
requirements.
No medication can be repacked or relabeled without prior approval from the Sponsor.
6.3.7.
Randomization
As this is a single arm trial, no randomization procedures are applicable.
6.3.8.
Blinding and Unblinding
As this is an open trial, blinding procedures are not applicable.
6.3.9.
Independent Data Monitoring Committee
An IDMC will be installed to monitor pharmacokinetic, efficacy, and safety/tolerability data
(including individual growth and pubertal development as part of physical examination), and to 
safeguard the subjects participating in this trial. The IDMC will include external experts only 
(two pediatric HIV specialists, a pediatric endocrinologist, a clinical pharmacologist, and a 
statistician). The main role of this IDMC is to evaluate accumulating pharmacokinetic, safety, 
and efficacy data, and to make recommendations regarding the continuation, modification, or 
termination of the trial.
Further details will be described in the IDMC charter.
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Cohort 1: Adolescents Aged ≥12 to <18 Years
Apart from the Part 1a analysis at Week 2 (which included 11 subjects) and the Part 1b analysis 
at Week 4 (which includes at least 10 [evaluable] subjects), and if applicable, the analysis which 
includes all Part 1 subjects treated for 4 weeks (+/-1 week) with the weight-adjusted dose (See 
Section 6.6), another analysis has been performed when all Part 1 subjects have reached Week 
12 (or discontinued earlier), a primary analysis when all subjects have reached Week 24 (or 
discontinued earlier), and an interim analysis when all subjects have reached Week 48 (or 
discontinued earlier). A final analysis will be performed when all subjects have completed the 
trial up to Week 240 (or discontinued earlier). The results of all analyses up to Week 48 will be 
shared and discussed with the IDMC. 
Note: At the time of protocol amendment 6 writing, all subjects had reached Week 48 or 
discontinued earlier and the Week 24 and 48 analyses have been conducted.
Cohort 2: Children Aged ≥6 to <12 Years
The IDMC will be the same committee as for study TMC278HTX2002 and data from both 
studies can be combined. The following analyses will be shared and discussed by the IDMC: 
%
The analysis when a mini-cohort of 5 subjects with a body weight of <25 kg has been 
treated at least 4 weeks with the original and/or adjusted RPV dose.
%
The analysis of overall intensive PK data when at least 12 subjects with a body weight of 
<25 kg, have been treated at least 4 weeks.
%
The analyses when all subjects have reached 12, 24, and 48 (primary analysis) weeks of 
treatment. 
6.3.10.
Drug Accountability
The investigator, his/her designee or the hospital pharmacist must maintain an adequate record of 
the receipt of RPV that are provided directly by the Sponsor. Dispensation, receipt, and return, or 
if applicable, destruction of RPV must be documented by using the appropriate forms. All these 
records must be up to date and available for inspection at any time. When subjects bring their 
medication to the site for counting, this is not considered as a return of supplies.
6.3.11.
Storage
All supplies of RPV must be stored at room temperature (15 to 30°C or 59 to 86°F) unless 
otherwise specified and in the original packaging. 
Should a deviation in storage conditions occur for RPV, the site should refrain from any further 
dispensation of the affected medication and provide the monitor immediately with the following 
information:
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Trial number
%
Reference and batch number(s)
%
Kit number
%
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 site will receive 
notification whether the affected medication can continue to be used.
RPV must be handled strictly in accordance with the protocol and the packaging labels and will 
be stored in a limited access area or in a locked cabinet under appropriate environmental 
conditions. Storage and dosing instructions and an expiration date will be supplied with RPV. 
Unused medication and used medication packs of RPV should be returned by the subject and 
should be kept at the site for drug accountability purposes.
Access to RPV should be restricted to designated trial personnel. 
The monitor will periodically check the supplies of RPV held by the investigator or pharmacist 
to ensure accountability and appropriate storage conditions of RPV. 
At the end of the trial, all unused supplies of RPV will be collected by the monitor and returned 
to the Sponsor or will be passed over for destruction at the site (conform local regulations), or by 
an authorized destruction unit after authorization by the Sponsor.
For storage conditions of the N(t)RTIs used in the background regimen, consult the respective 
package inserts.
In case of a discontinuation of ABC for a clinically suspected hypersensitivity reaction, the 
subject should be asked to return all unused supplies of the ABC-containing product for disposal 
to prevent an accidental rechallenge.
6.3.12.
Adherence
Drug adherence is critical to the success of any treatment regimen. Poor or even sub-optimal 
adherence to an ARV regimen can lead to incomplete suppression of viral replication and 
treatment failure, resulting in the emergence of drug-resistant virus.
There is evidence that adherence problems occur frequently in children. In a randomized 
treatment trial, caregivers reported that 30% of children missed one or more doses of ARV 
medications in the preceding 3 days22. These findings illustrate the difficulty of maintaining high 
levels of adherence and underscore the need to work in partnership with families to make 
adherence assessment, education, and support integral components of care. 
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To optimize adherence in this trial, counseling should be planned by the investigator/trial 
personnel with the subject, and their parent(s)/caregiver(s) at the screening visit to discuss the 
individual issues that may affect each adolescent’s or child's chances of successfully adhering to 
treatment. 
At the baseline visit, a second adherence counseling session should take place and clear 
instructions need to be given regarding the intake of the regimen.
A medication adherence check (e.g., review the adherence questionnaire or drug accountability) 
and additional medication adherence counseling should take place at every subsequent trial visit.
During the entire trial (i.e., in both parts of all cohorts of the trial), compliance to RPV and the 
background regimen will be assessed by the Study Adherence Questionnaire for Children and 
Teenagers or the Adherence Questionnaire for Caregivers (see Addenda 7 and 8) and for RPV as 
documented on the drug accountability form. Site staff, such as a counselor, should support the 
subject or their parent(s)/caregiver(s) to complete the questionnaire together, where the subject 
or their parent(s)/caregiver(s) provides the responses to the counselor. Once the subject or their 
parent(s)/caregiver(s) have completed the questionnaire, the site staff should review it for 
completeness. The questionnaire will be collected and the data will be entered into the trial 
database by the data manager.
In addition, from the start of RPV treatment until the day of intensive pharmacokinetic sampling,
subjects or their parent(s)/caregiver(s) should complete a diary documenting the intakes of RPV
from the start of treatment with RPV 25 mg q.d. (or adjusted dose if applicable) until the day of 
intensive pharmacokinetic sampling. For intakes of RPV and accompanying meals at home, 
subjects or their parent(s)/caregiver(s) should be asked to note the exact times of medication 
intakes and accompanying meals (stop times). The investigator or trial personnel should review 
the recorded data in the subject’s diary. The diaries should be provided to data management and 
entered into the trial database by the data manager. In Cohort 2, subjects or their 
parent(s)/caregiver(s) will also be contacted via telephone or email to assess adherence (to study 
drug and other ARVs) and to reinforce trial instructions every day for 3 days prior to the 
intensive pharmacokinetic visit. If the subject has missed a dose of RPV within 10 days prior to 
the intensive pharmacokinetic visit, the visit should be rescheduled so as to allow steady-state of 
RPV to be reached.
The subjects or their parent(s)/caregiver(s) will be requested to bring unused medication and 
empty packaging to the unit at each visit. If a subject’s medication intake is not according to the 
protocol, the investigator will take the necessary measures to ensure future adherence to the 
protocol.
6.3.13.
Prior and Concomitant Therapy
All medications (prescriptions or over-the-counter medications) continued at the start of the trial 
or started during the trial and different from RPV or the background N(t)RTIs, must be 
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documented in the Concomitant Therapy section of the eCRF. Reported information will include 
a description of the type of the drug, treatment period, dosing regimen, route of administration 
and its indication. Any change in dosage of the non-ARV medication must also be reported in 
the Concomitant Therapy eCRF section. Data on concomitant medication will be collected up to 
the last follow-up visit, even after withdrawal of a subject.
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
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 on the 
AE/HIV-related event section of the eCRF.
Heterosexually active boys and girls of childbearing potential must use birth control methods as 
outlined above in Section 6.2.4 and must be willing to continue practicing these birth control 
methods throughout the trial and for at least 30 days after the last intake of RPV. The use of oral, 
injectable, and implantable hormonal contraceptives is to be recorded in the Concomitant 
Therapy eCRF section.
6.3.13.1.
Disallowed Concomitant Medication
For coadministered comedication, the prescribing information should be consulted and reviewed 
carefully. The determinations listed in the respective contraindicated, warning, and precaution 
sections must be respected in order to prevent any potentially serious and/or life-threatening drug 
interactions.
%
The following medications are not allowed from 4 weeks prior to the baseline visit until 
the end of treatment/Withdrawal visit:
o
All investigational drugs
o
Drugs that can potentiate the activity of ARV drugs or have intrinsic ARV activity 
(but no indication for treatment of HIV infection): mycophenolic acid, 
hydroxyurea, hydroxychloroquine, foscarnet
o
All disallowed medication as mentioned in the package insert of AZT/3TC,
ABC/3TC, or TDF/FTC. For any alternative N(t)RTIs in the background regimen, 
the respective package inserts should be consulted for concomitant use with other 
medications and for contraindicated medications or medications that are not 
recommended for concomitant use
%
Subjects who discontinue their ketoconazole treatment at least 4 weeks prior to the baseline 
visit can be included in the trial.
%
Subjects in Cohort 1 who start ketoconazole treatment during the trial need to have an 
ACTH stimulation test performed 2 weeks into ketoconazole treatment. If all cortisol values 
(prior to and after ACTH stimulation) are <500 nmol/L (18.1 ∃g/dL), and this subject has 
clinical signs or symptoms of adrenal insufficiency (see Section 6.5.5), which are evaluated 
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in conjunction with other possible confounding factors (e.g., concomitant medication, 
AEs,…), the subject should be withdrawn from the trial after discussion with the Sponsor. In 
addition, for subjects in either cohort of the trial who start azole treatment during this trial, 
additional safety monitoring as specified below is required.
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During either cohort of the trial (i.e., until after the intensive pharmacokinetic sampling), all 
medications labeled as having a CYP3A4 inhibitory effect are disallowed. During the rest of 
the trial, all medications labeled as having a CYP3A4 inhibitory effect should be used with 
caution. Coadministration with these agents may result in increased RPV plasma 
concentrations. Alternative medications without CYP3A4 inhibitory effect should always be 
considered as the preferred option. In case there is no alternative, additional safety 
monitoring is required for subjects receiving CYP3A4 inhibitory comedications for >2 days. 
Additional safety monitoring is also required for subjects receiving medications associated 
with a risk of Torsade de Pointes for >2 days28. 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 intake of RPV. Also, a pharmacokinetic sample needs to be 
drawn within 10 minutes after this ECG. The time and date of sampling and last intake of 
RPV should be captured in the eCRF. If the subjects experience a QTcF !480 ms (subjects 
&16 years old) or !500 ms (subjects >16 years old) that is confirmed by another ECG 
(repeat ECG should be performed within 48 hours after the site has received the abnormal 
result), or a confirmed increase in QTcF from baseline of ! 60 ms (only applicable for 
subjects >16 years old), 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 subject should be 
withdrawn from the trial. Approximately 1 week after withdrawal, another ECG should be 
performed during an unscheduled visit to ensure normalization. Refer to Table 1 for specific 
examples of comedications that require additional safety monitoring. In addition, grapefruit 
and grapefruit juice are disallowed during the whole trial in either cohort, given its CYP3A4 
inhibitory effect. 
%
All medications labeled as having a potent CYP3A4 inducing effect are disallowed. 
Coadministration of RPV with these agents may result in decreased RPV plasma 
concentrations and potential loss of therapeutic effect. Refer to Table 1 for specific 
examples. 
%
The following medications are not allowed from baseline onwards: Any anti-HIV 
therapy other than RPV and the underlying N(t)RTIs.
%
No vaccines can be given within 4 weeks prior to baseline, and thereafter within 
4 weeks preceding a viral load measurement. Approved vaccines are allowed from 
Week 4 onwards as long as they are given after the sample for plasma viral load 
measurement is taken (if applicable). For an overview of childhood immunizations, see 
Addendum 10: Childhood Immunizations.
%
In Cohort 2, use of systemic chronic steroids within 30 days prior to baseline and during 
the trial is disallowed. Use of both chronic inhaled and intranasal steroids within 30 days 
prior to ACTH stimulation testing is disallowed. Use of either inhaled or intranasal steroids 
is allowed during the trial.
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H2 receptor antagonists (examples include, Pepcid, Zantac, and Axid) should only be 
administered either at least 12 hours before or at least 4 hours after RPV administration.
%
Antacids should only be administered either at least 2 hours before or at least 4 hours 
after RPV administration.
For details on drug interactions with RPV and specific disallowed medication, please consult 
Table 1.
For contraindicated medications or medications that are not recommended for concomitant use 
with the background regimen, the package inserts of the background N(t)RTIs should be 
consulted.
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Table 1: 
Established and Theoretical Drug Interactions With Commonly Used Comedications and RPV
Drug Class
Interaction Effect
Clinical Comment
● Antiarrhythmics
- Bepridil
Data on interaction with RPV
currently not available.
Disallowed. Potential for cardiac 
arrhythmias.
- Flecainide, propafenone, 
systemic lidocaine, mexilitine
Data on interaction with RPV
currently not available. 
Use with caution. Plasma 
concentrations of these 
medications may be affected 
when coadministered with RPV, 
and potential for cardiac 
arrhythmias. Additional safety 
monitoring is required if taken for 
>2 daysa.
- Quinidine, disopyramide, 
amiodarone
Data on interaction with RPV
currently not available.
Use with caution.  Plasma 
concentrations of these 
medications may be affected 
when coadministered with RPV, 
and potential for cardiac 
arrhythmias. Additional safety 
monitoring is required if taken for 
>2 daysa.
- Dofetilide, ibutilide, 
procainamide, sotalol
Data on interaction with RPV
currently not available.
Use with caution. Potential for 
cardiac arrhythmias. Additional 
safety monitoring is required if 
taken for >2 daysa
.
● Anticoagulants
- Warfarin, phenprocoumon, and 
acenocoumarol
Data on interaction with RPV
currently not available.
Use with caution. Plasma 
concentrations of these 
medications may be affected 
when coadministered with RPV.
Careful monitoring of the 
coagulation parameters is 
warranted.
●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.
● Antihyperlipidemic agents
- Probucol
Data on interaction with RPV
currently not available.
Use with caution. Potential for 
cardiac arrhythmias. Additional 
safety monitoring is required if 
taken for >2 daysa.
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Table 1: 
Established and Theoretical Drug Interactions With Commonly Used Comedications and RPV, 
Cont’d
Drug Class
Interaction Effect
Clinical Comment
● Calcium channel blockers
- Felodipine, nifedipine, 
nicardipine, amlodipine
Data on interaction with RPV
currently not available.
Use with caution. Plasma 
concentration of these 
medications may be reduced 
when coadministered with RPV. 
- Verapamil, diltiazem
Data on interaction with RPV
currently not available.
Disallowed prior to intensive 
PK. If no intensive PK, use with 
caution Plasma concentrations of 
RPV may be increased and/or 
plasma concentrations of these 
medications may be decreased 
when coadministered. Additional 
safety monitoring is required if 
taken for >2 daysa.
● Azole antifungal agents
- Ketoconazole, itraconazole, 
voriconazole
Note: fluconazole is preferred 
option
Ketoconazole increased the 
exposure to RPV by 50% for 
AUC and by 30% for Cmax.
Disallowed prior to intensive 
PK. If no intensive PK, use with 
caution. Plasma concentrations of 
RPV may be increased by 
coadministration of these 
medications. Additional safety 
monitoring is requireda when 
ketoconazole, itraconazole or 
voriconazole are coadministered 
with RPV for >2 days. 
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 requireda for 
fluconazole coadministration 
when used in doses of 
400-800 mg/day for >2 days. 
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Table 1: 
Established and Theoretical Drug Interactions With Commonly Used Comedications and RPV, 
Cont’d
Drug Class
Interaction Effect
Clinical Comment
● Antibiotics
- Clarithromycin, erythromycin, 
roxithromycin
Note: azithromycin is preferred 
option 
Data on interaction with RPV
currently not available.
Disallowed prior to intensive PK. If 
no intensive PK, use with caution. 
Plasma concentrations of RPV may 
be increased and/or plasma 
concentrations of these medications 
may be reduced when coadministered. 
Additional safety monitoring is 
required if taken for >2 daysa
. 
Clarithromycin and erythromycin 
have been associated with a risk for 
cardiac arrhythmias. 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.
- Rifabutin, rifampin, rifapentine
Rifabutin reduced exposure 
(AUC) to RPV by 46%. Rifampin 
reduced exposure (AUC) to RPV
by 80%.
No data available on interaction 
with rifapentine.
Disallowed. Coadministration may 
result in reduced RPV plasma 
concentrations an in loss of 
therapeutic effect.
- Telithromycin, troleandomycin
Data on interaction with RPV
currently not available.
Disallowed. Coadministration may 
result in increased RPV plasma 
concentrations.
- Sparfloxacin, pentamidine
Data on interaction with RPV
currently not available.
Use with caution.  Potential for 
cardiac arrythmias. Additional safety 
monitoring is required if taken for >2 
daysa.
● Antimalaria agents
- Chloroquine, halofantrine
Data on interaction with RPV
currently not available.
Use with caution.  Potential for 
cardiac arrythmias. Additional safety 
monitoring is required if taken for >2 
daysa.
● Glucocorticoids 
- Dexamethasone 
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.
*Note: In Cohort 2 use of both
chronic inhaled and intranasal 
dexamethasone within 30 days prior 
to ACTH stimulation testing is
disallowed. Occasional use of either
inhaled or intranasal steroids is
allowed.
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Table 1: 
Established and Theoretical Drug Interactions With Commonly Used Comedications and RPV, 
Cont’d
Drug Class
Interaction Effect
Clinical Comment
- Other glucocorticoids
Data on interaction with RPV
currently not available.
Disallowed. (only topical and 
inhalation products allowed*). 
Could suppress adrenal gland 
function.
*Note: In Cohort 2 use of both
chronic inhaled and intranasal 
steroids within 30 days prior to  
ACTH stimulation testing is
disallowed. 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
- e.g., 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 intake of 
RPV.
- Antacids (e.g. 
aluminum/magnesium hydroxide)
Data on interaction with RPV
currently not available. 
Use with caution. Antacids 
should be taken at least 2 hours 
before or 4 hours after intake of 
RPV.
● Immunomodulators 
- Cyclosporine, rapamycin, 
tacrolimus, sirolimus
Data on interaction with RPV
currently not available.
Use with caution. Plasma 
concentrations of these 
medications may be affected when 
coadministered with RPV.
- Thalidomide
Data on interaction with RPV
currently not available.
Use with caution. Thalidomide is 
not metabolized by CYPs and a 
pharmacokinetic interaction is not 
likely.
● Arsenic trioxide
Data on interaction with RPV
currently not available.
Use with caution. Potential for 
cardiac arrythmias. Additional 
safety monitoring is required if 
taken for >2 daysa.
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Table 1: 
Established and Theoretical Drug Interactions With Commonly Used Comedications and RPV, 
Cont’d
Drug Class
Interaction Effect
Clinical Comment
● 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 TMC278. No dose 
adjustments are required. Monitor 
for signs and symptoms of 
methadone withdrawal; some 
subjects may need an increase in 
the methadone dose.
Methadone has been associated 
with a risk for cardiac arrythmias. 
Additional safety monitoring is 
required if taken for >2 daysa.
● Levomethadyl
Data on interaction with RPV
currently not available.
Use with caution. Potential for 
cardiac arrythmias. Additional 
safety monitoring is required if 
taken for >2 daysa.
● Antihistamines
- Astemizole, terfenadine 
Data on interaction with RPV
currently not available.
Disallowed. Severe cardiac 
arrhythmias have been reported 
with astemizole and terfenadine.
● 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.
● Gastroprokinetic
- Cisapride
Data on interaction with RPV
currently not available.
Disallowed. Severe cardiac 
arrythmias have been reported 
with cisapride.
● Antiemetics
- Aprepitant
Data on interaction with RPV
currently not available.
Disallowed prior to intensive 
PK. If no intensive PK, use with 
caution. Coadministration may 
result in increased plasma 
concentrations of RPV and/or 
decreased plasma concentrations 
of aprepitant. Additional safety 
monitoring is required if taken for 
>2 daysa.
- Domperidone
Data on interaction with RPV
currently not available.
Use with caution.  Potential for 
cardiac arrythmias. Additional 
safety monitoring is required if 
taken for >2 daysa.
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Table 1: 
Established and Theoretical Drug Interactions With Commonly Used Comedications and RPV, 
Cont’d
Drug Class
Interaction Effect
Clinical Comment
● Antipsychotics, antidyskinetics
- Pimozide
Data on interaction with RPV
currently not available.
Disallowed. Severe cardiac 
arrythmias have been reported 
with pimozide.
- Chlorpromazine, haloperidol, 
mesoridazine, thioridazine, 
droperidol
Data on interaction with RPV
currently not available.
Use with caution.  Potential for 
cardiac arrythmias. Additional 
safety monitoring is required if 
taken for >2 daysa.
● 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.
● Ergot derivatives
- dihydroergotamine, ergonovine, 
ergometrine, ergotamine, 
methylergonovine
Data on interaction with RPV
currently not available.
Use with caution. Plasma 
concentrations of these 
medications may be affected when 
coadministered with RPV.
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 the intake of RPV. Also, a 
pharmacokinetic sample needs to be drawn within 10 minutes after this ECG. The date and time of 
sampling and last intake of RPV prior to pharmacokinetic sampling should be recorded on the eCRF. If 
the subjects experience a QTcF !480 ms (subjects &16 years old) or ! 500 ms (subjects >16 years old) 
that is confirmed by another ECG (repeat ECG should be performed within 48 hours after the site has 
received the abnormal result), or a confirmed increase in QTcF from baseline of !60 ms (only applicable 
for subjects >16 years old), 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 subject should be withdrawn from the trial. 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.
6.3.13.2.
Disallowed Antiretroviral Medication
The following ARVs are not allowed from baseline until the end of treatment/Withdrawal visit:
%
Any investigational ARVs (except for AZT/3TC and/or ABC/3TC and/or TDF/FTC, if not 
registered in the participating country)
%
Any PIs
%
Any fusion inhibitor
%
Any NNRTIs, except for RPV
%
N(t)RTIs other than AZT, 3TC, ABC, FTC and TDF (unless after switch due to predefined 
toxicities)
%
Any CCR5 inhibitors
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%
Any integrase inhibitor
%
Any generic drugs not tentatively approved by US FDA, not prequalified by world health 
organizations, not approved by local health authorities or not procured by UN international 
organizations (eg, UNICEF).
6.4.
Assessments
6.4.1.
Timing of Assessments
The exact timing of the assessments is presented in the flowchart (see Section 2).
During the screening period it is allowed to assess the viral load and CD4+ cell count before 
continuing with the other screening assessments. In such case, after obtaining informed consent, 
samples will be taken for determination of plasma viral load and CD4+ cell count. If plasma viral 
load results meet the inclusion criteria and the investigator considers initiation of ART 
appropriate (taking into account current treatment guidelines, including CD4+ cell count and the 
subject’s clinical situation), the subject will return to the site within 2 weeks after availability of 
the results, for the remainder of the screening procedures. If plasma viral load results do not meet 
the inclusion criteria, the subject will be considered a screen failure. This way unnecessary blood 
draws and assessments may be avoided in a lot of subjects since screening viral load being 
outside the limits for inclusion is the major reason for screen failure (i.e., 33% of all screen 
failures in Part 1a). Within 4 weeks after the screening visit, the site should have received all 
data to determine the subject’s eligibility.
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 assessment, if these were assessed 
separately before continuing with the other screening assessments), but in case of unforeseeable 
circumstances the screening period can be prolonged by 2 weeks maximum, resulting in a 
maximum screening period duration of 8 weeks.
RPV will be initiated at baseline (Day 1). Thereafter, subjects will return for visits at Week 1, 
Week 2, Week 4, then every 4 weeks until Week 16, every 8 weeks until Week 48, and if 
applicable every 3 months until Week 240.
Unscheduled visits should be planned:
%
To perform a confirmatory plasma viral load determination during the treatment period in 
the event of suspected virologic failure (see Section 6.2.5). For Cohort 2, during this 
unscheduled visit, also samples for pharmacokinetics will be taken.
Note:
The minimal time between 2 consecutive plasma viral load determination
measurements must be at least 2 weeks.
%
To repeat PK samples if needed (see Section 6.4.8).
%
To assess, confirm, and follow-up on clinically relevant AEs or laboratory abnormalities.
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Note:
In case a grade 3 or grade 4 laboratory abnormality occurs, a confirmatory retest 
should be performed by a local or central laboratory, preferably within 48 hours after receipt 
of the abnormal result by the site.
%
To assess and ensure appropriate follow-up on cutaneous reaction/rashes (see Section 6.5.1).
%
To assess and ensure appropriate follow-up on clinically suspected hypersensitivity 
reactions (see Section 6.5.11.3).
%
To perform additional safety monitoring in case certain concomitant medications are started 
(see Section 6.3.13.1).
%
To assess and ensure appropriate follow-up on abnormal basal or ACTH stimulated cortisol 
values and to perform an unscheduled ACTH stimulation test in case of clinical signs and 
symptoms or laboratory abnormalities (other than cortisol) indicative of adrenal 
insufficiency (see Section 6.4.9.2.3 and 6.5.5).
%
To assess, confirm, and follow-up on abnormal QTc values on ECG (see Section 6.2.5).
%
To switch subjects to an adjusted dose of RPV (dose switch visit), and to re-evaluate this 
dose (post switch visit[s]). The dose switch visit has to be performed as soon as possible 
after communication of the recommended adjusted dose.
Findings during these unscheduled visits need to be reported on designated sections of the eCRF.
Blood samples for biochemistry testing are to be taken under fasted conditions. See flowchart in 
Section 2 for the exact timing of these assessments.
6.4.2.
Time Windows
All study visits should be scheduled relative to the baseline visit date (eg, Day 1 + 7 days for 
Week 1). The following time windows are recommended:
%
For the Week 1 visit: ∋2 days
%
For the Week 2 visit (including Week 2 post switch): ∋2 days (Cohort 1); between Day 
14 and 18 (Cohort 2) 
%
For the Week 4 (including Week 4 post switch), Week 8, Week 12, Week 16, Week 24, 
Week 32, Week 40, and Week 48 visits, and the post Week 48 treatment extension
visits, if applicable: ∋1 week
%
Follow-up visit: 4 weeks ∋4 days after the Final/Withdrawal visit
If applicable, if the dose switch visit is done within 1 week of the next scheduled visit as 
indicated in the flowchart, this next planned visit can be cancelled but assessments of that visit 
will have to be performed at the dose switch visit. If the post switch visit is done within 1 week 
of the next planned visit as indicated in the flowchart, this next planned visit can be deleted but 
assessments of that visit that are not planned in the post switch visit will have to be added. 
The timing of visits from Week 1 to Week 48 (or to Week 240 if applicable) should be based on 
the start date of RPV intake (which should coincide with the date of the baseline visit or the 
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following day if for some reason it is not possible to start intake of RPV at baseline). Some 
flexibility in the planning of the visits is allowed (as indicated above); however, the initial 
treatment duration should be 48 weeks, and the extension period, if applicable, 192 weeks. If the 
subject cannot return within these time windows, it might be necessary to dispense extra ARV 
medication to avoid a situation where the subject runs out of medication.
6.4.3.
Handling of Biological Samples
All samples will be collected and processed according to the central laboratory manual. Handling 
and shipment of the samples and the materials will also be described in the manual. The actual 
dates and times of sample collection must be recorded in the eCRF or laboratory requisition 
form.
The sample tubes must be labeled as described in the laboratory manual.
Samples that remain after protocol-specific assessments have been performed, may be used for 
further exploratory work. This exploratory work can include pharmacokinetics, metabolites, 
proteins, plasma protein binding, biochemistry, virus characterization, characterization of 
hepatitis C virus (HCV) (if applicable), and characterization of viral drug resistance, and 
immunologic parameters. 
Apart from HLA-B*5701 testing in subjects without prior documented HLA-B*5701 negative 
results in whom the investigator considers ABC/3TC as the background regimen, no genomic 
testing will be done. All genetic samples will be destroyed after analysis.
6.4.4.
Initial Subject and Disease Characteristics
At the screening visit, after signing the ICF, the overall eligibility of the subject to participate in 
the trial will be assessed. The subject's demographics, smoking habits, clinically relevant medical 
and surgical history, or pre-existing conditions (active or non active) that may be expected to 
impact the subject’s clinical outcome during participation in this trial (e.g., diabetes, 
dyslipidemia, hypertension, liver disease, neoplasms, opportunistic infections, rash, allergic 
reactions, etc.) and all concomitant medication will be recorded. A comprehensive physical 
examination including all body parts (and specifically assessment of hyperpigmentation and 
hirsutism) will be performed and urine and blood samples will be collected for urinalysis, 
biochemistry, hematology, immunology, viral pheno-and genotype, and plasma viral load 
determinations. Vital signs and ECG will be recorded.
Since ABC has been associated with severe hypersensitivity reactions, and the risk for 
developing such reactions has been linked to the presence of the HLA-B*5701 allele, subjects 
without prior documented HLA-B*5701 negative results in whom the investigator considers 
using ABC as the background regimen should test negative for HLA-B*5701 at screening (see 
Section 6.5.11.3 for details).
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A serum pregnancy test will be performed at screening, and a urine pregnancy test will be 
performed at other visits for girls who have had their first menses only, i.e., girls of childbearing 
potential. 
At screening, it will be assessed whether girls already have had their first menses.
Height and weight will be recorded at the visits specified in the flowchart (see Section 2).
In addition, at screening, contraceptive and adherence counseling is done.
6.4.5.
Antiviral Activity
At the time points specified in the flowchart (see Section 2), samples for the determination of 
efficacy will be taken. 
Plasma viral load levels will be determined using a Roche HIV-1 viral load assay. Specimen 
preparation procedures are defined in the laboratory manual. Selected samples can also be tested 
using a 5-copy viral load test, for the purpose of exploratory analyses.
Changes in viral load, including rebound and incomplete virologic suppression, will be part of 
the efficacy analysis and should not be reported as AE/SAEs.
6.4.6.
Immunologic Change
At the time points specified in the flowchart (see Section 2), samples for the determination of the 
CD4+ cells (absolute and %) will be taken. 
Changes in CD4+ cells, either increases or decreases, will be part of the efficacy analysis and 
should not be reported as AE/SAEs.
6.4.7.
Resistance Determinations
At time points specified in the flowchart (see Section 2), samples for the determination of viral 
phenotype and genotype will be taken. Viral phenotypic and genotypic determinations will be 
performed centrally by a qualified provider. 
Note: An HIV-1 phenotyping and/or genotyping report will only be generated when the viral 
load is sufficiently high.
Samples collected at screening will be tested in real time for the determination of the HIV-1
genotype. Samples collected at baseline, at suspected virologic failure, at the Week 48 visit, and 
at the Final/Withdrawal visit will be tested for the determination of the HIV-1 genotype and 
phenotype, as long as the viral load is sufficiently high to allow HIV-1 genotyping and 
phenotyping. 
Samples collected at other intervals may be selected for determination of the HIV-1 genotype
and/or phenotype by the Protocol Virologist based on plasma viral load.
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In case of discontinuation, the subject’s new ARV regimen will be based on the results of the 
Withdrawal HIV-1 genotype. In case the trial is stopped after intensive pharmacokinetic 
sampling in either cohort, a sample of the subjects participating in this part will be analyzed in 
real time for the determination of HIV-1 genotype (as long as the viral load is sufficiently high to 
allow HIV-1 genotyping), in order to assist in the selection of a new ARV regimen. When HIV-1 
genotype determination on this sample is not possible, the new ARV regimen can be based on 
the screening HIV-1 genotyping result.
The results of the viral phenotypes and genotypes will be evaluated by the Protocol Virologist. 
Relevant changes in the viral phenotype and genotype, detected by the phenotyping and HIV-1
genotyping will be evaluated. These changes in viral phenotype and genotype will not be 
regarded as AEs.
In addition, a PBMC sample will be taken at screening and Week 48 to retrospectively 
characterize archived viral resistance. No human DNA analysis will be performed on these 
samples. Deep sequencing may be performed, considering the amounts of plasma available after 
standard resistance testing.
6.4.8.
Pharmacokinetic Evaluations
6.4.8.1.
Sample Collection and Handling
At the time points specified in the flowchart (see Section 2), blood samples will be taken to 
determine the RPV plasma concentrations. Samples for bioanalysis should be protected from 
light during sample processing and storage.
Use of local anesthetics creams is allowed to minimize the pain during the blood draw. Use of 
indwelling catheters is encouraged for the intensive pharmacokinetic sampling visit in order to 
minimize discomfort and distress due to repeated venipunctures for blood sampling.
Cohort 1: Adolescents Aged ≥12 to <18 Years:
Only in the subjects included in the first part of Cohort 1 (Part 1), intensive pharmacokinetic 
sampling was to be performed during a 24-hour dosing interval at the Week 2 visit (for Part 1a 
subjects) and at the Week 4 visit (for Part 1b subjects) to evaluate the steady-state 
pharmacokinetic parameters of RPV (see Section 2.1.2 for details). Plasma samples for RPV of 
the subjects in the first part of Cohort 1 (Part 1) were to be divided over 2 tubes. One sample was 
to be used for bioanalysis of RPV (main sample) and one sample is the back-up sample. The 
main sample had to contain at least 500 ∃L of plasma.
In all subjects, sparse pharmacokinetic sampling
will be performed for population 
pharmacokinetic analysis. A pharmacokinetic sample will be taken at all time points indicated in 
the flowchart (see Section 2).
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When additional safety monitoring ECGs are performed, one pharmacokinetic sample should be 
taken within 10 minutes after each of these ECGs in order to assess the impact of the 
comedication on the plasma levels of RPV and to evaluate the RPV concentration-safety 
relationship.
Exact date and time of blood sampling and last intake of RPV will be recorded in the eCRF.
Cohort 2: Children Aged ≥6 to <12 Years
For subjects with a body weight of <25 kg, intensive pharmacokinetic sampling will be 
performed during a 24-hour dosing interval at the Week 2 visit (between Day 14-18) and at the 
2-weeks Post Switch visit, if applicable to evaluate the steady-state pharmacokinetic parameters 
of RPV (see Section 2.1.2 for details).
Note: Subject or their parent(s)/caregiver(s) contact via telephone or email should take place to 
assess adherence (to study drug and other ARVs) and to reinforce trial instructions every 
day for 3 days prior to the intensive pharmacokinetic visit. If the subject has missed a 
dose of RPV within 10 days prior to the intensive pharmacokinetic visit, the visit should 
be rescheduled so as to allow steady-state of RPV to be reached.
In all subjects sparse pharmacokinetic sampling
will be performed for population 
pharmacokinetic analysis. For more details about the sampling times, see the flowchart 
(Section 2).
When additional safety monitoring ECGs are performed, a pharmacokinetic sample should be 
taken as specified in Section 6.3.13.1.
For all pharmacokinetic samples exact date and time of blood sampling and last intake of RPV
prior to this sample will be recorded in the eCRF.
6.4.8.2.
Bioanalysis
Plasma concentrations of RPV will be analyzed under the responsibility of the Sponsor, using a 
validated analytical method.
Plasma concentrations of the N(t)RTIs can be determined (using the RPV plasma sample) by a 
validated analytical method, if the Sponsor decides to perform this analysis.
The bioanalysis of RPV can be performed in batches. 
Results of the bioanalysis of RPV and other ARVs, as applicable, will not be made available to 
the investigator on real time basis, but will be included in the final study report.
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6.4.9.
Safety Evaluations
6.4.9.1.
Adverse Events/HIV-Related Events
At each visit, the subject will be asked about any untoward medical occurrences and these will 
be recorded as AEs from the signing of ICF onwards. HIV-related events and the occurrence of 
AIDS-defining illnesses will also be recorded. For detailed definitions and reporting procedures 
of AEs see AEs/HIV-Related Events (Part II, Section 1).
6.4.9.2.
Clinical Laboratory Tests
At the time points specified in the flowchart (see Section 2), samples for laboratory safety testing 
will be taken. The laboratory reports generated by the central laboratory will need to be 
interpreted for clinical significance, signed and dated by the investigator after which they need to 
be filed in the subject’s medical record. In case clinically relevant changes are observed from the 
signing of ICF onwards, these should be reported as AEs in the AE/HIV-Related Event section of 
the eCRF.
The central laboratory will send the investigator an alert form whenever a grade 3 or 4 laboratory 
abnormality (see Addendum 2: DAIDS Table) has been observed.
In case a grade 3 or grade 4 laboratory abnormality occurs, a confirmatory retest should 
be performed by a local or central laboratory, preferably within 48 hours after receipt of 
the abnormal result by the site.
The following laboratory abnormalities do not warrant mandatory confirmation within 48 hours:
%
asymptomatic grade 3 or 4 glucose elevations in subjects with pre-existing diabetes;
%
asymptomatic grade 3 or 4 glucose or triglyceride elevations, or asymptomatic grade 3 
cholesterol elevations;
%
asymptomatic grade 3 pancreatic amylase elevations in subjects with no history or 
concomitant disease of pancreatitis.
6.4.9.2.1.
Hematology
At the time points specified in the flowchart (see Section 2), blood samples for these tests will be 
drawn.
Hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin 
concentration (MCHC), mean corpuscular hemoglobin (MCH), red blood cell (RBC) count, 
white blood cell (WBC) count, WBC differential count (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils), and platelet count will be assessed.
6.4.9.2.2.
Biochemistry 
Subjects must fast overnight prior to having blood samples drawn for these tests (see 
flowchart, Section 2). Samples that were taken under non-fasted conditions and that reveal 
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values that are outside the normal ranges and deemed clinically relevant for parameters that are 
affected by food intake should be retested after the subject has fasted overnight 
Total protein, alkaline phosphatase (ALP), AST, ALT, total bilirubin, direct bilirubin, indirect 
bilirubin, urea, uric acid, creatinine, electrolytes (sodium, potassium, phosphate, chloride, 
calcium, calcium corrected for albumin, magnesium), human serum albumin, triglycerides, 
pancreatic amylase, lipase, total cholesterol, high-density lipoprotein (HDL), low density 
lipoprotein (LDL), glucose, and insulin will be assessed.
The central laboratory will calculate the estimated glomerular filtration rate (eGFR) according to 
the following formula29:
eGFR
=
k * L (cm)
Plasma creatinine (Pcr) (mg/dL)
k = 0.55 in adolescent girls aged 13-21 years, and 0.70 in adolescent boys aged 13-21 years and 
0.55 in children aged 2-12 years.
If the subject is >21 years of age, the Modification of Diet in Renal Disease (MDRD) eGFR 
equation will be used.58
Lactate will be assessed in case of suspicion of lactic acidosis syndrome (see Section 6.5.11.4) 
and creatine phosphokinase will be assessed in case of suspicion of rhabdomyolysis. These 
assessments will be done at the local laboratory. 
For girls of childbearing potential, the samples for biochemistry taken at screening will include a 
serum pregnancy test.
Additional tests may be performed at the central laboratory, if needed. However, additional 
testing requires approval of the Sponsor.
For more details, please see the central laboratory manual.
6.4.9.2.3.
Endocrine Assessments
6.4.9.2.3.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years
At time points specified in the flowchart (see Section 2) an ACTH stimulation test will be done 
for all subjects including measurements of cortisol, 17-hydroxyprogesterone, aldosterone. After a 
sample for the determination of these endocrine parameters has been drawn (T0), 250 μg of 
tetracosactide or cosyntropin is injected intravenously over 2 minutes or intramuscularly and 
additional blood samples collected 30 and 60 minutes after injection for the determination of 
cortisol, 17-hydroxyprogesterone and aldosterone. If the ACTH stimulation test is abnormal (i.e., 
all cortisol values [prior to and after ACTH stimulation] are <500 nmol/L [18.1 ∃g/dL]), a retest 
needs to be performed at the next scheduled visit or at least within the next 8 weeks.
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Also as specified in the flowchart (see Section 2), at certain time points, assessment of 
17-hydroxyprogesterone, aldosterone, FSH, LH, progesterone, androstenedione, testosterone, 
DHEAS will be performed in conjunction with the basal cortisol assessment, and no ACTH 
stimulation test will be performed.
A sample for the determination of basal cortisol will be drawn in the morning of the time points 
specified in the flowchart (see Section 2), between 7h30 and 9h30. If at any of these time points 
basal cortisol value is <248 nmol/L (9 μg/dL), a retest will be done at the subsequent visit or at 
least within the next 8 weeks.
If basal cortisol is <248 nmol/L (9 μg/dL) at two consecutive scheduled visits, an ACTH 
stimulation test, as described above, will be done at the next scheduled visit or at least within the 
next 8 weeks with measurements of cortisol and 17-hydroxyprogesterone.
In case of clinical signs or symptoms or laboratory abnormalities (other than cortisol) indicative 
of adrenal insufficiency (see Section 6.5.5), the ACTH stimulation test should be done as soon as 
possible during an unscheduled visit.
In case of withdrawal due to pregnancy, no ACTH stimulation test needs to be performed, but 
basal assessments need to be performed.
For more details, please see the central laboratory manual.
6.4.9.2.3.2.
Cohort 2: Children Aged ≥6 to <12 Years
At time points specified in the flowchart (see Section 2) an ACTH stimulation test will be 
performed for all subjects including measurements of cortisol and 17-hydroxyprogesterone.
After a sample for the determination of these endocrine parameters has been drawn (T0), 250 μg 
of tetracosactide or cosyntropin is injected intravenously over 2 minutes or intramuscularly and 
an additional blood sample is collected 60 minutes (T60) after injection for the determination of 
cortisol and 17-hydroxyprogesterone. 
Note: For subjects with laboratory findings suggestive of congenital adrenal hyperplasia at 
baseline, the Sponsor should be contacted for management guidance.
As specified in the flowchart (see Section 2), at certain time points, assessment of FSH, LH, 
androstenedione, testosterone, and DHEAS will be performed, in conjunction with basal cortisol
and 17-hydroxyprogesterone.
As of Amendment 10, an ACTH stimulation test is no longer required at baseline and Week 24. 
Only in case basal cortisol is <248 nmol/L (9 μg/dL) at two consecutive visits, a reflex ACTH 
stimulation test, must be performed at the next scheduled visit or at least within the next 8 weeks, 
with measurements of cortisol and 17-hydroxyprogesterone.
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If the ACTH stimulation test is abnormal (i.e., 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. 
o
If the repeat ACTH stimulation test results are normal, the subject should 
continue RPV treatment.
o
If the repeat ACTH stimulation test results are abnormal, but the subject is 
asymptomatic the Sponsor will be notified.
o
If the repeat ACTH stimulation test results are abnormal, and the subject has 
symptoms consistent with adrenal insufficiency (see Section 6.5.5) withdrawal of 
the subject should be discussed with the Sponsor.
In case of clinical signs or symptoms or laboratory abnormalities (other than cortisol) indicative
of adrenal insufficiency (see Section 6.5.5), an ACTH stimulation test should be done as soon as 
possible during an unscheduled visit. If the ACTH stimulation test is abnormal (i.e., the cortisol 
value after ACTH stimulation is <500 nmol/L [18.1 μg/dL]), withdrawal of the subject should be 
discussed with the Sponsor.
In case of withdrawal due to pregnancy, no ACTH stimulation test needs to be performed, but 
basal assessments need to be performed.
For more details, please see the central laboratory manual.
6.4.9.2.4.
Urinalysis
Urinalysis by dipstick for protein, RBC and glucose will be performed at specific time points 
(see flowchart, Section 2). If abnormal, a microscopic examination for WBC, RBC, and casts 
will be performed by the central laboratory.
Note: In the microscopic examination, observations other than the presence of WBC, RBC, and 
casts may also be reported by the laboratory.
At all time points throughout the trial (except at screening, Week 1, and Week 2), a urine 
pregnancy test will be performed for all girls of childbearing potential (see flowchart, Section 2). 
At baseline, a urine pregnancy test will be done prior to the first intake of RPV.
6.4.9.2.5.
Hepatitis Serology/Viremia
A sample will be taken for hepatitis A, B, and C testing at baseline. Whenever clinically relevant, 
the investigator can request additional tests at other visits.
The hepatitis A infection status will be confirmed by the hepatitis A immunoglobulin M 
antibody. Hepatitis B infection status will be confirmed by hepatitis B surface antigen. The 
HCV infection status will be confirmed by HCV-antibody and if applicable also by qualitative 
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HCV RNA. Qualitative HCV RNA will only be performed, at baseline, in case the CD4+ cell 
count at screening was <100 cells/mm3 or in case the HCV-antibody test at screening was 
positive.
6.4.9.3.
Cardiovascular Safety
At the time points specified in the flowchart (see Section 2), vital signs and ECG will be 
recorded. Any clinically relevant changes occurring from the signing of ICF onwards until the 
last trial-related visit must be recorded on the AE/HIV-Related Events section of the eCRF.
Please see Addendum 4: Cardiovascular Safety – Abnormalities for a detailed description of 
abnormalities.
6.4.9.3.1.
Vital Signs
Systolic and diastolic blood pressure (SBP and DBP) must be measured standing and supine 
(after 5 minutes of rest). Standing and supine pulse must also be recorded at the same time 
points.
6.4.9.3.2.
ECG
Central ECG readings will be performed by a central ECG lab. Instructions for ECG acquisition 
and ECG transmission will be described in the manual provided by the ECG lab. There will be 2 
ECG reports: a preliminary report and a final report. The final report will be reviewed by a board 
certified cardiologist from the central ECG lab.
Both ECG reports generated by the central ECG lab will need to be interpreted for clinical 
significance, signed and dated by the investigator, and filed in the subject’s medical record.
Whenever possible, the ECG should be taken around the expected Cmax (i.e., 4 hours after intake 
of RPV).
6.4.9.4.
Physical Examination
To evaluate the subject’s eligibility, a full physical examination, in which all body parts need to 
be reviewed, will be performed at screening. In addition, a full physical examination will be 
performed at time points shown in the flowchart (see Section 2). This assessment 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, central nervous system, peripheral nervous system, musculoskeletal 
system, genitourinary system. It does not include rectal or vaginal examination unless clinically 
indicated. Any clinically relevant changes occurring from signing the ICF onwards must be 
recorded on the AE/HIV-related event sections of the eCRF.
At several time points (specified in the flowchart, Section 2) 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), 
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lymph nodes, respiratory system, cardiovascular system, gastrointestinal, and central nervous 
system. It does not include rectal or vaginal examination unless clinically indicated.
At Week 2, only a skin examination will take place.
Body weight and height will be recorded at the visits specified in the flowchart (see Section 2). 
Growth will be followed regularly and evaluated consistently using standardized growth 
charts30,31,32. The subjects will be weighed in underwear, wearing no shoes. The same weighing 
scale will preferably be used at each visit. For the measurement of the height, the subjects will 
wear no shoes. The same stadiometer will preferably be used at each visit.
The assessment of pubertal development will be performed by a modified Tanner assessment33
consisting of a discrete visual inspection and comparison to the illustrated Tanner scales (see
Addendum 9: Tanner Scales). Tanner stages will be recorded at all visits indicated in the 
flowchart (see Section 2). For girls that have not yet had their first menses, the date of the first 
menses will be recorded as part of the evaluation of pubertal development at every visit. At 
screening, it will be assessed whether girls already have had their first menses.
Any clinically relevant changes in physical examination occurring from the signing of ICF 
onwards, until the last trial-related visit must be recorded on the AE /HIV-Related Event section
of the eCRF. 
6.4.10.
Adherence Questionnaire
At all visits indicated in the flowchart (see Section 2) a number of Sponsor-selected questions 
from the Pediatric European Network for the Treatment of AIDS (PENTA) adherence 
questionnaire will be used to assess compliance. The adherence questionnaire will be self-
administered by the subject at the visits as indicated at the flowchart. Depending on the age and 
literacy of the subject, the adherence questionnaire can be completed by the subject and/or by 
their parent or caregiver. If a subject and/or parent or caregiver has difficulties in completing the 
questionnaire, either because of the age, literacy or general health status, then the trial staff may 
assist in completing the questionnaire.
Once the subject and/or its parent or caregiver has completed the questionnaire, the site staff 
should review it for completeness. The questionnaire will be collected and the data will be
entered into the trial database by the data manager.
If based on the review of the questionnaire, there seems to be a compliance issue, this should 
trigger additional compliance counseling by the investigator staff.
Note that the 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.
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6.4.11.
Evaluation for Depression
At all visits indicated in the flowchart (see Section 2) an evaluation will be done using 
questionnaires or other means, as in use at the site as part of local standard of care for this 
population, to assess whether the subject needs to be referred for a complete mental health 
assessment. 
Subjects in whom a tendency for depression or suicidal thoughts is detected will be referred for a 
complete mental health assessment. Also, if the site staff feels that the child/adolescent has 
under-reported his/her symptoms, or if depression or suicidality are suspected, the subject should 
be referred for a complete mental health assessment. 
6.4.12.
Assessment of Palatability of RPV Formulation
Subjects who require RPV 15 mg (i.e. body weight <25 kg) or any other adjusted RPV dose
should use a formulation other than the 25 mg tablet formulation (see Section 6.3.1). 
Understanding the taste preferences of children who take RPV as 2.5-mg tablets (which must be 
dispersed) is important as palatability of the study drug plays a pivotal role in achieving patient 
acceptance and therefore compliance to treatment. Taste acceptability will be assessed at Day 1 
and Week 4 using a modified questionnaire form incorporating a 5 point hedonic facial scale (see 
Section 7.12, Addendum 12). This scale is a standard tool used in clinical trials to assess drug 
palatability in children55,56.
6.5.
Monitoring and Safety for Specific Toxicities
Guidelines in this section are applicable for the entire trial period, including the screening and 
follow-up period. 
For grade 3 or 4 laboratory abnormalities, subjects 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 elevations in subjects with pre-existing diabetes
%
Asymptomatic grade 3 or 4 glucose or triglyceride elevations, or asymptomatic grade 3 
cholesterol elevations
%
Asymptomatic grade 3 pancreatic amylase elevations in subjects with no history or 
concomitant disease of pancreatitis
AEs still ongoing at the end of the trial will be followed until satisfactory clinical resolution or 
stabilization. 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 one grade from baseline. Certain long-term AEs of ART cannot be followed to 
resolution within the setting of this trial; in these cases follow-up will be the responsibility of the 
investigator, which will be agreed upon with the Sponsor.
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In case a treatment interruption (only allowed after the intensive PK visit) is needed during the 
treatment period in the event of a suspected toxicity, the subject will not automatically be 
withdrawn from the trial, as long as treatment interruption for the suspected toxicity does not 
exceed 4 weeks or the total cumulative duration of the treatment interruptions for suspected 
toxicities does not exceed 8 weeks (interruptions are counted cumulatively within a time frame 
of 48 weeks). In case a permanent discontinuation of study drug is needed, all ARV medication 
(i.e., RPV and background regimen) should be discontinued, considering the guidelines on-
treatment discontinuation (Section 6.2.5) and specific considerations (Section 6.3.3).
Subjects who start ketoconazole treatment during the trial need to have an ACTH stimulation test 
performed 2 weeks into ketoconazole treatment (Cohort 1 only) and additional ECG monitoring 
is required (see Section 6.3.13.1). 
Additional ECG monitoring is also required for subjects receiving CYP3A4 inhibitory 
comedications for >2 days, as well as for subjects receiving drugs associated with a risk of 
Torsade de Pointes for > 2 days (see Section 6.3.13.1). If the use of certain comedication 
warrants additional ECG monitoring, a pharmacokinetic sample should be taken within 
10 minutes after this ECG on Days 3 to 7 after the start of the comedication in order to assess 
RPV concentration-safety relationships. The date and time of pharmacokinetic sampling and last 
intake of RPV should be recorded on the eCRF.
For subjects reporting cutaneous event/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:
6.5.1.
Cutaneous Event/Rash
Subjects who have a history of a grade 2 or 3 cutaneous reaction/rash may be at increased risk 
for RPV related skin reaction and should therefore be monitored closely during the first 4 weeks 
of treatment with the study drug.
All the information regarding cutaneous reactions occurring after the first intake of study drug
needs to be reported in the ‘Rash’ section of the eCRF within 24 hours and the trial site monitor 
needs to be informed. Cutaneous reactions occurring before the first intake of study drug are to 
be reported as medical events (see 1.4).
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), 
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ALP, bilirubin (total, direct and indirect), creatinine and a complete blood cell count (including 
hemoglobin, hematocrit, RBC count, WBC count, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, and platelet count). 
If the etiology of the cutaneous event/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 eCRF.
When describing cases of cutaneous/rash reactions in the eCRF, the Rash Guidance Manual, part 
of the Investigator Manual, should be consulted.
Dermatologist fees for evaluating subjects who experience cutaneous reactions/rash will be 
reimbursed by the Sponsor.
Grade 1 Cutaneous Reaction/Rash:
A grade 1 rash is defined as localized macular rash.
Subjects may continue the ARV medication for a grade 1 rash.
The subject 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. If 
the rash is considered to be most likely due to concomitant illness or non-study drug, standard 
management, including discontinuation of the likely causative agent, should be undertaken. If no 
other causative factor is found after clinical evaluation, the subject may be treated 
symptomatically until the rash resolves. Cetirizine (antihistamine), topical corticosteroids or 
antipruritic agents may be prescribed.
Referral to a dermatologist is optional for subjects experiencing a grade 1 rash. 
Subjects should be informed that they should visit the clinic 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 Cutaneous Reaction/Rash:
A grade 2 cutaneous reaction/rash is defined as diffuse macular, maculopapular, or morbilliform 
rash or target lesions.
Subjects may continue the ARV medication for a grade 2 rash. The ARV medication may also be 
continued for any grade 2 rash with an increase in ALT/AST (<2x baseline) provided the subject 
is followed weekly with repeated testing. For subjects with a grade 2 rash and elevations of 
ALT/AST >2x baseline but <5x ULN, ARV medication should be interrupted and should only be 
restarted when the cutaneous reaction has resolved.
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The subject should be advised to contact the investigator immediately if 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 for subjects experiencing a grade 2 rash. 
Subjects should be informed that they should visit the clinic 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 3 Cutaneous Reaction/Rash:
A grade 3 cutaneous reaction/rash is defined as the following:
%
Diffuse macular, maculopapular, or morbilliform rash with vesicles or limited number of 
bullae
%
Cutaneous reaction/rash with superficial ulcerations of mucous membrane limited to one site
%
Cutaneous reaction/rash with at least one of the following:
%
Elevations of ALT/AST >2x baseline but at least 5x ULN*
%
Fever !38°C or 100°F*
%
Serum sickness-like reaction* 
%
Eosinophil count >1,000/mm3*
* added by the Sponsor.
Subjects with a grade 3 rash will permanently discontinue the ARV medication and be 
withdrawn from the trial. 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 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.
Subjects should be informed that they should visit the clinic 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. 
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If on Day 1 (day of rash onset) of rash occurrence there are no increases in ALT/AST noted and 
there is no progression of rash (e.g., 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 of the rash occurrence the ALT/AST are at least 2 times baseline and at least 5 times 
ULN then safety blood samples should be taken daily for the first 5 days.
If on Day 5 of rash the ALT/AST are at least 2 times baseline and at least 5 times ULN, 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 Cutaneous Reaction/Rash:
A grade 4 cutaneous reaction/rash is defined as 1 of the following:
%
Extensive or generalized bullous lesions;
%
Stevens-Johnson Syndrome (SJS);
%
Ulceration of mucous membrane involving 2 or more distinct mucosal sites;
%
Toxic Epidermal Necrolysis (TEN).
Subjects with a grade 4 rash will permanently discontinue the ARV medication and be 
withdrawn from the trial. 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.
Subjects should be informed that they should visit the clinic 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. Subjects should be hospitalized whenever medically 
appropriate for management of grade 4 rashes. 
If on Day 1 (day of rash onset) of rash occurrence there are no increases in ALT/AST noted and 
there is no progression of rash (e.g., 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 of the rash occurrence the ALT/AST levels are at least 2 times baseline and at least 5 
times ULN then safety blood samples should be taken daily for the first 5 days.
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If on Day 5 of rash the ALT/AST levels are at least 2 times baseline and at least 5 times ULN, 
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 2:
Summary of Rash
Revised DAIDS 
Toxicity Grade
Definitions
Investigator Action
Rechallenge 
Instructions
Grade 1
Localized macular rash
May continue ARV 
medication.
NA
Grade 2
Diffuse macular, maculopapular rash 
or morbilliform rash or target lesions
May continue ARV 
medication.
NA
Diffuse macular, maculopapular or 
morbilliform rash or target lesions 
with an increase in ALT/AST <2x 
baseline
May continue ARV 
medication.
NA
Diffuse macular, maculopapular or 
morbilliform rash or target lesions 
with an increase in ALT/AST >2x 
baseline
Interrupt all ARV 
medication.
May resume all 
ART when rash 
has resolved
Grade 3
Diffuse macular, maculopapular, or 
morbilliform rash with vesicles or 
limited number of bullae
Cutaneous reaction/rash with 
superficial ulcerations of mucous 
membrane limited to one site
Cutaneous reaction/rash with at least 
one of the following*:
Elevations in ALT/AST (>2x 
baseline but at least 5x ULN);
Fever (!38 C or 100 F);
Serum sickness-like reaction;
Eosinophil >1,000/mm3.
Discontinue ARV 
medication.
No
Grade 4
Extensive or generalized bullous 
lesions;
Stevens-Johnson Syndrome (SJS);
Ulceration of mucous membrane 
involving 2 or more distinct mucosal 
sites;
Toxic Epidermal Necrolysis (TEN).
Discontinue ARV 
medication.
No
* Added by the Sponsor.
6.5.2.
Acute Systemic Allergic Reaction
Management will be at the discretion of the investigator, taking into account the following 
protocol-defined procedures (also see Table 3), and should follow generally accepted medical 
standards.
Subjects planning to use ABC in their background regimen, who develop 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 (see 
Section 6.5.11.3).
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Grade 1 (localized urticaria [wheals] with no medical intervention indicated):
Subjects may continue ARV medication for a grade 1 allergic reaction. The subject 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 or topical corticosteroids or antipruritic agents may be prescribed as long as these 
are in line with the package inserts of the N(t)RTIs in the background regimen or the 
(dis)allowed medication for RPV as indicated in Section 6.3.13.
Grade 2 (localized urticaria with medical intervention indicated or mild angioedema with no 
medical intervention indicated):
Subjects may continue ARV medication for a grade 2 allergic reaction. If there is any worsening 
of the allergic reaction, the subject should be advised to contact the investigator immediately and 
to discontinue ARV medication and be withdrawn from the trial.
Antihistamines or topical corticosteroids or antipruritic agents may be prescribed as long as these 
are in line with the package inserts of the N(t)RTIs in the background regimen or the 
(dis)allowed medication for RPV as indicated in Section 6.3.13.
Grade 3 (generalized urticaria, angioedema with medical intervention indicated or symptomatic 
mild bronchospasm) and Grade 4 (acute anaphylaxis, life-threatening bronchospasm or 
laryngeal edema):
Subjects will permanently discontinue ARV medication and be withdrawn from the trial (see 
Section 6.2.5). Subjects will be treated as clinically appropriate. Standard management should be 
undertaken.
Table 3:
Summary of Allergic Reaction
DAIDS Toxicity 
Grade
Definitions
Investigator Action Regarding ARV 
Medication (RPV and background 
regimen)
Grade 1
Localized urticaria [wheals] with no 
medical intervention indicated.
May continue ARV medication or have 
ARV medication interrupted at the 
investigator’s discretion.
Grade 2
Localized urticaria with medical 
intervention indicated, or
Mild Angiedema with no medical 
intervention indicated.
May continue ARV medication or have 
ARV medication interrupted at the 
investigator’s discretion.
Grade 3
Generalized urticaria, or
Angiedema with medical intervention 
indicated, or
Symptomatic mild bronchospasm.
Permanently discontinue ARV medication 
(see Section 6.2.5).
Grade 4
Acute anaphylaxis, or 
Life-threatening bronchospasm, or
Laryngeal edema.
Permanently discontinue ARV medication 
(see Section 6.2.5).
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6.5.3.
AST, ALT, and Total Bilirubin Elevation
Management will be at the discretion of the investigator, taking into account the following 
protocol-defined procedures (also see Table 4), and should follow generally accepted medical 
standards.
For grade 3 or 4 laboratory abnormalities, subjects 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.
Grade 1 AST or ALT Elevation (!1.25 to &2.5x ULN) and Grade 2 AST or ALT Elevation 
(>2.5 to &5.0x ULN) with Grade 1 or 2 Total Bilirubin Elevation (!1.1 to &2.5x ULN):
Subjects may continue ARV medication.
Grade 3 AST or ALT Elevation (>5.0 to &10.0x ULN) with Grade 1 or 2 Total Bilirubin 
Elevation (!1.1 to &2.5x ULN):
Subjects are to interrupt all ARV medication, 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 
(& grade 2), the subject may resume all ARV medication under the guidance of the investigator 
and preferably after the investigator has consulted with a Sponsor’s Physician.
If a subject is required to interrupt all ARV medication due to a grade 3 AST or ALT elevation, 
and after restarting ARV medication he/she has a recurrence of grade 3 or grade 4 AST or ALT 
elevation, he/she will permanently discontinue the ARV medication and be withdrawn from the 
trial (see Section 6.2.5).
For subjects with concomitant hepatitis A, B, or C:
Warning: Severe acute exacerbations of hepatitis B have been reported in subjects who are co-
infected with hepatitis B virus and HIV and have discontinued 3TC. Hepatic function 
should be monitored closely with both clinical and laboratory follow-up for at least 
several months in subjects who discontinue 3TC and are co-infected with HIV and 
HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
If a subject is diagnosed with acute viral hepatitis during the trial, the subject must be withdrawn 
from the trial immediately and the necessary follow-up visits performed (see Section 6.2.5). 
Subjects with chronic hepatitis B or C co-infection will be allowed to continue ARV treatment 
(RPV and background regimen) 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 subjects 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, jaundice, and liver tenderness. If signs or 
symptoms of clinically active hepatitis occur, or if AST or ALT increases to grade 4, then he/she 
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will permanently discontinue the ARV medication and be withdrawn from the trial (see Section 
6.2.5).
If for a subject co-infected with hepatitis B or C, experiencing grade 3 elevation in AST or ALT, 
ARV treatment is temporarily interrupted and he/she has a recurrence of grade 3 increase in AST 
or ALT after restarting ARV treatment, he/she may continue provided that ALP is not elevated to 
grade 2 or higher and total bilirubin is not elevated to grade 3 or higher, and he/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 all ARV treatment will be 
permanently discontinued and the subject will be withdrawn from the trial (see Section 6.2.5). If 
for the hepatitis B or C co-infected subject treatment is interrupted a second time because of a 
grade 3 elevation in AST or ALT, all ARV medication will be permanently discontinued and the 
subject will be withdrawn from the trial (see Section 6.2.5).
Grade 3 AST or ALT Elevation (>5.0 to &10.0x ULN) With at Least Grade 3 Total 
Bilirubin Elevation (>2.5x ULN) or Grade 4 AST or ALT Elevation (>10.0x ULN):
Subjects will permanently discontinue ARV medication and will be withdrawn from the trial (see 
Section 6.2.5).
Table 4:
Summary of AST and ALT Elevations
DAIDS Toxicity 
Grade 
Ranges
Investigator Action Regarding ARV 
Medication (RPV and background 
regimen)
Rechallenge 
instructions
Grade 1
≥1.25 to &2.5x ULN
May continue ARV medication if 
total bilirubin is & grade 2
NA
Grade 2
>2.5 to &5.0x ULN
May continue ARV medication if 
total bilirubin is & grade 2
NA
Grade 3
>5.0 to &10.0x ULN
If total bilirubin is & grade 2:
Interrupt ARV medication until 
toxicity & grade 2;
If co-infected with hepatitis B or C, 
ARV medication may be continued if 
ALP is & grade 2, bilirubin is 
& grade 3, and asymptomatic.
Allowed once
If recurrence after 
restart of ARV 
medication, 
discontinue ARV 
medication 
permanently
If total bilirubin is > grade 2:
Discontinue ARV medication (see 
Section 6.2.5)
No
Grade 4
>10.0x ULN
Discontinue ARV medication (see 
Section 6.2.5)
No
NA: not applicable.
6.5.4.
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, subjects should be carefully evaluated and followed closely. 
An overview of the laboratory ranges to assign grading to a laboratory value for pancreatic 
amylase and lipase is provided in Addendum 2: DAIDS Table.
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For confirmed asymptomatic grade 4 elevations of pancreatic amylase or confirmed 
asymptomatic grade 3 or grade 4 elevations of lipase, subjects should interrupt all ARV 
medication until pancreatic amylase returns to grade ≤3 or lipase returns to grade ≤2, at which 
time ARV medication could be re-introduced. If asymptomatic grade 4 elevations of pancreatic 
amylase or asymptomatic grade 3 or 4 lipase levels recur with reintroduction of ARV 
medication, all ARV medication should be permanently discontinued and the subject will be 
withdrawn from the trial (see Section 6.2.5).
6.5.5.
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 (see Section 2).
6.5.5.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years
In case of clinical signs or symptoms or laboratory abnormalities (other than cortisol) indicative 
for adrenal insufficiency, the ACTH stimulation test should be done as soon as possible during 
an unscheduled visit.
At the time point specific in the flowchart (see Section 2) an ACTH stimulation test will be 
performed for all subjects including measurements of cortisol, 17-hydroxyprogesterone, 
progesterone, DHEAS, androstenedione, testosterone, aldosterone, FSH, and LH (see 
Section 6.4.9.2.3). Cortisol, 17-hydroxyprogesterone, and aldosterone will be measured before, 
30, and 60 minutes after ACTH stimulation; all other endocrine parameters will only be 
measured before ACTH stimulation. If the ACTH stimulation test is abnormal (i.e., all cortisol 
values [prior to and after ACTH stimulation] are <500 nmol/L [18.1∃g/dL]), a retest needs to be 
performed at the next scheduled visit or at least within the next 8 weeks.
A sample for the determination of basal cortisol will be drawn in the morning of the time points 
specified in the flowchart (see Section 2), between 7h30 and 9h30. If at any of these time points 
basal cortisol value is <248 nmol/L (9 ∃g/dL), a retest will be done at the subsequent visit or at 
least within the next 8 weeks.
If basal cortisol is <248 nmol/L (9 ∃g/dL) at 2 consecutive scheduled visits, an ACTH 
stimulation test will be performed at the next scheduled visit or at least within the next 8 weeks 
with measurements of cortisol and 17-hydroxyprogesterone.
If the subject does not achieve a cortisol value of ≥500 nmol/L (18,1 μg/dL) on at least one of the 
3 time points of cortisol measurement during the ACTH stimulation test (i.e., morning cortisol, 
30 or 60 minutes after ACTH stimulation) at a trial visit where ACTH stimulation testing is done 
(as a result of 2 consecutive cortisol values being <248 nmol/L [9 μg/dL] or as a result of an 
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abnormal ACTH test at baseline or Week 48) and if this subject shows clinical signs and 
symptoms of adrenal insufficiency, which are evaluated in conjunction with other possible 
confounding factors (e.g., concomitant medication, AEs,…), withdrawal of the subject should be 
discussed with the Sponsor. 
Appropriate clinical follow-up, including further endocrine evaluations, should be installed24.
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 trial. 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 treatment with RPV if this is in the best 
interest of the subject. 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 subjects 
may be hypovolemic, hyponatremic, or hyperkalemic. In such case initial therapy may consist of 
intravenously administered saline and dextrose. In a hypotensive patient, a 20 mL/kg bolus of 
isotonic sodium chloride solution given over the first hour may be necessary to restore their 
blood pressure. This bolus may be repeated if the blood pressure remains low. After results for 
the subject’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 child 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.
If the unscheduled ACTH test is performed further to the presence of signs and symptoms of 
adrenal insufficiency (as listed above), and the subject does not achieve a cortisol value 
! 500 nmol/L (18.1 ∃g/dL) on at least one of the 3 time points of cortisol measurement during 
the ACTH stimulation test (i.e., morning cortisol, 30 or 60 minutes after ACTH stimulation), this 
should be discussed with the Sponsor, taking into account other possible confounding factors 
(e.g., concomitant medication, AEs,…), and the subject will be withdrawn from the trial if 
considered appropriate. Appropriate clinical follow-up, including further endocrine evaluations, 
should be installed24.
As ketoconazole is known to have an intrinsic effect of inhibition of certain adrenal enzymes, 
resulting in decreased synthesis of certain adrenal hormones such as cortisol, subjects who start 
ketoconazole treatment during the trial need to have an ACTH stimulation test performed 2 
weeks into ketoconazole treatment. If all cortisol values (prior to and after ACTH stimulation) 
are <500 nmol/L (18.1 ∃g/dL), and this subject has clinical signs and symptoms of adrenal 
insufficiency, which are evaluated in conjunction with other possible confounding factors (e.g., 
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concomitant medication, AEs,…), the subject should be withdrawn from the trial after discussion 
with the Sponsor.
6.5.5.2.
Cohort 2: Children Aged ≥6 to <12 Years
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, see Section 6.4.9.2.3.2.
If the unscheduled ACTH test is performed further to the presence of signs and symptoms of 
adrenal insufficiency (as listed above), and the subject 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 (i.e., morning cortisol or 60 minutes after ACTH stimulation), this should 
be discussed with the Sponsor, taking into account other possible confounding factors (e.g., 
concomitant medication, AEs,…), and the subject may discontinue RPV treatment and be 
withdrawn from the trial if considered appropriate.
Similar clinical follow-up as in Cohort 1, including seeking advice from an external 
endocrinologist if deemed appropriate will be applicable for Cohort 2. 
6.5.6.
Clinical Hepatitis
Non-Viral Hepatitis
Subjects 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.
Subjects with these signs and symptoms should seek medical attention immediately and hepatic 
parameters should be tested. All ARV medication must be permanently discontinued if the 
hepatitis is considered at least possibly related to RPV in the opinion of the investigator (see 
Section 6.2.5).
Viral Hepatitis
If acute viral hepatitis is diagnosed during the trial, the subject should be permanently withdrawn 
from the trial (see Section 6.2.5).
6.5.7.
Neuropsychological Symptoms
Subjects should be informed that RPV may cause dizziness, insomnia, somnolence, impaired 
concentration and/or abnormal dreaming and instructed that if they experience these symptoms 
they should avoid potentially hazardous tasks such as driving or operating machinery.
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There have been reports of delusions and inappropriate behavior in subjects receiving licensed 
NNRTIs, especially in subjects 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 flowchart (see Section 2) an evaluation will be done using questionnaires or 
other means, as in use at the site as part of local standard of care for this population, to assess 
whether the subject needs to be referred for a complete mental health assessment. In case a 
tendency for depression or suicidal thoughts is detected, a mental health assessment will need to 
be performed. Subjects who experience symptoms of depression should contact the investigator 
immediately because discontinuation of the ARV medication (RPV and background regimen) 
may be required. Investigators should refer subjects reporting such symptoms for immediate 
psychiatric evaluation/medical intervention. 
In case of grade 3 (alteration causing inability to perform usual social and functional activities) 
and grade 4 alterations in personality behavior or in mood (behavior potentially harmful to self 
or others (e.g., suicidal and homicidal ideation or attempt, acute psychosis) or causing inability to 
perform basic self-care functions): the ARV medication must be permanently discontinued if the 
neuropsychological symptoms are considered at least possibly related to RPV in the opinion of 
the investigator (see Section 6.2.5).
6.5.8.
Gastrointestinal Nausea (With or Without Vomiting)
Although common, nausea following initiation of ARV medication usually subsides or resolves 
during the first few weeks of treatment.
Subjects planning to use ABC in their background regimen, who develop gastrointestinal nausea 
should be evaluated for the possibility of ABC hypersensitivity reaction and follow instructions 
related to clinically suspected hypersensitivity to ABC (see Section 6.5.11.3).
Grade 1 nausea (transient or intermittent; no or minimal interference with oral intake 
<24 hours) and Grade 2 nausea (persistent nausea resulting in decreased oral intake for 24-48 
hours):
Subjects may continue with ARV medication and may be treated as needed with anti-emetics 
given orally or by suppository.
Grade 3 nausea (persistent nausea resulting in decreased intake for >48 hours or aggressive 
rehydration indicated): 
Subjects developing grade 3 nausea will have all ARV medication interrupted. The subject will 
be treated as needed with anti-emetics given orally or by suppository. All ARV medication may 
be resumed when the nausea resolves to grade & 2. 
If grade 3 nausea recurs after resuming the ARV medication despite the use of anti-emetics, 
subjects will discontinue all ARV medication and be withdrawn from the trial (see 
Section 6.2.5).
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Grade 4 nausea (life-threatening consequences):
Subjects developing grade 4 nausea will permanently discontinue all ARV medication and will 
be withdrawn from the trial (see Section 6.2.5).
6.5.9.
Diarrhea
Subjects planning to use ABC in their background regimen, who develop diarrhea should be 
evaluated for the possibility of ABC hypersensitivity reaction and follow instructions related to 
clinically suspected hypersensitivity to ABC (see Section 6.5.11.3).
Grade 1 diarrhea (transient or intermittent episodes of unformed stools or &3 stools over 
baseline per 24 hours) and Grade 2 diarrhea (persistent episodes of unformed to watery stools 
or &4-6 stools over baseline per 24 hours):
Subjects may continue ARV medication. Loperamide or diphenoxylate can be administered.
Grade 3 diarrhea (bloody diarrhea or !7 stools per 24 hours or intravenous fluid replacement 
required):
Subjects with grade 3 diarrhea will have all ARV treatment (RPV and background regimen) 
interrupted. All ARV medication (RPV and background regimen) may be resumed when the 
diarrhea resolves to grade &2.
If grade 3 diarrhea recurs after resuming the ARV medication despite the use of appropriate 
medication, subjects should permanently discontinue all ARV medication and will be withdrawn 
from the trial (see Section 6.2.5).
Grade 4 diarrhea (life-threatening consequences):
Subjects with grade 4 diarrhea will permanently discontinue all ARV medication and will be 
withdrawn from the trial (see Section 6.2.5).
6.5.10.
Other Toxicities
Grade 1
Subjects who develop a grade 1 AE or laboratory toxicity may continue intake of the ARV 
medication.
Grade 2
Subjects who develop a grade 2 AE or laboratory toxicity may continue intake of the ARV 
medication based on the investigator’s clinical judgment.
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Grade 3
Subjects who develop a grade 3 AE or laboratory toxicity should temporarily interrupt all ARV 
medication and may resume all therapy when the AE or laboratory abnormality resolved to 
within one grade level of the subject’s baseline but not higher than grade 2.
The following exceptions apply:
%
Subjects with pre-existing diabetes who experience a glucose elevation of grade 3.
%
Subjects who experience asymptomatic glucose, triglyceride or cholesterol elevations of 
grade 3.
%
Subjects who experience asymptomatic pancreatic amylase elevations of grade 3 with 
no history or concomitant disease of pancreatitis.
%
Subjects who experience an AE that is considered not related or doubtfully related to 
RPV.
Grade 4
Subjects experiencing a grade 4 AE or laboratory toxicity will permanently discontinue all ARV 
medication and will be withdrawn from the trial (see Section 6.2.5).
Exceptions are, unless clinical assessment foresees an immediate health risk to the subject:
%
Glucose elevation of grade 4 in subjects with pre-existing diabetes (see 
Section 6.5.11.1).
%
Asymptomatic glucose or triglyceride elevations of grade 4 (see Sections 6.5.11.1
and 6.5.11.2).
%
Confirmed pancreatic amylase and lipase elevations of grade 4 (see criterion 9) (see 
Section 6.5.4).
%
A grade 4 AE (except cutaneous reaction/rash, allergic reaction, or neuropsychological 
event) that is considered not related or doubtfully related to RPV.
Note: For grade 3 or 4 laboratory abnormalities, subjects should have a confirmatory 
measurement preferably within 48 hours after the laboratory results become available 
at the site. This management scheme is for confirmed laboratory abnormalities and 
not for isolated events.
6.5.11.
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.
6.5.11.1.
Hyperglycemia
Grade 3: 13.89-27.75 mmol/L (251-500 mg/dL);
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Grade 4: >27.75 mmol/L (>500 mg/dL).
If elevated glucose levels are from a non-fasting blood draw, the draw should be repeated after a 
10-hour fast. Management decisions should be based on fasted results. Subjects who experienced 
asymptomatic glucose elevations of grade 3 or 4 and subjects with pre-existing diabetes may 
continue ARV medication unless clinical assessment foresees an immediate health risk to the 
subject. 
Subjects, without pre-existing diabetes, with persistent grade 3 or 4 glucose elevations despite 
appropriate antidiabetic medication/management should permanently discontinue ARV 
medication (see Section 6.2.5). Appropriate clinical management of hyperglycemia must be 
started in a timely fashion.
6.5.11.2.
Hypertriglyceridemia and Hypercholesterolemia
Hypertriglyceridemia 
grade 3: 8.49-13.56 mmol/L (751-1,200 mg/dL);
grade 4: >13.56 mmol/L (>1,200 mg/dL).
Hypercholesterolemia
grade 3: >7.77 mmol/L (>300 mg/L); (grade 4: NA).
Management decisions should be based on fasted results. If elevated triglyceride or cholesterol 
levels are from a non-fasting blood draw, the draw should be repeated after a 10-hour fast. 
Subjects who experienced asymptomatic triglyceride elevations of grade 3 or 4 or cholesterol 
elevations of grade 3 may continue to receive ARV medication.
Hypertriglyceridemia and/or hypercholesterolemia should be treated according to the specific 
guidelines for treating HIV-infected subjects. 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 or clofibrate or niacin or a 3-hydroxy-3-
methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in addition to the usual counseling 
on diet and exercise. These medications should be introduced with caution. These medications 
may have overlapping adverse effects and niacin has the propensity to worsen the control of 
blood sugar in subjects with diabetes mellitus or a history of hyperglycemia.
6.5.11.3.
Hypersensitivity Reactions
In clinical studies, approximately 5% of subjects receiving an ABC-containing product 
developed a hypersensitivity reaction, which in rare cases has been proven fatal18.
At screening, all subjects without prior documented HLA-B*5701 negative results in whom the 
investigator considers ABC/3TC as the background regimen will be tested for HLA-B*5701. In 
those subjects where HLA-B*5701 is positive ABC/3TC cannot be administered19. In this case, 
the investigator should select AZT/3TC as the background regimen.
Also in case of switch to ABC due to intolerance of an N(t)RTI, the subject should test negative 
for HLA-B*5701. 
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It should also be noted that HLA screening and exclusion of HLA-B*5701 positive subjects does 
not completely eliminate the risk of hypersensitivity reactions.
Description of the Hypersensitivity Reaction
The ABC hypersensitivity reaction is characterized by the appearance of symptoms indicating 
multi-organ involvement. The majority of subjects have fever and/or rash as part of the 
syndrome; however reactions have occurred without rash or fever.
Symptoms can occur at any time during treatment with ABC, but usually appear within the first 
six weeks of initiation of treatment (median time to onset: 11 days). The symptoms worsen with 
continued therapy and can be life-threatening. These symptoms 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 or myolysis. 
Physical findings may include rash (usually maculopapular or urticarial), lymphadenopathy or 
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, or 
respiratory failure may occur.
Some subjects 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 of hypersensitivity has resulted in ABC being continued or 
re-introduced, leading to a more severe hypersensitivity reaction or death. Therefore, the 
diagnosis of hypersensitivity reaction should be carefully considered for subjects presenting with 
symptoms of these diseases. If a hypersensitivity reaction cannot be ruled out, no medicinal 
product containing ABC (Ziagen®, Trizivir®, or Epzicom®/Kivexa®) should be restarted.
Management of Hypersensitivity Reactions
Subjects developing signs or symptoms of hypersensitivity MUST contact their doctor 
IMMEDIATELY for advice. 
If a hypersensitivity reaction is diagnosed, the subject MUST discontinue ABC treatment 
IMMEDIATELY. The N(t)RTI background regimen will be replaced by alternative N(t)RTIs 
(Brand name versions or generics with tentative US FDA approval and/or WHO prequalified 
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drugs. If not available; generic drugs approved by the local Health Authorities or drugs procured 
by the UN international organizations can be allowed upon approval by the sponsor.). At all 
times the background regimen should consist of 2 N(t)RTIs and the subject’s HIV-1 genotype at 
screening should show sensitivity to the alternative N(t)RTIs. The subject should be asked to 
return all unused supplies of the ABC-containing product for disposal to prevent an accidental 
rechallenge.
An ABC-containing medicinal product (Ziagen®, Trizivir®, or Epzicom®/Kivexa®) MUST 
NEVER be administered following a hypersensitivity reaction, as more severe symptoms 
will recur within hours and may include life-threatening hypotension and death. 
To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity 
reaction, the ABC-containing product should be permanently discontinued if hypersensitivity 
cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, 
gastroenteritis, or reactions to other medications). 
Symptomatic support for ABC hypersensitivity may be indicated. This should include, for 
example, administration
of intravenous fluids to subjects who develop hypotension. 
Antihistamines or corticosteroids have been used in cases of ABC hypersensitivity; however 
there are no clinical data demonstrating the benefit of these in the management of the reaction. 
Laboratory and other investigations which may be useful in the evaluation and treatment of ABC 
hypersensitivity include, but may not be 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 Therapy
If therapy with ABC has been discontinued and restarting therapy is under consideration, the 
reason for discontinuation should be evaluated to ensure that the subject did not have symptoms 
of a hypersensitivity reaction. If a hypersensitivity reaction cannot be ruled out, no medicinal 
product containing ABC (Ziagen®, Trizivir®, or Epzicom®/Kivexa®) should be restarted.
There have been infrequent reports of a hypersensitivity reaction following reintroduction of an 
ABC-containing product where the interruption was preceded by a single key symptom of 
hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal symptoms, or a respiratory 
symptom). If a decision is made to restart any ABC-containing product in these subjects, this 
should be done only under direct medical supervision. 
On very rare occasions hypersensitivity reactions have been reported in subjects who have 
restarted therapy, and who had no preceding symptoms of a hypersensitivity reaction. If a 
decision is made to restart an ABC-containing product, this must be done only if the subject or 
others can access medical care readily.
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Essential Subject Information
Subjects 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 subjects are fully informed regarding the following information on 
the hypersensitivity reaction:
%
Subjects 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 subjects without prior documented HLA-B*5701 negative results in 
whom the investigator considers ABC/3TC as the background regimen will be tested for 
HLA-B*5701. In those subjects where HLA-B*5701 is positive ABC/3TC cannot be 
administered19. In addition, in case of switch to ABC during the trial, the subject should 
test negative for HLA-B*5701 (unless prior documented negative results are available).
%
Subjects developing signs or symptoms possibly linked with a hypersensitivity reaction 
MUST CONTACT their doctor IMMEDIATELY. 
%
Subjects who are hypersensitive to ABC should be reminded that they must never take any 
ABC-containing medicinal product (Ziagen®, Trizivir®, or Epzicom®/Kivexa®) again. 
%
In order to avoid restarting the ABC-containing product, subjects who have experienced a 
hypersensitivity reaction should be asked to return the remaining tablets to the site.
%
Subjects who have stopped taking an ABC-containing product for any reason, and 
particularly due to possible adverse reactions or illness, must be advised to contact their 
doctor before restarting.
Reporting of Hypersensitivity Reaction
All cases of potential ABC hypersensitivity should be reported as SAE (see 1.4).
6.5.11.4.
Lactic Acidosis
The relevance of asymptomatic lactic acid elevations is unclear, and serum lactate evaluation is 
not part of the routine safety evaluations for this trial. Routine lactate monitoring is not currently 
recommended. However, lactate monitoring should be performed at the local laboratory if there 
is a clinical suspicion of lactic acidosis (see description below).
A, sometimes fatal, syndrome of lactic acidosis, often associated with evidence of hepatic 
steatosis, is a recognized but rare complication of N(t)RTI therapy. This syndrome is felt to be 
secondary to mitochondrial toxicity induced by the inhibitory effect of N(t)RTIs on DNA 
polymerase gamma, a key enzyme needed for mitochondrial DNA synthesis. Current knowledge 
regarding this syndrome is incomplete. Obesity and prolonged N(t)RTI exposure may be risk 
factors. Symptoms of lactic acidosis frequently involve non-specific symptoms such as fatigue, 
weakness, and fever, but in the majority of cases also involve symptoms suggestive of hepatic 
dysfunction such as nausea, vomiting, abdominal or epigastric discomfort, abdominal distension, 
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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 over interpretation of lactic acid levels. N(t)RTI toxicity is only one 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 trial:
Symptomatic Hyperlactatemia
New, otherwise unexplained, and persistent (! 2 weeks) occurrence of one or more 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
Note:
All lactate >2x ULN should be repeated as soon as possible (local laboratory), 
generally within 1 week. If the second result confirms hyperlactatemia (>2x ULN), 
subjects should immediately interrupt their current ARV regimen (RPV and 
background regimen). Standard management should be initiated with follow-up to 
resolution. If causality is related to the background regimen only and NOT to the 
NNRTI regimen (RPV), N(t)RTIs must be changed. If causality is related to RPV, 
subjects must be withdrawn.
Processing of the lactate sample needs to be done according to strict guidelines both in the 
preparation of the subject (ideally, fasting and with no recent exercise) and in the blood 
drawing/processing procedure (ideally, blood drawn without a tourniquet, no hand clenching, 
blood drawn into a chilled tube and processed immediately) to minimize false elevations of 
lactates.
6.5.11.5.
Renal Complications
Renal safety will be monitored by evaluating serum creatinine levels, eGFR, serum chemistry 
and urinalysis results at every trial visit.
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If eGFR is decreased with >30% from baseline, the value must be confirmed by repeat testing 
within 72 hours using an unscheduled visit and ARV medication may be interrupted at the 
discretion of the investigator if the decrease in eGFR is confirmed. A sample for bioanalysis of 
RPV should be taken at the time of the unscheduled visit. If the abnormality is not confirmed, the 
subject may continue the ARV medication with continued close follow-up by the investigator. 
Unscheduled visits may be used to monitor renal function more closely. If the subject becomes 
22 years of age or older during the study, the eGFR formula used for children cannot be used. In 
this case, the MDRD equation will be used.58 The eGFR for these subjects calculated at 22 years 
of age or older cannot be compared with the original baseline, but with the value when first 
calculated with the MDRD equation.
Long-term follow-up of subjects who develop 
nephrotoxicity should be discussed with the Sponsor. Subjects who change their background 
regimen or permanently discontinue ARV medication due to nephrotoxicity must attend 
scheduled, unscheduled or post-trial follow-up visits to characterize resolution of renal 
abnormalities. Follow-up visits (scheduled, unscheduled, or post-trial follow-up) will be 
conducted every 4 weeks and must be maintained until stabilization for 3 months with 
fluctuations of eGFR of less than 20% or return to baseline levels.
Note:
In the Phase IIb trial with RPV there was a small decrease in mean creatinine clearance 
(ClCr) from baseline, which appeared to reach a plateau at Week 4. There was an 
apparent dose relationship, with decreases in ClCr being somewhat lower in the 
RPV 25 mg q.d. dose group than in the higher dose groups. The effect was more 
pronounced in subjects receiving TDF/FTC as the background regimen than in subjects 
receiving AZT/3TC. This small decrease was not considered to be clinically relevant. 
Also, in trial TMC278-TiDP6-C131 and the Phase III trial TMC278-TiDP6-C215, it 
was shown that RPV has no effect on the renal function, as assessed by the calculated 
cystatine C clearance11,4.
6.5.11.6.
Pancreatitis
Pancreatitis, which has been fatal in some cases, is a major clinical toxicity associated with 
didanosine (ddI) (with or without concomitant administration of TDF) and/or stavudine (d4T) 
therapy and has been reported with other ARVs. Pancreatitis must be considered whenever a 
subject receiving ddI (with or without concomitant administration of TDF) and/or d4T develops 
abdominal pain and nausea, vomiting, or elevated pancreatic amylase or lipase, and ddI (and/or 
TDF) and/or d4T use should be suspended until the diagnosis of pancreatitis is excluded.
In case the pancreatitis is considered at least possibly related to RPV, ARV medication must be 
permanently discontinued (see Section 6.2.5). The subject experiencing pancreatitis can however 
be rechallenged with the N(t)RTI background regimen, if pancreatitis is considered not related to 
TDF/FTC treatment.
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6.5.11.7.
Peripheral Neuropathy
Subjects 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.
6.6.
Statistical Methods Planned and Determination of the Sample Size
The statistical analysis will be performed by a qualified vendor under the supervision/ 
responsibility of the Sponsor.
A general description of the statistical methods to be used to analyze the data is outlined below. 
Specific details will be provided in the Statistical Analysis Plan (SAP).
An ITT population will be defined:
%
The ITT population will be defined as the set of all subjects who have taken at least 1 dose 
of RPV, regardless of their compliance with the protocol and adherence to the dosing 
regimen.
Cohort 1: Adolescents Aged ≥12 to <18 Years
A first analysis was performed when the first 11 Part 1a subjects had been treated for at least 
2 weeks (or discontinued earlier). This was followed by an analysis when the Part 1b subjects 
had been treated for 4 weeks (+/-1 week) (or discontinued earlier). The objective of these 
analyses was to determine whether it is appropriate to continue with the 25 mg q.d. dose for the 
treatment of adolescents, based primarily on the pharmacokinetics of these Part 1 subjects and 
the short-term antiviral activity and safety. Short-term safety, tolerability, and efficacy were
described in these analyses. All available data were included in these analyses, even if occurring 
after the time point for intensive pharmacokinetic sampling. The results of the Part 1 analysis 
indicated that no RPV dose adjustment was needed, as confirmed by the IDMC. In case the 
short-term Part 1 results would have indicated the need for a switch to a lower dose of RPV for 
all subjects up to a certain body weight, an additional analysis was to be done when all these 
subjects would have been treated for 4 weeks (+/-1week) with the weight-adjusted dose of RPV.
An analysis took place when all Part 1 subjects had reached 12 weeks of treatment (or 
discontinued earlier). This will be followed by an additional analysis when all Part 1 and Part 2 
subjects have reached Week 12 of treatment (or discontinued earlier). 
A primary analysis will take place when all subjects have reached Week 24 (or discontinued 
earlier). The objective of this Week 24 primary analysis is to evaluate the long-term safety, 
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tolerability and efficacy of RPV in HIV-1 infected adolescents. Another interim analysis will 
take place when all subjects have reached 48 weeks of treatment (or discontinued earlier). A final 
analysis (i.e., when all Cohort 1 subjects have reached 240 weeks of treatment [or discontinued 
earlier]) will take place when all Cohort 1 subjects have completed the trial.
The results of all analyses up to Week 48 will be shared and discussed with the IDMC.
A detailed SAP for each analysis will be written and signed off prior to database closure.
At the time of protocol amendment 6 writing, both the 24 week and 48 week analyses have been 
performed. For any changes to the planned analysis of Cohort 1, see the clinical study report of 
Cohort 153. A summary of the 48-week results is provided in Section 6.1.2.2.
Cohort 2: Children Aged ≥6 to <12 Years
An initial analysis will be performed when the 5 Part 1 subjects of the mini-cohort have been 
treated for at least 4 weeks (or discontinued earlier). This will be followed by an overall analysis 
when all Part 1 subjects have been treated for at least 4 weeks (or discontinued earlier). The 
objective of these analyses is to determine whether it is appropriate to continue with the 25 mg 
q.d. dose for the treatment of children, based primarily on the pharmacokinetics of these subjects 
(samples taken after 14 to 18 days of RPV dosing) and the antiviral activity/efficacy and safety 
data. All available antiviral activity/efficacy and safety data will be included in these analyses, 
even if they have been obtained after the intensive pharmacokinetic sampling. If the results of 
these analyses indicate the need for an RPV dose adjustment for all or a part of the subjects in 
Part 1, an analysis (including the intensive pharmacokinetic evaluation after 14 to 18 days on the 
original and/or adjusted dose) will be performed after these subjects have been treated at least 4 
weeks (or discontinued earlier) with the adjusted RPV dose. The overall Part 1 analysis and if 
applicable, analyses after RPV dose adjustments will be shared and discussed with the IDMC. 
For more details about the analyses, see Section 6.6. 
Additional analyses will take place when all subjects in this C213 study have reached 12 and 
24 weeks of treatment (or discontinued earlier). The objective of these analyses is to have the 
IDMC evaluate the interim safety, tolerability and efficacy results of RPV in children.
A final analysis will be performed when all Cohort 2 subjects have reached Week 48 (or 
discontinued earlier). The objective of this analysis is to evaluate the safety, tolerability and 
efficacy of RPV in HIV-1 infected children. The final, Week 48, analysis will be performed after 
a formal database lock.
A detailed statistical analysis plan (SAP) for each analysis will be written and signed off prior to 
database closure.
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6.6.1.
Determination of Sample Size
6.6.1.1.
Cohort 1: Adolescents Aged ≥12 to <18 Years
Ten subjects in Part 1a was considered sufficient to allow for conclusions on the steady-state 
exposure after 2 weeks of treatment. After review of these Part 1a Week 2 data, it was decided to 
enroll the additional subjects in smaller cohorts and gather more intensive pharmacokinetic data 
in order to increase the precision of the pharmacokinetic parameter ratios. To ensure that all 
subjects have reached steady-state, intensive pharmacokinetic sampling in these additional 
subjects will be performed at Week 4 (+/-1 week).
If in Part 1, subjects had discontinued the trial before receiving their first dose of study drug, 
additional subjects could have been recruited to have 10 subjects starting treatment each in 
Part 1a and Part 1b. If subjects were prematurely withdrawn from the trial after starting 
treatment, for reasons other than drug tolerability/safety, additional subjects could have been
recruited at the request of the Sponsor to aim for at least 10 evaluable subjects each at Week 2
(Part 1a)/Week 4 (Part 1b).
For Part 2, the precision of the efficacy parameter (proportion of subjects with viral load 
<50 HIV-1 RNA copies/mL, TLOVR) expressed as half the width of the (2-sided) 95% CI is 
presented in Table 5, assuming various sample sizes ranging from 25 to 35 subjects and response 
rates between 70 and 80%.
Table 5:
Half the Width of the (2-Sided) 95% CI for Various Assumptions, Using a Normal 
Approximation
Sample size (N)
Response Rate (%)
70
75
80
25
18.0
17.0
15.7
30
16.4
15.5
14.3
35
15.2
14.4
13.3
Related to safety, Table 6 provides the probability of at least 1 occurrence of an AE for various 
sample sizes, provided the true incidence rate is 1%, 5%, and 10%.
Table 6:
Probability (%) of !1 AE Reported, for Various Assumptions
Sample Size (N)
Incidence Rate (%)
10%
5%
1%
25
92.8
72.3
22.2
30
95.8
78.5
26.0
35
97.5
83.4
29.7
6.6.1.2.
Cohort 2: Children Aged ≥6 to <12 Years
Approximately 40 subjects will be enrolled in this Cohort 2 (children aged ≥6 to <12 years)  and 
in study TMC278HTX2002 (children aged ≥2 to <12 years with a body weight of ≥11 kg) 
combined: at least 12 subjects with a body weight of <25 kg, including 7 subjects with a body 
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weight of <20 kg. As of Amendment 10 the PK data from this Cohort 2 will be combined with 
the data from pediatric study TMC278HTX2002.
Given that the body weights of the first 10 subjects enrolled in Cohort 2 were all towards the 
higher end, and data for subjects <25 kg were very limited (see addendum 7.11), it was decided 
to continue intensive PK evaluation for newly enrolled subjects with a body weight of <25 kg. At 
least 12 subjects in the body weight category <25 kg with intensive PK data across the 2 studies 
(Cohort 2 of this C213 study and study TMC278HTX2002) is considered sufficient to allow for 
conclusions on the steady-state exposure of RPV.
If in the mini-cohort, subjects discontinue the trial before receiving their first dose of study drug, 
additional subjects can be recruited to have 5 subjects starting treatment in the mini-cohort. If 
subjects discontinue the trial after starting treatment for reasons other than drug 
tolerability/safety, additional subjects can be recruited to have at least an additional 12 subjects 
with intensive pharmacokinetic data. Additional subjects may also be recruited if the Sponsor 
and IDMC deem it necessary to have additional subjects with intensive pharmacokinetic data 
because interpretation of the data is hampered by e.g., study drug adherence issues prior to the 
intensive pharmacokinetic sampling time point.
The precision of the efficacy parameter (proportion of subjects with viral load <50 HIV-1 RNA 
copies/mL, TLOVR) expressed as half the width of the (2-sided) 95% CI is presented in Table 7, 
assuming various sample sizes ranging from 10 to 25 subjects and response rates between 70 and 
80%.
Table 7:
Half the Width of the (2-Sided) 95% CI for Various Assumptions, Using the Clopper-Pearson 
Method
Sample size (N)
Response Rate (%)
70
75
80
10
29.3
28.1
26.5
15
24.3
23.2
21.9
20
21.2
20.2
19.0
25
19.0
18.1
16.9
Related to safety, Table 8 provides the probability of at least 1 occurrence of an AE for various 
sample sizes, provided the true incidence rate is 1%, 5%, and 10%.
Table 8:
Probability (%) of ≥1 AE Reported, for Various Assumptions
Sample Size (N)
Incidence Rate (%)
10%
5%
1%
10
65.1
40.1
9.6
15
79.4
53.7
14.0
20
87.8
64.2
18.2
25
92.8
72.3
22.2
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6.6.2.
Statistical Analyses
6.6.2.1.
Initial Subject and Disease Characteristics
All demographic (age, height, weight, gender, body mass index [BMI], ethnic origin) and other 
initial subject characteristics (smoking habits, physical examination, medical and surgical 
history, concomitant diseases) will be tabulated and analyzed descriptively.
6.6.2.2.
Efficacy
6.6.2.2.1.
Plasma viral load
Throughout the analysis, plasma viral load will be log10 transformed. Plasma viral load reported 
as <50 HIV-1 RNA copies/mL will be scored as 49 HIV-1 RNA copies/mL, if not otherwise 
mentioned.
Parameters:
%
The change in plasma viral load from baseline at Week 2 /Week 4 (IDMC analyses 
only).
%
Proportion of subjects with a viral load <50 and <400 HIV-1 RNA copies/mL at all time 
points, and time to achieve these;
%
Proportion of subjects with a decrease from baseline in plasma viral load of 1.0 log10 at 
Week 12
%
Change from baseline in log10 viral load;
6.6.2.2.1.1.
Analysis
An outcome analysis using "Snapshot" approach will be performed, i.e., viral load <50 and <400 
HIV-1 RNA copies/mL observed and missing = failure (M=F). The Snapshot analysis is based 
on the last observed viral load data within the visit window (i.e. Weeks 24 and 48). Subjects who 
switched N(t)RTIs for tolerability reasons not allowed per protocol (see Section 6.3.5) will be 
considered as failures for this Snapshot approach. Proportion responders will be expressed as 
percentages with Clopper-Pearson 95% CI at each time point.
Raw data and changes in log10 plasma viral load will be descriptively and graphically presented. 
Changes in plasma viral load will be part of the efficacy analysis and will not be reported as 
AEs/SAEs.
6.6.2.2.2.
Immunology
Immunology parameter:
%
The change from baseline in CD4+ cell count (absolute and %).
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The analysis will be based on observed values and on imputed values using NC = F, i.e., subjects 
who prematurely discontinued the trial and will have their CD4+ cell count following 
discontinuation imputed with the baseline value (resulting in a change of 0), and will have LOCF
for intermediate missing values.
Raw data and changes versus baseline will be descriptively and graphically presented.
6.6.2.3.
Resistance Determinations
The results of the viral pheno- and genotypes will be evaluated by the Protocol Virologist.
Relevant changes in the viral phenotype and genotype and archived resistance, as applicable, will 
be tabulated and described, particularly for subjects with virologic failure. Changes in viral 
phenotype and genotype will not be regarded as AEs.
Furthermore, phenotypic resistance data, including the fold change in EC50 values, of RPV and 
other ARVs will be described.
6.6.2.4.
Pharmacokinetic Parameter Analyses
Applicable for Intensive PK data:
Pharmacokinetic and statistical analyses of the results will be done using WinNonlin 
Professional™ (Pharsight Corporation, Mountain View, California, U.S.A.), Microsoft Excel® 
(Microsoft Redmond, Washington, U.S.A.) and/or SAS (SAS Institute Inc. Cary, NC, U.S.A.). A 
non-compartmental model with extravascular input will be used for the pharmacokinetic 
analysis.
Based on the individual plasma concentration-time data, using the actual sampling times (see the 
flowchart for scheduled sampling times, Section 2), the following pharmacokinetic parameters 
are to be derived for RPV:
At the Week 2 or Week 4 visit for Cohort 1, and at the Week 2 visit (Day 14-18) for 
Cohort 2: C0h, Cmin, tmax, Cmax, AUC24h, Css,av, CL/F, fluctuation index 
For the pharmacokinetic parameters, definitions and methods of calculation are:
%
C0h: predose plasma concentration;
%
Cmin: minimum plasma concentration between 0 hour and τ (τ = dosing interval);
%
Cmax: maximum plasma concentration;
%
tmax: time to reach the maximum plasma concentration;
%
AUC24h: AUC from time of administration up to 24 hours post dosing, calculated by 
linear trapezoidal summation;
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%
Css,av: average steady-state plasma concentration, calculated by AUCτ / τ at steady-
state (τ = dosing interval);
%
CL/F: total apparent plasma clearance at steady-state, calculated by dose/AUC24h.
%
Fluctuation index, i.e., percentage fluctuation (variation between maximum and 
minimum plasma concentration at steady-state), calculated as 100x ([Cmax - Cmin] / 
Css,av).
The mean AUC24h in adolescents and children will be compared separately with the mean 
AUC24h of the 25 mg q.d. dose in adults.
Descriptive statistics will be calculated for the plasma concentrations of RPV at each time point 
and for the derived pharmacokinetic parameters. Statistics will include sample size (n), mean, 
standard deviation (SD), percentage of coefficient of variation (%CV), geometric mean, median, 
minimum, and maximum.
For each subject, 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.
Applicable for population PK analysis:
Based on the individual plasma concentration-time data, using the actual medication intake and 
sampling times, pharmacokinetic parameters of RPV will be derived for all subjects, using 
population pharmacokinetic modeling. The intensive pharmacokinetic sampling data will also be 
included in the population pharmacokinetic model for further evaluation of the RPV dose with 
modeling and simulation.
 
