Continued Access to Etravirine (ETR) in Treatment Experienced HIV-1 Infected Subjects
Phase: PHASE3
Conditions: HIV Infections, HIV-1
Sponsor: Janssen Sciences Ireland UC

1
For European Submissions the EudraCT number is: 2009-013126-16
GCP STATEMENT
This trial will be conducted in compliance with this protocol, Good Clinical Practices and applicable regulatory requirements.
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 law. 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 to all future 
information supplied to you which is indicated as privileged or confidential.
Version: 4.0
Date: 22 July 2019
Clinical Trial Protocol
Amendment III
TMC125-TiDP35
Department:
Clinical R&D
Nonproprietary name:
etravirine
Version:
4.0
Date:
22 July 2019
Status:
Approved
Title:
Continued access to etravirine in treatment experienced HIV-1 
infected subjects.
Trial No:
TMC125-TiDP35-C239
Clinical phase:
N/A
Summary:
This is a continued access trial for subjects who have completed 
treatment in a clinical (parent) trial with etravirine sponsored by or in 
collaboration with Janssen Research & Development and who 
continue to benefit from the use of etravirine.
At the baseline visit, inclusion/exclusion criteria will be checked to 
confirm eligibility. Once eligibility criteria are met, subjects will 
either continue on the etravirine dose they have received in the 
previous etravirine (parent) trial or on an adjusted dose if deemed 
necessary by the investigator. For pediatric subjects, etravirine dose 
adjustment will be based on weight using the dosing guidelines 
provided.
Assessment visits are recommended according to local generally 
accepted standard of care, but not less frequent than every three and 
six months for pediatric and adult subjects respectively. Adverse 
events leading to treatment interruption or discontinuation, adverse 
events at least possibly related to treatment with etravirine, serious 
adverse events (SAEs), and pregnancies are to be recorded at each 
visit. In addition to the assessments described in the flowchart, 
additional assessments not included in this protocol can be done 
locally at the investigator’s discretion as per local standard of care.
As per Protocol Amendment 3:
For ongoing subjects, the next planned visit will be a 
Final/Withdrawal Visit, which will be the last visit with data 
collection. For new subjects that rollover from (parent) trial 
TMC125-C234 (IMPAACT P1090), the next planned visit will be a 
NCT00980538

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Baseline Visit which will be performed per local standard of care and 
documented in the subject’s medical records only.
For all new and ongoing subjects, all subsequent visits and 
assessments will be performed per local standard of care and 
documented in the subject’s medical records only. Investigators will 
continue to report SAEs possibly related to etravirine and pregnancies 
to the sponsor using regular pharmacovigilance reporting. This 
information will only be entered in the company safety repository.
For all new and ongoing subjects, if the subject exits the trial, the last 
visit will be a local standard of care visit but without dispensation of 
investigational medication.
Treatment will be continued until one of the following criteria is met: 
the investigator determines that the subject no longer benefits from 
etravirine treatment (e.g., based on viral load); treatment limiting 
toxicity; loss to follow-up; patient withdrawal of consent; pregnancy; 
termination of the program by the sponsor; an etravirine-based 
treatment regimen becomes commercially available for the subject’s 
indication and is reimbursed, or can be accessed through another 
source (e.g. access program, government program) in the region the 
subject is living in, or subjects can be switched to local standard of 
care, as appropriate.
Investigator:
See local Informed Consent Form/Assent
Site address:
See local Informed Consent Form/Assent
Sponsor:
Janssen Research & Development*
Treatment: 
Subjects will continue to receive etravirine until an etravirine-based 
treatment regimen becomes commercially available for the subject's 
indication and is reimbursed, or can be accessed from another source 
(e.g. access program, government program) or subjects can be 
switched to local standard of care, as appropriate.
                                                
* Janssen Research & Development is a global organization that operates through different legal entities 
in various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & 
Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; 
Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen 
Sciences Ireland Unlimited Company; 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.

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PROTOCOL HISTORY
Protocol Historya
TMC125-TiDP35-C239
Document Type and
File Name
Document Identification
Amendment
Type
Comments
Initial Clinical Trial Protocol
TMC125-TiDP35-C239-CTP
0313504
07-Jul-2009
CTP Amendment I
TMC125-TiDP35-C239-CTPA-GEN-I
18-Aug-2011
Non-Substantial
First Revised Clinical Trial Protocol
TMC125-TiDP35-C239-CTP-v2
18-Aug-2011
Integrates the Initial Clinical Trial Protocol and CTP 
Amendment I
CTP Amendment II
TMC125-TiDP35-C239-CTPA-GEN-II
28-Oct-2016
Non-Substantial
For details, refer to Amendment GEN-II
CTP Amendment III
TMC125-TiDP35-C239-CTPA-GEN-III
This document
Substantial
For details, refer to Amendment GEN-III
a
This overview lists general amendments to the protocol only. Site and country specific amendments to the protocol are not included.

TMC125-TiDP35-C239
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TABLE OF CONTENTS
Protocol History...............................................................................................................................3
Table of Contents.............................................................................................................................4
Protocol Amendments......................................................................................................................7
PART I: Clinical Trial Protocol.....................................................................................................12
1
List of Abbreviatons AND DEFINITION OF TERMS..................................................12
1.1
List of Abbreviations ..........................................................................................12
1.2
Definition of Terms.............................................................................................13
2
Flowchart ........................................................................................................................14
2.1
Flowchart 1: Trial Follow-up..............................................................................14
2.2
Flowchart 2: Simplified Trial Follow-up............................................................15
3
Introduction.....................................................................................................................16
3.1
Aim of the Study.................................................................................................17
4
Trial Objectives...............................................................................................................17
4.1
Primary Objective...............................................................................................17
5
Methods...........................................................................................................................18
5.1
Trial Design ........................................................................................................18
5.1.1
Overview of Trial.................................................................................18
5.1.2
Discussion of Trial Design...................................................................19
5.1.3
Selection of Dose(s) in the Trial..........................................................19
5.2
Trial Population ..................................................................................................19
5.2.1
Sample Size..........................................................................................19
5.2.2
Inclusion Criteria .................................................................................19
5.2.3
Exclusion Criteria ................................................................................20
5.2.4
Prohibitions and Restrictions...............................................................20
5.2.5
Removal of Subjects From Therapy or Assessment............................21
5.3
Treatment ............................................................................................................22
5.3.1
Identity of Investigational Product.......................................................22
5.3.2
Other Medication Administered in the Trial........................................22
5.3.3
Dosage(s) and Treatment Overview per Subject .................................22
5.3.4
Individually Optimized Background Regimen/Underlying 
Antiretroviral Therapy.........................................................................23
5.3.5
Packaging and Labeling.......................................................................24
5.3.6
Randomization.....................................................................................24
5.3.7
Blinding and Unblinding......................................................................24
5.3.8
Drug Accountability.............................................................................25
5.3.9
Storage .................................................................................................25
5.3.10
Adherence ............................................................................................25
5.3.11
Prior and Concomitant Therapy...........................................................26
5.4
Assessments........................................................................................................27
5.4.1
Timing of Assessments........................................................................27
5.4.2
Subject and Disease Characteristics.....................................................27
5.4.3
Safety ...................................................................................................27
5.5
Safety Management Guidelines for Cutaneous Events.......................................28
5.5.1
Rash Management................................................................................28
5.5.2
Acute Systemic Allergic Reaction.......................................................30

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5.6
Toxicity Management for Specific Adverse Events With Concomitant 
Antiretrovirals.....................................................................................................30
5.6.1
Hyperglycemia.....................................................................................30
5.6.2
Hypertriglyceridemia and Hypercholesterolemia................................31
5.6.3
Lactic Acidosis.....................................................................................31
5.6.4
Lipodystrophy/Fat Redistribution/Body Changes ...............................32
5.6.5
Pancreatitis...........................................................................................33
5.6.6
Peripheral Neuropathy .........................................................................33
5.7
Statistical Methods Planned and Determination of the Sample Size..................34
5.7.1
Sample Size Calculation ......................................................................34
5.7.2
Initial Subject and Disease Characteristics..........................................34
5.7.3
Statistical Analysis...............................................................................34
5.8
Data Quality Assurance ......................................................................................35
6
References.......................................................................................................................36
7
Addenda ..........................................................................................................................37
7.1
Addendum 1: Trial Contact Persons...................................................................37
7.2
Addendum 2: DAIDS Grading Table .................................................................38
7.3
Addendum 3: HIV-Related Events or Outcomes................................................57
7.3.1
Clinical categories................................................................................57
7.4
Addendum 4: Visit Schedule for Rash Management in Pediatric Patients.........60
7.5
Addendum 5: Visit Schedule for Rash Management in Adult Patients..............62
PART II: Procedures......................................................................................................................65
1
Adverse Events ...............................................................................................................65
1.1
Definitions...........................................................................................................65
1.2
Attribution Definitions........................................................................................66
1.3
HIV-Related Events or Outcomes ......................................................................66
1.4
Reporting of Adverse Events..............................................................................67
2
Trial Closure Considerations ..........................................................................................68
3
Trial Materials.................................................................................................................69
3.1
Investigational Products......................................................................................69
3.2
Trial Documents..................................................................................................69
3.3
Participation Cards..............................................................................................70
3.4
Source Data.........................................................................................................70
3.5
Case Report Forms..............................................................................................71
3.6
Subject Identification Code List & Subject Screening and Enrollment Log......72
3.7
Archiving ............................................................................................................72
4
Confidentiality ................................................................................................................72
5
Reporting And Publication .............................................................................................73
5.1
Reporting.............................................................................................................73
5.2
Publication ..........................................................................................................73
6
Authorities/Ethics ...........................................................................................................73
6.1
Regulatory Authorities........................................................................................73
6.2
Independent Ethics Committee/Institutional Review Board...............................74
6.3
ICH-GCP Guidelines ..........................................................................................74
6.4
Subject Information and Informed Consent/Assent............................................74
6.5
Privacy of Personal Data.....................................................................................75
7
Financing and Insurance .................................................................................................76
7.1
Financial Disclosure............................................................................................76

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7.2
Indemnification...................................................................................................76
7.3
Insurance.............................................................................................................76
8
Data Quality Control/Assurance.....................................................................................76
Signature ........................................................................................................................................78

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Clinical Trial Protocol Amendment III
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PROTOCOLAMENDMENTS
Amendment GEN-III (This document)
The overall reason for the amendment: The aim of this roll-over study is to provide continued 
access to etravirine (ETR) for adult and pediatric subjects who continue to benefit from the use 
of ETR and who live in a country where ETR is either not commercially available, not 
reimbursed, or cannot be accessed through another source. As of this amendment, the follow-up 
in this study will be simplified for the reasons outlined below. 
ETR is approved since 2008 in adults and since 2012 in children as of the age of 6 years and has 
a well-established safety profile. The collection of additional data in Study TMC125-C239 is 
unlikely to provide substantial additional information on ETR or to impact the risk-benefit 
assessment. The TMC125-C239 is a roll-over study that has been ongoing since December 2009
and provides already substantial long-term safety information on ETR. The parent trials 
TMC125-C206 and TMC125-C216 (in adults) ended in August 2008, after which the subjects 
were able to roll-over in the TMC125-C217 trial and subsequently into this roll-over study. 
Parent trial TMC125-C213 (in subjects aged 6 to 18 years) ended in August 2011. The parent 
trial TMC125-C234 (or IMPAACT trial P1090), conducted in subjects aged 1 to 5 years, is still 
ongoing and subjects still in this trial are expected to roll-over to Study TMC125-C239. By the 
time of entry in Study TMC215-C239, most of these subjects will have completed 48 weeks of 
ETR treatment plus an additional few years (up till 5 years) of follow-up in the parent trial. 
Hence, the subjects from Study TMC125-C239 have been on ETR for a significant amount of 
time. Therefore, the long-term safety of ETR has been properly assessed in these subjects, 
thereby allowing the study follow-up to be simplified for all subjects in this roll-over study.
As of this amendment, ETR will continue to be provided through this study until the subject can 
be switched to locally available ETR-based treatment regimens (ie, commercially available and
reimbursed, or accessible through another source [eg, access program or government program])
or to local standard of care, as appropriate.
Furthermore, subjects aged 2 years and older are allowed to roll-over from parent trial 
TMC125-C234 and dosing instructions are added for pediatric subjects receiving another dose 
than provided in the dosing chart.
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/202EC of the European Parliament and the Council of the European Union.
The table below gives an overview of the rationale of all changes in the GEN-III
amendment and all applicable sections.

TMC125-TiDP35-C239
Clinical Trial Protocol Amendment III
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Rationale: The long-term safety of ETR has been established in patients aged 6 years or more,
and the collection of additional data in this study is unlikely to impact the risk-benefit 
assessment. Therefore, the study follow-up will be simplified, and study-related data will no 
longer be collected in the Case Report Form (CRF). The information that will continue to be 
collected consists of serious adverse events (SAEs) possibly related to etravirine and information 
on pregnancies. These are to be reported to the sponsor using regular pharmacovigilance 
reporting and will only be entered in the company safety repository. Medical records should be 
maintained according to the local standard of care and should continue to include details on the 
use of ETR.
PART I:2 Flowchart
PART I:4 Trial Objectives
PART I:5.1.1 Overview of Trial
PART I:5.1.2 Discussion of Trial Design
PART I:5.2.5 Removal of Subjects From Therapy or Assessment
PART I:5.3.10 Adherence
PART I:5.4.1 Timing of Assessments
PART I:5.4.3 Safety
PART I:5.5 Safety Management Guidelines for Cutaneous Events
PART I:5.6 Toxicity Management for Specific Adverse Events With Concomitant 
Antiretrovirals
PART II:1.3 HIV-Related Events or Outcomes
PART II:1.4 Reporting of Adverse Events
PART II:3.4 Source Data
PART II:3.5 Case Report Forms
PART II:5.1 Reporting
PART II:8 Data Quality Control/Assurance
Rationale: To allow continuation of viral suppression, ETR will continue to be provided through 
this roll-over study until the subject can be switched to locally available ETR-based treatment 
regimens (ie, commercially available and reimbursed, or accessible through another source 
[eg, access program or government program]) or to local standard of care, as appropriate.
PART I:4 Trial Objectives
PART I:5.1.1 Overview of Trial
PART I:5.2.5 Removal of Subjects From Therapy or Assessment
PART II:2 Trial Closure Considerations

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Rationale: Inclusion criterion 2 was modified to allow subjects older than 2 years to participate 
in this roll-over study. Furthermore, dosing instructions were added for pediatric subjects 
rolling-over from parent trial TMC125-234 who are receiving another dose than the doses
provided in the pediatric dosing chart.
PART I:5.2.2 Inclusion Criteria
PART I:5.3.3 Dosage(s) and Treatment Overview per Subject
Rationale: Instructions have been added for investigators to follow the guidance in the most 
recent Investigator’s Brochure regarding any contraindications, precautions for use, and other 
restrictions.
PART I:5.2.4 Prohibitions and Restrictions
PART I:5.3.11 Prior and Concomitant Therapy
Rationale: In line with the simplified study setting, information on the provision and destruction 
of study drug supplies was updated.
PART I:5.3.8 Drug Accountability
PART II:3.1 Investigational Products
Rationale: Information was added to clarify that the final analysis will be done once all subjects 
have completed the Final/Withdrawal Visit. After termination of data collection, no data will be 
collected in the CRF and no additional statistical analysis will be performed. The Clinical Study 
Report will contain CRF data from all study sites that participated in the study. Furthermore, the 
information on the statistical analysis was adapted based on the definition of pediatric and adult 
subjects. 
PART I:5.7.3 Statistical Analysis
PART II:5.1 Reporting
Rationale: A reference was added in the DAIDS grading table to provide guidance on the charts 
to be used to assess severity grade of abnormal blood pressure values in pediatric subjects.
PART I:7.2 Addendum 2: DAIDS Grading Table
Rationale: Adherence counseling was added to flowchart 1 to align with the information on 
adherence included in Section 5.3.10.
PART I:2 Flowchart
Rationale: The introduction section was updated and shortened.
PART I:3 Introduction
Rationale: The legal entity Janssen, Inc was replaced by Janssen Pharmaceutica NV, Janssen, 
Inc and Janssen Sciences Ireland UC was written in full. Furthermore, the legal entity Janssen 
Biopharma Inc was added.
Title page: Sponsor Footer

TMC125-TiDP35-C239
Clinical Trial Protocol Amendment III
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Rationale: Minor edits and corrections were made.
Throughout the document
Amendment GEN-II (28-Oct-2016)
This amendment is considered non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/202EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The name of the sponsor of the trial changed from 
‘Tibotec Pharmaceuticals’ to ‘Janssen Research & Development’ because of the transition of the 
Johnson & Johnson Research & Development companies to a unified Janssen identity, as of 
2 February 2012.
The table below gives an overview of the rationale of all changes in the GEN-II amendment 
and all applicable sections.
Rationale: The name of the sponsor of the trial changed from ‘Tibotec Pharmaceuticals’ to 
‘Janssen Research & Development’ because of the transition of the Johnson & Johnson Research 
& Development companies to a unified Janssen identity, as of 2 February 2012.
Title Page: Sponsor
PART I:3.2 Aim of the Study
PART I:4.1 Primary Objective
PART I:5.1.1 Overview of Trial
PART I:5.2.2 Inclusion Criteria
PART I:5.3.1 Identity of Investigational Product
PART I:5.3.2 Other Medication Administered in the Trial
PART I:5.3.4 Individually Optimized Background Regimen/Underlying Antiretroviral Therapy
PART I:5.3.5 Packaging and Labeling
PART I:5.3.11.1 Disallowed Non-ARV Medication
PART I:5.3.11.2 Disallowed ARV Medication
PART I:5.4.1 Timing of Assessments
PART I:5.5.1 Rash Management
PART I:5.7.1 Sample Size Calculation 
PART I:7.2 Addendum 2: DAIDS Grading Table
PART II:1.4 Reporting of Adverse Events
PART II:5.1 Reporting
Signature Page

