Clinical trial NCT01266902
Conditions: HIV-1 Infection
Keywords: HIV-1 Infection HIV-1 HIV TMC278-TiDP6-C222 TMC278-C222 TMC278 Rilpivirine
Sponsor: Janssen R&D Ireland
Start date: 2011-02-01; Completion date: 2020-02-01
Enrollment: 482 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to provide continued access to TMC278 in HIV-1 infected patients who were randomized and treated with TMC278 in the Phase IIb or Phase III trials.

Detailed description:
This is a Phase III, open-label (all people know the identity of the drug), multicenter, roll-over trial to provide continued access to TMC278 to HIV-1 infected patients who were randomized (the study drug is assigned by chance) and treated with TMC278 in the Phase IIb (TMC278-C204 \[C204\]) or Phase III trials (i.e., TMC278-TiDP6-C209 \[C209\] or TMC278-TiDP6-C215 \[C215\]) and who continue to benefit from their antiretroviral treatment, according to the investigator. In addition, information on the long-term safety and tolerability, including resistance data in case of virologic failures, of oral doses of TMC278 25 mg once daily (q.d.) in combination with a background regimen containing 2 N(t)RTIs will be collected. Available efficacy data will also be collected. Approximately 750 HIV-1 infected individuals are expected to participate in this trial. The duration of participation in the study for an individual participant will be 2 to 3 years. The final/withdrawal visit of the Phase IIb or Phase III trials will be the first visit of this trial. Safety and tolerability will be evaluated throughout the trial. Visits and assessments performed should be based on the local, generally accepted standard of care, with visits occurring at least every 6 months. Oral tablets of TMC278 25 mg once daily (q.d.) should be administered together with a meal.

Arms: arm 1: Rilpivirine 25 mg once daily
Interventions: intervention 1: Rilpivirine
Intervention descriptions: intervention 1: 25 mg once daily

Protocol documents:
Prot_000.pdf: 
Template Version: 2.0
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EUDRACT NUMBER: 2010-021209-18
COMPLIANCE STATEMENT
This study will be conducted in compliance with this protocol, Good Clinical Practice, 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 applicable law or regulations. In any event, persons to whom the information is disclosed must 
be informed that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will 
apply equally to all future information supplied to you that is indicated as privileged or confidential.
Clinical Trial Protocol
Amendment 3
Project No.:
TMC278-TiDP6
Department:
Clinical R&D
Generic name:
rilpivirine
hydrochloride
Status:
Approved
Issued Date:
28-Nov-2016
Protocol Title:
An open-label trial with TMC278 25 mg q.d. in combination with a 
background regimen containing 2 nucleoside/nucleotide reverse 
transcriptase inhibitors in HIV-1 infected subjects, who participated in 
TMC278 clinical trials.
Study No.:
TMC278-TiDP6-C222
Clinical Phase:
III
Sponsor:
Janssen Research & Development*
*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 Sciences Ireland UC; 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.
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-ERI-13797542, 7.0
NCT01266902


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Protocol History1
TMC278-TiDP6-C222
Document Type and
File Name
Issued Date
Amendment
Type
Comments
Initial Clinical Trial Protocol
TMC278-TiDP6-C222-CTP
30-Jul-2010
CTP Amendment I
TMC278-TiDP6-C222-CTPA-GEN-I
05-May-2011
Substantial
This amendment was created to incorporate the following 
changes to the clinical trial protocol:
1. Serum pregnancy test at the Roll-over visit was 
replaced by a urine pregnancy test.
2. A reminder for HLA-B*5701 testing and viral genotype 
determination were added.
3. From the Roll-over visit onwards switching to 
background N(t)RTIs other than those used in the 
previous trials is allowed. 
4. A list of established and theoretical drug interactions 
with commonly used co-medications and TMC278 was 
added as an attachment.
5. Effective methods of birth control for male and female 
subjects were updated.
6. Safety follow-up and management of toxicities were 
updated. 
7. Withdrawal criteria were updated.
8. Furthermore, some administrative and textual changes 
were made.
First Revised Clinical Trial Protocol
TMC278-TiDP6-C222-CTP-v2
05-May-2011
Integrates Initial Protocol + Amendment I
CTP Amendment II
TMC278-TiDP6-C222-CTPA-GEN-II
04-Aug-2011
Non-substantial
This amendment was created to make corrections to 
Attachment 3.
Second Revised Clinical Trial Protocol
TMC278-TiDP6-C222-CTP-v3
25-Aug-2011
Integrates First Revised Protocol + Amendment II
CTP Amendment III
TMC278-TiDP6-C222-CTPA-GEN-III
This document
Substantial
See PROTOCOL AMENDMENTS table
                                                
1 This overview lists general amendments to the protocol only. Site and country specific amendments to the protocol are not included.


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 3
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................... 9
TIME AND EVENTS SCHEDULE – UP TO AND INCLUDING PROTOCOL AMENDMENT 2................. 11
TIME AND EVENTS SCHEDULE – AS OF PROTOCOL AMENDMENT 3............................................... 13
ABBREVIATIONS....................................................................................................................................... 14
1
INTRODUCTION............................................................................................................................ 15
1.1
Background .................................................................................................................................... 15
1.2
Overall Rationale for the Study ...................................................................................................... 17
2
OBJECTIVES................................................................................................................................. 18
3
OVERVIEW OF STUDY DESIGN.................................................................................................. 18
3.1
Study Design .................................................................................................................................. 18
3.2
Study Design Rationale.................................................................................................................. 19
4
STUDY POPULATION .................................................................................................................. 20
4.1
General Considerations.................................................................................................................. 20
4.2
Inclusion Criteria............................................................................................................................. 20
4.3
Exclusion Criteria ........................................................................................................................... 20
4.4
Prohibitions and Restrictions.......................................................................................................... 21
5
TREATMENT ALLOCATION......................................................................................................... 22
6
DOSAGE AND ADMINISTRATION............................................................................................... 22
7
TREATMENT COMPLIANCE........................................................................................................ 23
8
PRESTUDY AND CONCOMITANT THERAPY............................................................................. 23
9
STUDY EVALUATIONS ................................................................................................................ 24
9.1
Study Procedures........................................................................................................................... 24
9.1.1
Overview ........................................................................................................................... 24
9.1.2
Pretreatment Phase .......................................................................................................... 24
9.1.3
Open-Label Treatment Phase........................................................................................... 24
9.1.4
Posttreatment Phase (Follow-Up)..................................................................................... 25
9.2
Efficacy........................................................................................................................................... 25
9.2.1
Evaluations........................................................................................................................ 25
9.2.2
Criteria............................................................................................................................... 26
9.3
Safety Evaluations.......................................................................................................................... 26
9.3.1
Adverse Events ................................................................................................................. 26
9.3.2
Pregnancies ...................................................................................................................... 26
9.3.3
Clinical Laboratory Tests................................................................................................... 26
9.3.3.1
Pregnancy Test .................................................................................................... 27
9.3.3.2
Plasma Viral Load................................................................................................ 27
9.3.3.3
Immunology.......................................................................................................... 27
9.3.3.4
Resistance Determinations .................................................................................. 27
9.3.4
Specific Toxicities.............................................................................................................. 28
9.3.4.1
Rash..................................................................................................................... 28


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9.3.4.2
Acute Systemic Allergic Reaction ........................................................................ 30
9.3.4.3
AST and ALT Elevation........................................................................................ 31
9.3.4.4
Pancreatic Amylase or Lipase Elevations ............................................................ 32
9.3.4.5
Clinical Hepatitis................................................................................................... 32
9.3.4.6
Renal Complications ............................................................................................ 32
9.3.4.7
Neuro-psychological Symptoms........................................................................... 33
9.3.4.8
Gastrointestinal Nausea (with or without Vomiting) ............................................. 33
9.3.4.9
Diarrhea ............................................................................................................... 33
9.3.4.10
Other Toxicities .................................................................................................... 34
10
SUBJECT COMPLETION/WITHDRAWAL ................................................................................... 35
10.1
Completion ..................................................................................................................................... 35
10.2
Withdrawal From the Study............................................................................................................ 35
11
STATISTICAL METHODS............................................................................................................. 36
11.1
Subject Information ........................................................................................................................ 36
11.2
Efficacy Analyses ........................................................................................................................... 36
11.3
Sample Size Determination............................................................................................................ 37
11.4
Safety Analyses.............................................................................................................................. 37
12
ADVERSE EVENT REPORTING................................................................................................... 37
12.1
Definitions....................................................................................................................................... 38
12.1.1
Adverse Event Definitions and Classifications.................................................................. 38
12.1.2
Attribution Definitions ........................................................................................................ 39
12.2
Procedures..................................................................................................................................... 39
12.2.1
All Adverse Events ............................................................................................................ 39
12.2.2
Serious Adverse Events.................................................................................................... 41
12.2.3
Pregnancy ......................................................................................................................... 42
12.3
Contacting Sponsor Regarding Safety........................................................................................... 42
13
PRODUCT QUALITY COMPLAINT HANDLING .......................................................................... 42
13.1
Procedures..................................................................................................................................... 43
13.2
Contacting Sponsor Regarding Product Quality............................................................................. 43
14
STUDY DRUG INFORMATION..................................................................................................... 43
14.1
Physical Description of Study Drug ................................................................................................ 43
14.2
Packaging....................................................................................................................................... 43
14.3
Labeling.......................................................................................................................................... 43
14.4
Preparation, Handling, and Storage............................................................................................... 44
14.5
Drug Accountability ........................................................................................................................ 44
15
STUDY SPECIFIC MATERIALS.................................................................................................... 45
16
ETHICAL ASPECTS...................................................................................................................... 45
16.1
Study-Specific Design Considerations ........................................................................................... 45
16.2
Regulatory Ethics Compliance ....................................................................................................... 46
16.2.1
Investigator Responsibilities.............................................................................................. 46
16.2.2
Independent Ethics Committee or Institutional Review Board (IEC/IRB).......................... 46
16.2.3
Informed Consent.............................................................................................................. 47
16.2.4
Privacy of Personal Data................................................................................................... 48
16.2.5
Country Selection.............................................................................................................. 49
17
ADMINISTRATIVE REQUIREMENTS........................................................................................... 49
17.1
Protocol Amendments.................................................................................................................... 49
17.2
Regulatory Documentation............................................................................................................. 50
17.2.1
Regulatory Approval/Notification....................................................................................... 50
17.2.2
Required Prestudy Documentation ................................................................................... 50


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17.3
Subject Identification, Enrollment, and Screening Logs................................................................. 51
17.4
Source Documentation................................................................................................................... 51
17.5
Case Report Form Completion ...................................................................................................... 51
17.6
Data Quality Control ....................................................................................................................... 52
17.7
Record Retention ........................................................................................................................... 53
17.8
Monitoring....................................................................................................................................... 53
17.9
Study Completion/Termination....................................................................................................... 54
17.9.1
Study Completion.............................................................................................................. 54
17.9.2
Study Termination ............................................................................................................. 54
17.10
On-Site Audits ................................................................................................................................ 55
17.11
Use of Information and Publication ................................................................................................ 55
REFERENCES............................................................................................................................................ 58
ATTACHMENT 1: DAIDS TABLE .............................................................................................................. 60
ATTACHMENT 2: VISIT SCHEDULE FOR GRADE 3/4 RASH MANAGEMENT (RASH FULLY 
CHARACTERIZED) ....................................................................................................................... 79
SIGNATURE PAGE SPONSOR ................................................................................................................. 82
INVESTIGATOR AGREEMENT ................................................................................................................. 83


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PROTOCOL AMENDMENTS
Amendment 3 (28-Nov-2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The TMC278-C222 trial has been ongoing for over 5 years (started in 
February 2011) and the subjects have been on TMC278 (rilpivirine) + 2 nucleos(t)ide reverse transcriptase 
inhibitors (N[t]RTIs) not only in this roll-over trial but also in the previous trials (TMC278-C209, -C215, and 
-C204). Therefore, long-term safety and efficacy of rilpivirine have been properly assessed, allowing the trial to be 
simplified and trial-related activities to be reduced to a minimum for the limited number of subjects remaining in this 
trial. The main component of this trial will remain to allow subjects who experience and are expected to continue 
experiencing clinical benefit from rilpivirine treatment to have continued access to rilpivirine in a simplified study 
setting or to be switched to local (rilpivirine-based) treatment options or local standard of care, as appropriate.
Rilpivirine has received Marketing Authorization in over 85 countries worldwide. In some countries, however, 
rilpivirine is not registered, or not reimbursed, or cannot be accessed through another source. In those countries, 
rilpivirine will continue to be provided through this trial until subjects can be switched to locally available rilpivirine 
(ie, commercially available AND reimbursed, OR accessible through another source [eg, access program or 
government program]), other local (rilpivirine-based) treatment options, or local standard of care, as appropriate.
This amendment provides details on the process and requirements for this simplified trial setting that will apply after 
approval of this amendment, which includes the provision of rilpivirine, clinical management of subjects as per local 
standard of care, more limited adverse event (AE) reporting requirements, and removal of data collection, source 
verification, and trial monitoring requirements (with the exception of a site closure visit).
The table below gives an overview of the rationale for each change and all applicable sections.
Rationale: Long-term safety and efficacy of rilpivirine have been assessed and the collection of additional data in 
this trial is unlikely to impact the risk-benefit assessment. Therefore, trial-related data will no longer be collected; 
medical records should be maintained as per local standard of care and should continue to include details on the use 
of rilpivirine. In the absence of trial-related data collection, no trial monitoring will be performed (with the exception
of a site closure visit) and no trial-related data will be analyzed or reported. The procedures for safety reporting were 
updated and will continue to include serious adverse events (SAEs) and pregnancies (using trial-specific reporting 
forms), and non-serious clinically important events (using regular pharmacovigilance reporting).
SYNOPSIS
Time and Events Schedule
1.2 Overall Rationale for the Study
3.1 Study Design
3.2 Study Design Rationale
8 PRESTUDY AND CONCOMITANT THERAPY
9.1.3 Open-Label Treatment Phase
9.1.4 Posttreatment Phase (Follow-Up)
9.2.1 Evaluations
9.2.2 Criteria
9.3 Safety Evaluations
10.2 Withdrawal From the Study
11 STATISTICAL METHODS
11.4 Safety Analyses
12 ADVERSE EVENT REPORTING
12.2.1 All Adverse Events
12.2.2 Serious Adverse Events
16.1 Study-Specific Design Considerations
17.4 Source Documentation


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17.5 Case Report Form Completion
17.6 Data Quality Control
17.8 Monitoring
17.11 Use of Information and Publication
Rationale: In some countries, rilpivirine is not registered, or not reimbursed, or cannot be accessed through another 
source. Rilpivirine will continue to be provided through this trial until subjects can be switched to locally available 
rilpivirine (ie, commercially available AND is reimbursed, OR can be accessed through another source [eg, access 
program or government program]). The trial will be stopped when all subjects have switched to locally available
rilpivirine, other local (rilpivirine-based) treatment options, or local standard of care, as appropriate.
SYNOPSIS
Time and Events Schedule
1.2 Overall Rationale for the Study
2 OBJECTIVES
3.1 Study Design
10.1 Completion
17.9.1 Study Completion
17.9.2 Study Termination
Rationale: Where rilpivirine is available locally, subjects should follow the local prescribing information for 
rilpivirine under the guidance of the investigator.
4.4 Prohibitions and Restrictions
8 PRESTUDY AND CONCOMITANT THERAPY
Rationale: In line with the simplified trial setting, information on the provision and destruction of study drug 
supplies was updated. A tool will continue to be available to order additional study drug supplies and will be used to 
record the date of last study drug intake.
6 DOSAGE AND ADMINISTRATION
9.1.4 Posttreatment Phase (Follow-Up)
14.4 Preparation, Handling, and Storage
14.5 Drug Accountability
Rationale: The name of the sponsor of the trial was changed from Tibotec Pharmaceuticals to Janssen Research & 
Development because of the transition of the Johnson & Johnson Research & Development companies to a unified 
Janssen identity.
Title Page
6 DOSAGE AND ADMINISTRATION
9.3.4.1 Rash
14.1 Physical Description of Study Drug
14.2 Packaging
17.11 Use of Information and Publication
Attachment 1
SIGNATURE PAGE SPONSOR
Rationale: The background section was updated as more current data have become available. The drug interactions 
table was deleted as prescribing information for rilpivirine has been approved and can be referenced where 
available. The references were updated according to the changes made. Minor editorial changes were made.
1 INTRODUCTION
1.1 Background
6 DOSAGE AND ADMINISTRATION
8 PRESTUDY AND CONCOMITANT THERAPY
10.2 Withdrawal From the Study


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15 STUDY SPECIFIC MATERIALS
REFERENCES
Attachment 2
Attachment 3
SIGNATURE PAGE SPONSOR
INVESTIGATOR AGREEMENT


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
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Approved, Issued Date: 28-Nov-2016
SYNOPSIS
An open-label roll-over trial with TMC278 (rilpivirine) 25 mg once daily (q.d.) in combination with a background 
regimen containing 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) in HIV-1 infected subjects, 
who participated in TMC278 clinical trials.
TMC278 (formerly known as R278474), a diarylpyrimidine derivative, is a potent non-nucleoside reverse 
transcriptase inhibitor (NNRTI) with in vitro activity against wild-type as well as NNRTI-resistant human 
immunodeficiency virus (HIV-1).
OBJECTIVES
Primary Objective
The primary objective of the trial is to provide continued access to TMC278 for subjects who were randomized and 
treated with TMC278 in the Phase IIb (TMC278-C204 [C204]) or Phase III trials (TMC278-TiDP6-C209 [C209]
and TMC278-TiDP6-C215 [C215]), and who, at the time of roll-over, experience and are expected to continue 
experiencing clinical benefit from TMC278 treatment.
Secondary Objectives
Up to and including Protocol Amendment 2, the secondary objective is to evaluate the long-term safety and 
tolerability of TMC278 25 mg q.d. in combination with a background regimen containing 2 N(t)RTIs. Available 
efficacy data will also be collected, including resistance data in case of virologic failure.
Protocol Amendment 3 Objective
As of Protocol Amendment 3, the objective is to provide continued access to TMC278 for subjects who experience 
and are expected to continue experiencing clinical benefit from TMC278 treatment until subjects can switch to 
locally available rilpivirine (ie, commercially available AND reimbursed, OR accessible through another source [eg, 
access program or government program]), other local (rilpivirine-based) treatment options, or local standard of care, 
as appropriate.
OVERVIEW OF STUDY DESIGN
This is a Phase III, open-label, multicenter, roll-over trial to provide continued access to TMC278 for HIV-1 
infected subjects who were randomized and treated with TMC278 in the Phase IIb (C204) or Phase III trials (C209 
or C215). At the time of roll-over the investigator should assess whether the subject benefits from TMC278 
treatment according to the efficacy and safety criteria as set out in the previous trial protocol. The investigator should 
also be confident that the subject is expected to continue benefiting from TMC278 treatment.
The Final visit of the previous trial will be the first visit of this trial (= the Roll-over visit). From this visit onwards, 
all enrolled subjects will continue to receive TMC278 25 mg q.d. in combination with a background regimen of 
2 N(t)RTIs until one of the following criteria is met (whichever comes first):

The subject meets at least one of the withdrawal criteria, or

Rilpivirine becomes commercially available AND is reimbursed, OR can be accessed through another source 
(e.g., access program or government program) by the subject in his/her country; or

The investigator finds it in the subject’s best interest to switch to other local (rilpivirine-based) treatment 
options or local standard of care, as appropriate.
The background regimen of 2 N(t)RTIs can be changed at the investigator’s discretion anytime during this study, as 
long as there is no evidence of resistance to the chosen N(t)RTIs, as determined by the last available genotype 
results.
As of Protocol Amendment 3, medical records should be maintained as per local standard of care and should 
continue to include details on the use of TMC278; data will no longer be recorded in the electronic Case Report 
Form (eCRF). 