 
The mean AUC24h in adolescents and children will be compared separately with the mean 
AUC24h of the 25 mg q.d. dose in adults.
Descriptive statistics will be calculated for the derived pharmacokinetic parameters. Summary 
statistics include sample size (n), mean, standard deviation, coefficient of variation (CV), 
geometric mean, median, minimum, and maximum.
Efficacy and safety parameters will be subjected to a pharmacokinetic/pharmacodynamic 
analysis. Various efficacy and safety parameters will be linked to the pharmacokinetics of RPV
applying graphical tools and statistical models, if applicable.
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6.6.2.5.
Safety
6.6.2.5.1.
Adverse Events/HIV-Related Events
Type (system organ class, preferred term) and incidence of all AEs and HIV-related events, 
between the signing of ICF and last trial-related activity, will be tabulated per trial period (i.e., 
screening, the treatment period and follow-up). Separate tabulations will be made by severity, 
drug relationship, and outcome of the AEs. Separate tabulations and listings will be made for 
those subjects who have discontinued the trial for an AE/HIV-related event, or who experienced 
a grade 3 or 4 AE, or an SAE.
6.6.2.5.2.
Clinical Laboratory Tests
For the clinical laboratory data, descriptive statistics will be generated for all tests performed 
(actual values and changes from baseline). Statistics to be presented include number of 
observations (n), mean, standard deviation, median, minimum and maximum.
Additionally, for the tests available, laboratory abnormalities will be calculated according to the 
DAIDS grading table (see Addendum 2: DAIDS Table). Worst toxicity grade after baseline will 
be cross-tabulated versus baseline. Separate tabulations and listings will be provided for those 
subjects who develop a grade 3 or 4 laboratory toxicity. For tests for which no DAIDS grading 
exists, a cross-tabulation versus baseline (with classes below/within/above normal range) will be 
performed.
Clinically significant changes in laboratory values, other diagnostic tests (except for changes in 
resistance pattern, plasma viral load, and CD4+ cell counts), and intercurrent illnesses are AEs.
Descriptive statistics of the actual values and changes from baseline of the endocrine 
assessments at 30 minutes (Cohort 1 only) and 60 minutes after ACTH stimulation as well as for 
the maximal increment after ACTH stimulation will be presented for the respective analytes 
(cortisol, 17-hydroxyprogesterone, aldosterone [Cohort 1 only]). In addition, the proportion of 
subjects with values at all 3 (Cohort 1) and all available (Cohort 2) assessments during ACTH 
stimulation (before, 30 minutes [Cohort 1 only] and 60 minutes after ACTH stimulation) of 
cortisol being <500 nmol/L (18.1 μg/dL), will be tabulated.
Results of the ACTH stimulation test during the concomitant use of ketoconazole (Cohort 1 
only) will be described separately.
Descriptive statistics of the actual values and changes from baseline of the other endocrine 
assessments will be generated.
6.6.2.5.3.
Cardiovascular Safety
The effects on cardiovascular and vital signs parameters will be evaluated by means of 
descriptive statistics (actual values and changes from baseline) and frequency tabulations. 
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Statistics to be presented include number of observations (n), mean, standard deviation, median, 
minimum and maximum.
Vital signs include pulse, SBP and DBP. For the BP parameters, the toxicity definition of the 
DAIDS grading (see Addendum 2: DAIDS Table) will be applied. The percentage of subjects 
with abnormal values (see Section 7.4 for age specific details) will be tabulated at each specific 
time point. 
The ECG parameters that will be analyzed are heart rate, PR interval, QRS interval, RR interval, 
QT interval, QTcB (QT corrected for heart rate according to Bazett34) and QTcF (QT corrected 
for heart rate according to Fridericia35). For the ECG parameters, the toxicity definition of the 
DAIDS grading (see Addendum 2: DAIDS Table) will be applied. The percentage of subjects 
with increases in QTc of <30, 30-60, or >60 milliseconds from screening and abnormal QTc, PR, 
QRS interval, RR interval values (see Section 7.4 for age specific details) will be tabulated at 
each time point.
All important abnormalities from the ECG readings will be reported.
6.6.2.5.4.
Physical Examination
Physical examination findings will be tabulated at each time point.
Body weight and height will be analyzed descriptively (actual values and changes from 
baseline). Statistics to be presented include number of observations (n), mean, standard 
deviation, median, minimum and maximum. These tables will include shifts from baseline values 
to allow detection of relevant changes in individuals.
6.6.2.6.
Diaries
A subject listing will be created with the date and time of intake of RPV from the start of 
treatment with RPV 25 mg q.d. (or adjusted dose if applicable) until the day of intensive 
pharmacokinetic sampling. 
6.6.2.7.
Questionnaires
Subject listings will be created so that adherence can be checked on an individual basis. The 
answers to the different questions will be tabulated at each time point
6.7.
Data Quality Assurance
See Data Quality Assurance (Part II, Section 8).
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7.
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1.
Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents Developed by the 
DHHS on Antiretroviral Guidelines for Adults and Adolescents – A working group of the Office of AIDS 
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2.
Guidelines for the Use of Antiretroviral Agents in Pediatric HIV-Infection. Developed by the Working Group 
on Antiretroviral Therapy and Medical Management of HIV-Infected Children. February 2008.
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Richman DD; HIV Chemotherapy. Nature 2001; 410: 995-1001
4.
TMC278 Investigator’s Brochure, Edition 8, November 2014.
5.
Woodfall B, Hoetelmans R, Peeters M, de Béthune MP. A multicenter Phase IIa, exploratory proof-of-
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Woodfall B, Boven K, Peeters M, Stevens M, van Heeswijk R, Rimsky L. A Phase Iib randomized, partially 
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12.
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Boven K, Vanveggel S, van Heeswijk R, Rimsky L. Rationale for the selection of TMC278 25 mg q.d. rather 
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16.
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Bulletin: NIAID Modifies HIV Antiretroviral Treatment Study, Combination Therapy that includes ABC/3TC 
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Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S. Prospective genetic screening decreases the 
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20.
Boven K, Buelens A, Crauwels H. A Phase I double-blind, double-dummy, randomized, placebo-controlled 
and active-controlled, trial to evaluate the effect of TMC278 25 mg q.d. at steady-state and the effect of 
efavirenz 600 mg q.d. at steady state on the QT/QTc interval in 2 randomized panels of healthy subjects. 
Tibotec Pharmaceuticals Ltd., Clinical Research Report, TMC278-TiDP6-C152, February 2010.
21.
Johnson VA, Brun-Vézinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: Fall 2006. 
IAS-USA Topics in HIV Medicine. 2006; 14: 125-130.
22.
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.
23.
Rimsza ME. Counseling the adolescent about contraception. Pediatrics in Review 2003; 24: 162-170.
24.
Abdulwahab MS et al. The low dose ACTH test does not provide a useful assessment of the hypothalamic-
pituitary-adrenal axis in secondary adrenal insufficiency. Clinical Endocrinology (2002) 56, 533-539.
25.
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): 180-4.
26.
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.
27.
Code of Federal Regulation (21), Parts 210 (current good manufacturing practice in manufacturing, processing, 
packing, or holding of drugs; general) and 211 (current good manufacturing practice for finished 
pharmaceuticals)
28.
Torsades List, Drugs with a risk of Torsades de Pointes, Arizona (USA) Center for Education and Research on 
Therapeutics, available at www.Qtdrugs.org, accessed June 2008
29.
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; 34:571-590
30.
Freeman JV, Cole TJ, Chin SS, et al. Cross sectional stature and weight reference curves for the UK, 1990, 
Arch Dis Child, 1995; 73: 17-24.
31.
National Center for Health Statistics: 2000 CDC Growth Charts. Available at 
http://www.cdc.gov/growthcharts.
32.
https://who.int/growthref/who2007_height_for_age/en/index.html
33.
Tanner JM. Growth at adolescence. Blackwell, 1962.
34.
Bazett HC. 1920. An analysis of the time-relationship of electrocardiograms. Heart; 70: 353-370.
35.
Fridericia LS. 1920. Die Systolendauer im Elektokardiogramm bei normalen Menschen und bei Herzkranken. 
Acta Med. Scand. 15: 335-642.
36.
Ginsberg G., et al. Pediatric pharmacokinetic data: Implications for environmental risk assessment for children. 
Pediatrics 2004; 113 (4): 973-83.
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37.
Note for guidance on clinical evaluation of medicinal products in the pediatric population. 
CPMP/ICH/2711/99, 2001.
38.
Shet A., et al. Anemia and growth failure among HIV-infected children in India: a retrospective analysis. 
BioMed Central Pediatrics 2009; 9(37).
39.
Van Shaick E. Exploratory covariate evaluation based on data up to Week 48 in trial TMC278-C204. Exprimo, 
Mechelen, Belgium. 6 July 2007.
40.
Boven K, Buelens A, Crauwels H. A A Phase I, open-label drug-drug interaction trial to investigate the effect 
of TMC278 25 mg q.d. on the steady-state pharmacokinetics of ethinylestradiol and norethindrone, in healthy 
women. Tibotec Pharmaceuticals Ltd., Clinical Research Report, TMC278-TiDP6-C136, June 2009.
41.
Boven K, Stevens M, Rimsky L, Hoogstoel A, Corbett C, Crauwels H, Vanveggel S. A Phase III, randomized, 
double-blind trial of TMC278 25 mg q.d. versus efavirenz 600 mg q.d. in combination with a fixed background 
regimen consisting of tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naïve HIV-1 infected 
subjects. Tibotec Pharmaceuticals Ltd., Clinical Research Report, TMC278-TiDP6-C209, May 2010.
42.
Boven K, Deckx H, Rimsky L, Hoogstoel A, Corbett C, Crauwels H, Vanveggel S. A Phase III, randomized, 
double-blind trial of TMC278 25 mg q.d. versus efavirenz 600 mg q.d. in combination with a background 
regimen containing 2 nucleoside/nucleotide reverse transcriptase inhibitors in antiretroviral-naïve HIV-1 
infected subjects. Tibotec Pharmaceuticals Ltd., Clinical Research Report, TMC278-TiDP6-C215, June 2010.
43.
TMC278: Module 2.7.3 Summary of Clinical Efficacy. Tibotec Pharmaceuticals Ltd. June 2010.
44.
SCS TMC278: Module 2.7.3 Summary of Clinical Safety. Tibotec Pharmaceuticals Ltd. June 2010.
45.
Responses to CHMP Day 120 List of Questions, March 2011.
46.
Independent Data Monitoring Committee: Meeting minutes, April 2011.
47.
CHMP Day 180 Assessment Report, June 2011.
48.
Antiretroviral therapy for HIV infection in infants and children: towards universal access. World Health 
Organization, 2010. 
(Available online http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf) Accessed on 24 June 
2011.
49.
Violari A, Lindsey JC, Hughes MD, et al.: Nevirapine versus ritonavir-boosted lopinavir for HIV-infected 
children. N Engl J Med 2012, 366: 2380-2389.
50.
Efavirenz [package insert]. Princeton, NJ, USA: Bristol-Myers Squibb Company; 2015.
51.
Clinical Management and Treatment of HIV Infected Adults in Europe. The European AIDS Clinical Society 
(EACS) Guidelines, October 2013. Available at: 
http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf
52.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents 
in HIV-1 infected adults and adolescents. Department of Health and Human Services (DHSS). February 12, 
2013. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
53.
Stevens M, Vanveggel S, Hoogstoel A, Crauwels H, Van Eygen V. 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. Janssen Research & Development. Clinical Research Report, 
TMC278-TiDP38-C213, December 2014.
54.
Lombaard J, Bunupuradah T, Flynn PM, et al. Week 48 safety and efficacy of a rilpivirine (TMC278)-based 
regimen in HIV-infected treatment-naïve adolescents: PAINT Phase II trial [abstract]. 8th IAS conference
(Abtract MOAB0106), Vancouver, Canada, 2015.
55.
Tolia V, Han C, North JD, Amer F.Taste Comparisons for Lansoprazole Strawberry-Flavoured Delayed-
Release Orally Disintegrating Tablet and Ranitidine Peppermint-Flavoured Syrup in Children. Clin Drug 
Invest. 2005;25(5):285-292.
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56.
Angelilli ML, Toscani M, Matsui DM, et al. Palatability of oral antibiotics among children in an urban primary 
care center. Arch Pediatr Adolesc Med 2000; 154: 267-70.
57.
Human Subject Protection Program Guidance Document: Maximum Blood Draw Limits. North Shore LIJ, 
version 15 January 2013.
58.
Levey AS, Bosch JP, Breyer Lewis J, et al. A more accurate method to estimate glomerular filtration rate from 
serum creatinine: A new prediction equation. Ann Int Med 1999; 130: 461-470.
59.
Consolidated Guidelines on the use of Antiretroviral Drugs for Treating and Preventing HIV Infection, second 
edition 2016, available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1
60.
The Normal ECG in Childhood and Adolescence, Heart 2005;91:1626-1630. doi: 10.1136/hrt.2004.057307
61.
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
62.
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.
63.
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.
64.
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
65.
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
66.
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, saferty, tolerability, and antiviral activity of TMC278 in antiviral-naïve HIV-1 
infected adolescents and children aged 6 to < 18 years.
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Addenda
7.1.
Addendum 1: Trial Contact Persons 
An up-to-date version of the contact details of Sponsor, central laboratories and other third 
parties will be available in the investigator site file. 
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7.2.
Addendum 2: DAIDS Table
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC 
ADVERSE EVENTS. PUBLISH DATE: DECEMBER, 2004
Quick Reference
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS 
grading table”) is a descriptive terminology to be utilized for AE reporting in this trial. A grading 
(severity) scale is provided for each AE term.
General Instructions
Estimating Severity Grade
If the need arises to grade a clinical AE that is not identified in the DAIDS grading table, use the category 
“Estimating Severity Grade” located at the top of the table on the following page. 
Grading Adult and Pediatric AEs
The DAIDS grading table includes parameters for grading both adult and pediatric AEs. When a single 
set of parameters is not appropriate for grading specific types of AEs for both adult and pediatric 
populations, separate sets of parameters for adult and/or pediatric populations (with specified respective 
age ranges) are provided. If there is no distinction in the table between adult and pediatric values for a 
type of AE, then the single set of parameters listed is to be used for grading the severity of both adult and 
pediatric events of that type.
Determining Severity Grade
If the severity of an AE could fall under either one of 2 grades (e.g., the severity of an AE could be either 
grade 2 or grade 3), select the higher of the 2 grades for the AE.
Note: The laboratory normal ranges should be taken into consideration to assign gradings to a laboratory 
value.
Definitions
Basic self-care functions
Adult: activities such as bathing, dressing, toileting, transfer/movement, 
continence, and feeding.
Young children: activities that are age and culturally appropriate 
(e.g., feeding self with culturally appropriate eating implement).
Usual social & functional 
activities
Adult: adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, pursuing a hobby, etc.
Young Children: activities that are age and culturally appropriate (e.g., 
social interactions, play activities, learning tasks, etc.).
Medical intervention
Use of pharmacologic or biologic agent(s) for treatment of an AE.
Operative intervention
Surgical OR other invasive mechanical procedures.
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7.4.
Addendum 4: Cardiovascular Safety – Abnormalities
ECGa
1) Adult >16 Years
All important abnormalities from the ECG readings will be reported.
The percentage of subjects with increases in QTc of <30, 30–60, or >60 ms from baseline will also be 
tabulated at each time point.
QTc (ms): 
%
Changes in QTc: increase of <30, 30–60 or >60ms from baseline
%
Normal <450 & borderline &480 < prolonged <500 ≤ pathologically prolonged
QRS (ms):
%
Normal <120 & abnormal
QTc change (ms):
%
Normal <30 & borderline &60 < abnormal high
2) Pediatric &16 Yearsb
Prolonged QTc:
Grade 1: Asymptomatic, QTc interval 0.450–0.464 s
Grade 2: Asymptomatic, QTc interval 0.465–0479 s
Grade 3: Asymptomatic, QTc interval !0.480 s
Grade 4: Life-threatening consequences, e.g., Torsade de Pointes or other associated serious ventricular 
dysrhythmia
                                                          