TMC125-TiDP35-C239
Clinical Trial Protocol Amendment III
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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 on the contact information page.
Title Page: Sponsor Footer

TMC125-TiDP35-C239
Clinical Trial Protocol Amendment III
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PART I: CLINICAL TRIAL PROTOCOL
1
LIST OF ABBREVIATONS AND DEFINITION OF TERMS
1.1
List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
ART
antiretroviral therapy
ARV
anti-retroviral
AST
aspartate aminotransferase
b.i.d.
bis in die (twice daily)
CCR5
chemokine (C-C motif) receptor 5
CPK
creatine phosphokinase
CRF
Case Report Form
CSR
Clinical Study Report
DAPY
diarylpirimidine
DNA
deoxyribonucleic acid
DRV
darunavir
EFV
efavirenz
ENF
enfuvirtide
ETR
etravirine (formerly known as TMC125)
GCP
Good Clinical Practice
HDL
high densitiy lipoprotein
HIV-1(2)
human immunodeficiency virus – type 1 (type 2)
HPMC
hydroxypropylmethylcellulose
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
ICF
Informed Consent Form
INR
international normalized ratio
IRB
Institutional Review Board
LDH
lactate dehydrogenase
LDL
low density lipoprotein
LPV
lopinavir
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular haemoglobin concentration
MCV
mean corpuscular volume
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside reverse transcriptase inhibitor
NtRTI
nucleotide reverse transcriptase inhibitor 
NVP
nevirapine
OBR
optimized background regimen
PI
protease inhibitor
PK
Pharmacokinetic(s)
QA
Quality Assurance
QC
Quality Control

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RAL
raltegravir
RAM
resistance-associated mutation
RBC
red blood cell
RNA
ribonucleic acid
RT
reverse transcriptase
SAE
serious adverse event
SJS
Stevens-Johnson Syndrome
SQV
saquinavir
TEN
toxic epidermal necrolysis
TLOVR
time to loss of virologic response
ULN
upper limit of normal
VL
viral load
WBC
white blood cell
WT
wild type
1.2
Definition of Terms
Pediatric subjects
subjects who are at age < 18 years old at the Baseline Visit in this trial
Adult subjects
subjects who are at age ≥ 18 years old at the Baseline Visit in this trial

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2
FLOWCHART
2.1
Flowchart 1: Trial Follow-up
Up to and including Protocol Amendment 2:
Type of Visit
Baselinea
Treatment period
Follow-up 
visitb
Time of Visit
Day 1
Every 3 
months for 
pediatric 
subjects
Every 6 
months for 
adult 
subjects
Final / 
Withdrawal 
visitc,i
4 weeks after 
withdrawal
Informed Consent/Assentg
X
Xj
Demographic datad
X
Heighth, Tanner stagingh
X
X
Weight
X
X
X
Urine pregnancy test, if applicablee
X
X
X
X
Inclusion/exclusion criteria
X
Dispensation of investigational medication
X
X
X
Xj
Drug accountability
X
X
X
Adherence Counseling
X
X
X
Xj
Collection of the following AEsf:
- AEs considered to be at least possibly 
related to ETR;
- AEs leading to discontinuations or 
treatment interruption;
- SAEs and pregnancies
X
X
X
X
X
a Subject will rollover from another (parent) trial. Baseline visit will coincide with the last visit of the previous
(parent) trial. Assessments and results from the last visit of the previous (parent) trial will be used for the Baseline 
Visit of this trial.
b Only for subjects who drop out of the study due to the occurrence of a (S)AE.
c Any AE event ongoing at the end of treatment should be followed up until satisfactory clinical resolution or 
stabilization at the investigator’s discretion, according to the local standard of care.
d Including Subject ID from parent trial.
e Urine pregnancy test for females of childbearing potential only.
f Other AEs will only be collected if required per local regulations.
g Informed assent only applicable to pediatric subjects.
h Only applicable to pediatric subjects.
i The next planned visit will be a Final/Withdrawal Visit for all subjects when discontinuing the trial or switching to
simplified data collection as per Protocol Amendment 3. For subjects continuing the trial under Protocol 
Amendment 3, all subsequent visits and assessments will be performed per local standard of care and documented in 
the subject's medical records only, as described in Flowchart 2: Simplified Trial Follow-up.
j Only applicable for subjects continuing the trial under Protocol Amendment 3.

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2.2
Flowchart 2: Simplified Trial Follow-up
As of Protocol Amendment 3:
For ongoing subjects, the next planned visit after approval of amendment 3 will be a 
Final/Withdrawal Visit (Figure 1). During this Final/Withdrawal Visit, the informed consent will 
be signed, final assessments will be carried out and recorded in the CRF, and the study 
medication will be dispensed as described in Flowchart 1: Trial Follow-up. For new subjects that 
roll-over from (parent) trial TMC125-C234 (IMPAACT P1090) after approval of amendment 3, 
the next planned visit will be a Baseline Visit (Figure 1). During this Baseline Visit, the informed 
consent will be signed and assessments will be performed per local standard of care and 
documented in the subject’s medical records only.
For all new and ongoing subjects, all subsequent visits and assessments will be performed per 
local standard of care and documented in the subject’s medical records only. Investigators will 
continue to report SAEs possibly related to ETR and pregnancies to the sponsor using regular 
pharmacovigilance reporting. This information will only be entered in the company safety 
repository.
For all new and ongoing subjects, if the subject exits the trial, the last visit will be a local 
standard of care visit but without dispensation of investigational medication.
Type of Visit
Baseline Visita
Local Standard of Care Visitb
Informed Consent/Assent
Xc
Refer to the Final/Withdrawal Visit 
in Flowchart 1: Trial Follow-up
Inclusion/exclusion criteria
X
Dispensation of investigational medication
X
Xf
Collection of SAEs possibly related to ETR and 
pregnanciesd
X
X
Study terminatione
X
Note: Assessments are to be performed per local standard of care and documented in the subject's medical 
records only.
a For new subjects that roll-over from (parent) trial TMC125-C234 (IMPAACT P1090). The Baseline Visit will 
coincide with the last visit of the previous trial.
b The next planned visit for ongoing subjects before switching to simplified data collection as per Protocol 
Amendment 3 will be a Final/Withdrawal Visit. During this Final/Withdrawal Visit, the informed consent will be 
signed, final assessments will be carried out and recorded in the CRF, and the study medication will be dispensed 
as described in Flowchart 1: Trial Follow-up.
c Informed assent only applicable to pediatric subjects coming from (parent) trial TMC125-C234.
d Investigators will continue to report SAEs possibly related to ETR and pregnancies to the sponsor using regular 
pharmacovigilance reporting.
e Study termination will be documented in the subject’s medical records and recorded on a separate, paper 
termination disposition form to be shared with the sponsor.
f If the subject exits the trial, the last visit will be a local standard of care visit but without dispensation of 
investigational medication.

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Figure 1:
Study Schematic
3
INTRODUCTION
Over the past decade, drugs for the treatment of human immunodeficiency virus (HIV) disease 
have been introduced sequentially for use in the clinic. As a consequence, a fraction of the 
HIV-infected population currently living in North America and Europe has been exposed serially 
to a variety of anti-HIV drugs and has developed resistance to these drugs. Resistance to 
antiretroviral (ARV) agents is a major reason for therapy failure. Based on their mechanism of 
action, six different classes of anti-HIV compounds exist. The following have been approved for 
the treatment of adult HIV infection so far: nucleo(side)/(tide) reverse transcriptase inhibitors 
(NRTIs/NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors 
(PIs), a fusion inhibitor, an integrase strand transfer inhibitor and a chemokine (C-C motif) 
receptor 5 (CCR5) antagonist.
Etravirine (ETR, also known as TMC125) is a diarylpyrimidine (DAPY) NNRTI, which has high 
intrinsic activity, not only against wild type (WT) HIV-1, but also against strains harboring 
NNRTI and other resistance-associated mutations (RAMs). In addition, ETR was shown to have 
an increased genetic barrier to the development of resistance as compared to first generation 
NNRTIs. 
ETR received accelerated approval in the US in January 2008, and has obtained conditional 
marketing authorization in Europe in August 2008 for the treatment of HIV-1 infection in ARV 
treatment-experienced adult patients. At the time of protocol writing, registration procedures are 
ongoing worldwide, and additional approvals in several regions have been obtained.
Based on the current edition of the IB1, 64 Phase I trials (58 trials in healthy subjects and 6 trials 
in HIV-1 infected subjects) have been completed to assess the safety, tolerability, and 
pharmacokinetics of ETR. A total of 1,281 healthy adults, 145 HIV-1 infected adults and 
35 HIV-1 infected children were included in these trials. Three proof-of-principle Phase IIa 
trials, in which 48 HIV-1 infected subjects received ETR, were conducted and reported. 

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Seven Phase IIb studies (TMC125-C203, -C209, -C223, -C227, -C211, -C229, and -C238 
[TEACH]) were completed, in which a total of 486 HIV-1 infected subjects were treated with 
ETR. In the 2 completed Phase III studies TMC125-C206 and TMC125-C216 (DUET 1 and 2) 
599 HIV-1 infected subjects were treated with ETR. The roll-over Phase III
study 
(TMC125-C217) for subjects from the DUET studies who had failed multiple regimens and had 
limited treatment options left, has also been completed. In total, 503 subjects were treated with 
ETR in this roll-over study, including 256 ETR treatment-naïve subjects, who were previously 
treated with DRV + OBR in the placebo arm of the DUET studies, and 247 ETR 
treatment-experienced subjects, who were previously treated with ETR + DRV + OBR in the 
ETR arm of the DUET studies. One Phase 4 study TMC125IFD3002 (VIOLIN) is completed.
One Phase II study TMC125-C213 (PIANO) in children as of 6 years of age and adolescents has 
been completed, in which 101 subjects were treated with ETR. One Phase I/II study 
TMC125-C234 (IMPAACT P1090) in 26 HIV-1 infected children aged ≥1 year to <6 years is 
ongoing.
The Early Access Program, TMC125-C214, aimed to provide access of ETR to HIV-1 infected 
subjects who had failed multiple ARV regimens and who had limited treatment options. In total, 
5,178 subjects have been treated with ETR in this program, which is now completed. For 
detailed and updated information on the clinical trial data, refer to the most recent Investigator's 
Brochure (IB) of ETR.1
3.1
Aim of the Study
The aim of the study is to provide continuous access to ETR for subjects who have completed a 
clinical study with ETR sponsored by or in collaboration with Janssen Research & Development.
4
TRIAL OBJECTIVES
4.1
Primary Objective
The primary objective is to continue the provision of ETR for subjects who previously received 
ETR in a clinical (parent) trial sponsored by or in collaboration with Janssen Research & 
Development, and who continue to benefit from the use of ETR, in countries where ETR is not 
commercially available for the subject’s indication, is not reimbursed, and cannot be accessed 
through another source (e.g. access program or government program), or where the subject is not 
eligible for ongoing trials/programs with ETR.

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Protocol Amendment 3 Objective:
As of Protocol Amendment 3, the objective of the trial is to provide ETR through this trial until 
the subjects can be switched to locally available ETR-based treatment regimens (ie, 
commercially available and reimbursed, or accessible through another source [eg, access 
program or government program]) or to local standard of care, as appropriate.
5
METHODS
5.1
Trial Design
5.1.1
OVERVIEW OF TRIAL
This is a continued access trial for subjects who have completed treatment in a clinical (parent)
trial with ETR sponsored by or in collaboration with Janssen Research & Development, and 
who continue to benefit from the use of ETR.
At the baseline visit, inclusion/exclusion criteria will be checked to confirm eligibility. Once 
eligibility criteria are met, subjects will either continue on the ETR dose they have received in 
the previous ETR (parent) trial or on an adjusted dose if deemed necessary by the investigator. 
For pediatric subjects, ETR dose adjustment will be based on weight using the dosing guidelines 
provided.
Assessment visits are recommended according to local generally accepted standard of care, but 
not less frequent than every three and six months for pediatric and adult subjects respectively. 
Adverse events leading to discontinuation or treatment interruption, adverse events at least 
possibly related to treatment with ETR, serious adverse events, and pregnancies are to be 
recorded at each visit. In addition to the assessments described in the flowchart, additional 
assessments not included in this protocol can be done locally at the investigator’s discretion as 
per local standard of care.
As per Protocol Amendment 3:
For ongoing subjects, the next planned visit will be a Final/Withdrawal Visit, which will be the 
last visit with data collection. For new subjects that roll-over from (parent) trial TMC125-C234
(IMPAACT P1090), the next planned visit will be a Baseline Visit which will be performed per 
local standard of care and documented in the subject’s medical records only.
For all new and ongoing subjects, all subsequent visits and assessments will be performed per 
local standard of care and documented in the subject’s medical records only. Investigators will 
continue to report SAEs possibly related to ETR and pregnancies to the sponsor using regular 
pharmacovigilance reporting. This information will only be entered in the company safety 
repository.
For all new and ongoing subjects, if the subject exits the trial, the last visit will be a local 
standard of care visit but without dispensation of investigational medication.
Treatment will be continued until one of the following criteria is met: the investigator 
determines that the subject no longer benefits from ETR treatment (e.g., based on viral load); 
treatment limiting toxicity; loss to follow-up; patient withdrawal of consent; pregnancy; 
termination of the program by the sponsor; an ETR-based treatment regimen becomes 
commercially available for the subject’s indication and is reimbursed, or can be accessed 

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through another source (e.g. access program, government program) in the region the subject is 
living in, or subjects can be switched to local standard of care, as appropriate.
Details on the timing of the treatment and assessments are given in the flowchart (see Section 2).
5.1.2
DISCUSSION OF TRIAL DESIGN
The primary objective of the trial is to continue to provide ETR to subjects who previously 
received ETR in a clinical (parent) trial and continue to benefit from the use of ETR, in countries 
where ETR is not commercially available for the subject’s indication, is not reimbursed, and 
cannot be accessed through another source (e.g. access program or government program), or 
where the subject is not eligible for ongoing trials/programs with ETR.
Selected safety data are to be collected while on treatment with ETR (see Section 5.4.3). 
Additional assessments not included in this protocol can be done locally at the investigator’s 
discretion as per local standard of care.
As per Protocol Amendment 3:
For ongoing subjects, the next planned visit will be a Final/Withdrawal Visit, which will be the 
last visit with data collection. For new subjects that roll-over from (parent) trial TMC125-C234
(IMPAACT P1090), the next planned visit will be a Baseline Visit which will be performed per 
local standard of care and documented in the subject’s medical records only.
For all new and ongoing subjects, all subsequent visits and assessments will be performed per 
local standard of care and documented in the subject’s medical records only. Serious Adverse 
Events (SAEs) possibly related to ETR and information on pregnancies will continue to be 
reported to the sponsor using regular pharmacovigilance reporting. This information will only be 
entered in the company safety repository.
For all new and ongoing subjects, if the subject exits the trial, the last visit will be a local 
standard of care visit but without dispensation of investigational medication.
5.1.3
SELECTION OF DOSE(S) IN THE TRIAL
The subject will continue on his/her current ETR dosage as received in the previous ETR
(parent) trial, with weight-based dose adjustment for pediatric subjects if necessary.
5.2
Trial Population
5.2.1
SAMPLE SIZE
No formal sample size calculation is done.
Subjects who completed treatment in a clinical study with ETR, and continue to benefit from the 
use of ETR, may be eligible to continue ETR via this trial.
5.2.2
INCLUSION CRITERIA
Subjects who meet all of the following criteria are eligible for this trial:
1.
Subjects with documented HIV-1 infection.
2.
Criterion modified per Amendment 3

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2.1.     Male or female subjects, aged 2 years and older.
3.
Subject has successfully completed a clinical (parent) trial with ETR sponsored by or in 
collaboration with Janssen Research & Development, and continues to receive benefit from 
the use of ETR.
4.
Adult has voluntarily signed the Informed Consent Form (ICF). Pediatric subject (where 
appropriate, depending on age) and their parent(s) or legal representative(s) have signed the 
ICF/Assent voluntarily. Children will be informed about the program and asked to give 
assent (where appropriate, depending on age).
5.
Negative urine pregnancy test for females of childbearing potential.
5.2.3
EXCLUSION CRITERIA
Subjects meeting one or more of the following criteria cannot be selected:
1.
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 treatment with ETR.
2.
Any active clinically significant disease (e.g., pancreatitis, cardiac dysfunction) or findings 
of medical history, laboratory or physical examination that, in the investigator’s opinion, 
would compromise the subject’s safety during treatment with ETR.
3.
Previously demonstrated clinically significant allergy or hypersensitivity to ETR or to any 
of the excipients of ETR.
4.
Pregnant or breastfeeding female subject.
5.
Non-vasectomized heterosexually active males not using safe and effective birth control 
methods (see Section 5.2.4), or not willing to continue practicing these birth control 
methods, during the trial and until 30 days after the end of the trial (or after the last intake of 
the investigational medication).
6.
Females, who are sexually active and able to become pregnant, not using safe and effective 
birth control methods (see Section 5.2.4), or not willing to continue practicing these birth 
control methods, during the trial and until 30 days after the end of the trial (or after the last 
intake of the investigational medication).
5.2.4
PROHIBITIONS AND RESTRICTIONS 
It is the investigator’s responsibility to provide appropriate counseling about precautions to avoid 
the risk of transmitting HIV. All HIV-infected subjects are advised to use a condom during 
intercourse to reduce the risk of transmitting HIV.
Since the effect of ETR on gestation is unknown, sexually active males, or females who are 
sexually active and of child-bearing potential, should receive counseling about birth control 
methods. They must either practice sexual abstinence during the trial, or use a safe and effective 
birth control method such as a double barrier method of contraception (i.e., using a condom with 
diaphragm or cervical cap) or hormone-based contraceptives in combination with a barrier 
contraceptive (i.e., male condom, diaphragm or cervical cap or female condom) during the trial. 
It is advised not to use a male and female condom together due to risk of breakage or damage as 
a result of latex friction.