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STUDY POPULATION
It was anticipated that approximately 750 HIV-1 infected subjects would continue to receive TMC278 treatment in 
combination with 2 N(t)RTIs at the start of this trial. At the time of execution of Protocol Amendment 3, most of 
the subjects involved in this trial will have been switched to locally available rilpivirine, other local (rilpivirine-
based) treatment options, or local standard of care.
To be eligible, subjects must satisfy all of the following criteria:
1.
Male or female subjects, aged 18 years or older.
2.
Subjects must have signed an informed consent form indicating that they are willing to participate in the trial 
and understand the purpose and procedures required for the trial.
3.
Subjects are HIV-1 infected and were previously randomized to receive TMC278 in a TMC278 clinical trial 
and completed the protocol defined treatment period.
4.
Subjects benefit from treatment with TMC278, according to the efficacy and safety criteria as set out in the 
previous trial protocol, and will continue to benefit from this treatment in the opinion of the investigator.
5.
Subjects can comply with the current protocol requirements.
6.
The subject's general medical condition, in the investigator's opinion, does not interfere with participation in the 
trial.
DOSAGE AND ADMINISTRATION
Oral tablets of TMC278 25 mg q.d. should be administered together with a meal.
EFFICACY EVALUATIONS/CRITERIA
It is recommended that subjects are followed as per local standard of care. All tests are to be performed locally. 
Efficacy measurements will be summarized descriptively. As of Protocol Amendment 3, efficacy assessments 
should still be conducted as per local standard of care but documented in the subject’s medical records only; data 
will no longer be recorded in the eCRF and therefore no further efficacy analyses will be performed.
SAFETY EVALUATIONS
Safety and tolerability will be evaluated throughout the trial (see the Time and Events Schedule for details).
As of Protocol Amendment 3, safety assessments should still be conducted as per local standard of care but 
documented in the subject’s medical records only; data will no longer be recorded in the eCRF. Investigators must 
continue to report serious adverse events, pregnancies, and non-serious clinically important events to the sponsor.
STATISTICAL METHODS
No formal sample size determination has been performed for this trial: any subject in the TMC278 Phase IIb or 
Phase III trials, who has given consent to participate and who is eligible and willing, may participate in this trial. 
Since the trial does not include a comparator, only descriptive statistical analyses will be performed on the data 
collected.


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TIME AND EVENTS SCHEDULE – UP TO AND INCLUDING 
PROTOCOL AMENDMENT 2
Study Part / Type of 
Visit
Roll-over Visit
Treatment Period
Post-treatment 
follow-up visit****
Time of Visit
At Final Visit in trial*
Study Visits**
Final/Withdrawal 
Visit***
Informed consent
X
Inclusion/exclusion 
criteria
X
Pregnancy test1
X
X
X
Collection of viral load 
and CD4+ cell count2
X
X
Collection of the 
following AEs3:
- AEs considered to be 
at least possibly related 
to TMC278;
X
X
X
X
- AEs leading to 
discontinuations;
X
X
X
X
- SAEs and 
pregnancies;
X
X
X
X
- Any grade 3/4 rash, 
regardless of causality
X
X
X
X
Safety laboratory tests
X
X4
X4
ARV therapy
X
X
X
Concomitant therapy 
administered for 
(S)AEs5 or 
contraception to be 
recorded
X
X
X
X
Dispensation of 
TMC278
X
X
Drug accountability
X
X
X
AEs: adverse events; ARV: antiretroviral; SAEs: serious adverse events.
* All assessments required in previous trial's Final visit need to be completed first.
** Visits should be performed according to local standard of care, but it is recommended to be no less frequent than every 
6 months.

*** The investigator will conduct the Final/Withdrawal visit when the subject meets at least one of the withdrawal 
criteria or when TMC278 becomes commercially available, is reimbursed, or can be accessed through another source 
(e.g., access program or government program) by the subject in his/country (whichever comes first).
In case of loss of virologic response: in order to assist in the selection of a new ARV regimen, determination of the genotype will 
be performed on the sample collected at the first visit where the viral load is sufficiently high to allow genotyping. Genotyping 
should be performed at a local/regional certified laboratory facility. In countries where such facilities are not available, the site 
will arrange for shipment of the sample to Virco Laboratories where a virco®TYPE HIV-1 will be performed. The genotype 
results will be provided to the investigator who will record these data in the electronic Case Report Form (eCRF).


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**** The follow-up visit (30 days ± 2 days) is only performed for subjects who have an ongoing AE or SAE at time of 
discontinuation.
1 A urine pregnancy test must be performed at the Roll-over visit (= Final visit in the previous trial). It is also recommended to 
perform a urine pregnancy test at every subsequent visit if it is not part of local standard of care.
2 It is recommended that viral load and CD4+ cell count information from procedures performed per local standard of care is
collected.
3 Other AEs will only be collected in the eCRF if required per local regulations.
4 Recommended to be done at all visits, or more frequently if indicated per local standard of care. Results of routine safety 
laboratory tests will only be collected in case of AE/SAE.
5 Only use of concomitant therapy administered for (S)AEs for which information is collected in the eCRF, and use of any oral, 
injectable, or implantable hormonal contraceptives are to be recorded.


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TIME AND EVENTS SCHEDULE – AS OF PROTOCOL 
AMENDMENT 3
As of Protocol Amendment 3, visits and assessments should still be performed as per local 
standard of care but documented in the subject’s medical records only; data will no longer be 
recorded in the eCRF.
Sites should continue to report SAEs, pregnancies, and non-serious clinically important events to 
the sponsor.
Concomitant therapies should be documented in the subject’s medical records only, as per local 
standard of care; data will no longer be recorded in the eCRF.
TMC278 will be provided in this trial until subjects can switch to locally available rilpivirine (ie, 
commercially available AND reimbursed, OR accessible through another source [eg, access 
program or government program]), other local (rilpivirine-based) treatment options, or local 
standard of care, as appropriate.


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ABBREVIATIONS
3TC
lamivudine
ABC
abacavir
AE
adverse event
ALT
alanine aminotransferase
ARV
antiretroviral
ASR
annual safety report
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-24h
area under the plasma concentration-time curve from time of administration to 24 hours 
after dosing
AZT
zidovudine
CTP
Clinical Trial Protocol
DAIDS
Division of Acquired Immunodeficiency Syndrome
ECG
electrocardiogram
eCRF
electronic Case Report Form
eDC
electronic Data Capture
EFV
efavirenz
ESI
events of special interest
FDA
Food and Drug Administration
FTC
emtricitabine 
GCP
Good Clinical Practice
HIV-1
human immunodeficiency virus - type 1 
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
NNRTI
non-nucleoside reverse transcriptase inhibitor
N(t)RTI
nucleos(t)ide reverse transcriptase inhibitor 
PI
protease inhibitor
PQC
Product Quality Complaint
q.d.
quaque die; once daily
QTcF
QT interval corrected for heart rate according to Fridericia
RBC
red blood cell
SAE
serious adverse event
SJS
Stevens-Johnson Syndrome
TDF
tenofovir disoproxil fumarate
TQT
thorough QT 
ULN
upper limit of laboratory normal range
WBC
white blood cell


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Approved, Issued Date: 28-Nov-2016
1
INTRODUCTION
Currently, human immunodeficiency virus (type 1) (HIV-1) infected subjects are routinely treated 
with combinations of 3 or 4 drugs, including nucleo(t)side reverse transcriptase inhibitors
(N[t]RTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), 
and/or fusion inhibitors. Improved tolerability, safety, and simple dosing regimens are important 
drivers of good adherence and hence low rates of resistance development and should, therefore, 
be considered as major elements in the development of new potent antiretroviral (ARV)
compounds with different resistance profiles, especially in the treatment-naïve population.1,2 The 
currently approved first generation NNRTIs in the United States and/or Europe are nevirapine 
(Viramune®), delavirdine (Rescriptor®) and efavirenz (EFV; Sustiva®, Stocrin®). These drugs 
show cross-resistance and are associated with safety problems (mainly hepatotoxicity, central 
nervous system symptoms, and/or rash).2 Novel NNRTIs with an increased in vitro genetic 
barrier to the development of resistance are being developed. Currently one novel NNRTI, 
etravirine (Intelence®), is approved for the use in treatment-experienced subjects. TMC278 
(rilpivirine, formerly known as R278474), a diarylpyrimidine derivative, is a potent NNRTI with 
in vitro activity against wild-type HIV-1 and NNRTI-resistant mutants. A median inhibitory 
activity of HIV-1 reverse transcriptase by TMC278 (50% inhibitory concentration) of 42 nM 
(15.4 ng/mL) was determined using a primer extension-based scintillation proximity assay. 
TMC278 is able to combine the convenience of once daily (q.d.) dosing with good antiviral 
effects and a higher barrier to resistance as compared to currently licensed NNRTIs (with the 
exception of etravirine).
For the most accurate and current information regarding the efficacy and safety of TMC278 refer 
to the latest version of the Investigator’s Brochure for TMC278.3
The term sponsor used throughout this document refers to the entities and their representatives 
listed in the Contact Information page(s), which will be provided as a separate document.
1.1
Background
Nonclinical Studies
Non-clinical safety and toxicology studies demonstrated that TMC278 is safe for use in clinical 
testing.4 In non-clinical studies in rats and dogs, changes in adrenal hormones and histopathology 
have been observed. In those studies, TMC278 appears to interfere with steroid biosynthesis, 
leading to decreases in cortisol and increases in progesterone and 17-OH-progesterone and as a 
result to increases in serum adrenocorticotropic hormone. Preclinical work with TMC278 also 
identified changes in the thyroid glands in rats. However, to date, no significant effects on 
adrenal or thyroid function were observed in clinical studies with TMC278.
TMC278 did not show a potential for genotoxicity, teratogenicity, phototoxicity, skin or mucous 
membrane irritation, or delayed-type sensitization. Fertility, early embryonic development, 
pre- and postnatal development, and the immune system were not affected by TMC278 at oral 
doses ranging from 160 to 1600 mg base eq./kg.


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Clinical Studies
Human Pharmacokinetics
In humans, TMC278 is well absorbed after single and multiple dosing and maximum 
concentrations are generally reached at 4 hours postdose. Steady-state concentrations of TMC278 
are usually reached within 11 days of dosing. The mean terminal elimination half-life after 
multiple dosing was approximately 45 hours. There was no indication of changes in the 
pharmacokinetics of TMC278 over a 96-week period in a trial in HIV-1 infected subjects. 
TMC278 exhibited linear pharmacokinetics for maximum plasma concentration and area under 
the plasma concentration-time curve (AUC) after single and multiple dose administration up to a 
dose of 150 mg q.d. in non-HIV infected subjects. In HIV-1 infected subjects the exposure to 
TMC278 increased less than proportional to the dose, particularly between 25 mg q.d. and 
75 mg q.d. The average exposure (AUC0-24h) to TMC278 after repeated administration (96 
weeks) of 25, 75, and 150 mg q.d. in HIV-1-infected subjects was, respectively, 2.8, 5.9, and 
10.3 µg.h/mL.
Single dose exposure to TMC278 when administered as the Phase III tablet formulation was 
approximately 40-50% lower when taken fasting or with a nutritional drink as compared to 
intake with a standard or high-fat breakfast. Therefore, TMC278 should always be taken with a 
meal.
Mild induction of CYP2C19 activity was observed after repeated administration of TMC278 
150 mg q.d. in non-HIV infected subjects. This effect is unlikely to cause clinically relevant 
changes in the pharmacokinetics of coadministered drugs that are metabolized by this enzyme. 
TMC278 at a dose of 75 mg q.d. was shown not to affect CYP3A4 activity in vivo. TMC278 at 
25 mg q.d. or higher did not influence the pharmacokinetics of any of the agents evaluated to a 
clinically relevant extent. The exposure to TMC278 can be affected by modulators of CYP3A4 
enzyme activity and by drugs that increase the gastric pH. Drugs that induce CYP3A4 activity 
(e.g., rifabutin and rifampin) can reduce the TMC278 exposure and should not be 
coadministered. Proton-pump inhibitors (e.g., omeprazole) should not be coadministered, given 
the reduced exposure to TMC278. H2-antagonists should only be administered at least 12 hours 
before or at least 4 hours after intake of TMC278, and antacids should only be administered 
either at least 2 hours before or at least 4 hours after intake of TMC278.
Efficacy/Safety Studies
At the time of writing this protocol, 35 clinical trials with TMC278 have been conducted with 
1834 HIV-1 infected subjects and 759 non-HIV infected subjects.
In the 30 Phase I trials (774 subjects), short-term administration of TMC278 in single and 
multiple dose trials has been generally safe and well tolerated. A thorough QT (TQT) trial at the 
TMC278 25 mg q.d. dose5 showed that TMC278 did not prolong the QT interval corrected for 
heart rate according to Fridericia (QTcF) interval at this dose. The upper limit of the 90% 
confidence interval of the difference versus placebo as well as the difference versus baseline in 
QTcF interval for TMC278 25 mg q.d. was less than 10 ms at all time points. Higher doses of 
TMC278 (75 mg and 300 mg q.d.) examined in this previous TQT trial, were associated with 
maximum mean QTcF prolongations > 10 ms, which were shown to be dose- and plasma 
concentration-dependent.