a   CPMP: Points to consider: The assessment of the potential for QTc interval prolongation by noncardiovascular 
medicinal products. 
b   See Addendum 2: DAIDS Table.
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Vital Signsc
The following abnormalities will be defined for vital signs:
1) Adult >17 Years
Pulse (beats per minute):
%
Abnormally high: !120 bpm
%
Abnormally low: &50 bpm
DBP (mmHg):
%
Abnormally high: Grade 1 or mild: >90 to <100 mmHg
Grade 2 or moderate: !100 to <110 mmHg
Grade 3 or severe: !110 mmHg
%
Abnormally low: &50 mmHg
SBP (mmHg):
%
Abnormally high: Grade 1 or mild: >140 to <160 mmHg
Grade 2 or moderate: !160 to <180 mmHg
Grade 3 or severe: !180 mmHg
%
Abnormally low: &90 mmHg
2) Pediatric &17 Years
Pulse (beats per minute):
%
abnormally high: !120 bpm
%
abnormally low: &50 bpm
DBP and SBP (mmHg):
Grade 1: Not applicable
Grade 2: 91st-94th percentile adjusted for age, height, and gender (systolic and/or diastolic)
Grade 3: !95th percentile adjusted for age, height, and gender (systolic and/or diastolic)
Grade 4: life-threatening consequences (e.g., malignant hypertension) OR hospitalization indicated 
(other than emergency room visit)
                                                          