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Women should not breastfeed when taking ETR, as the effects to their newborn child are 
unknown. Women who have a newborn child should talk to their physician about the best way to 
feed their child. They should be aware that HIV could be transmitted through breastfeeding.
These precautions apply from Baseline onwards, until 1 month after the last intake of 
investigational medication.
For details on the existing data with regard to the reproductive toxicity of ETR, please refer to 
the current IB1.
Investigators should follow the guidance in the most recent IB1 regarding any contraindications, 
precautions for use, and other restrictions.
5.2.5
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT
Subjects may be withdrawn from the trial if:
1.
a SAE occurs;
2.
they fail to comply with the protocol requirements or to cooperate with the investigator;
3.
a grade 3 AE (with the exception of skin events / allergic reaction) occurs according to the 
DAIDS grading scale. Exceptions (unless clinical assessment foresees an immediate health 
risk to the subject) are:
-
subjects with pre-existing diabetes who experience a glucose elevation of grade 3;
-
subjects who experience a glucose, triglyceride or cholesterol elevation of grade 3 under 
non-fasted conditions;
-
subjects who experience asymptomatic glucose, triglyceride or cholesterol elevations of 
grade 3;
-
subjects who experience asymptomatic pancreatic amylase elevations of grade 3 with no 
past or active history of pancreatitis;
-
subjects who experience a grade 3 AE that is considered not related or doubtfully related 
to the study medication;
-
subjects who experience grade 3 absolute neutrophil count or asymptomatic grade 
3 platelets.
Subjects must be withdrawn from the trial if:
1.
the parent(s) or legal representative(s) withdraws consent for a pediatric subject, or the 
subject withdraws consent or assent;
2.
the investigator considers, for safety reasons, it is in the best interest of the subject that he or 
she is withdrawn;
3.
they experience a grade 4 AE or grade 4 laboratory toxicity considered at least possibly 
related to ETR by the investigator;
4.
they experience a grade 3 or higher rash;
5.
they experience a grade 3 or higher allergic reaction;

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6.
they develop clinical hepatitis;
7.
pregnancy has been determined.
8.
they can be switched to locally available ETR-based treatment regimens (ie, commercially 
available and reimbursed, or accessible through another source [eg, access program or 
government program]) or to local standard of care, as appropriate.
The date and the reason for discontinuation must be noted on the Case Report Form (CRF). If
consent/assent is not withdrawn, all subjects prematurely discontinuing the trial must be seen for 
a follow-up visit, if they are not continuing treatment with ETR. The Trial Termination Section 
of the CRF is to be completed.
As per Protocol Amendment 3, study termination will be documented in the subject’s medical 
records and recorded on a separate, paper termination disposition form to be shared with the 
sponsor.
5.3
Treatment
5.3.1
IDENTITY OF INVESTIGATIONAL PRODUCT
The investigational medication will be provided under the responsibility of the sponsor.
ETR is formulated as an oral tablet containing 100 mg (formulation F060) or 25 mg (formulation 
F066) ETR base, in combination with hypromellose and microcrystalline cellulose, colloidal 
anhydrous silica, croscarmellose sodium, magnesium stearate, and lactose monohydrate. Adults 
will only be using the 100-mg tablet.
5.3.2
OTHER MEDICATION ADMINISTERED IN THE TRIAL
The subjects will receive the investigator-selected OBR medications according to locally 
applicable procedures. If they are not available commercially, the sponsor will provide ARVs 
which were provided by the sponsor in the previous (parent) trial until the end of the subject’s 
participation in the TMC125-C239 trial if these drugs are selected in the OBR based on the 
resistance profile. In regions where these ARVs are approved for the subject’s indication, 
reimbursed, and available via the health care system, or can be accessed through another source 
(e.g. access program, government program), subjects should use commercial supplies.
5.3.3
DOSAGE(S) AND TREATMENT OVERVIEW PER SUBJECT
Subjects will be instructed to take ETR following a meal, twice daily.
Adult subjects will receive a dose of ETR 200 mg b.i.d..
Pediatric subjects will receive ETR, dosed as they have received in the previous ETR (parent)
trial, with weight-based dose adjustment if necessary.
A pediatric ETR Dosing Chart is depicted in Table 1 and only provides dosing instructions for 
pediatric subjects of 6 years and older. Subjects coming from the parent trial TMC125-C234 
(IMPAACT P1090) and who received another dose than indicated in Table 1, may continue on 
the parent trial dose with weight-based dose adjustment as necessary (to be discussed with the 
sponsor).

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Table 1:
ETR Dosing Chart (Pediatric subjects only)
Weight
Dose
Tablets
10 to < 20 kg
100 mg b.i.d.
4 tablets 25 mg b.i.d. or 
1 tablet 100 mg b.i.d.
20 to < 25 kg
125 mg b.i.d.
5 tablets 25 mg b.i.d. or 
1 tablet 100 mg + 1 tablet 25 mg b.i.d.
25 to < 30 kg
150 mg b.i.d.
6 tablets 25 mg b.i.d. or 
1 tablet 100 mg + 2 tablets 25 mg b.i.d.
≥ 30 kg
200 mg b.i.d.
8 tablets 25 mg b.i.d. or 
2 tablets 100 mg b.i.d.
Tablets should be swallowed whole with a sufficient amount of water, fruit juice (with the 
exception of grapefruit juice), or milk. Subjects unable to swallow the tablets may disperse the 
tablets in a glass with a minimum of 5 mL of water. One minute should be allowed for the tablet 
to be dispersed. Once dispersed, subjects should stir the dispersion well and drink it immediately. 
The glass should be rinsed with a minimum of 5 mL of water, fruit juice (with the exception of 
grapefruit juice), milk or infant formula and the rinse completely swallowed to ensure the entire 
dose is consumed. This step may be repeated as needed. The dispersion should always be used 
immediately after preparation and the use of warm (>40°C) or carbonated beverages should be 
avoided. The dispersion should be consumed completely.
If a subject, parent(s) or legal representative(s) notices that the subject missed an investigational 
medication intake, and this is discovered within 6 hours of the time it is usually taken, the subject 
is advised to take the missed dose as soon as possible, with food. The subject may then continue 
his/her usual dosing schedule afterwards.
If a subject, parent(s) or legal representative(s) notices that the subject missed an investigational 
medication intake, and this is discovered more than 6 hours after the time it is usually taken, the 
subject is advised not to take the missed dose and simply resume the usual dosing schedule.
Other ARVs in the OBR should be administered according to their individual package inserts for 
those drugs that are labeled for the subject’s indication or by the sponsor-approved dosing and 
administration for those drugs that are not labeled for the subject’s indication.
5.3.4
INDIVIDUALLY OPTIMIZED BACKGROUND REGIMEN/UNDERLYING 
ANTIRETROVIRAL THERAPY
The OBR will be composed at the discretion of the investigator, according to the local standard 
of care and based on experience with previous therapies. An overview of the allowed and 
disallowed ARVs for pediatric subjects is provided in Table 2. It is recommended that the 
regimen consists of at least 2 active ARV drugs (not including low-dose rtv), including a boosted 
PI (either LPV, DRV, ATV or saquinavir [SQV]) in combination with N(t)RTI(s). Additional 
use of the fusion inhibitor ENF is optional.

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If abacavir is selected as an NRTI in the OBR, documentation should be available showing that a 
HLA-B*5701 test has been performed with a negative result.
Investigational ARV drugs are not allowed in pediatric subjects, unless appropriate pediatric 
dosing guidelines are available. For pediatric subjects meeting the aforementioned condition, and 
for all adults, investigational ARVs are allowed if favorable pharmacokinetic interaction and 
safety data exist for co-administration with ETR, and the use was discussed with and approved 
by the sponsor (e.g. Raltegravir [RAL] for those age groups where dosing guidelines have been 
established2,3).
Table 2 Allowed and Disallowed Antiretrovirals From Baseline and Throughout the Trial 
for Pediatric Subjects
ART Class
Allowed
Disallowed
PIs
LPV/rtv, DRV/rtv4, ATV/rtv, 
SQV/rtv5
All other PIs
NRTIs
All NRTIs approved for pediatric use
Tenofovir6-7
Investigational NRTIs or NRTIs approved in 
adults but not approved for pediatric use, unless 
dose recommendations for children are available 
and the use was discussed with, and approved by, 
the sponsor.
NNRTIs
ETR
NNRTIs other than ETR
FIs
ENF
-
Other 
Investigational 
ART Class
-
Integrase 
inhibitors
-
CCR5 
inhibitors
Allowed only if appropriate pediatric 
dosing guidelines are available and if 
favorable pharmacokinetic interaction 
and safety data exist for 
co-administration with ETR and the 
use was discussed with and approved 
by the sponsor (e.g. RAL for those age 
groups where dosing guidelines have 
been established2,3).
All other agents are disallowed
Note: generics are allowed, but should be (tentatively) approved by the FDA
For allowed and disallowed ARVs for adult subjects refer to the IB1.
5.3.5
PACKAGING AND LABELING
ETR will be packaged under the responsibility of the sponsor.
ETR will be labeled according to the local regulatory requirements. The labels will contain the 
protocol number, batch number, storage caution statements, dispensing instructions and ‘Keep 
out of reach of children’.
5.3.6
RANDOMIZATION
Randomization is not applicable.
5.3.7
BLINDING AND UNBLINDING
Since this is an open-label trial, blinding procedures are not applicable.

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5.3.8
DRUG ACCOUNTABILITY
The investigator, his/her designee, or the hospital pharmacist must maintain an adequate record
of the receipt of the investigational medication. Dispensation and return, or destruction 
(if applicable) of the investigational medication must be documented on an individual patient 
level by using the appropriate forms. All these records must be available for inspection at any 
time.
After termination of data collection (see Figure 1), compliance check - at pill count level - on 
unused and used trial medication returned by the subject will still be performed by the 
investigator or designee and will not be verified by the sponsor, however, drug accountability - at 
kit level - will be reviewed during the on-site monitoring visits.
5.3.9
STORAGE
All storage conditions and specific administration instructions regarding ETR will be provided to 
the investigator prior to drug delivery at the investigational site. Storage conditions will be 
mentioned on the label. At the trial site, temperature logging should be performed on a regular 
basis.
Access to the investigational medication should be restricted to designated trial personnel. The 
investigator or pharmacist will ensure accountability and appropriate storage conditions of all 
trial medication used.
At the subject’s home, the investigational medication should be stored in the childproof 
containers and out of reach of younger children and pets.
At the end of the trial, all unused medication will be handled as described in Part II, 
Section PART II:3.1.
5.3.10
ADHERENCE
Medication adherence is critical to successful antiretroviral therapy. In addition to compromising 
the efficacy of the current regimen, suboptimal adherence has implications for limiting future 
effective regimens for patients with resistant strains.
Evidence indicates that adherence problems occur frequently in children and adolescents. Studies 
have reported that fewer than 50% of children and/or their caretakers reported full adherence to 
ARV regimens8. Although a variety of factors have been associated with adherence, no clear
predictors of either good or poor adherence have been consistently identified in children.
The investigator will discuss the importance of good compliance to the entire treatment regimen, 
including ETR whether taken alone or in combination with other ARVs. It is recommended that 
the investigator regularly assesses the individual adherence to ETR, as well as all the other ARVs 
used in combination. If a subject’s medication intake is suggestive of inadequate adherence, the 
investigator should address the issues and help provide solutions to maximize adherence to the 
therapy. Adherence counseling of the subject/parent(s)/legal representative(s) by the investigator 
should be documented in the subject’s source document/chart.
After termination of data collection (see Figure 1), treatment adherence counseling should be 
performed per local standard of care and documented in the subject’s medical records only. Data 
will no longer be recorded in the CRF.

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5.3.11
PRIOR AND CONCOMITANT THERAPY
All non-ARVs, and all ARVs, which should not be co-administered with ETR are mentioned in 
Section PART I:5.3.11.1 and Section PART I:5.3.11.2. This list of disallowed medication is 
based on established or theoretical interactions with ETR. Investigators should refer to the 
current IB of ETR1 for an up-to-date overview of disallowed medications during clinical trials 
with ETR.
For other ARVs to be used in the combination therapy, please consult prescribing 
information/package inserts and the most current IBs for those individual ARVs as other 
medications may also be disallowed or cautioned for use given an individual subject’s specific 
situation.
5.3.11.1
Disallowed Non-ARV Medication
For an up to date overview of prohibited medications during trials with ETR please refer to the 
most current edition of the IB1.
The following medications are not allowed from the baseline visit until the end of treatment, or 
withdrawal visit:
-
All investigational medications or investigational vaccines, unless the use was discussed 
with and approved by the sponsor. An additional requirement for pediatric subjects is the 
availability of dose recommendations for children;
-
Chemotherapeutic agents unless previously allowed by the sponsor;
-
All disallowed medication as mentioned in the package insert of ARV drugs included in 
the OBR.
5.3.11.2
Disallowed ARV Medication
For allowed and disallowed ARVs, please refer to Section 5.3.4.
The following ARV drugs are not allowed from baseline onwards and throughout the trial:
-
All investigational ARVs, except for emtricitabine [FTC] where this is not licensed yet in 
a participating country. Another exception, for pediatric subjects, are ARVs approved in 
adults but not approved for pediatric use, with the exception of tenofovir. Investigational 
ARVs will be allowed only if favourable pharmacokinetic interaction and safety data 
exist for co-administration with ETR and the use was discussed with and approved by the 
sponsor. An additional requirement for pediatric subjects is the availability of dose 
recommendations for children (e.g. RAL for those age groups where dosing guidelines 
have been established2,3).
-
HIV vaccines;
-
NNRTIs (except for ETR);
-
PIs other than LPV/rtv, DRV/rtv, ATV/rtv and SQV/rtv for pediatric use. For adults refer 
to the IB1.

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5.4
Assessments
5.4.1
TIMING OF ASSESSMENTS
Subjects will rollover after completion of a previous (parent) trial sponsored by or in 
collaboration with Janssen Research & Development. Baseline visit will coincide with the last 
visit of the previous (parent) trial. 
Assessments and results from the last visit of the previous (parent) trial will be used for the 
Baseline visit of this trial; overlapping assessments only need to be conducted once. Additional 
assessments not included in this protocol can be done locally at the investigator’s discretion as 
per local standard of care.
As subjects roll over from a clinical (parent) trial, a urine pregnancy test is to be performed at the 
Baseline visit (females of childbearing potential only) and is repeated every 3 months (pediatric 
subjects) or every 6 months (adult subjects) thereafter.
If a subject is considered eligible after signing of the ICF/Assent, completion of the 
Baseline Form, and evaluation by the sponsor or its designee, the subject receives the 
investigational medication (ETR) at the Baseline visit.
It is recommended that subjects be evaluated every 3 months (pediatric subjects) or every 
6 months (adult subjects) after starting ETR. A Final/Withdrawal Visit is to be be performed.
The exact timing of the assessments is presented in the flowchart in Section 2.
As per Protocol Amendment 3:
For ongoing subjects, the next planned visit will be a Final/Withdrawal Visit, which will be the 
last visit with data collection. For new subjects that roll-over from (parent) trial TMC125-C234
(IMPAACT P1090), the next planned visit will be a Baseline Visit which will be performed per 
local standard of care and documented in the subject’s medical records only.
For all new and ongoing subjects, all subsequent visits and assessments will be performed per 
local standard of care and documented in the subject’s medical records only. Investigators will 
continue to report SAEs possibly related to ETR and pregnancies to the sponsor using regular 
pharmacovigilance reporting. This information will only be entered in the company safety 
repository.
For all new and ongoing subjects, if the subject exists the trial, the last visit will be a local 
standard of care visit but without dispensation of investigational medication.
5.4.2
SUBJECT AND DISEASE CHARACTERISTICS
At the baseline visit information will be copied from the previous (parent) trial. As of Protocol 
Amendment 3, this information will be documented in the subject’s medical records only for the 
subjects rolling-over from the TMC125-C234 (IMPAACT P1090) trial.
The overall eligibility of the subject to participate in the trial will be assessed.
5.4.3
SAFETY
Safety and toxicity monitoring is performed throughout the trial as per local standard of care.