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The 2 Phase IIa proof-of-principle trials6,7 (83 subjects) demonstrated the short-term (7 days)
antiviral activity in HIV-1 infected subjects who were naïve to ARV therapy as well as in HIV-1 
infected subjects with NNRTI experience and/or genotypic evidence of NNRTI resistance and 
who were failing ARV therapy. These data provided a strong rationale for further development of 
TMC278 in HIV-1 infected subjects at doses of 25 to 150 mg q.d. The results of these 2 trials 
demonstrated that TMC278 doses up to 150 mg q.d. for 7 days did not reveal any new or 
unexpected safety signals that would affect the risk/benefit balance as compared to Phase I trials.
The Phase IIb (C204) trial8 (368 subjects) was a randomized, active controlled, and partially 
blinded trial to evaluate the effect on efficacy, safety, and tolerability of TMC278, given at 
3 different doses (25 mg q.d.,75 mg q.d., and 150 mg q.d.), when added to a regimen of 
investigator selected N(t)RTIs. At Week 48 and Week 96, all TMC278 doses were highly active 
and associated with a substantial and sustained virologic response when considering the 
percentage of subjects reaching less than 50 HIV-1 ribonucleic acid copies/mL (time to loss of 
virologic response algorithm) and the mean change in viral load from baseline. TMC278 
25 mg q.d. was as effective as the higher doses of 75 mg q.d. and 150 mg q.d. up to 96 weeks of 
treatment. All TMC278 doses provided a clear immunologic benefit, up to 96 weeks of
treatment, in addition to the antiviral effect in HIV-1 ARV-naïve subjects. For subjects receiving 
the higher doses of TMC278, doses were switched to 25 mg q.d. after Week 96 once results of 
the TQT trial were available and the dose of 25 mg q.d. was selected for further development.
The total treatment duration of the trial was extended to 240 weeks in order to collect long-term 
efficacy and safety data from subjects who continued to benefit from their treatment. No loss of
efficacy was observed when the dose was decreased to 25 mg q.d. There was no clear dose 
differentiation for adverse events (AEs) or laboratory abnormalities. No clinically relevant effects 
were observed on adrenal function. Overall, there were no endocrine or cardiovascular signals to 
suggest safety issues with the use of TMC278. In conclusion, these data showed that TMC278 
was generally safe and well tolerated after long-term treatment at all doses tested, compared with 
EFV, when combined with zidovudine (AZT)/lamivudine (3TC) or tenofovir disoproxil fumarate 
(TDF)/emtricitabine (FTC). Data from the primary analysis at Week 48 and the analyses at 
Weeks 96, 144, 192, and 240 are available.9,10
The 2 Phase III (ECHO11 [C209] and THRIVE12 [C215]) trials (1368 subjects in total) are
multi-national, randomized, double-blind, double-dummy, active-controlled trials to compare the 
efficacy (including antiviral efficacy, immunologic changes, and evolution of HIV-1 genotypic 
and phenotypic characteristics), safety, and tolerability of TMC278 25 mg q.d. versus EFV both 
combined with a background regimen of 2 N(t)RTIs in treatment-naïve HIV-1 infected subjects. 
Data from the primary analysis at Week 48 and the analyses at Week 96 and post-Week 96 are 
available.13,14,15,16 These data demonstrated TMC278 to have substantial and sustained efficacy, 
that was non-inferior to EFV, and to be generally safe and well tolerated. Overall, there were no 
endocrine or cardiovascular signals to suggest safety issues with the use of TMC278, when 
combined with TDF/FTC, AZT/3TC or abacavir (ABC)/3TC.
1.2
Overall Rationale for the Study
The trial was designed to allow subjects who have benefited from treatment with TMC278 in a 
clinical trial to continue this treatment upon completion of this trial. The potential benefit of 
continuing TMC278 treatment should outweigh the potential risk of experiencing possible AEs 


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after switching to another (commercially available) NNRTI. Subjects will continue to receive 
TMC278 in this trial until one of the following criteria is met (whichever comes first):

The subject meets at least one of the withdrawal criteria, or

Rilpivirine becomes commercially available AND is reimbursed, OR can be accessed through 
another source (e.g., access program or government program) by the subject in his/her 
country, or

The investigator finds it in the subject’s best interest to switch to other local (rilpivirine-
based) treatment options or local standard of care, as appropriate.
The design of the trial also allows long-term safety and available efficacy information, including 
resistance data in case of virologic failure, to be gathered in these subjects. As of Protocol 
Amendment 3, visits and assessments should still be performed as per local standard of care but 
documented in the subject’s medical records only; data will no longer be recorded in the 
electronic Case Report Form (eCRF).
2
OBJECTIVES
Primary Objective
The primary objective of the trial is to provide continued access to TMC278 for subjects who 
were randomized and treated with TMC278 in the Phase IIb (C204) or Phase III trials (C209 and 
C215), and who, at the time of roll-over, experience and are expected to continue experiencing 
clinical benefit from TMC278 treatment.
Secondary Objectives
Up to and including Protocol Amendment 2, the secondary objective is to evaluate the long-
term safety and tolerability of TMC278 25 mg q.d. in combination with a background regimen 
containing 2 N(t)RTIs. Available efficacy data will also be collected, including resistance data in 
case of virologic failure.
Protocol Amendment 3 Objective
As of Protocol Amendment 3, the objective is to provide continued access to TMC278 for 
subjects who experience and are expected to continue experiencing clinical benefit from 
TMC278 treatment until subjects can switch to locally available rilpivirine (ie, commercially 
available AND reimbursed, OR accessible through another source [eg, access program or 
government program]), other local (rilpivirine-based) treatment options, or local standard of care, 
as appropriate.
3
OVERVIEW OF STUDY DESIGN
3.1
Study Design
This is a Phase III, open-label, multicenter, roll-over trial to provide continued access to 
TMC278 for HIV-1 infected subjects who were randomized and treated with TMC278 in the 


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Phase IIb (C204) or Phase III trials, (C209 or C215). At the time of roll-over the investigator 
should assess whether the subject benefits from TMC278 treatment according to the efficacy and 
safety criteria as set out in the previous trial protocol. The investigator should also be confident 
that the subject is expected to continue benefiting from TMC278 treatment. It was anticipated 
that approximately 750 subjects would participate in this trial. At the time of execution of
Protocol Amendment 3, most of the subjects involved in this trial will have been switched to 
locally available rilpivirine, other local (rilpivirine-based) treatment options, or local standard of 
care.
The Final visit of the previous trial will be the first visit of this trial (= the Roll-over visit). From 
this visit onwards, all enrolled subjects will continue to receive TMC278 25 mg q.d. in 
combination with a background regimen consisting of 2 N(t)RTIs until one of the following 
criteria is met (whichever comes first):

The subject meets at least one of the withdrawal criteria (see Section 10.2), or

Rilpivirine becomes commercially available AND is reimbursed, OR can be accessed through 
another source (e.g., access program or government program) by the subject in his/her 
country, or

The investigator finds it in the subject’s best interest to switch to other local (rilpivirine-
based) treatment options or local standard of care, as appropriate.
The background regimen of 2 N(t)RTIs can be changed at the investigator’s discretion anytime 
during this study, as long as there is no evidence of resistance to the chosen N(t)RTIs, as 
determined by the last available genotype results.
Visits and assessments performed should be based on the local generally accepted standard of 
care (see Time and Events Schedule). However, it is recommended that visits be planned no less 
frequently than every 6 months.
Information regarding AEs considered at least possibly related to the investigational medication
(TMC278), AEs leading to discontinuation, serious adverse events (SAEs), and any grade 3/4 
rash regardless of causality, should be recorded on the eCRF. Other AEs will be collected only if 
required as per local regulations.
As of Protocol Amendment 3, visits and assessments should still be performed as per local 
standard of care but documented in the subject’s medical records only; data will no longer be 
recorded in the eCRF. Safety and tolerability of TMC278 will continue to be documented 
through the reporting of SAEs, pregnancies, and non-serious clinically important events to the 
sponsor.
3.2
Study Design Rationale
The Week 48 analysis of the Phase III trials, C209 and C215, demonstrated TMC278 to have 
substantial and sustained efficacy that is non-inferior to EFV, and to be generally safe and well 
tolerated. This trial was designed to provide continued access to TMC278 for subjects who were 
previously treated with TMC278 in the Phase IIb or Phase III trials, and who, at the time of roll-
over, experience and are expected to continue experiencing clinical benefit from TMC278
treatment. Up to and including Protocol Amendment 2, this trial also allows long-term safety 


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and available efficacy information, including resistance data in case of virologic failures, to be 
gathered in these subjects. As of Protocol Amendment 3, safety and tolerability of TMC278 will 
continue to be documented through the reporting of SAEs, pregnancies, and non-serious 
clinically important events to the sponsor. The objective of this trial does not mandate any 
comparator drug, hence the open-label design. Efficacy and safety data will be analyzed in a 
descriptive way. Visits and assessments are recommended by this protocol; however, subjects are 
to be monitored according to the local standard of care for this subject population.
4
STUDY POPULATION
4.1
General Considerations
The inclusion and exclusion criteria for enrolling subjects in this trial are described in the 
following sections. If there is any uncertainty about the inclusion or exclusion criteria below, the 
investigator may consult with the appropriate sponsor representative before enrolling the subject 
in the trial. Approximately 750 HIV-1 infected subjects are expected to participate in this trial.
For discussion of the statistical considerations, refer to Section 11.3.
4.2
Inclusion Criteria
To be eligible, subjects must satisfy all of the following criteria:
1.
Male or female subjects, aged 18 years or older.
2.
Subjects must have signed an informed consent form (ICF) indicating that they are willing to 
participate in the trial and understand the purpose and procedures required for the trial.
3.
Subjects are HIV-1 infected and were previously randomized to receive TMC278 in a 
TMC278 clinical trial and completed the protocol defined treatment period.
4.
Subjects benefit from treatment with TMC278, according to the efficacy and safety criteria 
as set out in the previous protocol, and will continue to benefit from this treatment in the 
opinion of the investigator.
5.
Subjects can comply with the current protocol requirements.
6.
The subject's general medical condition, in the investigator's opinion, does not interfere with 
participation in the trial.
4.3
Exclusion Criteria
Potential subjects who meet any of the following criteria will be excluded from participating in 
the trial:
1.
Use of disallowed concomitant therapy (see Section 8).
2.
Females of childbearing potential* who are pregnant, or without the use of effective birth 
control methods, or not willing to continue practicing these birth control methods during the 
trial and for at least 1 month after the end of the trial (or after last intake of TMC278).


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Effective birth control methods**: 
(1) male condom*** in combination with diaphragm or cervical cap **** (“double barrier 
method”),
(2) intrauterine device or hormonal contraceptive in combination with a barrier contraceptive 
(i.e., male or female condom***, diaphragm, or cervical cap****), 
(3) be non-heterosexually active, practice sexual abstinence or have a vasectomized partner:
if no other effective birth control methods are being used, vasectomy should have been 
performed more than 1 month prior to withdrawal of these other effective birth control 
methods.
* Women who are postmenopausal for at least 2 years, women with total hysterectomy and 
women who have a bilateral tubal ligation are considered of non-childbearing potential.
** Spermicides should not be used as this can potentially increase the rate of HIV-1 
transmission17.
*** A male and female condom should not be used together due to risk of breakage or 
damage caused by latex friction.
**** A cervical cap has been shown to be less effective in parous women. Therefore, this 
barrier method is preferably not used in parous women in this trial.
3.
Non-vasectomized heterosexually active male subjects without the use of effective birth 
control methods or not willing to continue practicing these birth control methods during the 
trial and for at least 1 month after the end of the trial (or after last intake of TMC278).
4.4
Prohibitions and Restrictions 
During the conduct of the trial, subjects are not allowed to participate in any other clinical trials 
that include any blood sampling with a volume higher than 50 mL taken over the course of 
6 months, specimen collection, or other interventional procedure. Concurrent participation in 
non-interventional observational trials is allowed as long as there is no impact on the objectives 
of this trial.
All HIV-1 infected subjects should be advised to take the necessary precautions to reduce the risk 
of transmitting HIV.
Potential subjects must be willing/able to adhere to the following prohibitions and restrictions 
during the course of the trial to be eligible for participation:
1.
Women of childbearing potential must remain on a highly effective method of birth control 
(see Section 4.3). These precautions apply from the Roll-over visit onwards until 1 month 
after the last intake of TMC278 or 1 month after discontinuation of TMC278 in case of 
premature discontinuation.
2.
Men must use a highly efficient method of birth control and not donate sperm during the 
trial and for 1 month after receiving the last dose of TMC278 (see Section 4.3).
For details on the existing data with regard to the reproductive toxicity of TMC278, please see 
the current Investigator's Brochure.


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Where rilpivirine is available, investigators should follow the guidance in the local prescribing 
information for TMC278 regarding any contraindications, precautions for use, and other 
restrictions. Where local prescribing information is not available, investigators should follow the 
guidance in the Summary of Product Characteristics18, United States Prescribing Information19,
or the Investigator’s Brochure3.
5
TREATMENT ALLOCATION
As this is an open-label trial in which all subjects receive the same treatment, randomization and 
blinding procedures are not applicable.
6
DOSAGE AND ADMINISTRATION
From the Roll-over visit onwards, subjects can either continue the background regimen of 
2 N(t)RTIs that they are using or they can switch to another background regimen of 2 N(t)RTIs. 
The sponsor will not provide the medication for the background regimen. The subject will 
receive investigator-selected background medication according to locally applicable procedures. 
Please refer to the current product information for further details.
Subjects planning to use ABC in their background regimen, and who have no prior documented 
HLA-B*5701 negative results, should test negative for HLA-B*5701 before the start of ABC. In 
those subjects who test positive for HLA-B*5701, no ABC-containing background regimen can 
be administered. 
Oral tablets of TMC278 25 mg q.d. must be administered together with a meal. Starting on 
Day 1, whenever possible, TMC278 should be taken around the same time each day (each dose 
should be separated by approximately 24 hours). When TMC278 is taken with only a protein-rich 
nutritional drink, exposures are approximately 40-50% lower than when taken with a meal.
Up to and including Protocol Amendment 2, the date of the first intake of TMC278 will be
recorded on the eCRF. If a subject misses the intake of TMC278, and this is noticed within 
12 hours of the time of usual intake, the subject should take the missed dose as soon as possible, 
with food. The subject may then continue with the usual dosing schedule. If a subject misses the 
intake of TMC278, and this is noticed more than 12 hours after the time of usual intake, the 
subject should not take that dose and simply resume the usual dosing schedule. The subject 
should not take a double dose to make up for a missed one.
If a subject discontinues the trial early, for whatever reason, TMC278 treatment can immediately 
stop, with no need for dose modifications.
Subjects will visit the site for assessments as per the Time and Events Schedule.
As of Protocol Amendment 3, a tool will continue to be available to order additional supplies of 
TMC278. Sites should also use this tool to record the date of last intake of TMC278 for each 
individual subject in this study.


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7
TREATMENT COMPLIANCE
The investigator will discuss the importance of good compliance to the entire treatment regimen, 
including TMC278 taken in combination with other ARVs. The investigator or designated trial 
personnel will maintain a log of all drug dispensed and returned. Drug supplies for each subject 
will be inventoried and accounted for throughout the trial.
8
PRESTUDY AND CONCOMITANT THERAPY
The investigator is responsible for following guidance from product information/package inserts 
of TMC278 and all background ARVs regarding concomitant treatments, drug interactions, and 
other data.
The following medications are not allowed at any time during the trial from the Roll-over visit 
until the end of the study:

Disallowed medication, as detailed in the most recent version of the Investigator Brochure
for TMC278.

All investigational drugs, except TMC278.

All disallowed medication as mentioned in the product information/package insert of 
TMC278 and background ARVs. For any alternative N(t)RTIs in the background regimen, 
the respective package inserts should be consulted for concomitant use with other 
medications and for contraindicated medications or medications that are not recommended 
for concomitant use.
The following ARVs are not allowed at any time during the trial from the Roll-over visit until the 
end of the study:

Any investigational ARVs.

Any PIs.

CCR5 antagonists.

Integrase inhibitors.

Any fusion inhibitor.

Any NNRTIs, except for TMC278.
Nucleo(t)side reverse transcriptase inhibitors other than ABC/3TC, AZT/3TC, and TDF/FTC 
will be allowed. At all times, 2 N(t)RTIs must be administered as the background regimen.
Hormone replacement therapy is allowed in postmenopausal women. Applicable procedures and 
treatment guidance based on package inserts should be respected.
Female subjects of childbearing potential must use birth-control methods as outlined previously 
in Section 4.3 and must be willing to continue practicing these birth-control methods throughout 
the trial and for at least 1 month after the last intake of TMC278. Up to and including Protocol 
Amendment 2, the use of oral, injectable, and implantable hormonal contraceptives is to be 
recorded in the Concomitant Therapy eCRF section.


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Other comedication is allowed in the following cases:

In case of rash and/or an allergic reaction, the use of cetirizine (Zyrtec), levocetirizine 
(Xyzal), topical corticosteroids, or antipruritic agents in the recommended dosing schedule
is permitted.

In case of nausea, the use of antiemetics is permitted.

In case of diarrhea, the use of loperamide or diphenoxylate is permitted.
As of Protocol Amendment 3, concomitant therapies should be documented in the subject’s
medical records only, as per local standard of care; data will no longer be recorded in the eCRF.
Where rilpivirine is available locally, subjects should follow the local prescribing information for 
rilpivirine under the guidance of the investigator. Subjects should not take any medications 
which are listed as contraindicated in the prescribing information for rilpivirine. Where local 
prescribing information is not available, investigators should follow the guidance in Summary of 
Product Characteristics18, United States Prescribing Information19, or the Investigator’s 
Brochure3.
9
STUDY EVALUATIONS
9.1
Study Procedures
9.1.1
Overview
The Time and Events Schedule that follows the Synopsis summarizes the frequency and timing 
of efficacy and safety measurements applicable to this trial.
9.1.2
Pretreatment Phase
Subjects will continue to receive TMC278 without interruption.
At the Roll-over visit, all assessments required at the Final visit in the previous protocol need to 
be completed first.
9.1.3
Open-Label Treatment Phase
Up to and including Protocol Amendment 2, assessments will be performed as detailed in the 
Time and Events Schedule. Visits should be performed according to local standard of care, but it 
is recommended that visits be planned no less frequently than every 6 months. TMC278 will be 
dispensed at every visit until the time of the Final/Withdrawal Visit, and drug accountability 
assessed.
It is recommended to perform a urine pregnancy test at every visit if it is not part of local 
standard care.