c   The DAIDS grading scale will be used to classify AEs related to hypotension and hypertension.
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7.5.
Addendum 5: HIV-Related Events or Outcomes in Adolescents and 
Adults (>13 Years Old)
7.5.1.
Clinical categoriesd
The clinical categories of HIV infection are defined as follows.
7.5.1.1.
Category A
Category A consists of 1 or more of the conditions listed below in an adolescent or adult 
(! 13 years) with documented HIV infection. Conditions listed in Categories B and C must not 
have occurred.
%
Asymptomatic HIV infection
%
Persistent generalized lymphadenopathy
%
Acute (primary) HIV infection with accompanying illness or history of acute HIV 
infection
7.5.1.2.
Category B (Symptomatic Non-AIDS Conditions)
Category B consists of symptomatic conditions in an HIV-infected adolescent or adult that are 
not included among conditions listed in clinical Category C, and that meet at least 1 of the 
following criteria: a) the conditions are attributed to HIV infection or are indicative of a defect in 
cell-mediated immunity; or b) the conditions are considered by physicians to have a clinical 
course or to require management that is complicated by HIV infection. Examples of conditions 
in clinical category B include, but are not limited to the following.
%
Bacillary angiomatosis
%
Candidiasis, oropharyngeal (thrush)
%
Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy
%
Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
%
Constitutional symptoms, such as fever (38.5°C) or diarrhea lasting >1 month
%
Hairy leukoplakia, oral
%
Herpes zoster (shingles), involving at least 2 distinct episodes or more than one 
dermatome;
%
Idiopathic thrombocytopenic purpura
%
Listeriosis
%
Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess;
%
Peripheral neuropathy
                                                          