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5.4.3.1
Adverse Events/HIV-Related Events
For detailed definitions and reporting procedures of AEs refer to Section 1 in Part II of this 
protocol. For reported HIV events, further details will be recorded if these events are 
AIDS-defining illnesses (CDC category C conditions; see 7.3 Addendum 3).
For subjects experiencing specific adverse events, toxicity management should be performed as 
described in Section 5.5 (Rash Management, and Acute Systemic Allergic Reaction) and 
Section 5.6 (Hyperglycemia, Hypertriglyceridemia and Hypercholesterolemia, Lactic Acidosis,
and Lipodystrophy/Fat Redistribution/Body Changes).
After termination of data collection (see Figure 1), all visits and safety assessments will be 
performed per local standard of care and documented in the subject’s medical records only. 
Investigators must continue to report SAEs possibly related to ETR and pregnancies to the 
sponsor using regular pharmacovigilance reporting. This information will only be entered in the 
company safety repository.
5.4.3.1.1
Clinical Laboratory Tests
A urine pregnancy test is to be performed every 3 months (pediatric subjects) or every 6 months 
(adult subjects) after starting ETR (females of childbearing potential only).
After termination of data collection (see Figure 1), clinical laboratory tests will occur according 
to the local standard of care and documented in the subject’s medical records only.
5.5
Safety Management Guidelines for Cutaneous Events
Toxicity management is at the discretion of the investigator, and is to take into account the 
protocol-defined procedures defined under 5.5.1 and 5.5.2, and the local standard clinical 
practice.
After termination of data collection (see Figure 1), toxicity management will be performed per 
local standard of care and documented in the subject’s medical records only.
Clinical data in adults have shown that ETR is generally safe and well tolerated. As rash is a 
known class effect with NNRTIs, cutaneous events as described below have been closely 
monitored in trials with ETR. Rash events with ETR are now well characterized based on the 
large safety dataset from our double-blind placebo-controlled trials. This section describes the 
guidelines for management of rash and acute allergic reactions.
In general, all other AEs that are ongoing at the end of the treatment period should be followed 
up until satisfactory clinical resolution or stabilization at the investigator’s discretion as per the 
local standard clinical practice.
5.5.1
RASH MANAGEMENT
Rash
In case of rash, visits and assessments should be performed as described below and in the “Visit 
Schedule for Rash Management in Pediatric Patients” (see Section 7.4, Attachment 4) and “Visit 
Schedule for Rash Management in Adult Patients” (see Section 7.5, Attachment 5). Unscheduled 
follow-up visits for close follow-up of rash will be performed based on the grade (severity) of the 
rash. At the investigator’s discretion, additional visits and assessments can be performed.

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Dermatologist fees for evaluating subjects who experience a rash will be reimbursed by the 
sponsor.
The following grades are based on the DAIDS grading table (see Section 7.2, Attachment 2), 
with adaptations made by the sponsor.
Subjects (and/or their legally acceptable representative) should be informed that they 
should contact their doctor and visit the clinic immediately when they notice any rash.
Grade 1 and 2 Cutaneous Reaction/Rash
A grade 1 cutaneous reaction/rash is defined as localized macular rash.
A grade 2 cutaneous reaction/rash is defined as diffuse macular, maculopapular, or morbilliform 
rash or target lesions.
Subjects experiencing a grade 1 or 2 rash or cutaneous event may continue treatment or have 
their trial medication interrupted at the investigator’s discretion. Local safety sampling at the 
time of the rash and clinical follow-up for these AEs will be at the discretion of the investigator, 
however, close clinical follow-up is recommended to monitor for any progression of the AE.
Grade 3 or 4 Cutaneous Reaction/Rash
A grade 3 cutaneous reaction/rash is defined as:
-
Diffuse macular, maculo-papular, or morbilliform rash with vesicles or limited number of 
bullae
-
Superficial ulceration of mucous membrane limited to 1 site 
-
Cutaneous reaction/rash with at least 1 of the following*:
1. elevations of ALT/AST > 2 x baseline but at least 5 x ULN*
2. fever 38°C or 100 F*
3. serum sickness-like reaction*
4. eosinophil count > 1000/mm³*.
* added by the sponsor.
A grade 4 cutaneous reaction/rash is defined as:
-
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 experiencing a grade 3 or 4 rash or cutaneous event must have their trial medication 
discontinued and be withdrawn from the trial. Referral to a dermatologist is recommended for 
these events. Local safety sampling to determine determine possible liver or systemic 
abnormalities is recommended. Close clinical follow-up and appropriate medical intervention is 
recommended for these events; daily follow-up is recommended for 5 days from the onset of the 
event to monitor for progression of the event.

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5.5.2
ACUTE SYSTEMIC ALLERGIC REACTION
Grade 1 (localized urticaria [wheals] with no medication intervention indicated): 
Subjects may continue the investigational medication for a grade 1 acute systemic allergic 
reaction. The subject should be advised to contact the investigator immediately if there is any 
worsening of the localized urticaria, 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 ARVs or the (dis)allowed medications for ETR as indicated above.
Grade 2 (localized urticaria with medical intervention indicated, or mild angioedema with 
no medical intervention indicated):
Subjects may continue the investigational medication for a grade 2 acute systemic allergic 
reaction. If there is any worsening of the acute systemic allergic reaction, the subject should be 
advised to contact the investigator immediately and to discontinue the investigational medication 
and be withdrawn from the trial. Antihistamines or topical corticosteroids or antipruritic agents 
may be prescribed as supportive care as long as these are in line with the package inserts of the 
ARVs or the (dis)allowed medications for ETR as indicated above.
Grade 3 (generalized urticaria, or angioedema with medical intervention indicated, or 
symptomatic mild bronchospasm) and grade 4 (acute anaphylaxis, or life-threatening 
bronchospasm, or laryngeal edema):
Subjects will permanently discontinue trial medication and be withdrawn from the trial. 
Rechallenge with ETR is not allowed. Subjects will be treated as clinically appropriate. Standard 
management should be undertaken.
5.6
Toxicity Management for Specific Adverse Events With 
Concomitant Antiretrovirals
Toxicity management is at the discretion of the investigator, and is to take into account the 
protocol-defined procedures defined under 5.6.1, 5.6.2, 5.6.3, 5.6.4, 5.6.5, and 5.6.6, and the 
local standard clinical practice.
After termination of data collection (see Figure 1), toxicity management will be performed per 
local standard of care and documented in the subject’s medical records only.
(The information below does not imply that the following AEs are caused by concomitant ARVs 
alone, but may also be due to ETR.)
5.6.1
HYPERGLYCEMIA
Grade 3: 13.89-27.75 mmol/L (251-500 mg/dL)
Grade 4: > 27.75 mmol/L (> 500 mg/dL)
If elevated glucose levels are from a non-fasting blood draw, repeat the draw after a 10-hour fast. 
Management decisions must be based on fasted results. Subjects who experience asymptomatic 
glucose elevations of grade 3 or 4 and subjects with pre-existing diabetes may continue trial 
medication unless clinical assessment foresees an immediate health risk to the subject. Subjects 
with persistent grade 3 or 4 glucose elevations despite appropriate anti-hyperglycemic treatment 

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should be permanently discontinued with the exception of subjects with pre-existing diabetes. 
Appropriate clinical management of hyperglycemia must be started in a timely fashion.
5.6.2
HYPERTRIGLYCERIDEMIA AND HYPERCHOLESTEROLEMIA
Hypertriglyceridemia
Grade 3: 8.49-13.56 mmol/L (751-1200 mg/dL)
Grade 4: > 13.56 mmol/L (> 1200 mg/dL)
Hypercholesterolemia
Grade 3: > 7.77 mmol/L (> 300 mg/dL)
Grade 4: not applicable
Management decisions should be based on fasted results. If elevated triglyceride or cholesterol 
levels are from a non-fasting blood draw, repeat the draw 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 trial medication. 
Hypertriglyceridemia and hypercholesterolemia should be treated according to the specific 
guidelines for treating HIV-infected subjects. Appropriate clinical management of dyslipidemia 
in the setting of HIV disease should be started in a timely fashion. Investigators may choose to 
initiate pharmacologic treatment in addition to the usual counseling on diet and exercise.
Medications should be introduced with caution. Lovastatin and simvastatin are not allowed as 
there is the potential for a significant drug interaction with PIs (ATV/rtv).
5.6.3
LACTIC ACIDOSIS
The relevance of asymptomatic lactic acid elevations is unclear, and lactates are not part of the 
routine safety evaluations for this trial. Routine lactate monitoring is not currently recommended. 
However, lactate monitoring should be performed 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. Women are also at greater risk. Symptoms of lactic acidosis are frequently non-specific 
such as fatigue, weakness, and fever, but in the majority of cases also include symptoms 
suggestive of hepatic dysfunction such as nausea, vomiting, abdominal or epigastric discomfort, 
abdominal distension, hepatomegaly, and new onset elevated liver enzymes. A high index of 
suspicion may be required to diagnose this condition. Alternatively, it is possible that 
unwarranted concern may be raised by 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, defined differently for symptomatic vs 
asymptomatic individuals, will be used in this protocol:

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Symptomatic Hyperlactatemia
New, otherwise unexplained and persistent (2 weeks) occurrence of 1 or more of the following 
symptoms:

nausea and vomiting;

abdominal pain or gastric discomfort;

abdominal distention;

increased ALT or AST;

unexplained fatigue;

dyspnea;
AND

lactate level > 2 x ULN confirmed by repeat lactate level analysis.
Note: All lactates > 2 x ULN should be repeated as soon as possible, generally within 1 week. 
Lactate levels should not be assessed following physical exertion as this causes elevated 
lactate levels and may confound assessment of the clinical significance of these findings. If 
the second result confirms hyperlactatemia (> 2 x ULN) in subjects with symptoms as 
described above, subjects should immediately discontinue their current trial regimen 
(including ETR and other ARVs) and be withdrawn from the trial. Standard management 
should be initiated with follow-up to resolution.
Processing of the lactate 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.
5.6.4
LIPODYSTROPHY/FAT REDISTRIBUTION/BODY CHANGES
Assessment of fat redistribution in HIV-infected children is complicated by the normal, dynamic 
alterations in body composition that occur during childhood and adolescence.
Children can be considered to have abnormal fat accumulation if they had one or more of the 
following signs:
1.
Trunk with increased abdominal girth;
2.
Dorso-cervix with fat accumulation ‘buffalo hump’;
3.
Breast enlargement.

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Children can be considered to have lipoatrophy if they had one or more of the following signs:
1.
Face with sunken cheeks, sunken eyes with prominent zygomatic arch;
2.
Skinny arms with prominent veins; muscularity and bones;
3.
Skinny legs with prominent veins; muscularity and bones;
4.
Buttocks with loose skin folds, prominent muscles, loss of contour and fat.
Investigators should avoid using the term “lipodystrophy acquired” to describe and report fat 
redistribution abnormalities associated with ART as this term is not very descriptive. The 
different symptoms and gradings are listed in the DAIDS grading table under 
Endocrine/Metabolic. The relevant terms include: abnormal fat accumulation, lipoatrophy and 
gynecomastia.
Although metabolic abnormalities such as hyperlipidemia or hyperglycemia are often associated 
with body changes, these events should be reported separately for AE reporting.
5.6.5
PANCREATITIS
Pancreatitis, which has been fatal in some cases, is a major clinical toxicity associated with 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.
Laboratory Abnormalities
For asymptomatic grade 1 and 2 pancreatic amylase and/or lipase elevations, and confirmed 
asymptomatic grade 3 pancreatic amylase elevations with no past or active history of 
pancreatitis, subjects should be carefully evaluated and followed closely.
For confirmed grade 4 elevations of pancreatic amylase and confirmed grade 3 or 4 elevations of 
lipase, subjects should interrupt all trial medications until pancreatic amylase and/or lipase 
returns to grade 2, at which time trial medication could be reintroduced. N(t)RTIs such as ddI 
(with or without TDF) and d4T may be resumed at either reduced or full dose at the 
investigator’s discretion. If grade 4 elevations of pancreatic amylase and/or grade 3 or 4 lipase 
levels persist 14 days following interruption of all trial medications, or if the toxicity recurs 
more than twice, all trial medications should be permanently discontinued.
5.6.6
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 according to the physician, but generally begins with 
non-opioid analgesics, including non-steroidal anti-inflammatory agents and acetaminophen, and 
the use of tricyclic antidepressants and other agents when more severe symptoms are present.

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5.7
Statistical Methods Planned and Determination of the Sample Size
5.7.1
SAMPLE SIZE CALCULATION
No formal sample size calculation has been performed. The trial is not set up to show a specific 
statistical hypothesis but to provide ETR to subjects who previously received ETR in a clinical 
(parent) trial sponsored by Janssen Research & Development, and continue to benefit from the 
use of ETR, in countries where ETR is not commercially available to subjects, is not reimbursed, 
and is not accessible through another source (e.g. access program or government program), or 
where the subject is not eligible for ongoing trials/programs with ETR. Data from this trial may 
be included in Safety Updates.
5.7.2
INITIAL SUBJECT AND DISEASE CHARACTERISTICS 
The demographic and baseline disease characteristics of the subjects included in the trial, such as 
gender and race, will be tabulated when deemed necessary for submissions or safety updates.
5.7.3
STATISTICAL ANALYSIS
Data of adult and pediatric subjects will be analyzed separately. For the statistical analysis of 
TMC125-C239, a pediatric and adult subject will be defined as a subject who entered the current 
trial at age < 18 and ≥ 18 years old respectively. Final analysis will be done once all subjects 
have completed the Final/Withdrawal Visit. After termination of data collection in the CRF (see 
Figure 1), no additional statistical analysis will be performed. 
5.7.3.1
Safety
The safety of ETR will be summarized in terms of:
-
Mortality
-
All SAEs
-
AEs leading to discontinuation
-
AEs possibly related to ETR treatment
The number of and causes of deaths will be summarized.
The number of subjects who terminate treatment will be tabulated, and reasons for drug 
discontinuation will be summarized.
5.7.3.2
(S)AEs
From the collected (S)AE data in TMC125-C239, the following events will be subject to 
additional analysis:
-
Skin
-
Cardiac
-
Hepatobilliary
-
Neuropsychiatric

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5.8
Data Quality Assurance
See Data Quality Assurance (PART II:8)

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6
REFERENCES
1. TMC125-Etravirine, Investigator’s Brochure, Edition 20, November 2018.
2. Nachman S. et al. Raltegravir (RAL) pharmacokinetics (PK) and safety in adolescents: 
preliminary results from IMPAACT P1066. ICAAC/IDSA 2008; abstract H-4059a.
3. Nachman S et al. Pharmacokinetic (PK), safety and efficacy data on cohort IIA; youth aged 
6-11 from IMPAACT P1066: A Phase I/II study to evaluate raltegravir (RAL) in HIV-1 
infected youth. CROI 2010; abstract 873.
4. Spinosa-Guzman S, Vangeneugden T, Sekar V, Dierynck I. A Phase II, open-label trial, to 
investigate pharmacokinetics, safety, tolerability and antiviral activity of TMC114/rtv b.i.d. 
in treatment-experienced HIV-1 infected children and adolescents - Analysis with cut-off 
date of 10 April 2008, at which time all subjects had reached Week 48 or discontinued 
before. Tibotec Pharmaceuticals, Clinical Research Report TMC114-C212, January 2009.
5. Grub S, DeLora P, Lüdin E et al. Pharmacokinetics and pharmacodynamics of saquinavir in 
pediatric patients with human immunodeficiency virus infection. Clin Pharmacol Ther 
2002;71:122-30.
6. Hazra R, Balis FM, Tullio AN, et al. Single-dose and steady-state pharmacokinetics of 
tenofovir DF in HIV-infected children. Antimicrob Agents Chemother.2004;48(1):124-129.
7. Ramos JT, Gonzalez-Tome MI, Rojo P, Fernandez-Ibieta M, Vargas C, Garcia L. Experience 
with tenofovir disoproxil fumarate (TDF) in heavily pretreated HIV infected children 
[poster]. Paper presented at: XV International AIDS Conference; July 11-16, 2004; Bangkok, 
Thailand.
8. Rimsza ME. Counseling the adolescent about contraception. Pediatrics in Review 2003; 24: 
162-170.

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7
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 is available in the investigator site file. 

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7.2
Addendum 2: DAIDS Grading Table
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND 
PEDIATRIC ADVERSE EVENTS - PUBLISH DATE: DECEMBER 2004
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 adverse event reporting 
in this trial. A grading (severity) scale is provided for each adverse event term.
General Instructions
Estimating Severity Grade
If the need arises to grade a clinical adverse event 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 Adverse Events
The DAIDS grading table includes parameters for grading both adult and pediatric adverse 
events. When a single set of parameters is not appropriate for grading specific types of adverse 
events 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 adverse event, 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 adverse event.
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 
adverse event.
Operative intervention
Surgical OR other invasive mechanical procedures.

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse event 
NOT identified elsewhere 
in this DAIDS grading 
table
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
Symptoms causing 
inability to perform basic 
self-care functions OR 
Medical or operative 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death
SYSTEMIC
Acute systemic allergic 
reaction
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with 
medical intervention 
indicated OR Mild 
angioedema with no 
medical intervention 
indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
laryngeal edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
Incapacitating fatigue/ 
malaise symptoms 
causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7°C – 38.6°C
38.7°C – 39.3°C
39.4°C – 40.5°C
> 40.5°C
Pain (indicate body site)
DO NOT use for pain due 
to injection (See Injection 
site reactions: Injection 
site pain)
See also Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than 
minimal interference with 
usual social & functional 
activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization (other 
than emergency room 
visit) indicated
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.).