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If viral load and CD4+ cell count have been measured per local standard of care, the information 
will be collected at every visit.
The investigator will conduct the Final/Withdrawal visit when the subject meets at least one of 
the withdrawal criteria (see Section 10.2) or when TMC278 becomes commercially available, is 
reimbursed, or can be accessed through another source (e.g., access program or government 
program) by the subject in his/her country (whichever comes first).
As of Protocol Amendment 3, visits and assessments should still be be performed as per local 
standard of care but documented in the subject’s medical records only; data will no longer be 
recorded in the eCRF. A tool will be available that sites should use to record the date of last 
intake of TMC278 for each individual subject.
9.1.4
Posttreatment Phase (Follow-Up) 
Up to and including Protocol Amendment 2:
In case of loss of virologic response: in order to assist in the selection of a new ARV regimen, 
determination of the genotype will be performed on the sample collected at the first visit where 
the viral load is sufficiently high to allow genotyping. Genotyping should be performed at a 
local/regional certified laboratory facility. In countries where such facilities are not available, the 
site will arrange for shipment of the sample to Virco Laboratories where a virco®TYPE HIV-1 
will be performed. The genotype results will be provided to the investigator who will record 
these data in the eCRF.
Upon withdrawal from the trial, subjects with an ongoing AE, that is either considered to be at 
least possibly related to TMC278, a grade 3/4 rash regardless of causality, an AE leading to 
discontinuation or an SAE, at time of discontinuation will be followed for an additional 30 days 
(± 2 days).
Investigators may re-contact the subject to obtain long-term follow-up information to determine 
the subject's safety or survival status (see Section 16.2.3, Informed Consent).
As of Protocol Amendment 3, safety and efficacy will continue to be assessed as part of the 
local standard of care but should be documented in the subject’s medical records only; data will 
no longer be recorded in the eCRF. A tool will be available that sites should use to record the 
date of last intake of TMC278 for each individual subject.
9.2
Efficacy
9.2.1
Evaluations
Up to and including Protocol Amendment 2, assays will be performed locally, as per local 
practice. The results will be collected in the eCRF.


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As of Protocol Amendment 3, efficacy will continue to be assessed as part of the local standard 
of care but should be documented in the subject’s medical records only; data will no longer be 
recorded in the eCRF.
9.2.2
Criteria
Up to and including Protocol Amendment 2: Efficacy measurements will be summarized 
descriptively.
9.3
Safety Evaluations
Up to and including Protocol Amendment 2:
Any clinically significant abnormalities persisting at the Posttreatment follow-up visit will be 
followed by the investigator until satisfactory resolution (i.e., value back to baseline value) or 
until a clinically stable endpoint is reached (to be agreed upon in collaboration with the sponsor). 
The trial will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule.
As of Protocol Amendment 3, safety will continue to be assessed as part of the local standard of 
care but should be documented in the subject’s medical records only; data will no longer be 
recorded in the eCRF. Investigators should continue to report SAEs, pregnancies, and non-
serious clinically important events to the sponsor.
9.3.1
Adverse Events
Up to and including Protocol Amendment 2:
Starting with signing of the ICF onwards to the Final/Withdrawal visit or 30 days (± 2 days) after 
the Final/Withdrawal visit for AEs ongoing at this visit, AEs will be followed by the investigator. 
Adverse events considered to be at least possibly related to TMC278, AEs leading to 
discontinuation, SAEs, and any grade 3/4 rash regardless of causality, will be collected. Other 
AEs will be collected only if required as per local regulations. For detailed definitions and 
reporting procedures of AEs see Section 12.
9.3.2
Pregnancies
Up to and including Protocol Amendment 2:
For female subjects of childbearing potential only, a urine pregnancy test (by means of a dipstick) 
should be performed at the Roll-over visit (= Final visit in the previous trial). This urine 
pregnancy test is recommended at all other visits following the Roll-over visit, if it is not part of 
local standard care. The results of these tests will be collected in the eCRF.
9.3.3
Clinical Laboratory Tests
Up to and including Protocol Amendment 2:


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All tests will be performed by local laboratories. The sponsor recommends that the laboratory 
assessments (including hematology, biochemistry (including aspartate aminotransferase [AST], 
alanine aminotransferase [ALT], pancreatic enzymes, and lipid analyses), plasma viral load, and
CD4+ cell count), are done at all trial visits, or more frequently if indicated per local standard of 
care. The results of the routine laboratory tests (excluding plasma viral load and CD4+ cell 
count) will only be collected in case of AEs considered to be at least possibly related to TMC278, 
AEs leading to discontinuations, grade 3/4 rash regardless of causality, or SAEs. Plasma viral 
load and CD4+ cell count should be recorded in the eCRF at each trial visit, if available.
In case of grade 3 or 4 lab abnormalities, it is recommended to retest within 48 hours for 
confirmation (see Section 9.3.4 for further guidance and exceptions). In the case of safety 
concerns, and/or upon the sponsor’s request, the site will provide all relevant laboratory results, 
in which subject identifiers have been removed and/or masked with the exception of the subject’s 
initials, sex, CRF ID and date of birth. Laboratory safety assessments should be performed 
according to local standard of care taking into account the subject’s current medications and the 
clinical condition. Recommended laboratory safety assessments for TMC278 may be found in the 
Investigator’s Brochure under “Guidance for the Investigator”.
9.3.3.1
PREGNANCY TEST
Up to and including Protocol Amendment 2:
For female subjects of childbearing potential only, a urine pregnancy test (by means of a dipstick) 
should be performed at the Roll-over visit. This urine pregnancy test is recommended at all other 
visits following the Roll-over visit, if it is not part of local standard care. The results of these 
tests will be collected in the eCRF. 
9.3.3.2
PLASMA VIRAL LOAD
Up to and including Protocol Amendment 2:
Plasma viral load assessments are performed by a local laboratory, per local standard practice. 
The results will be collected in the eCRF.
9.3.3.3
IMMUNOLOGY
Up to and including Protocol Amendment 2:
Immunology assessments (CD4+ cell count analysis) are performed by a local laboratory, per 
local standard practice. The results will be collected in the eCRF.
9.3.3.4
RESISTANCE DETERMINATIONS
Up to and including Protocol Amendment 2:
When selecting an ARV regimen to be used in combination with TMC278, careful consideration 
must be given to previous ARV treatment history, allowed and disallowed ARVs and any 
information from resistance testing (including any genotype report available from the previous 
trial in which the subject was enrolled).
In case of loss of virologic response: in order to assist in the selection of a new ARV regimen, 
determination of the genotype will be performed on the sample collected at the first visit where 
the viral load is sufficiently high to allow genotyping. Genotyping should be performed at a 


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local/regional certified laboratory facility. In countries where such facilities are not available, the 
site will arrange for shipment of the sample to Virco Laboratories where a virco®TYPE HIV-1 
will be performed. The genotype results will be provided to the investigator who will record 
these data in the eCRF.
9.3.4
Specific Toxicities
Up to and including Protocol Amendment 2, management of toxicities will be at the discretion 
of the investigator, taking into account the following protocol defined procedures, and should 
follow local standard of care.
As of Protocol Amendment 3, safety should be assessed as part of the local standard of care and 
documented in the subject’s medical records only; data will no longer be recorded in the eCRF.
9.3.4.1
RASH 
Since in this trial only subjects who have been exposed to TMC278 for > 48 weeks are included, 
the emergence of TMC278-related rash is considered very unlikely. Therefore the safety 
management of rash will be less stringent than in the initial trials. However, specific attention 
will be given to severe rash of grade 3 or 4 and additional assessments will be required in those 
cases.
In case of severe (grade 3/4) rash, visits and assessments should be performed as described below 
and in the “Visit Schedule for Grade 3/4 Rash Management” (see Attachment Attachment 2). 
Subjects should be informed that they should contact their doctor and visit the clinic 
immediately, preferably within 24 hours after the onset of the grade 3/4 rash. Unscheduled 
follow-up visits for close follow-up of rash will be performed in case of grade 3/4 rash. At the 
investigator’s discretion, additional visits and assessments can be performed. The rash event, 
regardless of causality, should be captured in the Adverse Events Section of the eCRF. In case of 
severe (grade 3/4) rash, safety blood samples need to be taken, and processed by the local 
laboratory. These samples need to be taken during the unscheduled visits as described below and 
in Attachment Attachment 2. The values of the local laboratory assessments need to be 
transcribed in the eCRF by the site staff.
The following parameters need to be tested: AST, ALT, red blood cell (RBC) sedimentation rate 
and a complete blood cell count (including hemoglobin, hematocrit, RBC count, white blood cell 
[WBC] count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelet count). 
The subject may be treated symptomatically until the rash resolves. If the rash is considered to be 
most likely due to concomitant illness or medication other than TMC278, standard management, 
including discontinuation of the likely causative agent, should be undertaken, and the 
continuation of the subject in the trial should be discussed with the sponsor. Dermatologist fees 
for evaluating subjects who experience a rash will be reimbursed by Tibotec. The following 
grades are based on the Division of Aquired Immunodeficiency Syndrome (DAIDS) grading 
table, with adaptations made by the sponsor (see Attachment 1). 
Grade 1/2 Rash
A grade 1 rash is defined as localized macular rash.


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A grade 2 rash is defined as the following: diffuse macular, maculopapular, or morbilliform rash, 
OR target lesions.

Subjects may continue the intake of TMC278 (at the investigator’s discretion).

No unscheduled visits are required.
The subject should be advised to contact the investigator immediately if there is any 
worsening of the rash, if any systemic signs or symptoms worsen, or if mucosal involvement 
develops.
In case the rash evolves to grade 3 or 4 unscheduled visits have to be conducted according to the 
guidelines for grade 3/4 rash.
Grade 3/4 Rash
A grade 3 rash is defined as the following:

Diffuse macular, maculopapular, or morbilliform rash with vesicles or limited number of 
bullae OR

Rash with superficial ulcerations of mucous membranes limited to 1 anatomical site (revised 
by the sponsor) OR

Rash with at least one of the following (revised by the sponsor):
o Elevations in AST/ALT more than 2 x baseline value and at least 5 times upper 
limit of normal (ULN)
o Fever > 38°C or 100°F.
o Eosinophils > 1000/mm3.
o Serum sickness-like reaction.
A grade 4 rash is defined as the following: 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.
For grade 3/4 rash:
Subjects will permanently discontinue the intake of TMC278 and be withdrawn from the trial if 
in the investigator’s opinion, the rash is at least possibly related to TMC278. In that case no 
rechallenge will be allowed.
Unscheduled visits for rash evaluation are required as follows:
Day 0 (preferably within 24 hours after the onset of the rash) and Day 1:

Assessment of vital signs by the investigator and safety blood samples by the local laboratory 
is required. The values of these and all subsequent local laboratory assessments need to be 
transcribed in the eCRF by the site staff.

Digital pictures can only be taken if the subject gave consent. If the subject is taking ABC, 
digital pictures are required; otherwise they are the investigator’s discretion.


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
Referral to a dermatologist is required on Day 0. A copy of the dermatologist’s report should 
be made anonymous and will be collected by the monitor.

For grade 4 rash a biopsy should be performed on Day 0. For grade 3 rash a biopsy can be 
performed at the dermatologist’s discretion. A copy of the biopsy report should be made 
anonymous and will be collected by the monitor.
Days 2, 3, 4, and 5:

Additional safety blood samples are to be taken by the local laboratory, only if the subject’s 
AST/ALT on Day 0 and/or Day 1 of rash ≥2 x baseline value and/or ≥ 5 x ULN and/or in 
case of rash progression.

On Day 5 additional safety blood samples are to be taken by the local laboratory regardless of 
the Day 0 and/or Day 1 AST/ALT levels or rash progression.

Digital pictures are to be taken under the same conditions as on Day 0/1.
Weekly follow-up:

Thereafter, weekly follow-up visits are required (or more frequently at the investigator’s 
discretion) as long as grade 3/4 rash is present.

Weekly assessment of safety blood samples is required only if the subject’s AST/ALT on 
Day 5 of rash is still ≥ 2 x baseline value and/or ≥ 5 x ULN and/or in case of rash 
progression, until resolution or stabilization of the AST/ALT elevations.

Digital pictures are to be taken under the same conditions as on Day 0/1.

Once grade 3/4 rash has resolved to ≤ grade 2 rash, follow-up should be done at the 
investigator’s discretion.
Upon resolution/stabilization of the rash (to be agreed upon in collaboration with the sponsor), 
the final Cutaneous Reaction/Rash form should be completed. Digital pictures are to be taken 
under the same conditions as on Day 0/1.
Subjects should be advised to contact the investigator immediately if they notice any 
worsening of the rash.
A complete summary of the guidelines for grade 3/4 rash management is given in Attachment 
Attachment 2.
9.3.4.2
ACUTE SYSTEMIC ALLERGIC REACTION
Grade 1 (Localized Urticaria [Wheals] With no Medical Intervention Indicated)
Subjects may continue the intake of TMC278.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed, as long 
as these are in line with the package inserts of the ARV background regimen.
Subjects should be advised to contact the investigator immediately if there is any worsening of 
the acute systemic allergic reaction.


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Grade 2 (Localized Urticaria With Medical Intervention Indicated or Mild Angioedema 
With no Medical Intervention Indicated)
Subjects may continue the intake of TMC278.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed, as long 
as these are in line with the package inserts of the ARV background regimen.
Subjects should be advised to contact the investigator immediately if there is any worsening of 
the acute systemic allergic reaction.
Grade 3 (Generalized Urticaria, Angioedema With Medical Intervention Indicated,
Symptomatic Mild Bronchospasm) and Grade 4 (Acute Anaphylaxis, Life-Threatening 
Bronchospasm, or Laryngeal Edema)
Subjects will permanently discontinue the intake of TMC278 and be withdrawn from the trial. 
Rechallenge is not allowed.
Subjects will be treated as clinically appropriate. Subjects should be followed until resolution of 
the AE and standard management should be undertaken.
9.3.4.3
AST AND ALT ELEVATION
Grade 1 (≥ 1.25 to ≤ 2.5 x ULN) or Grade 2 (> 2.5 to ≤ 5.0 x ULN) AST or ALT elevation 
with Grade 1 or 2 total bilirubin elevation (1.1 to 2.5 x ULN):
Subjects may continue the intake of TMC278.
Subjects should be followed until resolution (return to baseline) or stabilization of AST/ALT 
elevation (to be agreed upon with the sponsor).
Grade 3 AST or ALT elevation (> 5.0 to 10.0 x ULN) with Grade 1 or 2 total bilirubin 
elevation (1.1 to 2.5 x ULN):
Subjects are to interrupt the intake of TMC278. Upon resolution of the laboratory abnormality to 
at least the lower grade level (grade 2), the subject may resume the intake of TMC278 under 
the guidance of the investigator and after the investigator has consulted with a sponsor’s
physician.
If a subject was required to interrupt the intake of TMC278 due to a grade 3 AST or ALT 
elevation, and after restarting the intake of TMC278 he/she has a recurrence of grade 3 or grade 4 
AST or ALT elevation, he/she will permanently discontinue the intake of TMC278 and be 
withdrawn from the trial.
Grade 3 AST or ALT elevation (> 5.0 to ≤ 10.0 x ULN) with at least Grade 3 total bilirubin 
elevation (> 2.5 x ULN) or Grade 4 AST or ALT elevation (> 10.0 x ULN):
Subjects will permanently discontinue the intake of TMC278 and be withdrawn from the trial.


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It is recommended that the investigator contacts the sponsor to discuss the case. Subjects should 
be followed until resolution (return to baseline) or stabilization of AST/ALT elevation.
9.3.4.4
PANCREATIC AMYLASE OR LIPASE ELEVATIONS
For confirmed asymptomatic grade 1 and grade 2 pancreatic amylase or lipase elevations, and 
confirmed asymptomatic grade 3 pancreatic amylase elevations with no history or concomitant 
disease of pancreatitis, subjects should be carefully evaluated and followed closely. An overview 
of the laboratory ranges to assign grading to a laboratory value for pancreatic amylase and lipase 
is provided in Attachment 1: DAIDS table.
For confirmed asymptomatic grade 4 elevations of pancreatic amylase or confirmed 
asymptomatic grade 3 or grade 4 elevations of lipase, subjects should interrupt the intake of 
TMC278 until pancreatic amylase returns to grade ≤ 3 or lipase returns to grade ≤ 2, at which 
time TMC278 therapy could be reintroduced. If asymptomatic grade 4 elevations of pancreatic 
amylase or asymptomatic grade 3 or 4 lipase levels recur with reintroduction of TMC278, the 
subject should permanently discontinue the intake of TMC278 and be withdrawn from the trial.
If the subject experiences symptomatic pancreatitis that is considered at least possibly related to 
TMC278, the subject should permanently discontinue the intake of TMC278 and be withdrawn 
from the trial.
9.3.4.5
CLINICAL HEPATITIS
Non-viral hepatitis
Subjects taking TMC278 should be monitored for the development of signs and symptoms of 
hepatitis which include but are not limited to fatigue, malaise, anorexia, nausea, dark urine and 
clay colored stools, bilirubinuria, jaundice, liver tenderness, or hepatomegaly, with or without 
initially abnormal serum transaminase levels.
Subjects with these signs and symptoms must seek medical attention immediately and have
hepatic parameters assessed. Relevant markers of viral hepatitis should also be assessed.
At the discretion of the investigator, subjects may permanently discontinue the intake of 
TMC278 and be withdrawn from the trial. Subjects need to be followed until resolution of the 
AE.
Viral Hepatitis
If a subject is diagnosed with acute clinical hepatitis A, B, or C infection (with signs and 
symptoms present) during the trial, the subject should permanently discontinue the intake of 
TMC278 and be withdrawn from the trial.
9.3.4.6
RENAL COMPLICATIONS
If renal complications develop, subjects should be closely monitored for disturbances in serum 
creatinine and for abnormalities in urine analysis (e.g., proteinuria). Additional investigations can 
be performed at the investigator´s discretion. Subjects must be treated as clinically appropriate.