d   1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among 
adolescents and adults. MMWR 1992; 41 (RR-17): 1-19.
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For classification purposes, Category B conditions take precedence over those in Category A. 
For example, someone previously treated for oral or persistent vaginal candidiasis (and who has 
not developed a Category C disease) but who is now asymptomatic should be classified in 
clinical Category B.
The following list of other non-CDC HIV-associated conditions was compiled, as the CDC notes 
that Category B is not limited to events listed in the CDC 1993 definition.
%
Aspergillosis
%
Leishmaniasis
%
Microsporidiosis
%
Molluscum contagiosum
%
Nocardiasis
%
Thrombotic 
microangiopathy 
(haemolytic 
uremic 
syndrome/thrombotic 
thrombocytopenia purpura)
7.5.1.3.
Category C (AIDS Indicator Conditions as Defined by Diagnostic or 
Presumptive Measures)
Category C includes the clinical conditions listed in the AIDS surveillance case definition. For 
classification purposes, once a Category C condition has occurred, the person will remain in 
Category C. Conditions in Category C include the following.
%
Candidiasis of bronchi, trachea, or lungs
%
Candidiasis, oesophageal
%
Cervical cancer, invasive
%
Coccidioidomycosis, disseminated or extrapulmonary
%
Cryptococcosis, extrapulmonary
%
Cryptosporidiosis, chronic intestinal (>1 month’s duration)
%
Cytomegalovirus disease (other than liver, spleen or nodes)
%
Cytomegalovirus retinitis (with loss of vision)
%
Encephalopathy, HIV-related
%
Herpes simplex: chronic ulcer(s) (>1 month’s duration); or bronchitis, pneumonitis, or 
oesophagitis
%
Histoplasmosis, disseminated or extrapulmonary
%
Isosporiasis, chronic intestinal (>1 month’s duration)
%
Kaposi’s sarcoma
%
Lymphoma, Burkitt’s (or equivalent term)
%
Lymphoma, immunoblastic (or equivalent term)
%
Lymphoma, primary, or brain
%
Mycobacterium avium complex or M. kansaii, disseminated or extrapulmonary
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%
Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
%
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
%
Pneumocystis carinii pneumonia or P. jiroveci pneumonia
%
Pneumonia, recurrent (more than one episode in one year period)
%
Progressive multifocal leukoencephalopathy
%
Salmonella septicaemia, recurrent
%
Toxoplasmosis of brain
%
Wasting syndrome due to HIV
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7.6.
Addendum 6: HIV-Related Events or Outcomes in Children (<13 Years 
Old)
7.6.1.
Clinical Categoriese
The clinical categories for children with HIV infection are defined as follows.
7.6.1.1.
Category N: Not Symptomatic
Children who have no signs or symptoms considered to be the result of HIV infection or who 
have only one of the conditions listed in Category A.
7.6.1.2.
Category A: Mildly Symptomatic
Children with two or more of the conditions listed below but none of the conditions listed in 
Categories B and C.
%
Lymphadenopathy (≥0.5 cm at more than two sites; bilateral = one site)
%
Hepatomegaly
%
Splenomegaly
%
Dermatitis
%
Parotitis
%
Recurrent or persistent upper respiratory infection, sinusitis, or otitis media
7.6.1.3.
Category B: Moderately Symptomatic
Children who have symptomatic conditions other than those listed for Category A or C that are 
attributed to HIV infection. Examples of conditions in clinical Category B include but are not 
limited to:
%
Anemia (<8 g/dL), neutropenia (<1.0x 109/L), or thrombocytopenia (<100x 109/L) 
persisting ≥30 days
%
Bacterial meningitis, pneumonia, or sepsis (single episode)
%
Candidiasis, oropharyngeal (thrush), persisting (>2 months) in children >6 months of 
age
%
Cardiomyopathy
%
Cytomegalovirus infection, with onset before 1 month of age
%
Diarrhea, recurrent or chronic
%
Hepatitis
%
Herpes Simplex virus (HSV) stomatitis, recurrent (>2 episodes within 1 year)
%
HSV bronchitis, pneumonitis, or esophagitis with onset before 1 month of age
                                                          