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Unintentional weight loss
NA
5% – 9% loss in body 
weight from baseline
10% – 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR 
Aggressive intervention 
indicated [e.g., tube feeding 
or total parenteral nutrition 
(TPN)]
INFECTION
Infection (any other than 
HIV infection)
Localized, no systemic 
antimicrobial treatment 
indicated AND 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Systemic antimicrobial 
treatment indicated OR 
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Systemic antimicrobial 
treatment indicated AND 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR Operative 
intervention (other than 
simple incision and 
drainage) indicated
Life-threatening 
consequences 
(e.g., septic shock)
INJECTION SITE REACTIONS
Injection site pain (pain 
without touching)
Or
Tenderness (pain when area 
is touched)
Pain/tenderness causing 
no or minimal limitation 
of use of limb
Pain/tenderness limiting 
use of limb OR 
Pain/tenderness causing 
greater than minimal 
interference with usual 
social & functional 
activities
Pain/tenderness causing 
inability to perform usual 
social & functional 
activities
Pain/tenderness causing 
inability to perform basic 
self-care function OR 
Hospitalization (other than 
emergency room visit) 
indicated for management of 
pain/tenderness
Injection site reaction (localized)
Adult > 15 years
Erythema OR Induration 
of 5 x 5 cm – 9 x 9 cm (or 
25 cm² – 81cm²)
Erythema OR Induration 
OR Edema 
> 9 cm any diameter 
(or > 81 cm²)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving dermis 
and deeper tissue)
Pediatric 
15 years
Erythema OR Induration 
OR Edema present but 
2.5 cm diameter
Erythema OR Induration 
OR Edema > 2.5 cm 
diameter but < 50% 
surface area of the 
extremity segment 
(e.g., upper arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment 
(e.g., upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage
Necrosis (involving dermis 
and deeper tissue)
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.).

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Pruritis associated with 
injection
See also Skin: Pruritis 
(itching - no skin lesions)
Itching localized to 
injection site AND 
Relieved spontaneously or 
with < 48 hours treatment
Itching beyond the 
injection site but not 
generalized OR Itching 
localized to injection site 
requiring 48 hours 
treatment
Generalized itching 
causing inability to 
perform usual social & 
functional activities
NA
SKIN – DERMATOLOGICAL
Alopecia
Thinning detectable by 
study participant (or by 
caregiver for young 
children and disabled 
adults)
Thinning or patchy hair 
loss detectable by health 
care provider
Complete hair loss
NA
Cutaneous reaction/rash
Localized macular rash
Diffuse macular, 
maculopapular, or 
morbilliform rash OR 
Target lesions
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited number 
of bullae OR 
Cutaneous reaction/rash 
with superficial 
ulcerations of mucous 
membrane limited to 
1 sitea OR
Cutaneous reaction/rash 
with at least 1 of the 
followinga: elevation of 
AST and/or ALT > 2 x 
baseline but at least > 5 x 
ULNa; fever (> 38°C or 
100°F) a; eosinophils > 
1000/mm3a; serum 
sickness-like reactiona
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson 
syndrome (SJS) OR 
Ulceration of mucous 
membrane involving 2 or 
more distinct mucosal 
sites OR Toxic epidermal 
necrolysis (TEN)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized
Marked or generalized
NA
NA
Pruritis (itching – no skin 
lesions)
(See also Injection site 
reactions: Pruritis 
associated with injection)
Itching causing no or 
minimal interference with 
usual social & functional 
activities
Itching causing greater 
than minimal interference 
with usual social & 
functional activities
Itching causing inability to 
perform usual social & 
functional activities
NA
CARDIOVASCULAR
Cardiac arrhythmia 
(general) (By ECG or 
physical exam)
Asymptomatic AND 
No intervention indicated
Asymptomatic AND 
Nonurgent medical 
intervention indicated
Symptomatic, non-life 
threatening AND 
Nonurgent medical 
intervention indicated
Life-threatening 
arrhythmia OR Urgent 
intervention indicated
a
Revised by the sponsor.
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.).

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Clinical Trial Protocol Amendment III
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Cardiac ischemia/
infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR 
Testing consistent with 
ischemia
Unstable angina OR Acute 
myocardial Infarction
Hemorrhage (significant 
acute blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for 
children 10 cc/kg) 
indicated
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for children 
> 10 cc/kg) indicated
Hypertensiona
Adult > 17 years
(with repeat testing at 
same visit)
> 140 to < 160 mmHg 
systolic
OR
> 90 to < 100 mmHg 
diastolic
≥ 160 to < 180 mmHg 
systolic
OR
≥ 100 to < 110 mmHg 
diastolic
≥ 180 mmHg systolic
OR
≥ 110 mmHg diastolic
Life-threatening 
consequences 
(e.g., malignant 
hypertension) OR 
Hospitalization indicated 
(other than emergency 
room visit)
Pediatric 
17 years
(with repeat testing at 
same visit)
NA
91st – 94th percentile 
adjusted for age, height, 
and gender (systolic 
and/or diastolic)
95th percentile adjusted 
for age, height, and 
gender (systolic and/or 
diastolic)
Life-threatening 
consequences 
(e.g., malignant 
hypertension) OR 
Hospitalization indicated 
(other than emergency 
room visit)
Hypotension
NA
Symptomatic, corrected 
with oral fluid 
replacement
Symptomatic, i.v. fluids 
indicated
Shock requiring use of 
vasopressors or 
mechanical assistance to 
maintain blood pressure
Pericardial effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate 
or larger effusion 
requiring no intervention
Effusion with non-life 
threatening physiologic 
consequences OR 
Effusion with nonurgent 
intervention indicated
Life-threatening
consequences 
(e.g., tamponade) OR 
Urgent intervention 
indicated
Prolonged PR interval
Adult > 16 years
PR interval 
0.21 – 0.25 s
PR interval > 0.25 s
Type II 2nd degree AV 
block OR Ventricular 
pause > 3.0 s
Complete AV block
Pediatric 
16 years
1st degree AV block (PR 
> normal for age and rate)
Type I 2nd degree AV 
block
Type II 2nd degree AV 
block
Complete AV block
a
Revised by the sponsor.
Use as a reference: Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 
14, 2011; DOI: 10.1542/peds.2009-2107C.
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.).

TMC125-TiDP35-C239
Clinical Trial Protocol Amendment III
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Prolonged QTc
Adult > 16 years
Asymptomatic, QTc 
interval 0.45 – 0.47 s OR 
Increase in interval 
< 0.03 s above baseline
Asymptomatic, QTc 
interval 0.48 – 0.49 s OR 
Increase in interval
0.03 – 0.05 s above 
baseline
Asymptomatic, QTc 
interval 0.50 s OR 
Increase in interval 
0.06 s above baseline
Life-threatening 
consequences, e.g., 
Torsade de pointes or 
other associated serious 
ventricular dysrhythmia
Pediatric 
16 years
Asymptomatic, QTc 
interval 
0.450 – 0.464 s
Asymptomatic, QTc 
interval 0.465 – 0.479 s
Asymptomatic, QTc 
interval 0.480 s
Life-threatening 
consequences, e.g., 
Torsade de pointes or 
other associated serious 
ventricular dysrhythmia
Thrombosis/embolism
NA
Deep vein thrombosis 
AND No intervention 
indicated 
(e.g., anticoagulation, 
lysis filter, invasive 
procedure)
Deep vein thrombosis 
AND Intervention 
indicated 
(e.g., anticoagulation, 
lysis filter, invasive 
procedure)
Embolic event 
(e.g., pulmonary 
embolism, life-
threatening thrombus)
Vasovagal episode 
(associated with a 
procedure of any kind)
Present without loss of 
consciousness
Present with transient loss 
of consciousness
NA
NA
Ventricular dysfunction 
(congestive heart failure)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with 
symptoms OR Worsening 
symptomatic congestive 
heart failure
Life-threatening 
congestive heart failure
GASTROINTESTINAL
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite 
associated with decreased 
oral intake without 
significant weight loss
Loss of appetite 
associated with 
significant weight loss
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding or total parenteral 
nutrition [TPN])
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated 
(e.g., diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening 
consequences
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.)

TMC125-TiDP35-C239
Clinical Trial Protocol Amendment III
44
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Cholecystitis
NA
Symptomatic AND 
Medical intervention 
indicated
Radiologic, endoscopic, 
or operative intervention 
indicated
Life-threatening 
consequences (e.g., sepsis 
or perforation)
Constipation
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences 
(e.g., obstruction)
Diarrhea
Adult and Pediatric 
1 year
Transient or intermittent 
episodes of unformed 
stools OR Increase of ≤ 3 
stools over baseline per 
24-hour period
Persistent episodes of 
unformed to watery stools 
OR Increase of 
4 – 6 stools over baseline 
per 24-hour period
Bloody diarrhea OR 
Increase of ≥ 7 stools per 
24-hour period OR i.v. 
fluid replacement 
indicated
Life-threatening 
consequences 
(e.g., hypotensive shock)
Pediatric < 1 year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with 
increased number of 
stools OR Mild 
dehydration
Liquid stools with 
moderate dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR 
Hypotensive shock
Dysphagia-Odynophagia
Symptomatic but able to 
eat usual diet
Symptoms causing 
altered dietary intake 
without medical 
intervention indicated
Symptoms causing 
severely altered dietary 
intake with medical 
intervention indicated
Life-threatening reduction 
in oral intake
Mucositis/stomatitis 
(clinical exam) 
Indicate site (e.g., larynx, 
oral) 
See Genito-urinary for 
Vulvovaginitis
See also Dysphagia-
Odynophagia and 
Proctitis
Erythema of the Mucosa
Patchy pseudomembranes 
or ulcerations
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor 
trauma
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding OR 
Life-threatening 
consequences 
(e.g., aspiration, choking)
Nausea
Transient (< 24 hours) or 
intermittent nausea with 
no or minimal 
interference with oral 
intake
Persistent nausea 
resulting in decreased oral 
intake for 
24 – 48 hours
Persistent nausea 
resulting in minimal oral 
intake for
> 48 hours OR 
Aggressive rehydration 
indicated (e.g., i.v. fluids)
Life-threatening 
consequences 
(e.g., hypotensive shock)
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.)

TMC125-TiDP35-C239
Clinical Trial Protocol Amendment III
45
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Pancreatitis
NA
Symptomatic AND 
Hospitalization not 
indicated (other than 
emergency room visit)
Symptomatic AND 
Hospitalization indicated 
(other than emergency 
room visit)
Life-threatening 
consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis)
Proctitis (functional-
symptomatic)
Also see 
Mucositis/stomatitis for 
clinical exam
Rectal discomfort AND 
No intervention Indicated
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Medical 
intervention indicated
Symptoms causing 
inability to perform usual 
social & functional 
activities OR Operative 
intervention indicated
Life-threatening 
consequences 
(e.g., perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of 
vomiting with no or mild 
dehydration
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive rehydration 
indicated (e.g., i.v. fluids)
Life-threatening 
consequences 
(e.g., hypotensive shock)
NEUROLOGIC
Alteration in personality-
behavior or in mood 
(e.g., agitation, anxiety, 
depression, mania, 
psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities
Alteration causing greater 
than minimal interference 
with usual social & 
functional activities
Alteration causing 
inability to perform usual 
social & functional 
activities
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
Altered Mental Status
For Dementia, see 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and attention 
deficit disorder)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with usual 
social & functional 
activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing 
inability to perform usual 
social & functional 
activities
Delirium OR 
obtundation, OR coma
Ataxia
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing 
no or minimal 
interference with usual 
social & functional 
activities
Symptomatic ataxia 
causing greater than 
minimal interference with 
usual social & functional 
activities
Symptomatic ataxia 
causing inability to 
perform usual social & 
functional activities
Disabling ataxia causing 
inability to perform basic 
self-care functions
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.)

TMC125-TiDP35-C239
Clinical Trial Protocol Amendment III
46
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and attention 
deficit disorder)
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater 
than minimal interference 
with usual social & 
functional activities OR 
Specialized resources on 
part-time basis indicated
Disability causing 
inability to perform usual 
social & functional 
activities OR Specialized 
resources on a full-time 
basis indicated
Disability causing 
inability to perform basic 
self-care functions OR 
Institutionalization 
Indicated
CNS ischemia (acute)
NA
NA
Transient ischemic Attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit
Developmental delay
Pediatric 16 years
Mild developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting
Moderate developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting
Severe developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting
Developmental 
regression, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting
Headache
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
Symptoms causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
(other than emergency 
room visit) OR Headache 
with significant 
impairment of alertness or 
other neurologic function
Insomnia
NA
Difficulty sleeping 
causing greater than
minimal interference with 
usual social & functional 
activities
Difficulty sleeping 
causing inability to 
perform usual social & 
functional activities
Disabling insomnia 
causing inability to 
perform basic self-care 
functions
Neuromuscular weakness 
(including myopathy & 
neuropathy)
Asymptomatic with 
decreased strength on 
exam OR Minimal muscle 
weakness causing no or 
minimal interference with 
usual social & functional 
activities
Muscle weakness causing 
greater than minimal 
interference with usual 
social & functional 
activities
Muscle weakness causing 
inability to perform usual 
social & functional 
activities
Disabling muscle 
weakness causing 
inability to perform basic 
self-care functions OR 
Respiratory muscle 
weakness impairing 
ventilation
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.)

TMC125-TiDP35-C239
Clinical Trial Protocol Amendment III
47
xCLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Neurosensory alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with 
sensory alteration on 
exam or minimal 
paresthesia causing no or 
minimal interference with 
usual social & functional 
activities
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with usual 
social & functional 
activities
Sensory alteration or 
paresthesia causing 
inability to perform usual 
social & functional 
activities
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions
Seizure: (new onset) 
Adult 18 years
See also Seizure: (known 
pre-existing seizure 
disorder)
NA
1 seizure
2 – 4 seizures
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult to 
control (e.g., refractory 
epilepsy)
Seizure: (known 
pre-existing seizure 
disorder)
Adult 18 years
For worsening of existing 
epilepsy the grades should 
be based on an increase 
from previous level of 
control to any of these 
levels.
NA
Increased frequency of 
pre-existing seizures 
(nonrepetitive) without 
change in seizure 
character OR Infrequent 
breakthrough seizures 
while on stable 
medication in a previously 
controlled seizure 
disorder
Change in seizure 
character from baseline 
either in duration or 
quality (e.g., severity or 
focality)
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult to 
control (e.g., refractory 
epilepsy)
Seizure
Pediatric < 18 years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with 
< 24 hours postictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
5 – 20 minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater 
than minimal interference 
with usual social & 
functional activities
Vertigo causing inability 
to perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic 
self-care functions
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.)

TMC125-TiDP35-C239
Clinical Trial Protocol Amendment III
48
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
RESPIRATORY
Bronchospasm (acute)
FEV1 or peak flow 
reduced to 70% – 80%
FEV1 or peak flow 
50% - 69%
FEV1 or peak flow 
25% – 49%
Cyanosis OR FEV1 or 
peak flow < 25% OR 
Intubation
Dyspnea or respiratory distress
Adult 14 years
Dyspnea on exertion with 
no or minimal interference 
with usual social & 
functional activities
Dyspnea on exertion 
causing greater than 
minimal interference with 
usual social & functional 
activities
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities
Respiratory failure with 
ventilatory support 
indicated
Pediatric 
< 14 years
Wheezing OR minimal 
increase in respiratory rate 
for age
Nasal flaring OR 
Intercostal retractions OR 
Pulse oximetry 
90% – 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities OR Pulse 
oximetry < 90%
Respiratory failure with 
ventilatory support 
indicated
MUSCULOSKELETAL
Arthralgia
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater 
than minimal interference 
with usual social & 
functional activities
Joint pain causing 
inability to perform usual 
social & functional 
activities
Disabling joint pain 
causing inability to 
perform basic self-care 
functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional 
activities
Stiffness or joint swelling 
causing greater than 
minimal interference with 
usual social & functional 
activities
Stiffness or joint swelling 
causing inability to 
perform usual social & 
functional activities
Disabling joint stiffness or 
swelling causing inability 
to perform basic self-care 
functions
Bone Mineral Loss
Adult 21 years
BMD t-score
-2.5 to -1.0
BMD t-score < -2.5
Pathological fracture 
(including loss of 
vertebral height)
Pathologic fracture 
causing life-threatening 
consequences
Pediatric 
< 21 years
BMD z-score
-2.5 to -1.0
BMD z-score < -2.5
Pathological fracture 
(including loss of 
vertebral height)
Pathologic fracture 
causing life-threatening 
consequences
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.)