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Subjects, who develop a renal complication considered to be at least possibly related to TMC278, 
will permanently discontinue the intake of TMC278 and should be followed appropriately until 
resolution of AE or toxicity. Rechallenge is not allowed.
9.3.4.7
NEURO-PSYCHOLOGICAL SYMPTOMS
Subjects should be informed that the investigational medication may cause dizziness, impaired 
concentration, drowsiness, sleeplessness, and/or abnormal dreaming, and instructed that if they 
experience these symptoms they should avoid potentially hazardous tasks such as driving or 
operating machinery.
There have been reports of delusions and inappropriate behavior in subjects receiving licensed 
NNRTIs, predominantly in subjects with a history of mental illness or substance abuse. Severe 
acute depression (including suicidal ideation/attempts) has also been infrequently reported. 
Subjects who experience these symptoms should contact the investigator immediately because 
discontinuation of the investigational medication may be required. Investigators should refer 
subjects reporting such symptoms for immediate psychiatric evaluation/medical intervention. 
In case of grade 3 alterations in personality behavior or in mood (alteration causing inability to 
perform usual social and functional activities) and grade 4 alterations in personality behavior or 
in mood (behavior potentially harmful to self or others [e.g., suicidal and homicidal ideation or 
attempt, acute psychosis] or causing inability to perform basic selfcare functions): if the neuro-
psychological symptoms are considered to be at least possibly related to TMC278, the 
investigational medication will be permanently discontinued, and the subject withdrawn from the 
trial.
9.3.4.8
GASTROINTESTINAL NAUSEA (WITH OR WITHOUT VOMITING)
Although common, nausea following initiation of therapy with (antiretroviral) medication usually 
subsides or resolves during the first few weeks of treatment.
Grade 1 (Transient [< 24 Hours] or Intermittent Nausea With No or Minimal Interference 
With Oral Intake) and Grade 2 (Persistent Nausea Resulting in Decreased Oral Intake for 
24 to 48 Hours)
Subjects may continue the intake of TMC278 and may be treated as needed with antiemetics 
given orally or rectally.
Grade 3 (Persistent Nausea Resulting in Minimal Oral Intake for > 48 Hours, or Aggressive 
Rehydration Indicated) and Grade 4 (Life-Threatening Consequences)
Subjects will permanently discontinue the intake of TMC278 and be withdrawn from the trial if 
nausea is considered to be at least possibly related to TMC278. Rechallenge is not allowed.
Subjects should be followed until resolution of the AE.
9.3.4.9
DIARRHEA
Grade 1 (Transient or Intermittent Episodes of Unformed Stools, or Increase of ≤ 3 Stools 
Over Baseline per 24-Hour Period) or Grade 2 (Persistent Episodes of Unformed to Watery 
Stools, or Increase of 4 to 6 Stools Over Baseline per 24-Hour Period)


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Subjects may continue the intake of TMC278. Loperamide or diphenoxylate can be administered.
Grade 3 (Bloody Diarrhea, Increase of ≥ 7 Stools per 24-Hour Period, or i.v. Fluid 
Replacement Indicated), or Grade 4 (Life-Threatening Consequences)
Subjects will permanently discontinue the intake of TMC278 and be withdrawn from the trial if 
diarrhea is considered to be at least possibly related to TMC278. Rechallenge is not allowed. 
Subjects should be followed until resolution of the AE.
9.3.4.10
OTHER TOXICITIES
Grade 1
Subjects who develop a grade 1 AE or laboratory toxicity may continue intake of the ARV 
medication (TMC278 and background regimen).
Grade 2
Subjects who develop a grade 2 AE or laboratory toxicity may continue intake of the ARV 
medication (TMC278 and background regimen) based on the investigator’s clinical judgment.
Grade 3
Subjects who develop a grade 3 AE or laboratory toxicity should temporarily interrupt all ARV 
medication (TMC278 and background regimen) and may resume all therapy when the AE or 
laboratory abnormality resolved to within one grade level of the subject’s baseline but not higher 
than grade 2.
The following exceptions apply:

subjects with pre-existing diabetes who experience a glucose elevation of grade 3.

subjects who experience asymptomatic glucose, triglyceride or cholesterol elevations of 
grade 3.

subjects who experience asymptomatic pancreatic amylase elevations of grade 3 with no 
history or concomitant disease of pancreatitis (see Section 9.3.4.4).

subjects who experience an AE or laboratory toxicity that is considered not related or 
doubtfully related to TMC278.
Grade 4
Subjects experiencing a grade 4 AE or laboratory toxicity will permanently discontinue all ARV 
treatment (TMC278 and background regimen) and will be withdrawn from the trial 
(see Section 10.2).
The following exceptions apply:

subjects with pre-existing diabetes who experience a glucose elevation of grade 4.

subjects who experience asymptomatic glucose or triglyceride elevations of grade 4.


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
subjects who experience asymptomatic pancreatic amylase and lipase elevations of grade 4 
(see Section 9.3.4.4).

subjects who experience an AE or laboratory toxicity that is considered not related or 
doubtfully related to TMC278 (except for allergic reaction: all subjects experiencing this type 
of grade 4 AE should be permanently discontinued, regardless of causality).
If the subject has pre-existing diabetes and experiences persistent grade 3 or 4 glucose elevations 
despite appropriate antidiabetic medication/management, the subject should permanently 
discontinue the intake of TMC278 and be withdrawn from the trial.
Note:  For grade 3 or 4 laboratory abnormalities, subjects should have a confirmatory 
measurement, preferably within 48 hours after the laboratory results become available to the site. 
This management scheme is for confirmed laboratory abnormalities and not for isolated events.
10
SUBJECT COMPLETION/WITHDRAWAL
10.1
Completion
A subject will be considered to have completed the trial if:

Rilpivirine becomes commercially available AND is reimbursed, OR 

Rilpivirine can be accessed through another source (e.g., access program or government 
program) by the subject in his/her country, OR

The investigator finds it in the subject’s best interest to switch to other local (rilpivirine-
based) treatment options or local standard of care as appropriate.
10.2
Withdrawal From the Study
Treatment with TMC278 must be discontinued and the subject must be withdrawn from the trial
if any of the following apply:

Termination of the trial by the sponsor.

The subject no longer benefits from TMC278 treatment, in the opinion of the investigator.

The subject dies.

The subject is lost to follow-up. In case a subject is lost to follow-up, every reasonable effort 
must be made by the trial site personnel to contact the subject and determine the reason for 
discontinuation/withdrawal The measures taken to follow-up must be documented.

The subject withdraws consent.

The investigator believes that for safety reasons (e.g., AE) it is in the best interest of the 
subject to stop treatment.

The subject becomes pregnant.

The subject demonstrates loss of virologic response, defined as per local standard practice.


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
The subject develops tuberculosis during the trial. He/she will be withdrawn from the trial to 
allow appropriate tuberculosis therapy to be installed.

The subject changes the ARV underlying regimen he/she is receiving while continuing to 
receive TMC278 treatment, with the exception of within class N(t)RTI substitutions and dose 
adjustments for tolerance reasons.

The subject fails to comply with the protocol or trial staff requirements.

The subject meets any of the criteria for withdrawal specified in Section 9.3.4.
Up to and including Protocol Amendment 2: Upon withdrawal from the trial, subjects with an 
ongoing AE, that is either considered to be at least possibly related to TMC278, a grade 3/4 rash, 
an AE leading to discontinuation, or SAE, at time of discontinuation will be seen for a 
withdrawal visit and a follow-up visit at 4 weeks posttreatment (except in the case of withdrawal 
of consent). For these subjects, the date and reason for withdrawal are to be documented in the 
eCRF and in the source document. Remaining data should be completed on the date of the last 
scheduled follow-up visit. 
After the last trial visit, the Investigator’s Signature page of the eCRF must be completed and 
signed.
TMC278 assigned to the withdrawn subject will not be assigned to another subject. Subjects who 
withdraw will not be replaced.
As of Protocol Amendment 3, visits and assessments should still be performed as per local 
standard of care, but documented in the subject’s medical records only.
11
STATISTICAL METHODS
As of Protocol Amendment 3, safety and efficacy will continue to be assessed as part of the 
local standard of care but should be documented in the subject’s medical records only; data will 
no longer be recorded in the eCRF and therefore no further analyses will be performed.
11.1
Subject Information
An intent-to treat analysis will be performed, i.e., all subjects who have signed an ICF and 
received at least 1 dose of TMC278 in this trial will be included in this analysis. Tabulations and 
descriptive statistics will be provided.
11.2
Efficacy Analyses
Tabulations and descriptive statistics analyses on collected viral load and CD4+ cell count data
will be provided.


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11.3
Sample Size Determination
No formal sample size determination has been performed for this trial: any subject in the
TMC278 Phase IIb or Phase III trials, who has given consent to participate and who is eligible 
and willing, may participate in this trial.
11.4
Safety Analyses
Adverse Events
Up to and including Protocol Amendment 2: Starting with signing of the ICF onwards to the 
Final/Withdrawal visit or 30 days (± 2 days) after the Final/Withdrawal visit for AEs ongoing at 
this visit, AEs will be followed by the investigator. Adverse events considered to be at least 
possibly related to TMC278, AEs leading to discontinuation, SAEs, and any grade 3/4 rash 
regardless of causality, will be collected. Other AEs will be collected only if required as per local 
regulations. The original terms used in the eCRFs by investigators to identify AEs will be coded 
using the Medical Dictionary for Regulatory Activities. All collected AEs with onset during the 
treatment period (i.e., treatment-emergent AEs) will be included in the tabulations. For each AE, 
the percentage of subjects who experienced at least 1 occurrence of the given event will be 
summarized.
As of Protocol Amendment 3, safety will continue to be assessed as part of the local standard of 
care but should be documented in the subject’s medical records only; data will no longer be 
recorded in the eCRF. Investigators should continue to report SAEs, pregnancies, and non-
serious clinically important events to the sponsor.
12
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical trials 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical trials conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
As of Protocol Amendment 3, safety will continue to be assessed as part of the local standard of 
care but should be documented in the subject’s medical records only. Investigators should
continue to report SAEs, pregnancies, and non-serious clinically important events to the sponsor.


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12.1
Definitions
12.1.1
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical trial subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product (definition per International 
Conference on Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.2.1, All 
Adverse Events, for time of last AE recording).
Changes in viral load should not be reported as an AE/SAE.
Changes in CD4+ cell counts, either decreases or increases, should not be reported as an 
AE/SAE.
Serious Adverse Event
An SAE as defined by ICH is any untoward medical occurrence that at any dose meets any of the 
following conditions:

Results in death.

Is life-threatening
(the subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect.
Note: Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in situations other than those listed above. For example, important 
medical events may not be immediately life threatening or result in death or hospitalization but 
may jeopardize the subject or may require intervention to prevent one of the outcomes listed in 
the definition above (e.g., suspected transmission of an infectious agent by a medicinal product 
should be reported as an SAE). Any AE is considered an SAE if it is associated with clinical 
signs or symptoms judged by the investigator to have a significant clinical impact.


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Unlisted (Unexpected) Adverse Event/Reference Safety Information
An unlisted AE is one of which the nature or severity is not consistent with the applicable 
product reference safety information. For an investigational product, the expectedness of an AE
will be determined by whether or not it is listed in the Investigator's Brochure and possible 
Addenda. 
Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.1.2.
12.1.2
Attribution Definitions
Not related
An AE that is not related to the use of the drug.
Doubtful
An AE for which an alternative explanation is more likely, e.g., concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug. An alternative explanation, e.g., concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(e.g., confirmed by dechallenge). An alternative explanation is less likely, e.g., concomitant 
drug(s), concomitant disease(s).
Very likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, e.g., concomitant drug(s), concomitant disease(s). The relationship in 
time is very suggestive (e.g., it is confirmed by dechallenge and rechallenge).
12.2
Procedures
12.2.1
All Adverse Events
Up to and including Protocol Amendment 2: 
Starting with signing of the ICF onwards to the Final/Withdrawal visit or 30 days (± 2 days) after 
the Final/Withdrawal visit for AEs ongoing at this visit, AEs will be followed by the investigator. 


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Adverse events considered to be at least possibly related to TMC278, AEs leading to 
discontinuation, SAEs, and any grade 3/4 rash regardless of causality, will be recorded in the 
eCRF. Other AEs will be collected only if required as per local regulations. Serious adverse 
events, including those spontaneously reported to the investigator within 30 days after the last 
dose of TMC278, must be reported using the Serious Adverse Event Form. The sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.
All AEs collected at any time during the trial will be followed until satisfactory resolution 
(e.g., value back to baseline value) or stabilization or until final database lock.
Certain long-term AEs related to therapy cannot be followed until resolution within the setting of 
this trial. In these cases follow-up will be the responsibility of the treating physician.
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether 
they are protocol-specific assessments. All AEs considered to be at least possibly related to 
TMC278, AEs leading to discontinuation, SAEs, and any grade 3/4 rash regardless of causality
must be recorded using medical terminology in the source document and the eCRF. All other 
AEs must be recorded in the source document as required per local regulations. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as “upper 
respiratory infection”). Investigators must record in the eCRF their opinion concerning the 
relationship of the AE to trial therapy. All measures required for AE management must be 
recorded in the source document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator all SAEs that are unlisted (unexpected) and 
associated with the use of the drug. The investigator (or sponsor where required) must report 
these events to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol unless otherwise required and documented by the IEC/IRB. 
Adverse events reporting, including suspected unexpected serious adverse reactions, will 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, will be reported by the sponsor as soon as possible to the competent 
authority(ies) concerned together with proposed actions.
Subjects (or their designees, if appropriate) must be provided with a “study card” indicating the 
name of the investigational study drug, the study number, the investigator’s name, a 24-hour 
emergency contact number, and excluded concomitant medications.
As of Protocol Amendment 3, safety will continue to be assessed as part of the local standard of 
care but should be documented in the subject’s medical records only; data will no longer be 


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recorded in the eCRF. Investigators should continue to report SAEs, pregnancies, and non-
serious clinically important events to the sponsor.
12.2.2
Serious Adverse Events
All SAEs occurring during clinical trials (between signing of informed consent and end of the 
study) must be reported to the appropriate sponsor contact person by investigational staff within 
24 hours of their knowledge of the event. For the names and contact details of the contact 
persons, see Contact Information pages provided separately. Any SAEs with at least a possible 
relationship to TMC278 occurring after the end of the trial must be reported, and will be handled 
by the sponsor.
The cause of death of a subject in a clinical trial, whether or not the event is expected or 
associated with the investigational agent, is considered an SAE. Suspected transmission of an 
infectious agent by a medicinal product should be reported as an SAE. Any event requiring 
hospitalization (or prolongation of hospitalization) that occurs during the course of a subject’s 
participation in a clinical trial must be reported as an SAE, except hospitalizations for the 
following:

Social reasons in absence of an AE.

Surgery or procedure planned before entry into the trial (must be documented in the eCRF) 
Note: Hospitalizations that were planned prior to the signing of informed consent, and where 
the underlying condition for which the hospitalization was planned has not worsened will not 
be considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a member of the investigational staff, and 
transmitted to the sponsor within 24 hours. The initial and follow-up reports of an SAE should be 
made by facsimile (fax).
The first report of an SAE may also be made by telephone. The investigator must provide the 
minimal information: i.e., study number, subject’s initials and date of birth, medication code 
number, period of intake, nature of the AE, and investigator’s attribution.
This report of an SAE by telephone must always be confirmed by a written, more detailed report 
(the Serious Adverse Event Form) to be completed and signed by the investigator. 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.
The start date of the SAE documented on the Serious Adverse Event Form must be the same as 
the start date of the corresponding AE documented on the eCRF. If a change in severity is noted 
for the existing AE, it must be recorded as a new AE. If a worsened AE meets the criteria for an 
SAE, the start date of the SAE must be the same as the start date of the worsened AE.


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All SAEs that have not resolved by the end of the trial or that have not resolved upon 
discontinuation of the subject’s participation in the trial, must be followed until any of the 
following occurs:

The event resolves.

The event stabilizes.

The event returns to baseline, if a baseline value is available.

The event can be attributed to agents other than TMC278 or to factors unrelated to trial
conduct.