e   CDC 1994 revised classification system for HIV infection in children. MMWR 1994; 43 (RR-12): 1-10.
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%
Herpes zoster (shingles) involving at least 2 distinct episodes or more than 1 dermatome
%
Leimyosarcoma
%
Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex
%
Nephropathy
%
Nocardiosis
%
Persistent fever (lasting >1 month)
%
Toxoplasmosis, onset before 1 month of age
%
Varicella, disseminated (complicated chickenpox)
7.6.1.4.
Category C: Severely Symptomatic
Serious bacterial infections, multiple or recurrent (i.e., any combination of at least two 
culture-confirmed infections within a 2-year period), of the following types: septicamia, 
pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity 
(excluding otitis media, superficial skin or mucosal abscesses, and indwelling catheter-related 
infections)
%
Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)
%
Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical 
or hilar lymph nodes)
%
Cryptococcosis, extrapulmonary
%
Cryptosporidiosis or isosporiasis with diarrhea persisting >1 month
%
Cytomegalovirus disease with onset of symptoms at age >1 month (at a site other than 
liver, spleen, or lymph nodes)
%
Encephalopathy (at least 1 of the following progressive findings present for at least 
2 months in the absence of a concurrent illness other than HIV infection that could 
explain the findings):
o
Failure to attain or loss of developmental milestones or loss of intellectual ability, 
verified by standard developmental scale or neuropsychological tests;
o
Impaired brain growth or acquired microcephaly demonstrated by head 
circumference measurements or brain atrophy demonstrated by computerized 
tomography or magnetic resonance imaging (serial imaging is required for children 
<2 years of age);
o
Acquired symmetric motor deficit manifested by 2 or more of the following: 
paresis, pathological reflexes, ataxia, or gait disturbance
%
Herpes simplex virus infection causing a mucocutaneous ulcer that persists for 
>1 month; or bronchitis, pneumonitis, or esophagitis for any duration affecting a child 
>1 month of age
%
Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or 
hilar lymph nodes)
%
Kaposi’s sarcoma
%
Lymphoma, primary, in brain
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%
Lymphoma, small, noncleaved cell (Burkitt’s), or immunoblastic or large cell 
lymphoma of B-cell or unknown immunological phenotype
%
Mycobacterium tuberculosis, disseminated or extrapulmonary
%
Mycobacterium, other species or unidentified species, disseminated (at a site other than 
or in addition to lungs, skin, or cervical or hilar lymph nodes)
%
Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site other 
than or in addition to lungs, skin, or cervical or hilar lymph nodes)
%
Pneumocystis carinii pneumonia or P. jiroveci pneumonia
%
Progressive multifocal leukoencephalopathy
%
Salmonella (nontyphoid) septicemia, recurrent
%
Toxoplasmosis of the brain with onset at >1 month of age
%
Wasting syndrome in the absence of a concurrent illness other than HIV infection that 
could explain the following findings:
o
Persistent weight loss >10% of baseline OR
o
Downward crossing of at least 2 of the following percentile lines on the 
weight-for-age chart (e.g., 95th, 75th, 50th, 25th, 5th) in a child ≥1 year of age OR
o
>5th percentile on weight-for-height chart on 2 consecutive measurements, 
≥30 days apart PLUS 
(
Chronic diarrhea (i.e., at least 2 loose stools per day for ≥30 days) OR
(
Documented fever (for ≥30 days, intermittent or constant)
Definitive diagnosis: microscopy (histology or cytology); culture; antigen detection.
Presumptive diagnosis: characteristic clinical presentation, supported by investigations other 
than microscopy or culture and after exclusion of other causes in the differential diagnosis.
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7.7.
Addendum 7: Study Adherence Questionnaire for Children and 
Teenagers
Note: This questionnaire is a sample questionnaire. The site should always use the most 
recently provided version of the questionnaire.
TMC278-TiDP38-C213
Study Adherence Questionnaire for Children and Teenagers
To the investigator/trial personnel: please complete the following table and write the names, colour and 
type of the medicines that the child/teenager has been taking in the tables in question 1 and 8.
To be completed by the investigator/trial personnel:
Clinic Number:
Date of Birth:
Pediatric European Network For 
The Treatment of AIDS 11/ Trial 
Number:
Initials:
Date of Assessment:
Week no. (please ring): 
baseline, 1, 2, 4, 8, 12, 16, 24, 
32, 40, and 48
Completed by subject alone?  
Yes     No  
If no, who else was involved? 
________________________
If not completed: Not enough 
time  Refusal  Other 
specify: _________
To be completed by the subject
We know that it can be difficult taking medicines everyday. 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 
Colour, 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 any one 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) 
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Text messages 
Support from Mum/Dad/Carer 
Knowing my blood results 
Knowing why I need to take medicines 
Other  Namely:___________________________
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)
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)
___________________________________________________________________________
Thank you for taking the time to fill out this form, please add any comments you have:
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7.8.
Addendum 8: Study Adherence Questionnaire for Caregivers
TMC278-TiDP38-C213
Note: This questionnaire is a sample questionnaire. The site should always use the most 
recently provided version of the questionnaire.
Study Adherence Questionnaire for Carers
To the investigator/trial personnel: please complete the following table and write the names, colour and 
type of medicines that the child has been taking in the tables in question 3 and 8.
Clinic Number:
Date of Birth:
Pediatric European Network 
For The Treatment of AIDS 
11/ Trial Number:
Initials:
Date of Assessment:
Week no. (please ring): 
baseline, 1, 2, 4, 8, 12, 
16, 24, 32, 40, and 48
Completed by 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 everyday. 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)
What is your relationship to the child? 
Mother 
Father 
Other (please specify) __________
2)
A. Do you give antiretroviral medicines to your child? __________________________
B. Who else gives antiretroviral medicines to your child? __________________________
3)
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.
4)
Which dose, if any, is the most difficult for you or your child? 
None 
morning 
lunchtime/after school 
evening 
all 
5)
How easily do you remember to give all the medicines to your child?
Easily 
quite easily 
with some difficulty 
with great difficulty 
6)
What helps you give the medicines? (tick all that apply)
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Labels  Medicine Chart 
Pill box 
MEM Caps 
Timer/alarm clock/beeper
Diary  Daily events (e.g., breakfast time) 
Other  Name them:
____________________________
7)
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 
How? __________________________________________________________________
8)
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 
9)
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.
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)?

You were too depressed or unwell?

You are fed up giving medicine?

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:
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7.9.
Addendum 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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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 for penis and 
testicle growth, Testicles 
become larger. Testicles 
between 4 and 6 millilitres 
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 millilitres 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 1/2 
inches long.
Pubic hair becomes 
adult type, but less.  
5
Penis growth enters final 
stage.  Average erect penis 
length 6 1/4 inches. 90% are 
5-7 inches. Glans penis or 
head is fully developed. 
Testicles 
16-27 millilitres in volume.
Testicles are about 1-
3/4 inches.
Pubic hair is thick 
spreading to medial 
thighs.  
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7.10.
Addendum 10: Childhood Immunizations
Routine Childhood Immunizations:
Diphtheria, tetanus, pertussis, meningococcus C, mumps, and rubella.
Exceptions for Children With HIV Infection:
1.
BCG. HIV positive individuals should not receive BCG vaccine; there have been reports of 
dissemination of BCG in HIV positive individuals.
2.
Measles. Measles vaccine has been reported to cause fatal disease in one severely 
immunosuppressed HIV positive adult. Some experts do not recommend giving measles 
vaccine to HIV positive children with severe immunosupression (i.e., CD4+ <15%).
No harmful effects have been reported following live attenuated vaccines for mumps or 
rubella in HIV positive children.
3.
Polio. The use of inactivated polio vaccine (IPV), which is safe in HIV-infected children, is 
recommended. The live, oral polio vaccine is not recommended.
No harmful effects have been reported following oral, live attenuated polio vaccine in HIV 
positive children, although some experts recommend IPV be used for all HIV positive 
children.
4.
Yellow fever. There is insufficient evidence as to the safety of Yellow fever vaccine in HIV 
positive people.
Additional Vaccines Can Be Safely Given When Needed:
Inactivated typhoid, inactivated cholera, hepatitis B, pneumococcal, rabies, hepatitis A, and 
meningococcal A+C vaccines.
Experts Recommendations:
Influenza vaccine annually
Pneumococcal vaccine (conjugate followed by polysacharide)
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7.11.
Addendum 11: Pharmacokinetic Modeling for Cohort 2 Dose Selection
As of Amendment 10
The modeling and simulation to define a bodyweight-adjusted RPV dose for children is an 
ongoing process, based on accumulating data over time. Recently the existing RPV population 
PK model for adults and adolescents was updated incorporating also the available RPV plasma 
concentration data from the ongoing subjects in Cohort 2 (≥6 to <12 years of age). The existing 
model was adjusted to better describe the RPV pediatric data by introducing allometric scaling 
(standard factor 0.75) on clearance and intercompartmental flow. Age was not found to be a 
significant covariate for the RPV model parameters. 
With this revised model, RPV exposures across the whole bodyweight range were simulated and 
the following initial RPV dosing scheme was determined for newly enrolled subjects in Study 
C213 Cohort 2 and other ongoing RPV pediatric studies (TMC278HTX2002), regardless of age:
∀
25 mg qd for children with a body weight of ≥25 kg; 
∀
15 mg qd for children with a body weight of ≥11 and <25 kg. 
The simulations indicated that for subjects with a bodyweight ≥25 kg, a RPV dose of 25 mg qd 
can be used safely. 
 
 
 
 
 
 the geometric mean AUC ratio for these pediatric subjects compared to 
adults, based on preliminary non-compartmental analysis of the 24 hour intensive PK visit, was 
1.49 (<150% of adult value).
Children with bodyweight ≥11 and <25 kg will be dosed with an adjusted RPV dose of 15 mg 
qd. 
 