TMC125-TiDP35-C239
Clinical Trial Protocol Amendment III
49
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Myalgia 
(noninjection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing 
greater than minimal 
interference with usual 
social & functional 
activities
Muscle pain causing 
inability to perform usual 
social & functional 
activities
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions
Osteonecrosis
NA
Asymptomatic with 
radiographic findings 
AND No operative 
intervention indicated
Symptomatic bone pain 
with radiographic findings 
OR Operative intervention 
indicated
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions
GENITO-URINARY
Cervicitis (symptoms)
(For use in studies 
evaluating topical study 
agents)
For other cervicitis see 
Infection: Infection (any 
other than HIV infection)
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
Symptoms causing 
inability to perform basic 
self-care functions
Cervicitis (clinical exam) 
(For use in studies 
evaluating topical study 
agents)
For other cervicitis, 
see Infection: Infection 
(any other than HIV 
infection)
Minimal cervical 
abnormalities on 
examination (erythema, 
mucopurulent discharge, 
or friability) OR 
Epithelial disruption 
< 25% of total surface
Moderate cervical 
abnormalities on 
examination (erythema, 
mucopurulent discharge, 
or friability) OR 
Epithelial disruption of 
25% – 49% total surface
Severe cervical 
abnormalities on 
examination (erythema, 
mucopurulent discharge, 
or friability) OR 
Epithelial disruption 
50% – 75% total surface
Epithelial disruption 
> 75% total surface
Intermenstrual bleeding 
(IMB)
Spotting observed by 
participant OR Minimal
blood observed during 
clinical or colposcopic 
examination
Inter-menstrual bleeding 
not greater in duration or 
amount than usual 
menstrual cycle
Inter-menstrual bleeding 
greater in duration or 
amount than usual 
menstrual cycle
Hemorrhage with 
lifethreatening 
hypotension OR 
Operative intervention 
indicated
Urinary tract
obstruction (e.g., stone)
NA
Signs or symptoms of 
urinary tract obstruction 
without hydronephrosis or 
renal dysfunction
Signs or symptoms of 
urinary tract obstruction 
with hydronephrosis or 
renal dysfunction
Obstruction causing 
lifethreatening 
Consequences
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.)

TMC125-TiDP35-C239
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50
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Vulvovaginitis 
(symptoms)
(Use in studies evaluating 
topical study agents)
For other vulvovaginitis 
see Infection: Infection 
(any other than HIV 
infection)
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
Symptoms causing 
inability to perform basic 
self-care functions
Vulvovaginitis (clinical 
exam)
(Use in studies evaluating 
topical study agents)
For other vulvovaginitis 
see Infection: Infection 
(any other than HIV 
infection)
Minimal vaginal 
abnormalities on 
examination OR 
Epithelial disruption 
< 25% of total surface
Moderate vaginal 
abnormalities on 
examination OR 
Epithelial disruption of 
25% – 49% total surface
Severe vaginal 
abnormalities on 
examination OR 
Epithelial disruption 
50% – 75% total surface
Vaginal perforation OR 
Epithelial disruption 
> 75% total surface
OCULAR/VISUAL
Uveitis
Asymptomatic but 
detectable on exam
Symptomatic anterior 
uveitis OR Medical 
intervention indicated
Posterior or pan-uveitis 
OR Operative intervention 
indicated
Disabling visual loss in 
affected eye(s)
Visual changes (from 
baseline)
Visual changes causing no 
or minimal interference 
with usual social & 
functional activities
Visual changes causing 
greater than minimal 
interference with usual 
social & functional 
activities
Visual changes causing 
inability to perform usual 
social & functional 
activities
Disabling visual loss in 
affected eye(s)
ENDOCRINE/METABOLIC
Abnormal fat 
accumulation (e.g., back 
of neck, breasts, 
abdomen)
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults)
Detectable on physical 
exam by health care 
provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.)

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Diabetes mellitus
NA
New onset without need 
to initiate medication OR 
Modification of current 
medications to regain 
glucose control
New onset with initiation 
of medication indicated 
OR Diabetes uncontrolled 
despite treatment 
modification
Life-threatening 
consequences 
(e.g., ketoacidosis, 
hyperosmolar nonketotic 
coma)
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical 
exam by health care 
provider
Disfiguring OR 
Obvious on casual visual 
inspection
NA
Hyperthyroidism
Asymptomatic
Symptomatic causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
suppression therapy 
indicated
Symptoms causing 
inability to perform usual 
social & functional 
activities OR 
Uncontrolled despite 
treatment modification
Life-threatening 
consequences 
(e.g., thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
replacement therapy 
indicated
Symptoms causing 
inability to perform usual 
social & functional 
activities OR 
Uncontrolled despite 
treatment modification
Life-threatening 
consequences 
(e.g., myxedema coma)
Lipoatrophy (e.g., fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults)
Detectable on physical 
exam by health care 
provider
Disfiguring OR Obvious 
on casual visual 
inspection
NA
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – 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.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.)

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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
HEMATOLOGY    Standard International Units are listed in italics
Absolute CD4+ count
Adult and Pediatric 
> 13 years 
(HIV negative only)
300 – 400/mm³
300 – 400/µL
200 – 299/mm³
200 – 299/µL
100 – 199/mm³
100 – 199/µL
< 100/mm³
< 100/µL
Absolute lymphocyte count
Adult and Pediatric
> 13 years 
(HIV negative only)
600 – 650/mm³
0.600 x 109 –
0.650 x 109/L
500 – 599/mm³
0.500 x 109 –
0.599 x 109/L
350 – 499/mm³
0.350 x 109 –
0.499 x 109/L
< 350/mm³
< 0.350 x 109/L
Absolute neutrophil count (ANC)
Adult and Pediatric > 
7 days
1,000 – 1,300/mm³
1.000 x 109 –
1.300 x 109/L
750 – 999/mm³
0.750 x 109 –
0.999 x 109/L
500 – 749/mm³
0.500 x 109 –
0.749 x 109/L
< 500/mm³
< 0.500 x 109/L
Infanta,b
2 – 7 days
1,250 – 1,500/mm³
1.250 x 109 –
1.500 x 109/L
1,000 – 1,249/mm³
1.000 x 109 –
1.249 x 109/L
750 – 999/mm³
0.750 x 109 –
0.999 x 109/L
< 750/mm³
< 0.750 x 109/L
Infanta,b 1 day
4,000 – 5,000/mm³
4.000 x 109 –
5.000 x 109/L
3,000 – 3,999/mm³
3.000 x 109 –
3.999 x109/L
1,500 – 2,999/mm³
1.500 x 109 –
2.999 x 109/L
< 1,500/mm³
< 1.500 x 109/L
Fibrinogen, decreasedc
100 – 200 mg/dL
1.00 – 2.00 g/L
OR
≥0.75 to < 1.00 x LLN
75 – 99 mg/dL
0.75 – 0.99 g/L
OR
≥0.50 to < 0.75 x LLN
50 – 74 mg/dL
0.50 – 0.74 g/L
OR
≥0.25 to < 0.50 x LLN
< 50 mg/dL
< 0.50 g/L
OR
< 0.25 x LLN
OR Associated with gross 
bleeding
Hemoglobin (Hgb)d
Adult and Pediatric
57 days
(HIV positive only)
8.5 – 10.0 g/dL
5.2 – 6.1 mmol/L
7.5 – 8.4 g/dL
4.6 – 5.1 mmol/L
6.5 – 7.4 g/dL
3.9 – 4.5 mmol/L
< 6.5 g/dL
< 3.9 mmol/L
Adult and Pediatric
57 days
(HIV negative only)
10.0 – 10.9 g/dL
6.1 – 6.6 mmol/L
OR
Any decrease
2.5 – 3.4 g/dL
1.5 – 2.0 mmol/L
9.0 – 9.9 g/dL
5.5 – 6.0 mmol/L
OR
Any decrease
3.5 – 4.4 g/dL
2.1 – 2.6 mmol/L
7.0 – 8.9 g/dL
4.2 – 5.4 mmol/L
OR
Any decrease
4.5 g/dL
2.7 mmol/L
< 7.0 g/dL
< 4.2 mmol/L
Infanta,b
36 – 56 days
(HIV positive or 
negative)
8.5 – 9.4 g/dL
5.2 – 5.7 mmol/L
7.0 – 8.4 g/dL
4.2 – 5.1 mmol/L
6.0 – 6.9 g/dL
3.6 – 4.1 mmol/L
< 6.0 g/dL
< 3.6 mmol/L
a
Values are for term infants.
b
Use age and sex appropriate values (e.g., bilirubin), including preterm infants.
c
Revised by the sponsor.
d
Revised by the sponsor; monomer conversion factor used for conversion from g/dL to mmol/L

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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Infanta,b
22 – 35 days
(HIV positive or 
negative)
9.5 – 10.5 g/dL
5.8 – 6.4 mmol/L
8.0 – 9.4 g/dL
4.8 – 5.7 mmol/L
7.0 – 7.9 g/dL
4.2 – 4.7 mmol/L
< 7.00 g/dL
< 4.2 mmol/L
Infanta,b
1 – 21 days
(HIV positive or 
negative)
12.0 – 13.0 g/dL
7.3 – 7.9 mmol/L
10.0 – 11.9 g/dL
6.1 – 7.2 mmol/L
9.0 – 9.9 g/dL
5.5 – 6.0 mmol/L
< 9.0 g/dL
< 5.5 mmol/L
International normalized 
ratio of prothrombin time
(INR)c
≥1.1 to ≤1.5 x ULN
> 1.5 to ≤ 2.0 x ULN
> 2.0 to ≤ 3.0 x ULN
> 3.0 x ULN
Methemoglobin
5.0% – 10.0%
10.1% – 15.0%
15.1% – 20.0%
> 20.0%
Prothrombin time (PT) d, c
≥1.1 to ≤1.25 x ULN
> 1.25 to ≤1.50 x ULN
> 1.50 to ≤3.00 x ULN
> 3.00 x ULN
Partial thromboplastin
time (PTT)d
≥ 1.1 to ≤1.66 x ULN
> 1.66 to ≤2.33 x ULN
> 2.33 to ≤3.00 x ULN
> 3.00 x ULN
Platelets, decreased
100,000 –
124,999/mm³
100.000 x 109 –
124.999 x 109/L
50,000 –
99,999/mm³
50.000 x 109–
99.999 x 109/L
25,000 –
49,999/mm³
25.000 x 109–
49.999 x 109/L
< 25,000/mm³
< 25.000 x 109/L
WBC, decreased
2,000 – 2,500/mm³
2.000 x 109 –
2.500 x 109/L
1,500 – 1,999/mm³
1.500 x 109–
1.999 x 109/L
1,000 – 1,499/mm³
1.000 x 109–
1.499 x 109/L
< 1,000/mm³
< 1.000 x 109/L
CHEMISTRIES   Standard International Units are listed in italics
Acidosis
NA
pH < normal, but 7.3
pH < 7.3 without 
life-threatening 
consequences
pH < 7.3 with 
life-threatening 
consequences
Albumin, serum, low
3.0 g/dL – < LLN
30 g/L – < LLN
2.0 – 2.9 g/dL
20 – 29 g/L
< 2.0 g/dL
< 20 g/L
NA
Alkaline phosphatasec
≥1.25 to ≤2.5 x ULNb
> 2.5 to ≤5.0 x ULNb
> 5.0 to ≤10.0 x ULNb
> 10.0 x ULNb
Alkalosis
NA
pH > normal, but 7.5
pH > 7.5 without 
life-threatening 
consequences
pH > 7.5 with 
life-threatening 
consequences
ALT (SGPT) c
≥1.25 to ≤2.5 x ULN
> 2.5 to ≤5.0 x ULN
> 5.0 to ≤10.0 x ULN
> 10.0 x ULN
AST (SGOT) c
≥1.25 to ≤2.5 x ULN
> 2.5 to ≤5.0 x ULN
> 5.0 to ≤10.0 x ULN
> 10.0 x ULN
Bicarbonate, serum, low
16.0 mEq/L – < LLN
16.0 mmol/L – < LLN
11.0 – 15.9 mEq/L
11.0 – 15.9 mmol/L
8.0 – 10.9 mEq/L
8.0 – 10.9 mmol/L
< 8.0 mEq/L
< 8.0 mmol/L
a
Values are for term infants.
b
Use age- and sex-appropriate values (e.g., bilirubin), including preterm infants.
c
Revised by the sponsor.
d
If the local laboratory is reporting PT as percentage, only INR value will be considered for reporting PT related abnormalities and adverse events.

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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Bilirubin (Total) a
Adult and Pediatric 
>14 days
≥1.1 to ≤1.5 x ULN
> 1.5 to ≤2.5 x ULN
> 2.5 to ≤5.0 x ULN
> 5.0 x ULN
Infantb,c 14 days
(non-hemolytic)
NA
20.0 – 25.0 mg/dL
342 – 428 µmol/L
25.1 – 30.0 mg/dL
429 – 513 µmol/L
> 30.0 mg/dL
> 513.0 µmol/L
Infantb,c 14 days
(hemolytic)
NA
NA
20.0 – 25.0 mg/dL
342 – 428 µmol/L
> 25.0 mg/dL
> 428 µmol/L
Calcium, serum, high (corrected for albumin)
Adult and Pediatric 
7 days
10.6 – 11.5 mg/dL
2.65 – 2.88 mmol/L
11.6 – 12.5 mg/dL
2.89 – 3.13 mmol/L
12.6 – 13.5 mg/dL
3.14 – 3.38 mmol/L
> 13.5 mg/dL
> 3.38 mmol/L
Infantb,c < 7 days
11.5 – 12.4 mg/dL
2.88 – 3.10 mmol/L
12.5 – 12.9 mg/dL
3.11 – 3.23 mmol/L
13.0 – 13.5 mg/dL
3.24 – 3.38 mmol/L
> 13.5 mg/dL
> 3.38 mmol/L
Calcium, serum, low (corrected for albumin)
Adult and Pediatric 
7 days
7.8 – 8.4 mg/dL
1.95 – 2.10 mmol/L
7.0 – 7.7 mg/dL
1.75 – 1.94 mmol/L
6.1 – 6.9 mg/dL
1.53 – 1.74 mmol/L
< 6.1 mg/dL
< 1.53 mmol/L
Infantb, c < 7 days
6.5 – 7.5 mg/dL
1.63 – 1.88 mmol/L
6.0 – 6.4 mg/dL
1.50 – 1.62 mmol/L
5.50 – 5.90 mg/dL
1.38 – 1.49 mmol/L
< 5.50 mg/dL
< 1.38 mmol/L
Cardiac troponin I (cTnI)
NA
NA
NA
Levels consistent with 
myocardial infarction or 
unstable angina as defined 
by the manufacturer
Cardiac troponin T 
(cTnT)
NA
NA
NA
0.20 ng/mL OR
Levels consistent with 
myocardial infarction or 
unstable angina as defined 
by the manufacturer
Cholesterol (fasting)
Adult 18 years
200 – 239 mg/dL
5.18 – 6.19 mmol/L
240 – 300 mg/dL
6.20 – 7.77 mmol/L
> 300 mg/dL
> 7.77 mmol/L
NA
Pediatric 
< 18 years
170 – 199 mg/dL
4.40 – 5.15 mmol/L
200 – 300 mg/dL
5.16 – 7.77 mmol/L
> 300 mg/dL
> 7.77 mmol/L
NA
Creatine kinasea
≥3.0 to ≤5.9 x ULNc
> 5.9 to ≤ 9.9 x ULNc
> 9.9 to ≤19.9 x ULNc
> 19.9 x ULNc
Creatininea
≥1.1 to ≤1.3 x ULNc
> 1.3 to ≤1.8 x ULNc
> 1.8 to ≤3.4 x ULNc
> 3.4 x ULNc
Glucose, serum, high
Nonfasting
116 – 160 mg/dL
6.44 – 8.88 mmol/L
161 – 250 mg/dL
8.89 – 13.88 mmol/L
251 – 500 mg/dL
13.89 – 27.75 mmol/L
> 500 mg/dL
> 27.75 mmol/L
Fasting
110 – 125 mg/dL
6.11 – 6.94 mmol/L
126 – 250 mg/dL
6.95 – 13.88 mmol/L
251 – 500 mg/dL
13.89 – 27.75 mmol/L
> 500 mg/dL
> 27.75 mmol/L
a
Revised by the sponsor.
b
Values are for term infants.
c
Use age- and sex-appropriate values (e.g., bilirubin), including preterm infants.