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts).
12.2.3
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the investigational staff within
24 hours of their knowledge of the event using the appropriate pregnancy notification form/a
Serious Adverse Event Form. Abnormal pregnancy outcomes are considered SAEs and must be 
reported using the Serious Adverse Event Form. Any subject who becomes pregnant during the 
trial must be promptly withdrawn from the trial. 
Because the effect of TMC278 on sperm is unknown, pregnancies in partners of male subjects 
included in the trial will be reported by the investigational staff within 24 hours of their knowledge 
of the event using the appropriate pregnancy notification form/ a Serious Adverse Event Form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.3
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the trial are listed in the Contact Information 
page(s), which will be provided as a separate document.
13
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity, quality, 
durability, reliability of a product, including its labeling or package integrity. A product quality 
complaint may have an impact on the safety and efficacy of the product. Timely, accurate, and 
complete reporting and analysis of PQC information from clinical trials are crucial for the 
protection of subjects, investigators, and the sponsor, and are mandated by regulatory agencies 
worldwide. The sponsor has established procedures in conformity with regulatory requirements 


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worldwide to ensure appropriate reporting of PQC information; all clinical trials conducted by 
the sponsor or its affiliates will be conducted in accordance with those procedures.
13.1
Procedures
All initial PQCs must be reported to the sponsor by the investigational staff as soon as possible 
after being made aware of the event.
If the defect is combined with an SAE, the investigational staff must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.2.2). A sample of the 
suspected product should be maintained for further investigation if requested by the sponsor.
13.2
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14
STUDY DRUG INFORMATION
14.1
Physical Description of Study Drug
The investigational medication, TMC278, will be manufactured and provided under the 
responsibility of the sponsor. TMC278 is formulated as an oral tablet (F006), containing 
27.5 mg of TMC278 as the hydrochloric acid salt R314585, equivalent to 25 mg of TMC278 as 
the free base, in combination with lactose monohydrate, croscarmellose sodium, povidone (K30), 
polysorbate 20, silicified microcrystalline cellulose, and magnesium stearate, and coated with a 
white coating powder and purified water (processing solvent, minimized in final formulation).
14.2
Packaging
TMC278 25 mg oral tablets will be packaged in 30 count, child-proof bottles under the 
responsibility of the sponsor.
Background regimen will not be provided by the sponsor.
14.3
Labeling
TMC278 labels will contain information to meet the applicable regulatory requirements.
Labels will contain the protocol number, batch or reference number, storage caution statements, 
dispensing instructions and ‘keep out of reach of children’ warning.
No medication can be relabeled without prior approval from the sponsor.


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14.4
Preparation, Handling, and Storage 
Storage conditions will be detailed on the label. Supplies need to be stored in the original 
container.
Regular temperature logging of the medication storage room at the investigational site should be 
performed. Should a deviation in storage conditions occur, the site must not further dispense the 
affected medication and must provide the monitor immediately with the following information:

study number.

reference or batch number(s).

kit number.

site number.

temperature log (including date and duration of the deviation, and the minimum temperature 
below the range and/or maximum temperature above the range that the product was exposed 
to).

used units (C or °F).
Deviations in storage conditions will be evaluated by the sponsor/stability manager.
Antiretroviral medication must be handled strictly in accordance with the protocol and the 
packaging labels and will be stored in a limited access area or in a locked cabinet under 
appropriate environmental conditions. Storage and dosing instructions and an expiration date will 
be supplied with TMC278. Used medication packs should be returned by the subject and should 
be kept at the site for drug accountability purposes. Access to ARV medication should be 
restricted to designated trial personnel. 
Background medication must be stored according to locally applicable procedures and conditions 
and as stipulated in the prescribing information.
Up to and including Protocol Amendment 2, the monitor will periodically check the supplies 
of TMC278 held by the investigator or pharmacist to ensure accountability and appropriate 
storage conditions.
As of Protocol Amendment 3, the investigator or pharmacist remains responsible for 
accountability and appropriate storage conditions of TMC278 supplies but supplies will no 
longer be checked by the monitor. At the end of the trial, all unused TMC278 medication will be 
returned to the sponsor unless other arrangements have been agreed to with the sponsor.
14.5
Drug Accountability
The investigator is responsible for ensuring that all TMC278 received at the site is inventoried 
and accounted for throughout the trial. The dispensing of TMC278 to the subject, and the return 
of TMC278 from the subject (if applicable), must be documented on the drug accountability 
form. Subjects must be instructed to return all original containers, whether empty or containing 
TMC278. TMC278 returned by trial subjects will be stored and disposed of according to the 
sponsor’s instructions. Site staff must not combine contents of TMC278 containers.


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TMC278 must be handled in strict accordance with the protocol and the container label and will 
be stored in a limited access area or in a locked cabinet under appropriate environmental 
conditions.
Up to and including Protocol Amendment 2, unused TMC278, and TMC278 returned by the 
subject (if applicable), must be available for verification by the sponsor’s site monitor during on-
site monitoring visits.
The return to the sponsor of unused TMC278, or used returned TMC278 for destruction, will be 
documented on the Drug Return Form. When the site is an authorized destruction unit and 
TMC278 supplies are destroyed on site, this must also be documented on the Drug Return Form.
Returned TMC278 must not be dispensed again, even to the same subject. TMC278 may not be 
relabeled or reassigned for use by other subjects. The investigator agrees neither to dispense 
TMC278 from, nor store it at, any location other than the trial sites agreed upon with the sponsor.
As of Protocol Amendment 3, unused TMC278 and TMC278 returned by the subject will not 
be verified by the sponsor. 
15
STUDY SPECIFIC MATERIALS
Investigators will be provided with the latest version of the Investigator’s Brochure for TMC278.
16
ETHICAL ASPECTS
16.1
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the trial and, during the 
trial, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the trial is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
they would otherwise be entitled. Only subjects who are fully able to understand the risks, 
benefits, and potential AEs of the trial, and provide their consent voluntarily will be enrolled. 
This trial is designed to provide continued access to TMC278 to HIV-1 infected subjects who 
were previously treated with TMC278 in a clinical trial, and who, at the time of roll-over,
experience and are expected to continue experiencing clinical benefit from TMC278 treatment.
In addition, information on the long-term safety and tolerability of oral doses of TMC278 
25 mg q.d. in combination with a background regimen containing 2 N(t)RTIs will be collected
up to and including Protocol Amendment 2. 
Subjects will only continue to receive TMC278 25 mg q.d. in the trial until one of the criteria 
detailed in Section 10.2 is met.


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16.2
Regulatory Ethics Compliance
16.2.1
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical trial is performed in accordance with 
the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory 
and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies 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 originated in the Declaration of 
Helsinki, and that the clinical trial data are credible.
16.2.2
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB)
Before the start of the trial, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents:

Final protocol and, if applicable, amendments.

Sponsor-approved ICF (and any other written materials to be provided to the subjects).

Investigator’s Brochure (or equivalent information) and addenda.

Sponsor-approved subject recruiting materials.

Information on compensation for trial-related injuries or payment to subjects for participation 
in the trial, if applicable.

Investigator’s curriculum vitae or equivalent information (unless not required, as documented 
by IEC/IRB).

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects.

Any other documents that the IEC/IRB requests to fulfill its obligation.
This trial will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
substantial/major amendments (if any), the informed consent form, applicable recruiting 
materials, and subject compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the trial, the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Substantial/major protocol amendments.


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
Revision(s) to informed consent form and any other written materials to be provided to 
subjects.

If applicable, new or revised subject recruiting materials approved by the sponsor.

Revisions to compensation for trial-related injuries or payment to subjects for participation in 
the trial, if applicable.

Investigator’s Brochure addenda or new edition(s).

Summaries of the status of the trial at intervals stipulated in guidelines of the IEC/IRB (at 
least annually).

Reports of AEs that are serious, unlisted, and associated with the investigational drug.

New information that may adversely affect the safety of the subjects or the conduct of the 
trial.

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects.

Report of deaths of subjects under the investigator's care.

Notification if a new investigator is responsible for the trial at the site.

Annual Safety Report, Short Term Study Specific Safety Summary and Line Listings, where 
applicable.

Any other requirements of the IEC/IRB.
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or trial conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s), except when necessary to eliminate immediate hazard to the trial subjects. If a 
deviation from, or a change to the protocol was implemented to eliminate an immediate hazard to 
trial subjects, then the implemented deviation or change, the reasons for it, and, if appropriate, 
the protocol amendment should be submitted to the IEC/IRB as soon as possible.
At least once a year, the IEC/IRB will be asked to review and reapprove this clinical trial. The 
reapproval should be documented in writing.
At the end of the trial, the investigator (or sponsor where required) will notify the IEC/IRB about 
the trial completion.
16.2.3
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
trial has been fully explained. The consent form must be signed before performance of any 
trial-related activity. The consent form that is used must be approved by both the sponsor and by
the reviewing IEC/IRB. The informed consent should be in accordance with principles that 
originated in the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor policy.


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Before enrollment in the trial, the investigator or an authorized member of the investigational 
staff must explain to potential subjects the aims, methods, reasonably anticipated benefits, and 
potential hazards of the trial, and any discomfort participation in the trial may entail. Subjects
will be informed that their participation is voluntary and that they may withdraw consent to 
participate at any time. They will be informed that choosing not to participate will not affect the 
care he/she will receive for the treatment of his or her disease. Subjects will be told that 
alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that their records 
may be accessed by health authorities and authorized sponsor staff without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the informed consent form the subject is authorizing such access, and agrees to allow his 
or her trial physician to recontact the subject for the purpose of obtaining consent for additional 
safety evaluations, if needed, or to obtain information about his or her survival status.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the trial, consent should be appropriately recorded by 
means of the subject's personally dated signature. After having obtained the consent, a copy of 
the informed consent form must be given to the subject.
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the subject is obtained, if 
permitted by local law.
Written assent should be obtained from subjects who are able to write. After having obtained the 
assent, a copy of the assent form must be given to the subject.
16.2.4
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this trial will be limited 
to those data that are necessary to investigate the efficacy, safety, quality, and utility of the 
investigational study drug(s) used in this trial.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of trial subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator to allow direct access to his or her original medical records 
for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.


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The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the trial, and the applicable laws and regulations. However, this access to personal 
data may be postponed until the end of the trial if such access would interfere with the conduct of 
the trial. Even if the subject withdraws consent, certain personal data obtained within the scope 
of this trial may still be processed by the sponsor if permitted by the applicable legislation. If the 
results of the trial are published, the identity of the subjects will remain confidential. If reference
is made to specific subjects, this will only be done by using code numbers.
16.2.5
Country Selection
Unless explicitly addressed as a specific ethical consideration in Section 16.1 this trial will only 
be conducted in those countries where the intent is to help ensure access to the developed 
product.
17
ADMINISTRATIVE REQUIREMENTS
17.1
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment. 
All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Substantial/major protocol amendments must not be implemented without prior 
IEC/IRB approval, or when the relevant competent authority has raised any grounds for 
non-acceptance, except when necessary to eliminate immediate hazards to the subjects, in which 
case the amendment must be promptly submitted to the IEC/IRB and relevant competent 
authority. Documentation of amendment approval by the investigator and IEC/IRB must be 
provided to the sponsor or its designee. When the change(s) involves only logistic or 
administrative aspects of the trial, the IRB (and IEC where required) only needs to be notified.
During the course of the trial, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information pages provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the eCRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.


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17.2
Regulatory Documentation
17.2.1
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A trial may not be initiated until all local regulatory 
requirements are met.
17.2.2
Required Prestudy Documentation
The following documents must be provided to the sponsor or its representative before shipment 
of TMC278 to the investigational site:

Protocol and amendment(s), if any, signed and dated by the investigator. 

A copy of the dated and signed written IEC/IRB approval of the protocol, amendments, 
informed consent form, any recruiting materials, and if applicable, subject compensation 
programs. This approval must clearly identify the specific protocol by title and number and 
must be signed by the chairman or authorized designee. 

Name and address of the IEC/IRB including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the investigational staff is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the trial. 

Regulatory authority approval or notification, if applicable. 

Signed and dated statement of investigator (e.g., Form FDA 1572), if applicable. 

Documentation of investigator qualifications (e.g., curriculum vitae). 

Completed investigator financial disclosure form from the investigator, where required. 
Note: The investigator should promptly update this information if any relevant changes 
occur up to 1 year following trial completion. 

Signed and dated clinical trial agreement, which includes the financial agreement. 

Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators. 

Documentation of subinvestigator qualifications (e.g., curriculum vitae). 

Photocopy of the site signature log, describing delegation of roles and responsibilities at the 
start of the trial. 


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
Name and address of any local laboratory conducting tests for the trial, and a dated copy of 
current laboratory normal ranges for these tests. 

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(e.g., accreditation/license), if applicable.
17.3
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the trial. This document will be reviewed by the 
sponsor site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the trial file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the trial will identify subjects by initials and/or assigned 
number only.
The investigator must also complete a subject-screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the trial.
17.4
Source Documentation
Up to and including Protocol Amendment 2: 
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and trial identification; trial discussion 
and date of informed consent; dates of visits; results of safety and efficacy parameters as required 
by the protocol; record of all AEs; and follow-up of AEs; concomitant medication; drug 
receipt/dispensing/return records; TMC278 administration information; and date of trial
completion, and reason for early discontinuation of trial drug or withdrawal from the trial, if 
applicable. Direct access to source documentation (medical records) must be allowed for the 
purpose of verifying that the data recorded on the eCRF are consistent with the original source 
data.
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a trial subject should be 
consistent with that commonly recorded at the site as a basis for standard medical care. Specific 
details required as source data for the trial will be reviewed with the investigator before the trial 
and will be described in the monitoring guidelines (or other equivalent document). The nature 
and location of all source documents will be identified in the Source Document Identification 
Form.
All data recorded in the eCRF must have a source in the subject’s medical records.
17.5
Case Report Form Completion
Up to and including Protocol Amendment 2: 


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Case report forms are provided for each subject in electronic format.
Electronic Data Capture (eDC) will be used for this trial. The trial data will be transcribed by trial
personnel from the source documents onto an electronic CRF, and transmitted in a secure manner 
to the sponsor within 7 days of the subject’s visit. The electronic file will be considered to be the 
eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject’s source documentation. Such worksheets 
should not resemble an eCRF and should not be generated by the sponsor. All data relating to the 
trial must be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs in 
English. Designated site personnel must complete eCRFs as soon as possible after a subject visit, 
and the forms should be available for review at the next scheduled monitoring visit.
The investigator must verify that all data entries in the eCRFs are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized trial-site personnel.
If necessary, queries will be generated in the eDC tool. The investigator or an authorized member 
of the investigational staff must adjust the eCRF (if applicable) and complete the query. If 
corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different ways:

Site personnel can make corrections in the eDC tool at their own initiative or as a response to 
an auto query (generated by the eDC tool).

Site manager can generate a query (field Data Correction Form) for resolution by the 
investigational staff.

Clinical data manager can generate a query for resolution by the investigational staff.
As of Protocol Amendment 3, visits and assessments should still be performed as per local 
standard of care but documented in the subject’s medical records only; data will no longer be 
recorded in the eCRF.
17.6
Data Quality Control
Up to and including Protocol Amendment 2:
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate trial centers, review of protocol procedures with the investigator 
and associated personnel before the trial, and periodic monitoring visits by the sponsor, and 
direct transmission of clinical laboratory data from the selected laboratory into the sponsor’s data 
base. Written instructions will be provided for collection, preparation, and shipment of blood, 
plasma, and urine samples.
Guidelines for eCRF completion will be provided and reviewed with trial personnel before the 
start of the trial.


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The sponsor will review eCRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the clinical trial database they will be 
verified for accuracy.
As of Protocol Amendment 3, no data collection will take place.
17.7
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all trial
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all trial documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the trial records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any trial
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this trial, the investigator must permit access to such reports.
17.8
Monitoring
Up to and including Protocol Amendment 2: 
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a trial center visit log that will be kept at the site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRFs with the hospital or clinic records 
(source documents). The nature and location of all source documents will be identified to ensure 
that all sources of original data required to substantiate the eCRF are known to the sponsor and 
investigational staff and are accessible for verification by the sponsor site contact. If electronic 
records are maintained at the investigational site, the method of verification must be discussed 
with the investigational staff. 


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Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the investigational staff. 
The sponsor expects that, during monitoring visits, the relevant investigational staff will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of trial-related documents. The monitor will meet with the investigator on a 
regular basis during the trial to provide feedback on the trial conduct.
As of Protocol Amendment 3, no data collection will take place, hence study monitoring and 
source data verification will not be performed (with the exception of a site closure visit).
17.9
Study Completion/Termination
17.9.1
Study Completion
The trial is considered completed when all subjects have switched to locally available rilpivirine
(ie, commercially available AND reimbursed, OR accessible through another source [eg, access 
program or government program]), other local (rilpivirine-based) treatment options, or local 
standard of care, as appropriate.
The trial is considered completed with the last visit of the last subject participating in the trial. 
The final data from the investigational site will be sent to the sponsor (or designee) after 
completion of the final subject visit at that site, in the time frame specified in the Clinical Trial 
Agreement.
17.9.2
Study Termination
The sponsor reserves the right to close the investigational site or terminate the trial at any time 
for any reason at the sole discretion of the sponsor. 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.
Investigational sites will be closed upon trial completion. An investigational site is considered 
closed when all required documents and trial supplies have been collected and a site closure visit 
has been performed.
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of an investigational site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the sponsor’s procedures, or GCP 
guidelines.

Inadequate recruitment of subjects by the investigator.


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
Discontinuation of further drug development.
The sponsor is committed to provide TMC278 in a participating country until all subjects have 
switched to locally available rilpivirine (ie, commercially available AND reimbursed, OR 
accessible through another source [eg, access program or government program]), other local
(rilpivirine-based) treatment options, or local standard of care, as appropriate.
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.
17.10
On-Site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the site at any 
time during or after completion of the trial to conduct an audit of the trial in compliance with 
regulatory guidelines and company policy. These audits will require access to all trial records, 
including source documents, for inspection and comparison with the eCRFs. Subject privacy 
must, however, be respected. The investigator and staff are responsible for being present and 
available for consultation during routinely scheduled site audit visits conducted by the sponsor or 
its designees. 
Similar procedures may also be conducted by agents of any regulatory body, either as part of a 
national GCP compliance program or to review the results of this trial in support of a regulatory 
submission. The investigator should immediately notify the sponsor if they have been contacted 
by a regulatory agency concerning an upcoming inspection.
17.11
Use of Information and Publication
All information, including but not limited to information regarding TMC278 or the sponsor’s 
operations (e.g., patent application, formulas, manufacturing processes, basic scientific data, 
prior clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomic research data, generated as a 
result of this trial, are considered confidential and remain the sole property of the sponsor. The 
investigator agrees to maintain this information in confidence and use this information only to 
accomplish this trial, and will not use it for other purposes without the sponsor’s prior written 
consent.
The investigator understands that the information developed in the clinical trial will be used by 
the sponsor in connection with the continued development of TMC278 and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the trial.