 
 This dose is further supported by the fact that it is generally 
preferred, if safety allows, to dose antiretrovirals (ARVs) at the high rather than at the low end, 
from an efficacy perspective. In addition, the 0.75 allometric scaling factor may be a 
conservative estimate potentially overestimating the effect of bodyweight on the RPV PK, given 
the currently limited data for children with lower bodyweight.
The data and strategy were discussed with and supported by the IDMC for studies C213 and 
TMC278HTX2002.
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Prior to Amendment 10
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7.12.
Addendum 12: Taste Assessment Form for Children
Note: This questionnaire is a sample questionnaire. The site should always use the most 
recently provided version of the questionnaire.
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Appendix 1
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Appendix  2
  Can you tell us what this study medication tasted like?
            ) ----------------  )
Tasted like WATER                  Tasted like ---------------?
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PART 2.
PROCEDURES
1.
ADVERSE EVENTS
1.1.
Definitions
ADVERSE EVENT 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(International Conference on Harmonization - ICH E6; 1.2).
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.
SERIOUS ADVERSE EVENT
Any untoward medical occurrence that at any dose:
%
Results in death
%
Is life-threatening
(The subject 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 (ICH E6; 1.50)
%
Is a suspected transmission of any infectious agent via a medicinal product;
%
Is Medically Important.
Note 
%
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is 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 subject or may require intervention to prevent 1 of the outcomes listed in 
the definition above. These events should usually be considered serious.
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Hospitalizations that were planned prior to 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 (see also Section 1.4).
%
For convenience the investigator may choose to hospitalize the subject for the duration 
of the treatment period; this will not be considered as a SAE.
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 Investigator's Brochure.
LIFE-THREATENING
Any event in which the subject was at risk of death at the time of the event; it does not refer to an 
event, which hypothetically might have caused death if it were more severe.
ASSOCIATED WITH THE USE OF THE DRUG
An AE is considered associated with the use of the drug if the attribution is possible, probable or 
very likely.
1.2.
Attribution Definitions
NOT RELATED
An AE which is not related to the use of the drug.
DOUBTFUL
An AE for which an alternative explanation is more likely, e.g., concomitant drug(s) or 
concomitant disease(s), and/or the relationship in time suggests that a causal relationship is 
unlikely.
POSSIBLE
An AE which might be due to the use of the drug. An alternative explanation, e.g., concomitant 
drug(s) or concomitant disease(s), is inconclusive. The relationship in time is reasonable; 
therefore the causal relationship cannot be excluded.
PROBABLE
An AE which might be due to the use of the drug. The relationship in time is suggestive, e.g., 
confirmed by dechallenge. An alternative explanation is less likely, e.g., concomitant drug(s) or 
concomitant disease(s).
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VERY LIKELY
An AE, which is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, e.g., concomitant drug(s) or concomitant disease(s). The relationship in 
time is very suggestive (e.g., it is confirmed by dechallenge and rechallenge).
1.3.
HIV-Related Events or Outcomes
The events or outcomes listed in the classification list (see Part I, Addendum 5: HIV-Related 
Events or Outcomes in Adolescents and Adults and Addendum 6: HIV-Related Events or 
Outcomes in Children) will be recorded as HIV-related events on the eCRF. These events or 
outcomes, as well as any sign, symptom, diagnosis, illness, and/or clinical laboratory 
abnormalities that can be linked to any of these events or outcomes, are not to be reported as an 
AE.
1.4.
Reporting of AEs and HIV-Related Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, 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.
AEs and HIV-related events will be collected from the signing of the ICF until completion of the 
subject's last trial-related procedure (which may include contact for follow-up of safety). 
Occurrence of AEs and HIV-related events will be reported in the AE and HIV-Related Events 
sections of the eCRF, respectively.
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (e.g., cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). Investigators must record in the eCRF their opinion concerning the relationship of 
the AE to trial therapy. All measures required for AE management must be recorded in the 
source document and reported according to Sponsor instructions.
All AEs still ongoing at the end of the treatment will be followed until satisfactory resolution 
(i.e., value back to baseline value) or stabilization (to be agreed upon in collaboration with the 
Sponsor). 
New AEs reported during the follow-up period of the trial will be followed as agreed between 
the Sponsor and investigator.
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Certain long-term AEs of ARTcannot 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.
SAEs occurring within the clinical trial (between signing of the ICF and last follow-up visit) and 
those spontaneously reported to the investigator within 30 days after the last dose of study drug
must be reported using the Serious Adverse Event Form. The Sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
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 a SAE, the start date of the SAE must be the 
same as the start date of the worsened AE.
The cause of death of a subject in a clinical trial, whether the event is expected or associated with 
the investigational agent, is a SAE. 
Information regarding SAEs will be transmitted to the Sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a physician from the trial site, and transmitted to 
the Sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by 
facsimile (fax).
All SAEs that have not resolved by the end of the trial, or that have not resolved upon 
discontinuation of the subject's participation in the trial, 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 drug or to factors unrelated to 
trial conduct
%
It becomes unlikely that any additional information can be obtained (subject 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 subject's participation in a trial must be reported as an SAE, except hospitalizations 
for the following:
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%
Surgery or procedure planned before entry into the trial (must be documented in the 
eCRF). 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.
%
For convenience the investigator may choose to hospitalize the subject for the duration 
of the treatment period.
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the Sponsor by the trial-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (e.g., spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs
and must be reported using the Serious Adverse Event Form. Any subject who becomes pregnant 
during the trial must be promptly withdrawn from the trial and discontinue further trial treatment.
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the trial are listed on the Contact Information 
page(s), which will be provided as a separate document.
The Sponsor or its representatives will assume responsibility for appropriate reporting of AEs to 
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 (IEC)/Institutional Review Board (IRB) that approved the 
protocol unless otherwise required and documented by the IEC/IRB.
After termination of the clinical trial (last subject last visit in the trial), any unexpected safety 
issue that changes the risks benefit analysis and is likely to have an impact on the subjects who 
have participated in it, should be reported as soon as possible to the competent authority(ies) 
concerned together with proposed actions.
Special reporting situations
Safety events of interest on a Sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:
%
Overdose of a Sponsor study drug
%
Suspected abuse/misuse of a Sponsor study drug
%
Inadvertent or accidental exposure to a Sponsor study drug
%
Medication error involving a Sponsor study drug (with or without subject/patient 
exposure to the Sponsor study drug, e.g., name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
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2.
TRIAL CLOSURE CONSIDERATIONS
2.1.
Trial Completion
The trial is considered completed with the last trial visit for the last subject participating in the 
trial. The final data from the trial site will be sent to the Sponsor (or designee) after completion 
of the final subject visit at that trial site, in the time frame specified in the Clinical Trial 
Agreement.
2.2.
Trial Termination
The Sponsor reserves the right to close an investigational site or terminate the trial at any time 
for any reason. Trial sites will be closed upon trial completion. A trial site is considered closed 
when all required documents and trial supplies have been collected and a trial-site closure visit 
has been performed.
Reasons for the closure of an investigational site or termination of a trial by the Sponsor may 
include but are not limited to:
%
Successful completion of the trial at the center
%
The overall required number of subjects for the trial has been recruited
%
Failure of the investigator to comply with the protocol, ICH-Good Clincial Practice 
(GCP) guidelines or local requirements
%
Safety concerns
%
Sufficient data suggesting lack of efficacy
%
Inadequate recruitment of subjects by the investigator
%
Discontinuation of further study drug development
3.
TRIAL MATERIALS
3.1.
Investigational Products
The investigator acknowledges that the drug supplies are investigational and as such must be 
handled strictly in accordance with the protocol and the container label. Supplies must be 
retained in a limited access area and under the appropriate environmental conditions as specified 
on delivery. Supplies should be dispensed under the supervision of the investigator or 
subinvestigator, or by a hospital pharmacist. Local regulations should be adhered to.
It is the investigator’s responsibility to ensure that subjects or those held to be responsible for 
subjects, return their medication (including empty packages, e.g., empty blisters). Returned 
supplies must not be dispensed again, even not to the same subject. Each time medication is 
dispensed to or returned by the subject, this must be documented on the Drug Accountability 
Form. Whenever a subject brings his/her medication to the site for pill count this is not seen as a 
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return of supplies. Unused medication and medication returned by the subject must be available 
for verification by the monitor. 
All used and unused study drug will be returned to the Sponsor or will be passed over for 
destruction on-site (conform local regulations), or by an authorized destruction unit after 
authorization by the Sponsor. This will be documented on the Drug Return Form and a 
destruction certificate or on the Investigational Product Destruction Form, if applicable.
3.2.
Trial Documents
For Cohort 1 the following documents must be provided to the Sponsor or representatives before 
shipment of RPV to the trial center. 
%
A signed and dated protocol and amendment(s), if any.
%
A copy of the signed and dated written IEC/IRB approval specifying the documents 
being approved: the protocol, amendments, ICF, Informed Assent Form, any other 
written information provided to the subject, if applicable, subject compensation 
programs and subject recruitment materials. This approval must clearly identify the trial 
by protocol title and trial number and must be signed by the chairman or authorized 
designee.
%
Regulatory authority approval or notification, if required.
%
Documentation on which the assessment of the investigator’s qualifications was based 
(e.g., curriculum vitae).
For Cohort 2, in addition to the items mentioned above also the items below must be provided to 
the Sponsor or representatives before shipment of RPV to the trial center:
%
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 trial-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 trial.
%
Signed and dated statement of investigator (e.g., Form FDA 1572), if applicable.
%
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.
For both cohorts, the following documents must be provided to the Sponsor or representatives 
prior to enrollment of the first subject (unless it was already required to be provided before 
shipment of RPV to the trial center [see above for Cohort 2]).
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The names of the current members or composition of the IEC/IRB and their position in 
the health-care institution or their credentials. In case the (sub)investigator is a member 
of the IEC/IRB, documentation must be obtained to state that this person did not 
participate in the voting for the trial.
%
Completed Investigator Financial Disclosure Forms from the investigator and all 
subinvestigators.
%
Signed and dated trial agreement, if applicable.
%
Signed and dated financial agreement.
%
Documentation on which the assessment of the subinvestigators’ qualifications was 
based (e.g., curriculum vitae).
%
Name and address of any local laboratory conducting tests for the trial and current 
laboratory normal ranges for all tests required by the protocol that will be performed.
%
Laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(e.g., accreditation/license), if applicable.
For Cohort 2, the following documents must also be provided:
%
Completed 
Site 
Signature 
Log–Delegation 
of 
Responsibilities 
(SSL-DoR) 
(FRM-15505), mandatory task-related training, and completed Investigational Staff 
Training Documentation (ISTD) (FRM-15506) for Principal Investigator, Head 
Pharmacist (if applicable) and other identified key investigational staff (e.g., Rater, Trial
Coordinator, if applicable).
The investigator will be provided with the following supplies:
%
Investigator's Brochure
%
Pharmacy manual/trial site investigational product manual
%
Laboratory manual
%
Questionnaires and user manuals
%
Electronic Data Capture (EDC) manual
%
Central ECG machine and ECG manual
%
Any other manual, as applicable
%
Sample ICF and assent form
%
Subject diaries
%
Contact Information page(s)
%
Subject Participation Card
%
Recruitment and enrollment tools
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3.3.
Participation Cards
Cohort 1: Adolescents Aged ≥12 to <18 Years
If the subjects are not under 24-hour supervision of the investigator or his/her staff 
(out-subjects), they must be provided with a Subject Participation Card indicating the name of 
the investigational product, the trial number, the investigator’s name and a 24-hour emergency 
contact number. The subject should be advised to keep the participation card in his/her wallet at 
all times.
Cohort 2: Children Aged ≥6 to <12 Years
For all studies with an outpatient phase, including open label studies, the subject must be 
provided with a "wallet (trial) card" and instructed to carry this card with them for the duration of 
the trial indicating the following: 
%
Trial number
%
Statement, in the local language(s), that the subject is participating in a clinical trial
%
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
%
Subject number
The wallet (trial) card has to be in the subject's local language and may also include a translation 
in an additional language, as appropriate.
3.4.
Source Data
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF:
%
Subject identification (name, date of birth, gender)
%
Documentation that subject meets eligibility criteria, i.e., history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria)
%
Trial identification
%
Trial discussed and date of informed consent
%
Dates of all visits
%
Results of efficacy parameters, as required by the protocol
%
Drug receipt/dispension/return records, study drug administration information
%
Record of all AEs and follow-up of AEs
%
Concomitant medication
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%
Date of trial completion and reason for early discontinuation of study drug or 
withdrawal from the trial, if applicable
In addition, the author of an entry in the source documents should be identifiable. Direct access 
to source documentation (medical records) must be allowed for the purpose of verifying that the 
data recorded on the eCRF are consistent with the original source data.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the trial site as a basis for standard medical care. 
Specific details required as source data for the trial will be reviewed with the investigator before 
the trial and will be described in the monitoring guidelines (or other equivalent document).
The following data will be recorded directly into the eCRF and will be considered source data: 
%
Race
%
History of smoking
%
Blood pressure and pulse/heart rate 
%
Height and weight
%
Details of physical examination
Subject- and investigator-completed scales, assessments, and diaries designated by the Sponsor 
will be recorded and will be considered source data. Information from the diary, provided to 
subjects, will be reviewed by the investigator or designee before data management transcribes 
the data into the relevant parts of the eCRF. Refer to the CRF Completion Guideline for more 
details about how the source data is transferred to the eCRF.
The minimum source documentation requirements for Section 6.2.2, Inclusion Criteria and 
Section 6.2.3, 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 subject interview or other protocol required assessment (e.g., physical examination, 
laboratory assessment) and documented in the source documents.
3.5.
Electronic Case Report Forms 
Case report forms are provided for each subject in electronic format.
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Electronic Data Capture  will be used for this trial, meaning that all data will be entered in eCRF 
at the investigational site.
All data must be entered in English.
The eCRFs should always reflect the latest observations on the subjects participating in the trial. 
Therefore, the eCRFs are to be completed as soon as possible during or after the subject’s visit. 
To avoid interobserver variability, every effort should be made to ensure that the same individual 
who made the initial baseline determinations completes all efficacy/safety evaluations. The 
investigator must verify that all data entries in the eCRFs are accurate and correct. If some 
assessments are not done, or if certain information is not available, not applicable, or unknown, 
the investigator should indicate this in the eCRF. The investigator will be required to 
electronically sign off the clinical data. 
The monitor will review the eCRFs, evaluate them for completeness and consistency. The eCRF 
will be compared with the source documents to ensure that there are no discrepancies between 
critical data. All entries, corrections and alterations are to be made by the responsible 
investigator or his/her designee. The monitor cannot enter data in the eCRFs. Once clinical data 
of the eCRF have been submitted to the central server, corrections to the data fields will be audit 
trailed, meaning that the reason for change, the name of the person who performed the change, 
together with time and date will be logged. Roles and rights of the site personnel responsible for 
entering the clinical data into the eCRF will be determined in advance. 
If additional corrections are needed, the responsible monitor or data manger will raise a query in 
the EDC application. The appropriate investigational staff will answer queries sent to the 
investigator. This will be audit-trailed by the EDC application meaning that the name of 
investigational staff, time and date stamp are captured.
3.6.
Subject Identification Code List & Subject Screening and Enrollment 
Log
In order to permit easy identification of the individual subject during and after the trial, the 
investigator is responsible for keeping an updated Subject Identification Code List or subject 
identification and enrollment log. The monitor will review this document for completeness. 
However, in order to ensure subject confidentiality, this document will remain at the center and 
no copy will be made. All reports and communications relating to the trial will identify subjects 
by subject identification and date of birth. In cases where the subject is not enrolled into the trial, 
the date seen and date of birth will be used.
A Subject Screening and Enrollment Log on all subjects who were seen to determine eligibility 
for inclusion in the trial also has to be completed by the investigator.
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3.7.
Archiving
The investigator shall maintain the trial documents as specified in “Essential Documents for the 
Conduct of a Clinical Trial” (ICH E6; 8.2-8.4) and as required by the applicable regulatory 
requirement(s). The investigator should take measures to prevent accidental or premature 
destruction of these documents.
Essential documents should 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 at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period however, if required by the applicable regulatory requirements.
It is the responsibility of the Sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained.
Under no circumstance shall the investigator relocate or dispose of any trial documents before 
having obtained a written approval of the Sponsor.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the trial records, 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. 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation relating to this trial, the investigator must permit access to such reports. The 
subject is granting access to his/her source data by signing the ICF.
Any difficulty in storing original documents must be discussed with the monitor prior to the 
initiation of the trial.
3.8.
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 subjects, 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) involves only logistic or administrative aspects of the trial, the IRB 
(and IEC where required) only needs to be notified.
During the course of the trial, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate Sponsor 
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representative (see Contact Information page(s) provided separately). 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 eCRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
3.9.
Monitoring
The Sponsor will use a combination of monitoring techniques to monitor this trial.
The Sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a trial site visit log that will be kept at the trial 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 eCRFs with the hospital or clinic records 
(source documents). The nature and location of all source documents will be identified to ensure 
that all sources of original data required to complete the eCRF are known to the Sponsor and 
trial-site personnel and are accessible for verification by the Sponsor trial-site contact. If 
electronic records are maintained at the trial site, the method of verification must be discussed 
with the trial-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the trial-site personnel. 
The Sponsor expects that, during monitoring visits, the relevant trial-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of trial-related documents. The monitor will meet with the investigator on a 
regular basis during the trial to provide feedback on the trial conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, trial-site personnel will be available to provide an update on the progress 
of the trial at the site. 
Central monitoring will take place for data identified by the Sponsor as requiring central review.
4.
CONFIDENTIALITY
All information concerning the product and the Sponsor’s operations (such as patent 
applications, formulae, manufacturing processes, basic scientific data, or formulation 
information supplied to the investigator by the Sponsor and not previously published) is 
considered confidential by the Sponsor and should not be disclosed by the investigator to any 
third party without the Sponsor’s prior written approval. The investigator agrees to use this 
information only in accomplishing the trial and will not use it for other purposes.
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5.
REPORTING AND PUBLICATION
5.1.
Reporting
The Sponsor will create a Development Safety Update Report (DSUR) and Line Listings in 
accordance with the ICH guideline E2F with a data-lock date of 20 May. This trial 
TMC278-TiDP38-C213 will be included in the first DSUR produced after approval of this 
protocol, which may be less than 1-year's time from this particular trial approval date, and in all 
subsequent DSURs, as appropriate, until trial closure.
The results of the trial will be reported in clinical study reports per Cohort. A summary of the 
final report will be provided to the investigators, to the applicable regulatory authorities, and 
IECs/IRBs, if required by the applicable regulatory requirements, within 1 year after end of trial.
If deemed appropriate, additional interim clinical study reports will be created to describe 
information from other analyses (e.g., primary analysis, interim analysis).
One investigator will be appointed for signing off the final clinical study report. The selection of 
this investigator will be determined by the recruitment performance and specific expertise related 
to the nature and the key assessment parameter(s).
5.2.
Use of Information and Publication
All information, including but not limited to information regarding RPV or the Sponsor's 
operations (e.g., patent application, formulas, manufacturing processes, basic scientific data, 
prior 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 trial, 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 trial, 
and will not use it for other purposes without the Sponsor's prior written consent.
The investigator understands that the information developed in the trial 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 trial.
Results of analyses performed after the clinical study reports have been issued will be reported in 
a separate report and will not require a revision of the clinical study report. Trial subject 
identifiers will not be used in publication of results. Any work created in connection with 
performance of the trial and contained in the data that can benefit from copyright protection 
(except any publication by the investigator as provided for below) 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 guidelines, the Sponsor shall have the right to publish such primary (multicenter) data 
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and information without approval from the investigator. The investigator has the right to publish 
trial site-specific data after the primary data are published. If an investigator wishes to publish 
information from the trial, 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. In the event that 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 trial designs and subtrial approaches, secondary results generally 
should not be published before the primary endpoints of a trial have been published. Similarly, 
investigators will recognize the integrity of a multicenter trial by not submitting for publication 
data derived from the individual trial site until the combined results from the completed trial
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the Sponsor confirms there will be no multicenter trial publication. 
Authorship of publications resulting from this trial will be based on the guidelines on authorship, 
such as those described in the Uniform Requirements for Manuscripts Submitted to Biomedical 
Journals, which state that the named authors must have made a significant contribution to the 
design of the trial or analysis and interpretation of the data, provided critical review of the paper, 
and given final approval of the final version.
Registration of clinical studies and disclosure of results
The Sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
6.
AUTHORITIES/ETHICS
6.1.
Regulatory Authorities
This trial will be submitted to the local regulatory authority for approval or notification 
whichever is applicable. The trial will only be undertaken in compliance with the local 
regulatory requirements.
6.2.
Independent Ethics Committee/Institutional Review Board
Before the start of the trial, the investigator (or Sponsor where required) 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 subjects)
%
Investigator's Brochure (or equivalent information) and amendments/addenda
%
Sponsor-approved subject recruiting materials
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%
Information on compensation for trial-related injuries or payment to subjects for 
participation in the trial, 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 subjects
%
Any other documents that the IEC/IRB requests to fulfill its obligation
This trial can only be undertaken after full approval of the protocol, informed consent, any other 
written information given to subjects, and subject recruitment materials has been obtained from 
the IEC/IRB. This document must be dated and clearly identify the trial and the documents being 
approved, including the subject compensation programs.
During the trial the following documents will be sent to the IEC/IRB for their review:
%
Changes to the Investigator’s Brochure
%
Reports of AEs that are serious, unlisted and associated with the investigational drug
%
DSUR and Line Listings
%
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or trial conduct)
%
Revision(s) to ICF and any other written materials to be provided to subjects
%
If applicable, new or revised subject recruiting materials approved by the Sponsor
%
Revisions to compensation for trial-related injuries or payment to subjects for 
participation in the trial, if applicable
%
Summaries of the status of the trial at intervals stipulated in guidelines of the IEC/IRB 
(at least annually)
%
New information that may adversely affect the safety of the subjects or the conduct of 
the trial
%
Deviations from or changes to the protocol to eliminate immediate hazards to the 
subjects
%
Report of deaths of subjects under the investigator's care
%
Notification if a new investigator is responsible for the trial at the site
%
Any other requirements of the IEC/IRB
Substantial amendments and applicable ICF revisions must promptly be submitted to the 
IEC/IRB for review and approval prior to implementation of the change(s), except when 
necessary to eliminate an immediate hazard to the trial subjects.
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The IEC/IRB is responsible for continuous review of the trial. At least once a year, the 
investigator will provide the IEC/IRB with a progress report to allow review of the trial. 
Additional progress reports should be provided if required by the IEC/IRB. 
These requests and (re)approvals, if applicable, should be documented in writing. 
At the end of the trial, the investigator (or Sponsor where required) will notify the IEC/IRB 
about the trial completion.
6.3.
ICH-GCP Guidelines
This trial will be conducted in accordance with the current ICH-GCP Guidelines. 
Good Clinical Practice  is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting trials that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety and well being of 
trial subjects are protected, consistent with the principles that have their origin in the Declaration 
of Helsinki, and that the clinical trial data are credible.
6.4.
Subject Information and Informed Consent
General
Prior to entry in the trial, the investigator or a person designated by the investigator must explain 
to potential subjects and/or their parent(s) or legally authorized representative(s) the trial and the 
implications of participation (the aims, methods, reasonably anticipated benefits, and potential 
hazards of the trial, and any discomfort participation in the trial may entail). During the trial, 
subjects and/or their parent(s) or legally authorized representative(s) will be given any new 
information that may affect their decision to continue participation. Subjects will be informed 
that their participation is voluntary and that they may withdraw from the trial at any time with no 
reason given and without penalty or loss of benefits to which they would otherwise be entitled. 
They will be informed that choosing not to participate or to withdraw from the trial will not have 
an impact on the care the subject will receive for the treatment of his/her disease. Subjects will 
be told that alternative treatments are available if they refuse to take part in this trial. Finally, 
they will be told that their records may be accessed by the IEC/IRB, competent authorities and 
authorized representatives of the Sponsor or the contract research organization (CRO) without 
violating the confidentiality of the subject, to the extent permitted by the applicable law(s) and/or 
regulations. By signing the ICF, the subject or their parent(s)/legally authorized representative(s)
are authorizing such access, and agree to allow his or her trial physician to recontact the subject
and/or their parent(s) or legally authorized representative(s) for the purpose of obtaining consent 
for additional safety evaluations, if needed. Only subjects and/or their parent(s) or legally 
authorized representative(s) who are fully able to understand the risks, benefits, and potential 
adverse events of the trial, and provide their consent/assent voluntarily will be enrolled.
The ICF(s) must be signed before performance of any trial-related activity. The ICF(s) and 
assent form(s) that are used must be approved by both the Sponsor and by the reviewing 
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IEC/IRB and be in a language that the subject and their parent(s) or legally authorized 
representative(s) can read and understand. The informed consent should be in accordance with 
principles that originated in the Declaration of Helsinki, current ICH and GCP guidelines, 
applicable regulatory requirements, and Sponsor policy.
If a subject and his/her parent or legally authorized representative are unable to read, an impartial
witness must be present during the entire informed consent discussion. The signature of the 
impartial witness will certify the subject’s or parent's or legally authorized representative's
consent. The subject and/or their parent(s) or legally authorized representative(s) will be given 
sufficient time to read the ICF and to ask additional questions. After this explanation and before 
entry in the trial, consent should be appropriately recorded by means of either the subject's or his 
or her parent's or legally authorized representative's personally dated signature or by the 
signature of an independent witness who certifies the subject's or his or her parent's or legally 
authorized representative's consent in writing. After having obtained the consent, a copy of the 
signed and dated ICF must be given to the subject.
Any information relevant to the subject’s willingness to participate in the trial will be provided to 
the subject and/or their parent(s) or legally authorized representative(s) in a timely manner by 
means of an updated ICF. This amended ICF will be signed by either the subject or their 
parent(s) or legally authorized representative(s) and the investigator to document the willingness 
of the subject to continue with the trial. This signed and dated amended version will be filed 
together with the initial signed and dated ICF.
Pediatric subjects
The special vulnerability of children requires specific measures in the informed consent process 
in order to safeguard their interests and to protect them from harm.
As a rule, a pediatric subject is legally unable to provide informed consent. Therefore children 
are dependent on their parent(s)/legal guardian to assume responsibility for their participation in 
the clinical trial. While children are legally incapable of giving informed consent, they 
nevertheless may possess the ability to assent or to dissent from participation. Out of respect for 
children as developing persons, children will be asked whether or not they wish to participate in 
the research, after having been informed about the trial 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. Where appropriate, participants should assent to 
enroll in a trial (age of assent is to be determined by IEC/IRB or to be consistent with local legal 
requirements). The parent(s)/legal guardian will be responsible for the actual informed consent, 
while the child will be asked to assent. Minors who assent to a trial and later withdraw that 
assent should not be maintained in the trial against their will, even if their parents still want them 
to participate.
The following information forms (including consent / assent form) will be used by the 
investigational staff:
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%
Parent / legal guardian and adolescent information sheet and consent form
%
Children information sheet and assent form
The way these forms are composed and used will be in accordance with local laws and
regulations (e.g., the age at which adolescents are legally declared ‘mature’ may differ from 
country to country, and in case children can not write their names, drawing for example a smiley 
face to assent is allowed practice in some countries).
All applicable forms will be submitted for review and approval to IECs/IRBs.
If local regulations allow, the investigator/trial nurse or social worker could also consider having 
a private session with the subject to address sensitive issues related to alcohol use, sexual 
activity, drug screen and any other.
6.5.
Privacy of Personal Data
The processing of personal data in pursuit of this trial will be limited to those data that are 
reasonably necessary to investigate the efficacy, safety, quality, and utility of the investigational 
product(s) used in this trial. These data will be processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and regulations.
The Sponsor or its representatives whose responsibilities require access to personal data are 
obliged to keep the identity of trial subjects confidential. 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. This 
confidentiality will be maintained throughout the complete data processing. Trial subjects will be 
entitled to request confirmation of the existence of personal data held by the Sponsor and will
have the right to rectify erroneous or inaccurate data. Reasonable steps will be taken to respond 
to such a request, taking into consideration the nature of the request, the conditions of the trial, 
and the applicable laws and regulations.
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for trial-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.
6.6.
Country Selection
This trial will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product.
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7.
FINANCING AND INSURANCE
7.1.
Financial Disclosure
The disclosed financial interest of the investigator must be collected before enrollment of the 
first subject. The investigator should promptly update this information if any relevant changes 
occur up to 1 year following trial completion.
Disclosable financial interests will be recorded on the Investigator Financial Disclosure Form. 
Any investigator(s) added as investigational staff must complete the Investigator Financial 
Disclosure Form at the beginning of their participation in the trial. For any investigator(s) 
leaving the site prior to trial completion, an Investigator Financial Disclosure Form should be 
obtained in case of updates at the end of their participation.
7.2.
Indemnification
The Sponsor undertakes to indemnify and hold harmless the investigator and his/her medical 
staff from any claim, demand or cost arising from the activities to be carried out in compliance 
with the protocol, as further specified in the Clinical Trial Agreement. 
7.3.
Insurance
Sponsor ensures that an appropriate liability insurance is available covering injuries arising from 
the participation of the trial subject in this trial, as further specified in the Informed Consent and 
the Clinical Trial Agreement.
8.
DATA QUALITY CONTROL/ASSURANCE
The trial will be monitored by the Sponsor or representatives according to the current Standard 
Operating Procedure for the monitoring of clinical trials.
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate trial sites, review of protocol procedures with the investigator and 
trial-site personnel before the trial, and periodic monitoring visits by the Sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples.
Shortly before the trial starts, the monitor will meet with the investigator and all staff involved to 
review the procedures regarding trial conduct and recording the data into the eCRF system. 
During the trial, the investigator shall permit the Site Manager to verify the progress of the trial 
at the center as frequently as necessary. The Sponsor will review eCRFs for accuracy and 
completeness during on-site monitoring visits and after transmission to the Sponsor After upload 
of the data into the trial database they will be verified for accuracy and consistency with the data 
sources. The investigator shall make the electronic data screens available, provide missing or 
corrected data, and will correct the data in the eCRF system. Personal information will be treated 
as strictly confidential and will not be made publicly available. 
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Approved, Issued Date: 03-FEB-2020
The Sponsor will ensure that appropriate Quality Control (QC) steps are included into the 
different clinical processes to guarantee adequate protection of the trial subjects and quality of 
the data.
An independent Quality Assurance (QA) department, regulatory authorities and/or IECs/IRBs 
may review this trial. This implies that auditors/inspectors will have the right to inspect the trial 
center(s) at any time during and/or after completion of the trial and will have access to source 
documents, including the subject’s file. By participating in this trial, investigators agree to this 
requirement. The investigator and trial-site personnel are responsible for being present and 
available for consultation during routinely scheduled trial-site audit visits conducted by the 
Sponsor or its designees.
The investigator should immediately notify the Sponsor if he or she has been contacted by a 
regulatory agency concerning an upcoming inspection (both announced and unannounced).
For any data transfer, measures will be undertaken to protect subject data handed over against 
disclosure to unauthorized third parties and subject confidentiality will be maintained at all 
times.
9.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e., 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 subjects, 
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.
9.1.
Procedures
All initial PQCs must be reported to the Sponsor by the trial-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with an SAE, the trial-site personnel must report the PQC to the 
Sponsor according to the SAE reporting timelines (refer to Section 1.4). A sample of the 
suspected product should be maintained for further investigation if requested by the Sponsor.
9.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
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TMC278-TiDP38-C213
Clinical Trial Protocol Amendment X
225
Approved, Issued Date: 03-FEB-2020
SIGNATURE PAGE
Global Medical Leader/Trial Physician:
This document has been reviewed and approved by the Sponsor in order to ensure compliance with Good 
Clinical Practices.
Name: 
Affiliation:
Janssen Research & Development
See appended electronic signature page
Investigator:
The trial will be performed in compliance with Good Clinical Practices, including the archiving of 
essential documents.
Name:
Affiliation:
Signature & Date:
PPD
NCT00799864


SIGNATURES
Signed by  
Date 
Justification
03Feb2020, 15:38:43 PM, UTC
Document Approval
PPD
NCT00799864


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 3 June 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
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
Protocol TMC278-TiDP38-C213; Phase II   
TMC278  rilpivirine
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF THE 
PROTOCOL EDMS-ERI-102141585
*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
UC; Janssen Biopharma Inc.; 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.
EudraCT NUMBER:         2008-001696-30
Status:
Approved
Date:
3 June 2020
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-RIM-60771 v1.0
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.
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COVID-19 Appendix
TMC278 rilpivirine
Clinical Protocol TMC278-TiDP38-C213
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 3 June 2020
COVID-19 APPENDIX
GENERAL GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by patients and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study 
related patient management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of patients and site staff and to maintain oversight 
of delegated trial activities. If, at any time, a patient’s safety is considered to be at risk, study drug 
will be discontinued, and study follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, patients will be interviewed to collect safety data. Sampling for efficacy endpoint 
assessments should be conducted and stored on-site or performed locally in case sample shipments 
to the central laboratory are disrupted. Patients will also be questioned regarding general health 
status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for patients, including 
follow up. Modifications to protocol-required assessments may be permitted after consultation 
with the patient, investigator, and the sponsor. Missed assessments/visits will be documented as
protocol deviations with the prefix "COVID-19 related". Discontinuation of study drug and 
withdrawal from the study should be documented with the prefix “COVID-19 related” in the case 
report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance.  
If a patient has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study drug and follow-up. Modifications made to 
the study conduct as a result of the COVID-19 pandemic will be summarized in the clinical study 
report.
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COVID-19 Appendix
TMC278 rilpivirine
Clinical Protocol TMC278-TiDP38-C213
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 3 June 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL
The following emergency provisions are meant to ensure patient safety on study while site 
capabilities are compromised by COVID-19 related restrictions. Remote medical consultation and 
alternatives to study drug dispensing, administration, and clinical laboratory assessments may 
allow continued study participation for patients in this trial.
As local restrictions are lifted and the acute phase of the COVID-19 pandemic resolves, sites 
should revert to original protocol conduct as soon as feasible and in accordance with any country-
specific regulatory requirements.
1. Study visits and procedures 
!
The feasibility for each patient to return for scheduled visits should be evaluated based on 
the site's local, regional, and institutional situation. 
!
Sites with full capacity to conduct study visits in-person at the study site should continue 
to do so in full compliance with the protocol. 
!
Patients who miss a scheduled visit may be rescheduled at the next appropriate opportunity. 
The patient’s situation should be evaluated on a case-by-case basis and the study 
responsible physician should be contacted for discussion and decision. Every effort will be 
made to keep patients on treatment if it is in their best interest. 
!
Adherence counseling regarding the importance of maintaining the RPV-based ARV 
regimen should be conducted for all study patients at each study visit, or via telephone as 
applicable, if visits cannot be performed.
!
In addition, patients may have tele-health visits conducted by qualified site personnel via 
phone or video conversation as per local regulation. Assessments may include review of 
adverse events, concomitant medications and study intervention accountability. Patients
will also be questioned regarding general health status to fulfill any physical examination 
requirement. If questionnaires need to be performed during tele-health visits, a mitigation 
plan for collecting responses to questionnaires will be installed.
!
If blood samples cannot be sent in real-time to the central laboratory (Covance) for central 
assessments, the study site should verify if the sample can be stored locally per Covance 
instructions, until shipping can be performed. If real-time laboratory results for safety 
and/or efficacy are considered needed by the investigator, a local laboratory can be used.
2. Dispensation of RPV
!
The dispensation of RPV in the study is done at certain visits specified in the protocol with 
some flexibility in the planning of the visits allowed. Given the exceptional nature of the 
COVID‐19 pandemic, and the potential that study patients may not be able to attend site 
visits within the study-specified visit windows, it is recommended to dispense an additional 
NCT00799864


COVID-19 Appendix
TMC278 rilpivirine
Clinical Protocol TMC278-TiDP38-C213
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 3 June 2020
kit of RPV, if required, to ensure that patients have sufficient supply of RPV. A table for 
reference can be found in Addendum 1 with visit windows and number of RPV kits which 
can be dispensed.
!
The patients should bring all available study drug at their study visits. The patients should 
be instructed to keep the new kit as a buffer, and open only one kit at a time. The buffer kit
should be re-dispensed at the following visit to the same patient if the kit is unopened. Re-
dispensation of an unopened kit will be considered a minor protocol deviation and needs 
to be recorded in the source document and eCRF with the prefix "COVID-19 related" 
added.
3. Exposure to coronavirus/development of COVID-19.
In the event a patient develops a SARS-CoV-2 infection, local and institutional guidelines will be 
followed. The event will be reported to the sponsor and usual Adverse Event/SAE reporting 
requirements will be implemented. 
4. Monitoring by the sponsor
Depending on local restrictions, routine on-site monitoring visits may be postponed. The site 
monitor may set up remote visits in accordance with site and local requirements instead. Additional 
monitoring visits may be needed in the future to catch up on monitoring activities that can only be 
performed on-site. 
5. Site audits
During the COVID-19 pandemic and at the impacted sites, study site GCP audits with direct 
impact/engagement from the investigator and study site personnel will not be conducted, to comply 
with national, local, and/or organizational social distancing restrictions. Additional quality 
assurance activities such as remote audits or focused review of study related documents may take 
place with limited impact/engagement if possible.
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COVID-19 Appendix
TMC278 rilpivirine
Clinical Protocol TMC278-TiDP38-C213
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date: 3 June 2020
Addendum 1: Dispensing Table
25mg dose. Unit: Dose pack of 34 tablets of 25mg
Visit
Duration
to next visit
(weeks)
Visit 
window
Number of 
pack(s) to 
dispense 
NO visit 
window
Number of 
pack(s) to 
dispense  
PLUS visit 
window
Day 1
4
0
1
2
Week 1
---
2 day
0
0
Week 2
---
2 day
0
0
Week 4
4
1 week
1
2
Week 8
4
1 week
1
2
Week 12
4
1 week
1
2
Week 16
8
1 week
2
2
Week 24
8
1 week
2
2
Week 32
8
1 week
2
2
Week 40
8
1 week
2
2
Week 48
12
1 week
3
3
Week 60
12
1 week
3
3
Week 72
12
1 week
3
3
Week 84
12
1 week
3
3
Week 96
12
1 week
3
3
Week 108
12
1 week
3
3
Week 120
12
1 week
3
3
Week 132
12
1 week
3
3
Week 144
12
1 week
3
3
Week 156
12
1 week
3
3
Week 168
12
1 week
3
3
Week 180
12
1 week
3
3
Week 192
12
1 week
3
3
Week 204
12
1 week
3
3
Week 216
12
1 week
3
3
Week 228
12
1 week
3
3
Week 240
---
1 week
0
0
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COVID-19 Appendix
TMC278 rilpivirine
Clinical Protocol TMC278-TiDP38-C213
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved,  Date: 3 June 2020
15mg dose. Unit: Bottle of 65 tablets of 2.5mg
Visit
Duration
to next visit
(weeks)
Visit 
window
Number of 
bottle(s) to 
dispense 
NO visit 
window
Number of 
bottle(s) to 
dispense 
PLUS visit 
window
Day 1
4
0
3
3
Week 1
---
2 day
0
0
Week 2
---
2 day
0
0
Week 4
4
1 week
3
4
Week 8
4
1 week
3
4
Week 12
4
1 week
3
4
Week 16
8
1 week
6
6
Week 24
8
1 week
6
6
Week 32
8
1 week
6
6
Week 40
8
1 week
6
6
Week 48
8
1 week
0
0
15mg dose. Unit: Dose pack of 48 tablets of 2.5mg
Visit
Duration
to next visit
(weeks)
Visit 
window
Number of 
pack(s) to 
dispense 
NO visit 
window
Number of 
pack(s) to 
dispense 
PLUS visit 
window
Day 1
4
0
4
4
Week 1
---
2 day
0
0
Week 2
---
2 day
0
0
Week 4
4
1 week
4
5
Week 8
4
1 week
4
5
Week 12
4
1 week
4
5
Week 16
8
1 week
7
8
Week 24
8
1 week
7
8
Week 32
8
1 week
7
8
Week 40
8
1 week
7
8
Week 48
8
1 week
0
0
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COVID-19 Appendix
TMC278 rilpivirine
Clinical Protocol TMC278-TiDP38-C213
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Status: Approved,  Date: 3 June 2020
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. 
I will conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study intervention, the conduct of the study, and the obligations 
of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Institution:
Janssen Research & Development 
Signature:
[electronic signature appended at the end of the protocol]
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT00799864