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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Glucose, serum, low
Adult and Pediatric 
1 month
55 – 64 mg/dL
3.05 – 3.55 mmol/L
40 – 54 mg/dL
2.22 – 3.00 mmol/L
30 – 39 mg/dL
1.67 – 2.21 mmol/L
< 30 mg/dL
< 1.67 mmol/L
Infanta,b
< 1 month
50 – 54 mg/dL
2.78 – 3.00 mmol/L
40 – 49 mg/dL
2.22 – 2.77 mmol/L
30 – 39 mg/dL
1.67 – 2.21 mmol/L
< 30 mg/dL
< 1.67 mmol/L
Lactate
< 2.0 x ULN without 
acidosis
2.0 x ULN without 
acidosis
Increased lactate with pH 
< 7.3 without life-
threatening consequences
Increased lactate with pH 
< 7.3 with life-threatening 
consequences
LDL cholesterol (fasting)
Adult 18 years
130 – 159 mg/dL
3.37 – 4.12 mmol/L
160 – 190 mg/dL
4.13 – 4.90 mmol/L
191 mg/dL
4.91 mmol/L
NA
Pediatric 
> 2 – < 18 Years
110 – 129 mg/dL
2.85 – 3.34 mmol/L
130 – 189 mg/dL
3.35 – 4.90 mmol/L
190 mg/dL
4.91 mmol/L
NA
Lipasec
≥1.1 to ≤1.5 x ULN
> 1.5 to ≤3.0 x ULN
> 3.0 to ≤5.0 x ULN
> 5.0 x ULN
Magnesium, serum, low
1.2 – 1.4 mEq/L
0.60 – 0.70 mmol/L
0.9 – 1.1 mEq/L
0.45 – 0.59 mmol/L
0.6 – 0.8 mEq/L
0.30 – 0.44 mmol/L
< 0.60 mEq/L
< 0.30 mmol/L
Pancreatic amylasec
≥ 1.1 to ≤1.5 x ULN
> 1.5 to ≤2.0 x ULN
> 2.0 to ≤5.0 x ULN
> 5.0 x ULN
Phosphate, serum, low
Adult and Pediatric 
> 14 years
2.5 mg/dL – < LLN
0.81 mmol/L – < LLN
2.0 – 2.4 mg/dL
0.65 – 0.80 mmol/L
1.0 – 1.9 mg/dL
0.32 – 0.64 mmol/L
< 1.00 mg/dL
< 0.32 mmol/L
Pediatric 
1 – 14 years
3.0 – 3.5 mg/dL
0.97 – 1.13 mmol/L
2.5 – 2.9 mg/dL
0.81 – 0.96 mmol/L
1.5 – 2.4 mg/dL
0.48 – 0.80 mmol/L
< 1.50 mg/dL
< 0.48 mmol/L
Pediatric < 1 year
3.5 – 4.5 mg/dL
1.13 – 1.45 mmol/L
2.5 – 3.4 mg/dL
0.81 – 1.12 mmol/L
1.5 – 2.4 mg/dL
0.48 – 0.80 mmol/L
< 1.50 mg/dL
< 0.48 mmol/L
Potassium, serum, high
5.6 – 6.0 mEq/L
5.6 – 6.0 mmol/L
6.1 – 6.5 mEq/L
6.1 – 6.5 mmol/L
6.6 – 7.0 mEq/L
6.6 – 7.0 mmol/L
> 7.0 mEq/L
> 7.0 mmol/L
Potassium, serum, low
3.0 – 3.4 mEq/L
3.0 – 3.4 mmol/L
2.5 – 2.9 mEq/L
2.5 – 2.9 mmol/L
2.0 – 2.4 mEq/L
2.0 – 2.4 mmol/L
< 2.0 mEq/L
< 2.0 mmol/L
Sodium, serum, high
146 – 150 mEq/L
146 – 150 mmol/L
151 – 154 mEq/L
151 – 154 mmol/L
155 – 159 mEq/L
155 – 159 mmol/L
160 mEq/L
160 mmol/L
Sodium, serum, low
130 – 135 mEq/L
130 – 135 mmol/L
125 – 129 mEq/L
125 – 129 mmol/L
121 – 124 mEq/L
121 – 124 mmol/L
120 mEq/L
120 mmol/L
Triglycerides (fasting)
NA
500 – 750 mg/dL
5.65 – 8.48 mmol/L
751 – 1,200 mg/dL
8.49 – 13.56 mmol/L
> 1,200 mg/dL
> 13.56 mmol/L
Uric acid
7.5 – 10.0 mg/dL
0.45 – 0.59 mmol/L
10.1 – 12.0 mg/dL
0.60 – 0.71 mmol/L
12.1 – 15.0 mg/dL
0.72 – 0.89 mmol/L
> 15.0 mg/dL
> 0.89 mmol/L
a
Values are for term infants.
b
Use age- and sex-appropriate values (e.g., bilirubin), including preterm infants.
c
Revised by the sponsor.

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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
URINALYSIS    Standard International Units are listed in italics
Hematuria (microscopic)
6 – 10 RBC/HPF
> 10 RBC/HPF
Gross, with or without 
clots OR with RBC casts
Transfusion indicated
Proteinuria, random 
collection
1 +
2 – 3 +
4 +
NA
Proteinuria, 24 hour collection
Adult and Pediatric 
10 years
200 – 999 mg/24 h
0.200 – 0.999 g/d
1,000 – 1,999 mg/24 h
1.000 – 1.999 g/d
2,000 – 3,500 mg/24 h
2.000 – 3.500 g/d
> 3,500 mg/24 h
> 3.500 g/d
Pediatric 
> 3 months –
< 10 years
201 – 499 mg/m2/24 h
0.201 – 0.499 g/d
500 – 799 mg/m2/24 h
0.500 – 0.799 g/d
800 – 1,000 mg/m2/24 h
0.800 – 1.000 g/d
> 1,000 mg/ m2/24 h
> 1.000 sg/d

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7.3
Addendum 3: HIV-Related Events or Outcomes
7.3.1
CLINICAL CATEGORIESa
The clinical categories of HIV infection are defined as follows.
7.3.1.1
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
7.3.1.2
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 absces;
-
Peripheral neuropathy
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. 
                                                
a   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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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 HUS/thrombotic 
thrombocytopenia purpura TTP)
7.3.1.3
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
-
Coccidiomycosis, 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) (> I 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
-
Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
-
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
-
Pneumocystis carinii pneumonia
-
Pneumonia, recurrent

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-
Progressive multifocal leukoencephalopathy
-
Salmonella septicaemia, recurrent
-
Toxoplasmosis of brain
-
Wasting syndrome due to HIV

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7.4
Addendum 4: Visit Schedule for Rash Management in Pediatric Patients
This visit schedule summarizes the visits and assessments to be performed in case of rash. At the investigator’s discretion, additional 
visits and assessments can be performed.
Grade 1 Rash
Grade 2 Rash
Grade 3 or 4 Rash
Day 0a

Study medication MAY be CONTINUED.

Unscheduled visit for initial rash evaluation 
REQUIRED.

Referral to dermatologist ONLY IF rash
diagnosis uncertain (within 24h).

Study medication MAY be CONTINUED.

Unscheduled visit for initial rash evaluation 
REQUIRED.

Referral to dermatologist REQUIRED
(within 24h). 

Assessment of safety blood sample by local 
laboratory ONLY IF requested by 
investigator or dermatologist.

Biopsy ONLY IF required by dermatologist.

Study medication MUST be permanently 
DISCONTINUED. Rechallenge is NOT 
ALLOWED.

Unscheduled visit for initial rash evaluation 
REQUIRED.

Referral to dermatologist REQUIRED
(within 24h).

Assessment of safety blood sample by local 
laboratory ONLY IF requested by 
investigator or dermatologist.

Biopsy ONLY IF required by 
dermatologist.
Day 1

Follow-up visit REQUIRED.

Digital pictures REQUIRED.

Follow-up visit REQUIRED.

Follow-up visit REQUIRED.
Day 2
No Rash follow-up visit requiredb
No Rash follow-up visit requiredb

Follow-up visit REQUIRED.

Assessment of safety blood sample by local 
laboratory ONLY IF requested by 
investigator or dermatologist.
Day 3
No Rash follow-up visit requiredb
No Rash follow-up visit requiredb

Follow-up visit REQUIRED.

Assessment of safety blood sample by local 
laboratory ONLY IF requested by 
investigator or dermatologist.
                                                
a Note that Day 0 of the rash is the first day of investigator assessment and not the first day of rash as reported by the subject.
b In case rash progresses from a grade 1 or a grade 2 to a higher grade, start follow-up schedule for grade 2, 3 or 4 rash as appropriate.

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Grade 1 Rash
Grade 2 Rash
Grade 3 or 4 Rash
Day 4
No Rash follow-up visit requiredb
No Rash follow-up visit requiredb

Follow-up visit REQUIRED.

Assessment of safety blood sample by local 
laboratory ONLY IF requested by 
investigator or dermatologist.
Day 5
No Rash follow-up visit requiredb
No Rash follow-up visit requiredb

Follow-up visit REQUIRED.

Assessment of safety blood sample by local 
laboratory ONLY IF requested by 
investigator or dermatologist.
Day 6
No Rash follow-up visit requiredb
No Rash follow-up visit requiredb
No Rash follow-up visit required
Day 7

Follow-up visit REQUIRED.b

Follow-up visit REQUIRED.b

Digital pictures REQUIRED.
No Rash follow-up visit required
Further Visits
If rash is unresolved after second follow-up 
visit, further visits at the investigator’s 
discretion.b
If rash is unresolved after second follow-up visit, 
further visits at the investigator’s discretion.b
Weekly follow-up visits REQUIRED until 
resolution of grade 3-4 rash to grade ≤ 2 rash 
(further follow-up visits according to grade 1 or 
grade 2 rash instructions).
                                                
b In case rash progresses from a grade 1 or a grade 2 to a higher grade, start follow-up schedule for grade 2, 3 or 4 rash as appropriate.

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7.5
Addendum 5: Visit Schedule for Rash Management in Adult Patients
This visit schedule summarizes the visits and assessments to be performed in case of rash. At the investigator’s discretion, additional 
visits and assessments can be performed.
Grade 1 Rash
Grade 2 Rash
Grade 3 or 4 Rash
Day 01

Study medication MAY be CONTINUED.

Unscheduled visit for initial rash evaluation 
REQUIRED.

Study medication MAY be CONTINUED.

Unscheduled visit for initial rash evaluation
REQUIRED.

Assessment of safety blood sample by local 
laboratory OPTIONAL.

Referral to dermatologist OPTIONAL 
(within 24h).

Study medication MUST be permanently 
DISCONTINUED. Rechallenge is NOT 
ALLOWED.

Unscheduled visit for initial rash evaluation 
REQUIRED.

Assessment of safety blood sample by local 
laboratory REQUIRED.

Digital pictures OPTIONAL (within 24h).

Referral to dermatologist REQUIRED
(within 24h).

Biopsy REQUIRED for Grade 4 rash
(within 24h). Biopsy at the dermatologist’s 
discretion for Grade 3 rash.
Day 1

Follow-up visit REQUIRED.

Follow-up visit REQUIRED.

Assessment of safety blood sample by local 
laboratory OPTIONAL.

Follow-up visit REQUIRED.

Assessment of safety blood sample by local 
laboratory REQUIRED.

Digital pictures OPTIONAL.
Day 2
No Rash follow-up visit required2
No Rash follow-up visit required2

Follow-up visit REQUIRED.

Assessment of safety blood sample by local 
laboratory REQUIRED only if on Days 0
and/or 1 of rash AST/ALT > 2 x baseline 
value, AND/OR 5 x ULN, AND/OR in 
case of rash progression. 

Digital pictures OPTIONAL
                                                
1 Note that Day 0 of the rash is the first day of investigator assessment and not the first day of rash as reported by the subject.
2 In case rash progresses from a grade 1 or a grade 2 to a higher grade, start follow-up schedule for grade 2, 3 or 4 rash as appropriate.

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Day 3
No Rash follow-up visit required2
No Rash follow-up visit required2

Follow-up visit REQUIRED.

Assessment of safety blood sample by local 
laboratory REQUIRED only if on Days 0 
and/or 1 of rash AST/ALT > 2 x baseline 
value, AND/OR 5 x ULN, AND/OR in 
case of rash progression.

Digital pictures OPTIONAL
Day 4
No Rash follow-up visit required2
No Rash follow-up visit required2

Follow-up visit REQUIRED.

Assessment of safety blood sample by local 
laboratory REQUIRED only if on Days 0 
and/or 1 of rash AST/ALT > 2 x baseline 
value, AND/OR 5 x ULN, AND/OR in 
case of rash progression.

Digital pictures OPTIONAL
Day 5
No Rash follow-up visit required2
No Rash follow-up visit required2

Follow-up visit REQUIRED.

Assessment of safety blood sample by local 
laboratory REQUIRED.

Digital pictures OPTIONAL.
Day 6
No Rash follow-up visit required2
No Rash follow-up visit required2
No Rash follow-up visit required
Day 7

Follow-up visit REQUIRED.2

Follow-up visit REQUIRED.2

Assessment of safety blood sample by local 
laboratory OPTIONAL.
No Rash follow-up visit required
Further Visits
If rash is unresolved after second follow-up 
visit, further visits at the investigator’s 
discretion.2
If rash is unresolved after second follow-up visit, 
further visits at the investigator’s discretion.2

Weekly follow-up visits REQUIRED until 
resolution of grade 3-4 rash to grade ≤ 2 
rash (further follow-up visits according to 
grade 1 or grade 2 rash instructions)

Weekly assessment of safety blood sample 
by local laboratory REQUIRED as long as 
grade 3 or 4 rash is present but only if on 
Day 5 of rash AST/ALT > 2 x baseline 
value, AND/OR 5 x ULN, AND/OR in
case of rash progression, until resolution of 
AST/ALT abnormalities.
                                                
2 In case rash progresses from a grade 1 or a grade 2 to a higher grade, start follow-up schedule for grade 2, 3 or 4 rash as appropriate.

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
Digital pictures OPTIONAL
Upon Rash 
Resolution/
Stabilization3
Take digital pictures (OPTIONAL).
                                                
3 Stabilization: to be agreed upon in collaboration with the sponsor.

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PART II: PROCEDURES
1
ADVERSE EVENTS
1.1
Definitions
ADVERSE EVENT (AE)
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 adverse event can therefore be any unfavourable 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).
SERIOUS ADVERSE EVENT (SAE)
Any untoward medical occurrence that at any dose:
-
results in death;
-
is life threatening;
-
requires inpatient hospitalization or prolongation of existing hospitalization;
-
results in persistent or significant disability/incapacity;
or 
-
is a congenital anomaly/birth defect (ICH E6; 1.50).
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.
-
Hospitalizations that were planned prior to the signing of C/assent, and where the 
underlying condition for which the hospitalization was planned has not worsened, will 
not be considered serious adverse events. Any adverse event that results in a prolongation 
of the originally planned hospitalization is to be reported as a new serious adverse event.
-
For convenience the investigator may choose to hospitalize the subject for the duration of 
the treatment period; this will not be considered as a serious adverse event.
UNLISTED (UNEXPECTED) ADVERSE EVENT
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g., Investigator’s Brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product). 

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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 adverse event 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 adverse event, which is not related to the use of the drug.
DOUBTFUL
An adverse event 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 adverse event, 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 adverse event, 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).
VERY LIKELY
An adverse event, 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, Section 7.3, Addendum 5) are
to be recorded as HIV-related events on the CRF. 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 adverse event.
After termination of data collection (see Figure 1), safety will continue to be assessed per local 
standard of care and documented in the subject’s medical records only. Data will no longer be 
recorded in the CRF. Investigators will continue to report SAEs possibly related to ETR and 
pregnancies to the sponsor using regular pharmacovigilance reporting. This information will only 
be entered in the company safety repository.

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1.4
Reporting of Adverse Events
Adverse events considered to be at least possibly related to ETR treatment, adverse events 
leading to treatment interruption or discontinuation, serious adverse events and pregnancies are
to be collected from the signing of ICF/assent onwards. All other adverse events that do not meet 
criteria for seriousness are only to be collected if required per local regulations. Occurrence of 
adverse events is to be reported in the Adverse Event section of the CRF.
All reportable adverse events and adverse events leading to treatment interruption or 
discontinuation still ongoing at the end of the treatment are to be followed by the investigator 
according to the local standard of care.
New adverse events considered to be at least possibly related to ETR treatment, adverse events 
leading to treatment interruption or discontinuation, and serious adverse events reported during 
the follow-up period of the trial are to be followed as agreed between the sponsor and 
investigator.
Certain long-term adverse events of antiretroviral therapy cannot be followed until resolution 
within the setting of this protocol; in these cases follow-up is the responsibility of the treating 
physician. However, this has to be agreed upon with the sponsor.
Serious adverse events occurring within the clinical trial (between signing of C/assent and last 
follow-up visit) are to be reported. Any SAEs with at least a possible relationship to the study 
medication occurring after the end of the trial must be reported, and are to be handled by the 
sponsor.
The start date of the serious adverse event documented on the Serious Adverse Event form must 
be the same as the start date of the corresponding adverse event documented on the CRF. If a 
change in severity is noted for the existing adverse event, it must be recorded as a new adverse 
event. If a worsened adverse event meets the criteria for a serious adverse event, the start date of 
the serious adverse event must be the same as the start date of the worsened adverse event.
The cause of death of a subject in a clinical trial, whether the event is expected or associated with 
the investigational agent, is a serious adverse event. 
All serious adverse events and pregnancies occurring during clinical trials must be 
reported to the Drug Safety Officer as specified on the Serious Adverse Event Form 
immediately (i.e., within 24 hours) after the investigator becoming aware of the event. For 
the names and phone numbers of the contact person(s) see Part I, Section 7.1, Addendum 1.
The first report of a serious adverse event may be made by telephone or facsimile (FAX). The 
investigator must provide the minimal information: i.e., trial number, subject’s initials and date 
of birth, medication code number, period of intake, nature of the adverse event, and 
investigator’s attribution.
This report of a serious adverse event by telephone must always be confirmed by a written, more 
detailed report. For this purpose, the monitor provides the investigator with a Serious Adverse 
Event Form, to be completed and signed by the latter. If initial reporting was done by telephone, 
the person answering the phone can complete the Serious Adverse Event Form according to the 
information provided by the investigator. This form needs to be reviewed, completed if 
applicable, signed, and dated for approval by the investigator.