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The sponsor will create an Annual Safety Report (ASR) and Line Listings in accordance with the 
European Community Clinical Trials Directive, with a data lock date of 19 May. This trial
TMC278-TiDP6-C222 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 trial approval date, and in all 
subsequent ASRs, as appropriate, until trial closure.
The results of the trial will be reported in a Clinical Research Report generated by the sponsor 
and will contain eCRF data from all investigational sites that participated in the trial. Only 
limited safety data are being collected as of Protocol Amendment 3, which will be included in 
an addendum to the Clinical Research Report; additionally, appropriate safety reports will 
continue to be provided to IECs/IRBs and regulatory authorities, as required.
Recruitment performance or specific expertise related to the nature and the key assessment 
parameters of the trial will be used to determine a coordinating investigator.
Clinical narratives will be written for the following events (if applicable):

All deaths (irrespective of drug relationship).

All other SAEs with an at least possible relationship to the active investigational drug 
(i.e., only for the treatment arm[s] with active investigational drug[s]).

All discontinuations due to AEs with an at least possible relationship to TMC278 (including 
investigational drug[s] and any other study drugs [e.g., control drug, background 
regimen/standard of care]).

All grade 3 or 4 events of special interest (ESI) as defined in the Clinical Trial Protocol 
(CTP) (irrespective of drug relationship) occurring in the active investigational drug 
treatment arm(s) and starting during the treatment period with the investigational drug(s). For 
some of these ESIs, which are specified in the CTP, narratives will also be written for grade 1 
and 2.

At the discretion of the team and after statistical analysis of the data, certain discontinuations 
not related to AEs of treatment failure, i.e., related to lost to follow-up or withdrawal of 
consent (irrespective of treatment arm).

Any additional ESIs explicitly requested by the regulatory agencies.

Any additional ESIs (and severity grades) identified after statistical analysis of the data as 
potential safety hazards, occurring in the active investigational drug treatment arm(s) and 
starting during the treatment period with the investigational drug(s).
One investigator will be appointed for signing off the final Clinical Research Report. The 
selection of this investigator will be determined by recruitment performance and specific 
expertise related to the nature of the trial and the key assessment parameter(s). A summary of this 
final version will be provided to the investigators, to the applicable regulatory authorities, and 
IECs/IRBs, if required by the applicable regulatory requirements, within 1 year of the end of the 
trial (LastPatientLastVisit).
The sponsor shall have the right to publish such data and information without approval from the 
investigator. If an investigator wishes to publish information from the trial, a copy of the 


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manuscript must be provided to the sponsor for review at least 60 days before submission for 
publication or presentation. Expedited reviews will be arranged for abstracts, poster 
presentations, or other materials. If requested by the sponsor in writing, the investigator will 
withhold such publication for up to an additional 60 days to allow for filing of a patent 
application. In the event that issues arise regarding scientific integrity or regulatory compliance, 
the sponsor will review these issues with the investigator. The sponsor will not mandate 
modifications to scientific content and does not have the right to suppress information. For
multicenter trial designs and substudy approaches, results may need to be published in a given 
sequence (e.g., substudies should not generally be published before the primary endpoints of a 
trial have been published). Similarly, investigators will recognize the integrity of a multicenter 
trial by not publishing data derived from the individual site until the combined results from the 
completed trial have been published in full, within 12 months after conclusion, abandonment, or 
termination of the trial at all sites, or the sponsor confirms there will be no multicenter trial
publication. Authorship of publications resulting from this trial will be based on the guidelines 
on authorship, such as those described in the Uniform Requirements for Manuscripts Submitted 
to Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the trial or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.


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REFERENCES
1
Richman D. HIV chemotherapy. Nature 2001: 410: 995-1001.
2
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in 
HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2009; 1-161. 
Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed (13 July 2010).
3
TMC278 Integrated Investigator's Brochure Edition 9 (April 2016).
4
TMC278 Investigator's Brochure Edition 9 (October 2009).
5
Boven K, Buelens A, et al. A Phase I, double-blind, double-dummy, randomized, placebo controlled and active 
controlled trial to evaluate the effect of TMC278 25 mg q.d. at steady-state and the effect of efavirenz (EFV) 
600 mg q.d. at steady-state on the QT/QTc interval, in 2 randomized panels of healthy subjects Tibotec 
Pharmaceuticals Ltd., Clinical Research Report, TMC278-TiDP6-C152, 08 February 2010.
6
Woodfall B, Hoetelmans R, et al. A multicenter Phase IIa, exploratory proof-of-principle, randomized, 
double-blind, placebo-controlled, dose-escalation trial in antiretroviral-naïve, HIV-1 infected subjects receiving 
25, 50, 100, or 150 mg of R278474 once daily as monotherapy for 7 days. Tibotec Pharmaceuticals Ltd., Clinical 
Research Report, R278474-C201, version 1.0, 21 March 2005.
7
Woodfall B, Peeters M, et al. A phase II, proof of principle (POP), randomized, open label trial in human 
immunodeficiency virus (HIV)-1 infected subjects with non-nucleoside reverse transcriptase inhibitors (NNRTI) 
experience and/or genotypic evidence of NNRTI resistance, who received R278474 once daily for 7 days in 
substitution for the NNRTI or protease inhibitor (PI) in failing antiretroviral therapy (ART). Tibotec 
Pharmaceuticals Ltd., Clinical Research Report, R278474-C202, version 1.0, 28 February 2006.
8
Boven K, Buelens A, et al. A Phase IIb randomized, partially blinded, dose-finding study of TMC278 in 
antiretroviral naive HIV-1 infected subjects. Tibotec Pharmaceuticals Ltd., Clinical Research Report 
TMC278-TiDP6-C204, 25 February 2009.
9
Boven K, Stevens M, van Heeswijk R, Rimsky L, Vanveggel S. A Phase IIb randomized, partially blinded, dose-
finding trial of TMC289 in antiretroviral-naïve HIV-1 infected subjects. 96-Week analysis. Tibotec 
Pharmaceuticals Ltd., Clinical Research Report, TMC278-C204-W240, December 2010.
10 Woodfall B, Boven K, Peeters M, Stevens M, van Heeswijk R, Rimsky L. A Phase Iib randomized, partially 
blinded, dose-finding trial of TMC278 in antiretroviral naive HIV-infected subjects. Tibotec Pharmaceuticals 
Ltd., Clinical Research Report, TMC278-C204-W48, June 2007.
11 Boven K, Stevens M, et al. A Phase III, randomized, double-blind trial of TMC278 25 mg q.d. versus efavirenz 
600 mg q.d. in combination with a fixed background regimen consisting of tenofovir disoproxil fumarate and 
emtricitabine in antiretroviral-naïve HIV-1 infected subjects. Tibotec Pharmaceuticals Ltd., Clinical Research 
Report, TMC278-TiDP6-C209, 28 May 2010.
12 Boven, K., Deckx H et al. A Phase III, randomized, double-blind trial of TMC278 25 mg q.d. versus efavirenz 
600 mg q.d. in combination with a background regimen containing 2 nucleoside/nucleotide reverse transcriptase 
inhibitors in antiretroviral-naïve HIV-1 infected subjects. Tibotec Pharmaceuticals Ltd., Clinical Research 
Report, TMC278-TiDP6-C215, 28 May 2010.
13 Boven K, Stevens M, et al. A Phase III, randomized, double-blind trial of TMC278 25 mg q.d. versus efavirenz 
600 mg q.d. in combination with a fixed background regimen consisting of tenofovir disoproxil fumarate and 
emtricitabine in antiretroviral-naïve HIV-1 infected subjects. Tibotec Pharmaceuticals Ltd., Clinical Research 
Report, TMC278-TiDP6-C209-W96, 24 October 2011.
14 Boven K, Stevens M, et al. A Phase III, randomized, double-blind trial of TMC278 25 mg q.d. versus efavirenz 
600 mg q.d. in combination with a fixed background regimen consisting of tenofovir disoproxil fumarate and 
emtricitabine in antiretroviral-naïve HIV-1 infected subjects. Tibotec Pharmaceuticals Ltd., Clinical Research 
Report, TMC278-TiDP6-C209-Post-W96, 11 December 2012.


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15 Boven, K., Deckx H et al. A Phase III, randomized, double-blind trial of TMC278 25 mg q.d. versus efavirenz 
600 mg q.d. in combination with a background regimen containing 2 nucleoside/nucleotide reverse transcriptase 
inhibitors in antiretroviral-naïve HIV-1 infected subjects. Tibotec Pharmaceuticals Ltd., Clinical Research 
Report, TMC278-TiDP6-C215-W96, 24 October 2011.
16 Boven, K., Deckx H et al. A Phase III, randomized, double-blind trial of TMC278 25 mg q.d. versus efavirenz 
600 mg q.d. in combination with a background regimen containing 2 nucleoside/nucleotide reverse transcriptase 
inhibitors in antiretroviral-naïve HIV-1 infected subjects. Tibotec Pharmaceuticals Ltd., Clinical Research 
Report, TMC278-TiDP6-C215-Post-W96, 11 December 2012.
17 WHO/CONRAD Technical Consultation on nonoxynol-9. World Health Organization, Summary Report,
Geneva, 9-10 October 2001.
18 EDURANT [Summary of Product Characteristics]. Beerse, Belgium: Janssen-Cilag International NV; 2016.
19 EDURANT [United States Prescribing Information]. New Jersey, USA: Janssen Products; 2015.


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ATTACHMENT 1: DAIDS TABLE
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND 
PEDIATRIC ADVERSE EVENTS. PUBLISH DATE: DECEMBER, 2004
Quick Reference
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(“DAIDS grading table”) is a descriptive terminology to be utilized for 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 adverse event could fall under either one of 2 grades (e.g., the severity of an 
adverse event 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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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.).


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
63/83
Approved, Issued Date: 28-Nov-2016
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.).


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
64/83
Approved, Issued Date: 28-Nov-2016
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.
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.).


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
65/83
Approved, Issued Date: 28-Nov-2016
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.)


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
66/83
Approved, Issued Date: 28-Nov-2016
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 Genitourinary 
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.)


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
67/83
Approved, Issued Date: 28-Nov-2016
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.)


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
68/83
Approved, Issued Date: 28-Nov-2016
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-THREATENING
Cognitive and 
behavioral/attentiona
l 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.)


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
69/83
Approved, Issued Date: 28-Nov-2016
CLINICAL
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.)


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
70/83
Approved, Issued Date: 28-Nov-2016
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.)


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
71/83
Approved, Issued Date: 28-Nov-2016
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
GENITOURINARY
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.)


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
72/83
Approved, Issued Date: 28-Nov-2016
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.)


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
73/83
Approved, Issued Date: 28-Nov-2016
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.)


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
74/83
Approved, Issued Date: 28-Nov-2016
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


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
75/83
Approved, Issued Date: 28-Nov-2016
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) c,d
≥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)c
≥ 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 
lifethreatening
consequences
pH > 7.5 with 
lifethreatening
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.


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
76/83
Approved, Issued Date: 28-Nov-2016
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.


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
77/83
Approved, Issued Date: 28-Nov-2016
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.


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
78/83
Approved, Issued Date: 28-Nov-2016
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


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
79/83
Approved, Issued Date: 28-Nov-2016
ATTACHMENT 2: VISIT SCHEDULE FOR GRADE 3/4 RASH 
MANAGEMENT (RASH FULLY CHARACTERIZED)
This visit schedule summarizes the visits and assessments to be performed in case of 
grade 3/4 rash. At the investigator’s discretion, additional visits and assessments can be 
performed. Local laboratory blood sample assessments will be documented/collected as 
described.
Grade 3 or 4 Rash
Day 01
(preferably 
within 24 hours 
after onset of 
rash)

TMC278 MUST be permanently DISCONTINUED, if in the investigator’s opinion, 
the rash is at least possibly related to TMC278. Rechallenge is NOT ALLOWED.

Unscheduled visit for initial rash evaluation REQUIRED.

Assessment of vital signs by the investigator and safety blood sample by local 
laboratory REQUIRED.

Digital pictures can only be taken if subject gave consent. REQUIRED if subject is 
taking ABC; otherwise they are the investigator’s discretion.

Referral to dermatologist REQUIRED.

Biopsy REQUIRED for grade 4 rash. Biopsy at the dermatologist’s discretion for 
grade 3 rash.
Day 1

Follow-up visit REQUIRED.

Assessment of safety blood sample by local laboratory REQUIRED.

Digital pictures2.
Day 2

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 pictures2.
Day 3

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 pictures2.
Day 4

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 pictures2.
Day 5

Follow-up visit REQUIRED.

Assessment of safety blood sample by local laboratory REQUIRED.

Digital pictures2.
Further Visits

Weekly follow-up visits REQUIRED (or more frequently at the investigator’s 
discretion) until resolution/stabilization of grade 3/4 rash to grade ≤2 rash 

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.

Digital pictures2.
Upon Rash 
Resolution/
Stabilization3

Digital pictures2.

Final Cutaneous Reaction/Rash form should be completed.
                                                
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 Digital pictures can only be taken if subject gave consent. They are required if subject is taking ABC; otherwise they are 
the investigator’s discretion.
3 Stabilization: to be agreed upon in collaboration with the sponsor.


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
80/83
Approved, Issued Date: 28-Nov-2016


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
81/83
Approved, Issued Date: 28-Nov-2016


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
82/83
Approved, Issued Date: 28-Nov-2016
SIGNATURE PAGE SPONSOR
Sponsor’s Responsible Medical Officer:
This Clinical Trial Protocol Amendment has been reviewed and approved by the sponsor in order 
to ensure compliance with Good Clinical Practices.
Name:
Rodica 
Van 
Solingen-Ristea, M.D.
Affiliation:
Janssen 
Research 
& 
Development
See Attached Electronic Signature Page


TMC278-TiDP6-C222
Clinical Trial Protocol Amendment 3
83/83
Approved, Issued Date: 28-Nov-2016
INVESTIGATOR AGREEMENT
I have read this document and agree that it contains all necessary details for carrying out this trial. 
I will conduct the trial as outlined herein and will complete the trial within the time designated.
I will provide copies of the document and all pertinent information to all individuals responsible 
to me who assist in the conduct of this trial. I will discuss this material with them to ensure that 
they are fully informed regarding the study drug, the conduct of the trial, 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)
LAST PAGE


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rodica Van Solingen-Ristea
29Nov2016, 15:53:10 PM, UTC
Document Approval

SAP_001.pdf: 
Statistical Analysis Plan
An open-label trial with TMC278 25 mg q.d. in combination with a background regimen containing 2 
nucleoside/nucleotide reverse transcriptase inhibitors in HIV-1 infected subjects, who participated in 
TMC278 clinical trials  
Protocol TMC278-C222; Phase III
TMC278  (Rilpivirine)
Status:
Approved
Date:
26 March 2018
Prepared by:
Janssen Research and Development, a division of Janssen Pharmaceutica NV  
Document No.:
EDMS-ERI-157462123
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice 
(GCP).
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In 
any event, persons to whom the information is disclosed must be informed that the information is privileged 
or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally 
to all future information supplied to you that is indicated as privileged or confidential.
NCT01266902


2
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
ABBREVIATIONS ........................................................................................................................................ 3
1.
INTRODUCTION.................................................................................................................................. 4
1.1.
Trial Objectives ................................................................................................................................ 4
1.2.
Trial Design ...................................................................................................................................... 4
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 5
1.4.
Sample Size Justification ................................................................................................................. 5
1.5.
Randomization and Blinding ............................................................................................................ 5
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 5
2.1.
Visit Windows................................................................................................................................... 5
2.1.1.
Trial Phases.................................................................................................................................. 5
2.1.2.
Analysis Time points.................................................................................................................. 6
2.2.
Analysis Sets.................................................................................................................................... 6
2.2.1.
Definition of Subgroups ................................................................................................................ 6
3.
SUBJECT INFORMATION.................................................................................................................. 7
3.1.
Demographics and Baseline Characteristics ................................................................................... 7
3.2.
Disposition Information..................................................................................................................... 7
3.3.
Extent of Exposure........................................................................................................................... 8
3.4.
Protocol Deviations .......................................................................................................................... 8
3.5.
Concomitant Medications................................................................................................................. 8
3.6.
Adherence........................................................................................................................................ 8
4.
EFFICACY ........................................................................................................................................... 9
4.1.
Analysis Specifications..................................................................................................................... 9
4.1.1.
Level of Significance..................................................................................................................... 9
4.1.2.
Data Handling Rules..................................................................................................................... 9
4.2.
Efficacy Endpoints.......................................................................................................................... 10
4.2.1.
CD4+ cell count............................................................................................................................. 10
4.2.2.
Analysis Methods........................................................................................................................ 11
5.
RESISTANCE DETERMINATIONS .................................................................................................. 11
6.
SAFETY............................................................................................................................................. 11
6.1.
Adverse Events .............................................................................................................................. 11
6.2.
Clinical Laboratory Tests................................................................................................................ 12
6.2.1.
Overall Laboratory Safety........................................................................................................... 12
REFERENCES............................................................................................................................................ 13
APPENDIX 1: ADVERSE EVENTS OF INTEREST................................................................................... 14