Signature
User
Date
Reason
03-Jun-2020
16:31:27
(GMT)
Document Approval
PPD
NCT00799864

SAP_001.pdf: 
1
Approved, Date: 7 October 2022
Janssen Research & Development
Statistical Analysis Plan
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
Protocol TMC278-C213 (cohort 2, Final Analysis); Phase II
Edurant®/TMC278 (rilpivirine) oral
Status:
Approved  
Date:
7 October 2022
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
Document No.: EDMS-ERI-788547
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) oral                   Statistical Analysis Plan TMC278-C213 (cohort 2, Final Analysis)
2
Approved, Date: 7 October 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY ............................................................................................................................ 4
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION ................................................................................................................................ 6
1.1.
Trial Objectives.................................................................................................................................. 6
1.2.
Trial Design ....................................................................................................................................... 6
1.3.
Statistical Hypotheses for Trial Objectives............................................................................................ 7
1.4.
Sample Size Justification..................................................................................................................... 7
1.5.
Randomization and Blinding................................................................................................................ 8
1.6.
Changes to planned analyses................................................................................................................ 8
2.
GENERAL ANALYSIS DEFINITIONS ............................................................................................... 8
2.1.
Analysis Phases.................................................................................................................................. 8
2.2.
Analysis Time Points .......................................................................................................................... 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 .................................................................................................................... 10
2.6.
Study Day and Relative Day.............................................................................................................. 10
2.7.
Baseline........................................................................................................................................... 10
2.8.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ........................................................ 11
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW.................................. 11
4.
SUBJECT INFORMATION ............................................................................................................... 12
4.1.
Demographics and Baseline Characteristics ........................................................................................ 12
4.2.
Disposition Information .................................................................................................................... 13
4.3.
Treatment Adherence........................................................................................................................ 13
4.4.
Extent of Exposure ........................................................................................................................... 15
4.4.1.
Diaries.......................................................................................................................................... 15
4.5.
Protocol Deviations........................................................................................................................... 15
4.6.
Prior and Concomitant Medications.................................................................................................... 16
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............................................................................................................................ 17
5.2.1.
Definitions.................................................................................................................................... 17
5.2.2.
Analysis Methods.......................................................................................................................... 19
5.3.
Other Efficacy Variables ................................................................................................................... 19
5.3.1.
Resistance..................................................................................................................................... 19
6.
SAFETY............................................................................................................................................. 21
6.1.
Adverse Events (AE) ........................................................................................................................ 21
6.2.
Clinical Laboratory Tests .................................................................................................................. 23
6.3.
Vital Signs and Physical Examination Findings................................................................................... 24
6.4.
Electrocardiogram ............................................................................................................................ 25
7.
PHARMACOLOGY........................................................................................................................... 27
7.1.
Population Pharmacokinetics ............................................................................................................. 27
Pharmacokinetic/Pharmacodynamic Relationships ........................................................................................... 27
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Edurant®/TMC278 (rilpivirine) oral                   Statistical Analysis Plan TMC278-C213 (cohort 2, Final Analysis)
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Approved, Date: 7 October 2022
7.2.
Other Pharmacology Endpoints.......................................................................................................... 28
REFERENCES ............................................................................................................................................ 29
ATTACHMENTS ........................................................................................................................................ 30
ATTACHMENT 1: DAIDS GRADING TABLE .......................................................................................... 30
ATTACHMENT 2: BLOOD PRESSURE LEVELS BY AGE AND HEIGHT PERCENTILES.................... 35
ATTACHMENT 3: STAGE-3-DEFINING OPPORTUNISTIC ILLNESSES IN HIV INFECTION............. 39
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AMENDMENT HISTORY
NA
ABBREVIATIONS
17-OH
17-hydroxyprogesteron
3TC
lamivudine
ABC
abacavir
ACTH
adrenocorticotropic hormone
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
CI
Confidence Interval
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
FDA
Food and Drug Administration
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
kg
Kilogram
LH
luteinizing hormone
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
mL
millilitre
NAP
Not Applicable
N(t)RTI
nucleoside/nucleotide reverse transcriptase inhibitors
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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
SE
Standard Error
WHO-DD
World Health Organization-Drug Dictionary
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Edurant®/TMC278 (rilpivirine) oral                   Statistical Analysis Plan TMC278-C213 (cohort 2, Final Analysis)
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Approved, Date: 7 October 2022
1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and statistical 
methods for the final analysis of efficacy (antiviral activity), safety, tolerability and pharmacokinetics (PK)
of the study TMC278-C213 Cohort 2 (children aged >6 to <12 years) for oral rilpivirine (RPV; TMC278). 
The SAP is to be interpreted in conjunction with the protocol amendment 10 dated 03 February 2020.
The final analysis will be performed when all participants of Cohort 2 have completed the Week 48 visit or 
discontinued earlier. It will also include the analysis of the post week 48 treatment extension period.
Analyses of TMC278-C213 Cohort 1 (adolescents aged >12 to <18 years) data at Week 24 (primary 
analysis), at Week 48 (interim analysis) and at Week 240 (final analysis) were described in the 
corresponding SAPs. These analyses have been completed. Therefore, this document focuses only on 
Cohort 2 (children aged > 6 to < 12 years) analysis.
The Pediatric development of oral RPV is comprised of 2 studies: ie, TMC278-C213 (cohort 2) in HIV-1 
infected ARV-naïve subjects aged >6 to <12 years and TMC278HTX2002 in HIV-1 infected virologically 
suppressed subjects aged >2 to <12 years. All Efficacy and Safety analyses described in this SAP will be 
performed separately for study TMC278HTX2002 (see the SAP for HTX2002 Week 24 and Week 48 
Analysis), whereas PK analyses will be performed on pooled pharmacokinetic data from both 
TMC278HTX2002 and TMC278-C213 Cohort 2 studies.
1.1.
Trial Objectives
The objectives are: 
- to evaluate the steady-state pharmacokinetic (based on intensive PK analysis) of RPV 25 mg q.d. or 
adjusted dose of RPV (q.d.) in subjects aged ≥12 to <18 years and ≥6 to <12 years; 
- to evaluate short-term safety, tolerability and antiviral activity/efficacy of RPV in these age groups;
- to evaluate safety, tolerability and efficacy of RPV over a 24-week (Cohort 1 only) and 48-week
(Cohort 1 and 2) treatment period; 
- to evaluate immunologic changes (as measured by CD4+ cell parameters) over 24 weeks (Cohort 1 
only) and 48 weeks (Cohort 1 and 2) of treatment with RPV; 
- to assess the evolution of viral genotype and phenotype over 24 weeks (Cohort 1 only) and 48 weeks 
(Cohort 1 and 2) of treatment with RPV; 
- to evaluate pharmacokinetics (by means of population pharmacokinetics) and pharmacokinetic-
pharmacodynamic relationships for safety and efficacy of RPV; 
- to evaluate treatment adherence as measured by the Study Adherence Questionnaire for Children and 
Teenagers/Caregivers (see Addendum 7 and 8 of the Clinical Trial Protocol respectively).
- to evaluate safety, tolerability and efficacy of RPV for up to 240 weeks of treatment (Cohort 1 only).
- to assess the palatability of the 2.5-mg tablet formulation of RPV, if applicable. 
1.2.
Trial Design
This is a Phase II, open label, single arm trial to evaluate the pharmacokinetics, safety, tolerability and 
efficacy of RPV 25 mg q.d. or adjusted dose of RPV (q.d.) in combination with an investigator-selected 
background regimen containing 2 nucleoside/nucleotide analogue reverse transcriptase inhibitors (N(t)RTIs 
[AZT, ABC, or TDF in combination with 3TC or FTC, age-appropriate formulations are to be used]), in 
antiretroviral (ARV) treatment-naïve adolescents and children aged 6 to <18 years. The study includes 
two cohorts:
-
Cohort 1: adolescents aged >12 to <18 Years
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Edurant®/TMC278 (rilpivirine) oral                   Statistical Analysis Plan TMC278-C213 (cohort 2, Final Analysis)
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Approved, Date: 7 October 2022
-
Cohort 2: children aged >6 to <12 Years
As Cohort 1 has been completed, this document focuses on Cohort 2.
In Cohort 2 of the trial, per the study protocol Amendment 10, ARV treatment-naïve HIV-1 infected 
participants aged >6 to <12 years with a plasma viral load >500 HIV-1 RNA copies/mL but <100,000 HIV-
1 RNA copies/mL are included.
Up to study protocol Amendment 9, the study consisted of an initial treatment period of 48 weeks and a 
post Week 48 treatment extension period of 4 years (192 weeks). As of the study protocol Amendment 10, 
the post Week 48 treatment extension period of 4 years was removed for Cohort 2 participants. Participants
who continue experiencing clinical benefit from RPV and their background regimen comprising 2 
investigator-selected N(t)RTIs at the end of the initial 48-week treatment period, or ongoing participants 
who were already in the post Week 48 treatment extension period at the time of study protocol Amendment 
10, continue treatment (ie, RPV + 2 N[t]RTIs) in the roll-over study TMC278IFD3004 or 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. 
The analysis of the first 10 participants in Cohort 2, including PK modeling and simulation to further assess 
the RPV pediatric dose based on accumulating data, was discussed with and endorsed by the Independent 
Data Monitoring Committee (IDMC). With this, at the time of the study protocol Amendment 10, the 
following RPV dose recommendations were applied to newly enrolled subjects: 
-
RPV 25 mg q.d. for subjects with a body weight of ≥25 kg 
-
RPV 15 mg q.d. for subjects with a body weight of <25 kg
All ongoing participants in Cohort 2 (who are already in the post Week 48 treatment extension period at 
the time of the study protocol Amendment 10) remain on the RPV 25 mg q.d. dose + 2 N(t)RTIs 
(investigator-selected), until their roll-over to study TMC278IFD3004 has been completed. All newly 
recruited participants start treatment with the weight-appropriate RPV dose stated above + 2 N(t)RTIs 
(investigator-selected), until they reach a total treatment duration of 48 weeks or discontinue earlier. Newly 
recruited participants with a body weight of <25 kg and increase in weight such that they require a 25 mg 
RPV dose, can change to the 25 mg tablet formulation.
After the IDMC meeting on 16 October 2020, based on evaluation of all available PK (intensive and sparse), 
safety/tolerability and efficacy data, the RPV dose for newly recruited participants with body weight <20 
kg in any pediatric trial for RPV, including study TMC278-C213, was confirmed as 12.5 mg once daily.
For more details refer section 6.1.1 Overview of Trial of the Clinical Trial Protocol.
1.3.
Statistical Hypotheses for Trial Objectives
No formal hypothesis will be tested.
1.4.
Sample Size Justification
No formal sample size calculation was performed. 
For more details refer section 6.6.1.2. Cohort 2: Children Age >6 to <12 Years of the Clinical Trial 
Protocol.
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1.5.
Randomization and Blinding
Randomization 
As this is a single arm trial, no randomization procedures are applicable. 
Blinding 
Since this is an open label trial, blinding procedures are not applicable.
1.6.
Changes to planned analyses
Not applicable
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: minimum of 

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, maximum of (early withdrawal 
visit date; discontinuation date) + 7 days 

date of last contact 
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.
Analysis Time Points
All visits/assessments will be allocated to the following time points as per the Table 2, based on the number 
of days in the respective phase, calculated as “assessment date – start date of phase + 1 day” for Treatment 
and Follow-up phase and “assessment date – start date of Treatment phase” for Screening phase. 
If two visits fall within the same interval, the one closest to the target day is used for the analysis displays 
and graphics in order to have only one evaluation per participant per analysis time point. 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. All data are presented in the listings. If distances of both visits to the target 
day are equal, the visit latest in time is used.
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Table 2 – Time intervals for reporting of efficacy and safety data
Phase
Visit
Target day
Analysis time 
point
Time interval 
(days)
Screening
1
-∞
Screening
<0
Treatment
2
1
Baseline*
[-∞, 1]
3
8
Week 1
[2,11]
4
15
Week 2
[12,21]
5
29
Week 4
[22,42]
6
57
Week 8
[43,70]
7
85
Week 12
[71,98]
8
113
Week 16
[99,140]
9
169
Week 24
[141,196]
10
225
Week 32
[197,252]
11
281
Week 40
[253,308]
12
337
Week 48
[309,350]
13
421
Week 60
[351,462]
14
505
Week 72
[463,546]
15
589
Week 84
[547,630]
16
673
Week 96
[631,714]
17
757
Week 108
[715,798]
18
841
Week 120
[799,882]
19
925
Week 132
[883,966]
20
1009
Week 144
[967,1050]
21
1093
Week 156
[1051,1134]
22
1177
Week 168
[1135,1218]
23
1261
Week 180
[1219,1302]
24
1345
Week 192
[1303,1386]
25
1429
Week 204
[1387,1470]
26
1513
Week 216
[1471,1554]
27
1597
Week 228
[1555,1638]
28
1681
Week 240
[1639,1722]
Follow-up
29
(3 x7) +1=22 after 
start FU phase
Post-treatment 
Follow-up week 
4
[Start FU phase,
∞]
* 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
Not applicable
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.
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2.5.
Definition of Subgroups
All results will be presented by dose and weight group: 
-
12.5 mg q.d. <20kg
-
15 mg q.d. <20kg; 
-
15 mg q.d. 20-<25kg; 
-
25 mg q.d. <25kg; 
-
25 mg q.d. >25kg; 
-
All RPV Recommended Dose;
-
All Participants;
‘All RPV Recommended Dose’ group includes any patients with an initial administered weight-adjusted 
dose as per following dose scheme: 12.5 mg q.d. <20kg; 15 mg q.d. 20-<25kg; 25 mg q.d. >25kg.
In addition, the following subgroups are defined: 
Efficacy:

CD4+ count at baseline (< 200, 200< - < 400, > 400 cells/μL)

Background regimen
o
ABACAVIR/LAMIVUDINE (ABC/3TC)
o
ZIDOVUDINE/LAMIVUDINE (AZT/3TC)
o
LAMIVUDINE/ TENOFOVIR DISOPROXIL FUMARATE (3TC/TDF)

Adherence based on drug accountability (<80%, 80 - <95%, >95%) cumulative up to Week 48 for 
analysis up to 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 (< 200, 200< - < 400, > 400 cells/μL)

Background regimen
o
ABACAVIR/LAMIVUDINE (ABC/3TC)
o
ZIDOVUDINE/LAMIVUDINE (AZT/3TC)
o
LAMIVUDINE/ TENOFOVIR DISOPROXIL FUMARATE (3TC/TDF)
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.
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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, if month/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 of the 
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,

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 IDMC was installed to monitor pharmacokinetic, efficacy, and safety data of cohort 2, and to safeguard 
the participants in this trial.
The following analyses are shared and discussed by the IDMC: 
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- The first analysis (mini-cohort of 5 participants) is not discussed, only shared with the IDMC; can be 
discussed if requested by the IDMC. 
- The analysis when at least 12 participants with body weight <25 kg from TMC278-C213 Cohort 2 and 
TMC278HTX2002 combined have been treated for at least 4 weeks with the original and/or adjusted 
RPV dose will be shared and discussed.
- The analyses when all participants have reached 12, 24, and 48 (final analysis) weeks of treatment will 
be shared and discussed.
Further details are described in the IDMC charter.
4.
SUBJECT INFORMATION
The number of participants in FAS will be summarized and listed by dose and weight group 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
Frequency distribution with the 
number and percentage of 
participants in each category.
Age (≥6 - < 9years; ≥9 - < 12years)
Weight (<20kg; 20 - <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
Tanner Stage
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, SD, 
median, and range [minimum and 
maximum]).
CD4+ count (%) at Baseline
HIV-1 viral load (copies/ml / log10 copies/ml) at Baseline
Duration of known HIV Infection (years):
[screening date – date of first confirmed positive HIV test + 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
Frequency distribution with the 
number and percentage of participants 
in each category.
ARV Prevention mother to child transmission (Yes, No)
HIV – 1 subtype
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Hepatitis B/C co-infection status (Yes, No, NAV)
Mode of HIV infection (Blood transfusion, Hemophilia-associated 
injections, Heterosexual contact, Intravenously injectable drug use, 
Mother to Child transmission, MSM, Occupational exposure, Other)
Clinical stage of HIV infection at screening according to the CDC 
classification system for HIV infection and AIDS (N, A, B, C)
CD4+ count at Baseline (≤ 350, 350 - < 500, 500 - <750, ≥750 cells/μL)
HIV-1 viral load at Baseline (<100,000 copies/mL; >100,000 
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 dose and weight group 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 48-week initial treatment period
Participants who terminated the 48-week initial treatment period prematurelyReasons for termination 
the 48-week initial treatment period 
Participants completing the post week 48 treatment extension (up to Week 240)
Participants who terminated the post week 48 treatment extension prematurely
Reasons for termination of the post week 48 treatment extension
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 
Addendum 7: Study Adherence Questionnaire for Children and Teenagers and Addendum 8: Study 
Adherence Questionnaire for Caregivers of the Clinical Trial Protocol).
The following parameters are derived cumulatively up to week 48 or post Week 48 periods/ last intake for 
discontinued participants. Treatment adherence will be summarized descriptively by dose and weight group
and overall.
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 48):

impute with value based on next available time point for which a DA calculation can be done,
eg. if cumulative DA up to week 48 cannot be derived, derive DA up to week 60; if not 
calculable, derive DA up to week 72 etc.

otherwise, use value based on closest preceding time point
Total Amount to be taken (in mg) = 
∑
(number of days on same RPV dose x strength in mg of RPV dose)
  !" #$
. 
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Number of days on same RPV dose 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) = 
∑
((number of tablets dispensed – number of tablets returned) x strength in mg of RPV dose)
  !" #$
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. 
Interruptions (for adverse events [AEs]) are not to be considered for the calculation of adherence: ie, they 
will not be subtracted from the 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 10).
ii.
Report of missed doses over the last 2 weeks (Question 11).
If both child and a caregiver completed the questionnaire, the Child Questionnaire will be given precedence.
Results will be summarized for RPV and for the background regimen separately, and further as follows:
i.
Missed doses in last 3 days (Q10):

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
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ii. Missed doses (Y/N) in the last 2 weeks (Q11):

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 RPV and 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 dose and weight group 
and overall. 
Exposure is defined as the duration of RPV treatment. The duration is calculated as follows:
(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 
[min, max]) will be presented by dose and weight group and overall for the initial treatment period, and the 
initial treatment and post Week 48 periods combined.
In addition, duration of exposure will be summarized by dose and weight group and overall 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, 40-48 weeks and then every 24 weeks until week 240.
Total subject years of exposure is calculated as [sum of (days of exposure)/365.25]. Total subject years of 
exposure will be presented by dose and weight group and overall for the initial treatment period, and the 
initial treatment and post Week 48 periods combined. 
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.
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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 dose and weight group 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.
Participants who switched ARV therapy during treatment will be listed. 
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 (ie, 
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.
Regardless of which assay was used to define response (undetectable)/loss of response (detectable) in the 
analysis, a cut-off of 50 copies/mL will be applied.
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.
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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 log-transformed parameters (including change in log10 viral load): 2 decimals
-
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 of decimals for according point estimate + 1 decimal.
5.2.
Efficacy Endpoints
The following efficacy parameters will be analyzed: 
Virology
-
The change in plasma viral load in log10 from baseline up to Week 48 (the initial treatment period 
only). 
The viral load change from baseline at a given time point is defined as: 
viral load at a given time point - baseline viral load
Observed data are used to calculate the change in viral load. No imputation will be done for missing 
values;
-
Proportion of participants with a viral load <50 and <400 HIV-1 RNA copies/mL (virologic 
response) at all time points up to Week 48 and post Week 48 (observed case);
-
Virologic outcome < 50 and <400 HIV-1 RNA copies/mL using the FDA Snapshot approach
analysis algorithm for the 48-week treatment period ;
-
Proportion of participants with virologic failure (see definitions below) for the 48-week treatment 
period and till end of study: ie, 48-week treatment and post Week 48 periods combined.
Immunology
-
The change in CD4+ cell count (absolute and %) from baseline up to Week 48 and post Week 48. 
5.2.1.
Definitions
Virologic response
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 
The following threshold criteria are considered:
-
<50: viral load below 50 copies/mL
-
<400: viral load below 400 copies/mL
Observed case: a participant is considered a responder, respectively non-responder, if the viral load test 
result is below, respectively above, the threshold defining response (<50 or <400); with a missing value are 
disregarded in the analysis for that time point
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Virologic failure
Lack of response: confirmed decrease in plasma viral load of <1.0 log10 at Week 12 from the baseline viral 
load.
Loss of response: two consecutive measurements of ≥400 HIV-1 RNA copies/mL after having been 
confirmed virologic responder (confirmed responder is defined as two consecutive measurements of <50
copies/mL).
Suspected Virologic Failure: HIV-1 RNA ≥200 copies/mL after confirmed HIV-1 RNA of <50 
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 N(t)RTI 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 48 week window, are assigned 
outcome subcategory = 'Virologic failure – switch in background N(t)RTIs 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 48 then outcome subcategory = ' Virologic failure - leading to discontinuation'; 
3) Viral load data in the Week 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 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 48; 
4) No HIV RNA data in Week 48 window; 
-
if the participant completed Week 48 but HIV RNA data at Week 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’; 
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 350, Window 44-54 weeks, baseline = day 1).
Changes from baseline in CD4+ count:  
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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, NC=F). Analysis results based on 
observed data only will also be presented.
5.2.2.
Analysis Methods 
Tabulations (numbers and proportions) per time point by dose and weight and overall for the categorical 
parameters; 95% CIs (Clopper-Pearson) for the virologic response and failure rates over time will be 
calculated. 
Descriptive statistics (n, mean, standard error [SE], median, and range [min and max]) per time point and 
graphical display for the continuous parameters(log10 HIV-1 RNA and changes from baseline in log10 HIV-
1 RNA and CD4+ cell count and 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: ie, up to Week 48 and post Week 48 treatment extension.
The first and the last post-baseline time point within the treatment phase for which genotypic data are 
available will be analyzed and presented. Phenotypic data will be reported only if there is also genotypic 
data available for the corresponding time points.
Sequencing of HIV-1 protease, reverse transcriptase and integrase will be performed in real time on plasma 
for participants with (suspected) virologic failure (see definition above).
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 
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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 Data Presentation 
Specifications (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:
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 or Week 48 or final/withdrawal visit.
Results from archival viral resistance from PBMC sample will be tabulated and described, particularly for 
participants with virologic failure.
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6.
SAFETY
All safety analyses will be based on the FAS
For all continuous safety variables, descriptive statistics will include the N, mean, SD, median, minimum, 
and maximum. Categorical variables will be summarized using frequency counts and percentages.
Safety data will be presented by dose and weight and overall for the treatment phase:
-
48-week initial treatment period: 48-week treatment period
-
Post week 48 treatment extension period: Post Week 48 till end of study
-
Treatment phase: both periods combined
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 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 RPV through 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 dose and weight group 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
-
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/System Organ Class 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. 
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Number of occurrences of an AE:
Number of recorded events of the same preferred term, during the trial phase. Combined events (ie, within 
the same phase) will be counted only once.
AE grading:
Reported AE parameters and grades are based on the Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events (see 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 of interest: 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.
-
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.
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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 dose and weight group 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 (see 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 (eg, 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.
-
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 baseline per laboratory test will be reported. Separate 
tabulations and listings will be provided for those participants who develop a grade 3 or 4 laboratory 
toxicity. For tests for which no DAIDS grading exists, a cross-tabulation versus baseline (with classes 
below/within/above normal range) will be performed.
Endocrine safety: Adrenocorticotropic hormone (ACTH) stimulation testing 
Abnormal ACTH response: 
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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 timepoints: Week 48, worst on-treatment 
measurement till end of study. 
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 dose and weight group 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 Table 5, will be summarized for 
participants who had at least 1 postbaseline assessment for that vital sign.
Table 5 - Markedly Abnormal Vital Sign
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)
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).
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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 dose and weight group and overall. 
Physical examination abnormalities will be listed.
Growth Examination:
Growth will be followed regularly and evaluated consistently using WHO standardized growth charts.
-
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 dose and weight group and overall. 
Descriptive statistics (mean, SD, median, minimum and maximum) will be presented.
Tanner Stage:
Tanner stage (for pubic hair and genitalia/breasts) will be cross-tabulated versus baseline. 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  pre-dose and post-dose at Baseline and at Week 4 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).
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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 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 copied 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

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:
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
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) using FDA Snapshot (yes/no) at Week 48, will be created.
PK and Safety
Relationship between RPV pharmacokinetics (AUC24h only) and the following AE groups / abnormalities
will be explored graphically by 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.
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])
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Endocrine (Cortisol, 17-OH Progesterone)
Cortisol
17-OH Progesterone
morning/T0 (non-ACTH) 
([min])
morning/T0 (non-ACTH) ([max])
[min] or [max] indicates which value to use, ie, 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 at Day 
1 and Week-4 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 dose and weight group and overall.
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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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