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Pregnancies occurring during clinical trials are considered immediately reportable events. They 
must be reported as soon as possible using the same Serious Adverse Event Form. The outcome 
of the pregnancy must also be reported to the Drug Safety Officer.
The sponsor or its representatives assumes responsibility for appropriate reporting of adverse 
events to Regulatory Authorities. Adverse Events reporting, including suspected unexpected 
serious adverse reactions, is to be carried out in accordance with applicable local regulations. For 
reported deaths, the investigator should supply the sponsor and the IEC/IRB with any additional 
requested information (e.g., autopsy reports and terminal medical reports).
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.
After termination of data collection (see Figure 1), safety will continue to be assessed per local 
standard of care and documented in the subject’s medical records only. Data will no longer be 
recorded in the CRF. Investigators will continue to report SAEs possibly related to ETR and 
pregnancies to the sponsor using regular pharmacovigilance reporting. This information will only 
be entered in the company safety repository.
2
TRIAL CLOSURE CONSIDERATIONS
The sponsor reserves the right to close an investigational site or terminate the trial at any time for 
any reason. In case of an early termination of the trial or temporary halt by the sponsor, the 
IEC/IRB should be notified within 15 calendar days, including a detailed written explanation of 
the reasons for the termination/halt. 
When the trial ends in a particular country, the sponsor will submit an end of trial declaration, to 
both the IEC/IRB and regulatory authority for that particular country by using the “Declaration 
of the end of trial form”. The declaration will be submitted within 90 days of the end of the trial.
The end of trial declaration will be submitted a second time to the regulatory authorities and 
IEC/IRB after the complete trial has ended in all participating centers, in all countries. This 
notification will also be submitted within 90 days of the end of the trial.
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 centre;
-
failure of the investigator to comply with the protocol, ICH-GCP guidelines or local 
requirements;
-
safety concerns;
-
sufficient data suggesting lack of efficacy;
-
inadequate recruitment of subjects by the investigator;
-
switch of all subjects enrolled at the site to locally available ETR-based treatment 
regimens (ie, commercially available and reimbursed, or accessible through another 
source [eg, access program or government program]) or to local standard of care, as 
appropriate.

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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. Unused medication and medication returned by the subject must be available for 
verification by the monitor. 
After termination of data collection (see Figure 1), compliance check - at pill count level - on 
unused and used trial medication returned by the subject will still be performed by the 
investigator or designee and will not be verified by the sponsor, however, drug accountability - at 
kit level - will be reviewed during the on-site monitoring visits.
All used and unused investigational medication 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, if 
applicable.
3.2
Trial Documents
The following documents must be provided to the sponsor or representatives before shipment of 
trial medication to the trial centre.
-
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/Assent, any other written information 
provided to the subject, and subject recruitment materials. This approval must clearly 
identify the trial by protocol title and trial number.
-
Regulatory authority approval or notification, if required.
-
Documentation on which the assessment of the investigator’s qualifications was based 
(e.g., curriculum vitae written in English).
The following documents must be provided to the sponsor or representatives prior to enrolment 
of the first subject.
-
Current list of the IEC/IRB members, their function and affiliation or equivalent, 
officially authorized assurance on the IEC/IRB composition.
-
Statement or equivalent documentation* that the IEC/IRB operation is in compliance 
with ICH-GCP, and local regulatory requirements
(* Equivalent documentation applies to countries where the IEC/IRB is certified through the Local Health 
Authorities.)

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-
Current license to prescribe and distribute controlled substances, when applicable.
-
Completed Investigator Financial Disclosure Forms from the investigator and all 
subinvestigators.
-
Signed and dated FDA Form 1572 received and, when applicable, the FDA Waiver Letter 
provided to non-US investigators.
-
Completed Investigator Financial Disclosure Form from the Principal Investigator
-
Signed and dated Clinical Trial Agreement, if applicable.
-
Import License if required
-
Signed and dated financial agreement.
-
Documentation on which the assessment of the subinvestigators’ qualifications was based 
(e.g., curriculum vitae).
-
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.
-
Signed and dated agreement between the investigator and Local Health Authority
3.3
Participation Cards
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.
3.4
Source Data
The nature and location of all source documents is to be identified in the Source Document 
Verification Plan to ensure that all sources of original data required to complete the CRF are 
known and are accessible for verification by the monitor. If electronic records are maintained, 
the method of verification must be discussed and agreed upon between the investigational staff 
and the monitor.
The required source data are listed in the Source Document Verification Plan, and should include 
sequential notes containing at least the following information for each subject:
-
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);
-
participation in trial (including trial number);
-
trial discussed and date of informed consent/assent, a copy of the C/assent was given to 
the subject;
-
dates of all visits;
-
documentation that protocol specific procedures were performed;

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-
start and end date (including dose regimen) of trial medication (preferably drug 
dispensing and return should be documented as well);
-
record of all reportable adverse events (see Section 1.4), and other safety parameters 
(start and end date, and preferably including causality and intensity);
-
concomitant medication;
-
date of trial completion and reason for early discontinuation, if applicable;
It is recommended that the author of an entry in the source documents is identifiable. Direct 
access to source documentation (medical records) must be allowed for the purpose of verifying 
that the data recorded on the CRF are consistent with the original source data.
After termination of data collection (see Figure 1), all visits and assessments will be performed 
per local standard of care and documented in the subject’s medical records only. Data will no 
longer be recorded in the CRF.
3.5
Case Report Forms 
CRFs are provided for each subject. All forms must be filled out legibly in durable black 
ballpoint pen.
Data Management may make changes to the entries made by the site (self-evident corrections or 
global rulings such as correction of obvious spelling errors). If global rulings (self-evident 
corrections) are applied to the clinical database by data management during the trial, the rules are
to be documented in a global rulings document and provided to the site for review and sign-off 
prior to applying the global rulings. If required, an investigator may request a detailed list of 
corrections applied to the data from his/her site through the trial monitor.
All data must be entered in English.
All data relating to the trial must be recorded on CRFs prepared by the sponsor. These CRFs 
should always reflect the latest observations on the subjects participating in the trial. Therefore, 
CRFs are to be completed as soon as possible after (or during) the subject’s visit. The 
investigator must verify that all data entries on the CRFs are accurate and correct. If some 
assessments are not done, or if certain information is not available, not applicable, or unknown, 
the investigator must enter “ND”, “NAV”, “NAP”, or “UN/UNK”, respectively, in the 
appropriate space.
Monitoring in this trial is to be done by means of telephone contacts or monitoring visits as per 
monitoring guidelines. During monitoring visits, the monitor reviews the CRFs and evaluate 
them for completeness, legibility and consistency. The CRF is to 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 write on the CRF pages. Corrections must be made in such a way that the original entry is 
not obscured. Correction fluid must NOT be used. The correct data must be inserted, dated, and 
initialled by the person making the correction. The persons entering data on the CRFs, must be 
identified on the Signature Sheet. The investigational staff must not write on NCR copies of 
CRFs left at the site once the original is transmitted to the sponsor or representative.
A CRF must be completed and the original must be returned to the sponsor or representative. A 
copy must be archived by the investigator as specified in Section 3.7 (of Part II).

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In case corrections to a CRF are needed after removal of the original CRF copy from the site, a 
Data Correction Form (DCF) is to be used. All DCFs sent to the investigator are to be answered 
by the appropriate investigational staff and signed and dated for approval. 
After termination of data collection (see Figure 1), all visits and assessments will be performed 
per local standard of care and documented in the subject’s medical records only. Data will no 
longer be recorded in the CRF. Investigators will continue to report SAEs possibly related to 
ETR and pregnancies to the sponsor using regular pharmacovigilance reporting. This information 
will only be entered in the company safety repository.
3.6
Subject Identification Code List & Subject Screening and 
Enrollment Log
The sponsor will provide the site with a subject identification code list, and screening and 
enrollment log. Both documents are to be completed for each new screened and enrolled subject 
to assure subject identification at any point in time during the trial. The subject identification 
code list will not be transferred to the sponsor to maintain the confidentiality of the subject.
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 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 C/assent.
Any difficulty in storing original documents must be discussed with the monitor prior to the 
initiation of the trial.
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 

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prior written approval. The investigator agrees to use this information only in accomplishing the 
trial and will not use it for other purposes.
5
REPORTING AND PUBLICATION
5.1
Reporting
The sponsor will create an Annual Safety Report (ASR) and Line Listings in accordance with the 
EU Clinical Trials Directive with a data-lock date of 27-MAR.This study TMC125-C239 will be 
included in the first ASR produced after approval of this protocol, which may be less than 
1-year's time from this particular study approval date, and in all subsequent ASRs, as 
appropriate, until study closure.
The results of the trial will be reported in a CSR and will contain CRF data from all study sites 
that participated in the study. A summary of the Clinical Study 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.
After termination of data collection (see Figure 1), only limited safety data (SAEs possibly 
related to ETR and pregnancies) will continue to be reported using regular pharmacovigilance 
reporting and will only be entered in the company safety repository. Appropriate safety reports 
will continue to be provided to IECs/IRBs and regulatory authorities, as required.
One investigator will be appointed for signing off the final CSR. 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
Publication
The sponsor will not unreasonably withhold consent to publish the data generated in this trial. 
However, it is the policy of the sponsor not to allow the investigators to publish their results or 
findings prior to the sponsor’s publication of the overall trial results. The investigator agrees that 
before he/she publishes any results of this trial, he/she shall allow at least 45 days for the sponsor 
to review the pre-publication manuscript prior to submission of the manuscript to the publisher, 
as specified in the Clinical Trial Agreement between Institution/Investigator and sponsor. In 
accordance with generally recognized principles of scientific collaboration, co-authorship with 
any company personnel will be discussed and mutually agreed upon before submission of a 
manuscript to a publisher.
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.

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6.2
Independent Ethics Committee/Institutional Review Board
This trial can only be undertaken after full approval of the protocol, informed consent/assent, 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 adverse events that are serious, unlisted and associated with the investigational 
drug;
-
ASR and Quarterly Line Listings.
Substantial amendments and applicable ICF/Assent 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.
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.
6.3
ICH-GCP Guidelines
This trial will be conducted in accordance with the current ICH-GCP Guidelines.
Good Clinical Practice (GCP) 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/Assent
General
Prior to entry in the trial, the investigator or a person designated by the investigator must explain 
to potential subjects or their legally acceptable representative the trial and the implications of 
participation. Subjects will be informed that their participation is voluntary and that they may 
withdraw from the trial at any time. 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 
decide not to take part in this trial. Finally, they will be told that their records may be accessed by 
the IEC/IRB, regulatory authorities and authorized representatives of the sponsor without 
violating the confidentiality of the subject, to the extent permitted by the applicable law(s) and/or 
regulations. By signing the ICF/Assent, the subject is authorizing such access.
In case the subject is unable to read and write, an impartial witness must confirm the informed 
consent/assent.

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The subject will be given sufficient time to read the ICF/Assent, and to ask additional questions. 
After this explanation and before entry in the trial, consent should be appropriately recorded by 
means of the subject’s personally dated signature or by the signature of an independent witness 
who certifies the subject’s consent in writing. After having obtained the consent, a copy of the 
signed and dated ICF/Assent 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 or his/her legally acceptable representative in a timely manner by means of an 
updated ICF/Assent. This amended ICF/Assent will be signed and dated by the subject 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/Assent, and a copy of the signed and dated ICF/Assent must be given to the subject.
Pediatric subjects
The special vulnerability of children requires specific measures in the informed consent process 
sin 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. The following information forms (including consent/assent form) will be used 
by the investigational staff:
- 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 issues as needed.
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.

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The sponsor ensures that the personal data are:
-
collected for a specified and legitimate purpose;
-
processed fairly and lawfully;
-
credible.
Explicit consent for the processing of personal data will be obtained from the participating 
subjects or their legally acceptable representative prior to any processing of personal data.
The sponsor or its representatives whose responsibilities require access to personal data are 
obliged to keep the identity of trial subjects confidential. 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.
7
FINANCING AND INSURANCE
7.1
Financial Disclosure
The disclosed financial interest of the investigator must be collected before enrolment of the first 
subject, following centre completion, and 1 year following trial completion. The investigator 
should promptly update this information if any relevant changes occur during this period.
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 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 ICF/Assent and the 
Clinical Trial Agreement.
8
DATA QUALITY CONTROL/ASSURANCE
The trial is to be monitored by the sponsor or representative.
Shortly before the trial starts, the monitor meets with the investigator and all staff involved to 
review the procedures regarding trial conduct and recording the data on the CRF. During the 
trial, the investigator shall permit the monitor to verify the progress of the trial at the centre as 
frequently as necessary. The investigator shall make the CRFs available, provide missing or 
corrected data and sign the CRFs. Key data transcribed onto the CRFs, such as the subject’s sex, 

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date of birth, assessment dates, test results, etc., are to be reviewed against source documents.
Personal information is to be treated as strictly confidential and is not to be made publicly 
available. Any inconsistency between source data and data recorded on the CRF is to be
corrected.
After termination of data collection (see Figure 1), all visits and assessments will be performed 
per local standard of care and documented in the subject’s medical records only. Data will no 
longer be recorded in the CRF.
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 
centre(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.
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.

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SIGNATURE
Global Medical Leader:
This Clinical Trial Protocol has been reviewed and approved by the sponsor in order to ensure 
compliance with Good Clinical Practices.
Name:
Magda Opsomer, M.D.
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:

 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Magda Opsomer
25Jul2019, 16:36:01 PM, UTC
Document Approval

CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 15 May 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Protocol Title
Continued Access to Etravirine in Treatment Experienced HIV-1 Infected Subjects
Protocol TMC125-TiDP35-C239; Phase [N/A]
TMC125  (etravirine)
*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.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
EudraCT NUMBER: 2009-013126-16
Status:
Approved  
Date:
15 May 2020
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-RIM-56255, 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
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.
NCT00980538

COVID-19 Appendix
TMC125 (etravirine)
Clinical Protocol TMC125-TiDP35-C239
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 May 2020
COVID-19 APPENDIX
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 participants 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 participant 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 participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, study intervention 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, participants will be interviewed to collect safety data. Participants 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 participants on study 
intervention, including follow up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the 
sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions 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 participant has tested positive for COVID 19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.

COVID-19 Appendix
TMC125 (etravirine)
Clinical Protocol TMC125-TiDP35-C239
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 May 2020
Drug Supply:

Normal study drug shipment from the Janssen depots to the sites will continue until further 
notice. 

Normal study drug dispensation to subject by site.

If study treatment dispensation to subject at site might be impacted, the local sponsor team 
should be informed by the site. Direct-to-patient (DTP) process, when permitted by local 
regulations in the country, will be initiated to allow sites to ship study treatment to the subjects. 
Only after approval by the sponsor, the granted site may ship treatment to subjects with 
support of the sponsor’s supply team. Where DTP shipments are deemed necessary, the 
process must be coordinated between the site and sponsor staff following standard DTP 
procedures for arranging shipment and adhering to associated approvals and documentation 
requirements.

Sites are requested to send their SOPs, related to drug supply and dispensation, for sponsor 
approval prior to implementation.

Where necessary upon local guidance, subjects will consent upfront before the DTP process 
will be implemented. 

In case of remote visits, the subject should keep used and un-used kits at home at a secure 
location. The subject will be requested to bring the used and un-used kits back to the site at 
the next on-site visit.

There will be no central study drug return organized by the sponsor. 

Sites need to continue to assess the levels of investigational product (IP) inventory to ensure 
the site has enough IP to cover all patients for at least 6 months. If the inventory is not 
sufficient the site is to contact the site manager to organize shipment of new IP. 
Verification and Monitoring Visits:

Interim monitoring visits will be replaced by remote monitoring visits until such time that 
on-site visits can be resumed. 
Remote Assessment Visits:

Remote assessment visits may be performed until such time that on-site visits can be resumed. 
Site staff will be asked to collect any assessments that can be made remotely. These 
assessments are important for the continued evaluation of safety and efficacy as patients 
complete the study period. Conducting remote assessment visits enables this important data 
to be collected without risking patient, family, and site staff safety. As allowable per local 
regulations, these remote assessments can be conducted via telephone with patients in their 
homes. Assessments that can be completed remotely include a review of adverse events and 
concomitant medications. Site staff will be asked to adhere to the Time and Events Schedule 
outlined in the protocol, to the extent feasible, when scheduling remote assessments. Some of 
the assessments required in the Time and Events Schedule are not in scope for remote visits
including weight and urine pregnancy test (if applicable). Drug accountability can be 
discussed remotely but will be confirmed at the first visit back on site. These data will be 
missing for patients that are unable to attend site visits.

COVID-19 Appendix
TMC125 (etravirine)
Clinical Protocol TMC125-TiDP35-C239
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 May 2020

The relationship to COVID-19 for missing protocol-specified information/procedures will be 
documented in the patient source documents. 

Where necessary upon local guidance, subjects will consent upfront before remote visits will 
be implemented. 
Early Withdrawal from the Study:

If a subject is lost to follow-up, or is unwilling to have a remote assessment performed, the 
subject will be considered an early withdrawal. Sites will be reminded to follow the procedures 
outlined in the protocol. 
Protocol Deviations: 

All COVID‑19 related protocol deviations will be reported and summarized in the Clinical 
Study Report.

COVID-19 Appendix
TMC125 (etravirine)
Clinical Protocol TMC125-TiDP35-C239
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Status: Approved,  Date: 15 May 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):
Magda Opsomer, MD
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.