TMC278  (Rilpivirine)
Statistical Analysis Plan TMC278-C222 (Week 240)
3
ABBREVIATIONS
AE
AIDS
Adverse Event
Acquired Immunodeficiency Syndrome
ARV
Antiretroviral
CI
Confidence Interval
CM
Concomitant medications
CRF
Case Report Form
DAIDS
Division of AIDS, National Institute of Allergy and Infectious Diseases, USA
DPS
Data Presentation Specifications
eCRF
Electronic Case Report Form
FDA
Food and Drug Administration
HIV-1
Human immunodeficiency virus – type 1
ICH
International Conference on Harmonization
ITT
Intent-to-Treat
MedDRA
Medical Dictionary for Regulatory Activities
NNRTI
Non-Nucleoside Reverse Transcriptase Inhibitor
NRTI
Nucleoside/Nucleotide Analogue Reverse Transcriptase Inhibitor
LOCF
Last Observation Carried Forward
PI
Protease Inhibitor
q.d.
quaque die; once daily
RNA
Ribonucleic acid
RPV
Rilpivirine
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
TMC
Tibotec Medicinal Compound
VF
Virologic Failure


4
1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for the Final analysis (Week 360) of safety and efficacy (antiviral activity) for 
the continued access study TMC278-C222. The data cut-off is 08 February 2018.
1.1.
Trial Objectives
The objectives of this study were:
-
Primary objective: to provide continued access to RPV for subjects who were randomized 
and treated with RPV in the Phase IIb (C204) or Phase III trials (C209 and C215).
-
Secondary objective: to evaluate the long-term safety and tolerability of RPV 25 mg q.d. 
in combination with a background regimen containing 2 NRTIs. Available efficacy data 
will also be collected. 
1.2.
Trial Design
This was a Phase III, open label, multicenter, roll-over trial to provide continued access to RPV 
(rilpivirine) in HIV-1 infected subjects who were randomized and treated with RPV in the Phase 
IIb (C204) or Phase III trials (C209 and C215), and who continued to benefit from their ARV 
treatment. Information on safety and tolerability was collected. In addition, local information on 
viral load, ARV resistance and CD4+ count was also collected.
At the baseline visit (roll-over visit), inclusion and exclusion criteria were assessed to confirm 
eligibility. Once eligibility criteria were met, subjects were to continue treatment with RPV 25 
mg q.d. in comination with a background regimen containing 2 NRTIs. 
Treatment was to be continued until one of the following criteria were met:
-
Virologic failure
-
Adverse event (AE)
-
Pregnancy
-
Loss to follow-up
-
Withdrawal of consent
-
Subject reached a virologic endpoint
-
Sponsor’s decision
-
Switch to commercially available medication
Visits and assessments were to be performed based on local generally accepted standard of care 
(see time and events schedule in the protocol). However, it was recommended that visits be 
planned no less frequently than every 6 months.
Adverse event reporting was limited to:
-
AEs considered a least possibly related to RPV
-
AEs leading to discontinaution
-
serious advese events (SAEs) and pregnancies
-
Grade 3/4 rash, irrespective of causality
Other AEs were only collected if required as per local regulation.


TMC278  (Rilpivirine)
Statistical Analysis Plan TMC278-C222 (Week 240)
5
1.3.
Statistical Hypotheses for Trial Objectives
No formal hypothesis will be tested.
1.4.
Sample Size Justification
No sample size calculation was done as this is a continued access single arm trial.
1.5.
Randomization and Blinding
Randomization
As this was a continued access single arm trial, randomization procedures were not applicable.
Blinding
Since this was an open label, continued access single-arm trial, blinding procedures were not 
applicable.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
2.1.1.
Trial Phases
Analysis phases are constructed as follows:
Table 1: Analysis Phases for Efficacy and Safety Analysis
Trial phase
Start date
End date
Enrollment
Date of signing 
informed consent
Day before the start of the treatment phase.
Treatment
Date of the first intake 
of RPV (in this study)
If the subject died: min (date of last RPV
intake + 7 days; date of death)
Otherwise: minimum of:

date of last RPV intake + 7 days, if 
missing, max(early withdrawal visit date; 
discontinuation date)+ 7 days (early 
withdrawal visit date is from dataset sv 
and discontinuation date is dsstdtc)

date of last contact (=dm.rfendtc which is 
the last complete date)
Follow-up (not defined 
when derived End date is 
before Start date of this 
phase)
End date of the 
Treatment phase + 1 
day
If the subject died: date of death
Otherwise: date of last contact
If the date of first intake of the study medication is missing, this should be substituted by the 
baseline visit date.
The number of days in the phase is defined as:
relday = visit day – reference day+1 for visits on or after the reference
relday = visit day – reference day for visits before the reference
where the reference day equals the actual start date of intake of RPV.


6
2.1.2.
Analysis Time points
Subjects were to rollover after completion of one of the three parent trials. The baseline visit of 
this roll-over study coincided with the last visit of the treatment phase of the previous trial. If a 
subject was deemed eligible to participate in this trial, the subject was to receive trial medication 
at the baseline visit. After the baseline visit, subjects were to be evaluated as per local 
regulations, but it was advised that the duration between consecutive visits be no longer than 6 
months.
All visits/assessments will be allocated to the following time points as per the table below, based 
on the number of days in the respective phase, calculated as “assessment date – start date of 
phase + 1 day” for Treatment and Follow-up phase.
The following time intervals are used for reporting of efficacy data
Table 2: Cut-points and Windows per 24-Week Intervals
Phase 
Target day
Analysis time point
Time interval (days)
Treatment
169
Week 24
[1, 252]
337
Week 48
[253, 420]
505
Week 72
[421, 588]
673
Week 96
[589, 756]
841
Week 120
[757, 924]
1009
Week 144
[925, 1092]
1177
Week 168
[1093, 1260]
1345
Week192
[1261, 1428]
1513
Week 216
[1429, 1596]
1681
Week 240
[1597, 1764]
1849
Week 264
[1765, 1932]
2017
Week 288
[1933, 2100]
2185
Week 312
[2101, 2268]
2353
Week 336
[2269, 2436]
2521
Week 360
[2437, +∞]
Follow-up
30
Follow-up
[1, +∞]
Only the record prior to or on the first dose closest to target day 1 will be allocated to analysis time point ‘Baseline’.
If two visits fall within the same interval, the one closest to the target day is used for the analysis
displays and graphics to have only one evaluation per subject per analysis time point. However, 
all data are presented in the listings. If distances of both visits to the target day are equal, the visit 
latest in time is used.
Baseline
Baseline refers to the last visit in the parent study, which is the first visit in C222.
2.2.
Analysis Sets
Intent-to-treat (ITT) population: the set of all subjects who have taken at least 1 dose of RPV, 
regardless of their compliance with the protocol and adherence to the dosing regimen.  
The intent-to-treat population will be used as primary and only population for all analyses.
2.2.1.
Definition of Subgroups
All displays will be created by previous trial (both phase III trials, C209 and C215, will be 
analyzed together) and overall. The following labels will be used:


TMC278  (Rilpivirine)
Statistical Analysis Plan TMC278-C222 (Week 240)
7
-
RPV (C204)
-
RPV (C209 and C215)
-
All subjects
The following subgroups will be defined for efficacy:

Gender

Race

Age (<50; >=50 to < 65; >= 65 years at baseline)

Cumulative adherence based on drug accountability (95%, >95%)

Truvada in background ARV regimen (yes/no)

Clade
The following subgroups will be defined for Safety:

Truvada in ARV regimen (yes/no)

Hepatitis B/C Co-infection (based on medical history in parent study)

Hepatitis B infection (based on medical history in parent study)

Hepatitis C infection (based on medical history in parent study)

Age (<50; >=50 to < 65; >= 65 years at baseline)

CDC classification (based on screening information from the parent study)

Gender

Race
3.
SUBJECT INFORMATION
3.1.
Demographics and Baseline Characteristics
The following parameters will be analyzed:
-
Gender (male/female)
-
Race (from parent studies)
-
Age at baseline
-
Age at baseline by categories (<50, ≥50 to <65; ≥65)
-
Country/site
-
History of Hepatitis B/C
-
History of Hepatitis B
-
History of Hepatitis C
-
Clade
3.2.
Disposition Information
Discontinuations, plus reasons for discontinuation will be analyzed:
Summary statistics (count, percentage and rate per 100 person-years) will be provided. Rate per 
100 person-years is calculated as (the total number of discontinuations x 100) divided by (the 


8
total number of days summed over all subjects)/365.25. Exact 95% confidence intervals4 for the 
number of discontinuation per 100 person-years will also be provided.
3.3.
Extent of Exposure
Exposure is defined as the duration of RPV treatment during the active treatment phase (in 
Days). The extent of exposure will be summarized in years, and the total person-years-of 
exposure will be provided. 
Treatment duration is calculated as follows:  last day of treatment phase – Day of first dose +1.
Note that the above definition implies that drug interruptions are ignored in calculating exposure.
The total person-years-of-exposure will be calculated by taking the sum of the RPV treatment 
duration (years) over all subjects. 
In addition, the proportion of subjects in the study exposed to RPV will be tabulated using 48-
week intervals, i.e. based on 1 x 48 weeks (337 days), 2 x 48 weeks (673 days), etc. as cut-points 
(see Table 2).
3.4.
Protocol Deviations
Major protocol deviations will be tabulated and listed.
3.5.
Concomitant Medications
Concomitant therapies are defined as therapies listed on the concomitant medications (CM)
domain. Concomitant medications are allocated to each phase during which they were 
administered, based on their start and end dates. For phase allocation, the following rules are 
applied to deal with (partially) missing start or end dates: 
- a start date with the day only missing has the day imputed with the first day of the 
month;
- a start date with the day and month missing has the day imputed with the 1st of January;
- an entirely missing start date is considered as having started before the study;
- an end date with the day only missing has the day imputed with the last day of the 
month;
- an end date with the day and month missing has the day imputed with the 31st of 
December;
- an entirely missing end date is considered as having ended after the study.
Number and percent of subjects per ARV therapy (as started or ongoing at baseline) will be 
summarized. In addition, all ARV and non-ARV therapies will be listed separately. A separate 
listing for all subjects who switched ARV therapy during treatment will also be listed. Note: 
combination drugs will be split into their respective compounds.
3.6.
Adherence
Treatment adherence is defined based on drug accountability from tablet counts.
The following parameters are derived over the entire treatment period.


TMC278  (Rilpivirine)
Statistical Analysis Plan TMC278-C222 (Week 240)
9
Drug accountability
Amount to be taken = (number of days since start of treatment x number of tablets to be taken 
per day).
Number of days since start of treatment in C222 is:
-
based on last RPV study medication intake date (if available) or, in case subject 
discontinued and last RPV study medication intake date is missing, discontinuation 
date
-
if not available, the last dispensation visit will be used.
Actual amount taken in C222 = (number of tablets dispensed – number of tablets returned)
Tablets dispensed after or on the date of last dose (based on exposure data) should not be taken 
into account if there is no information on all dispensed tablets available.
Level of adherence = (actual amount taken / amount to be taken) x 100%
Treatment adherence is defined as:
-
adherent: the level of adherence is > 95%
-
non-adherent: the level of adherence is ≤ 95%
Additionally, following categories of level of adherence will be defined:
-
> 95%
-
]80%; 95%]
-
]65%; 80%]
-
]50%; 65%]
-
≤ 50%
The numbers and percentages of subjects adherent during the trial will be tabulated and 
descriptive statistics of adherence (%) will be shown.
Interruptions (for AEs) are not to be considered for the calculation of adherence, i.e. they will not 
be subtracted from the amount to be taken.
Results will be summarized for RPV only.
4.
EFFICACY
4.1.
Analysis Specifications
4.1.1.
Level of Significance
No statistical testing will be done as this is a single arm trial.
4.1.2.
Data Handling Rules
Viral load testing was performed locally using several assays. Viral load will be analyzed 
irrespective of which viral load assay was used (there will be no separate reporting). Regardless 


10
of which assay was used to define response (undetectable)/loss of response (detectable) in the 
analysis, a cut-off of 50 and 200 copies/mL2 will be applied.
Imputation of left censored values: 49 copies/mL for values below the detection limit.
Reanalyzed samples will not be used in any of the calculations or summary statistics.
Only samples obtained during the treatment phase will be used for the analyses.
4.2.
Efficacy Endpoints
The following viral load parameters will be analyzed:
-
Time to Virologic rebound defined as the time to (first) HIV-1 RNA ≥50/200
copies/mL. Following rules apply:
o
Virologic rebound needs to be confirmed at 2 consecutive visits with the 
following exception: loss of response at the last study visit where no 
confirmation sample is available will be considered as rebound.
o
The analysis will be censored at the time of discontinuation (discontinuation 
due to ANY reason).
o
This is the time (in days) calculated from baseline until the failure time point. 
Subjects never losing the acquired response will be censored at the end of the 
treatment phase.
-
Time to Treatment failure is defined as
o
The time to virologic rebound (see above) or discontinuation, whichever 
comes first
o
Subjects who would otherwise had continued will be censored at the end of 
the treatment phase.
o
This is the time (in days) calculated from baseline until the failure time point. 
Subjects never losing the acquired response will be censored at the end of the 
treatment phase.
4.2.1.
CD4+ cell count
Actual CD4+ cell count and change in CD4+ cell count (absolute) from baseline up to Week 360 
by 24 Week intervals.
Change from baseline in CD4+ count is defined as CD4+ at a given timepoint - baseline CD4+.
  
-
Subjects who discontinued because RPV became commercially available or rolled over to 
IFD3004 will be censored at that time.
-
Subjects who discontinued for any other reason will have their CD4+ values after 
discontinuation imputed with their baseline value (baseline from roll-over study), thus 
resulting in a 0 change.
-
Intermittently missing values will be imputed using a last observation carried forward
approach.


TMC278  (Rilpivirine)
Statistical Analysis Plan TMC278-C222 (Week 240)
11
4.2.2.
Analysis Methods
For “time to” parameters, Kaplan Meier estimates and 95% CIs will be calculated. Kaplan-Meier 
curves will be constructed. 
In addition, the cumulative number of events (rebound/treatment failure) and the cumulative 
number per 100 person-years will be summarized by 24-Week treatment period and for the entire 
treatment period (Week 360 time point). Rate per 100 person-years is calculated as (the number 
of failures x 100) divided by (the total number of days summed over all subjects)/(365.25). Exact 
95% confidence intervals4 for the number of events per 100 person-years will also be provided.
For continuous parameters, descriptive statistics (n, mean (se), median, and ranges) per time 
point and graphical display will be presented.
HIV-1 RNA levels will be listed for all subjects with virologic rebound.
5.
RESISTANCE DETERMINATIONS
Resistance data will only be analyzed if available for at least 20 subjects. If there are less than 20 
subjects, resistance data will be listed. Inclusion of subjects for resistance analysis will solely be 
based on the availability of post-baseline genotypic data within the treatment phase.
Note: no phenotypic data was collected in this trial.
6.
SAFETY
Safety results will be summarized for the Treatment phase only; all safety data (including 
Follow-up phase) will be included in listings.
6.1.
Adverse Events
AE incidence (count, percentage) will be tabulated, overall and by SOC/preferred term.
Overall AE summary tables by preferred term/SOC for serious AEs and pregnancies, AEs 
leading to discontinuation, AEs at least grade 3, AEs at least grade 4, Grade 3-4 rash, HIV-
related AEs and AEs at least possibly related to RPV will be presented throughout the treatment 
phase only; any AEs in the Follow-up phase will be listed only.
AEs are categorized in different groups of AEs of interest (see Appendix 1).
The different classes of events of interest that will be investigated are the following:

AEs leading to discontinuation

Skin events of interest (with subcategories: Rash)

Neuropsychiatric events of interest (with subcategories: Neurologic events of interest, 
Psychiatric events of interest). The subcategories are based on System Organ Class.

Potential QT prolongation-related events

Hepatic events of interest


12

Endocrinology events
Note: the above is based on adverse events of interest analyses in previous Phase 3 studies.
Clinical narratives will be written for: deaths, pregnancies, SAEs at least possibly related to 
RPV, AEs leading to permanent discontinuation of RPV, grade 3/4 AEs of special interest.
6.2.
Clinical Laboratory Tests
6.2.1.
Overall Laboratory Safety
Results from local laboratory testing will be included in the analysis. Lab assessments were only 
collected for following cases: serious AEs, AEs leading to discontinuation, AEs considered at 
least possibly related to RPV, grade 3/4 rash.
All laboratory values and pregnancy results collected will be listed. Original units will be 
reported. All lab values will be used, including those from unscheduled laboratory visits and 
pregnancy results.
UToxicity grades are determined according to the 
UDAIDS grading list (see protocol). More 
detailed information will be provided in the DPS.


TMC278  (Rilpivirine)
Statistical Analysis Plan TMC278-C222 (Week 240)
13
REFERENCES
1.
Top HIV Med. 2013;21(1):6-14 2013, International Antiviral Society-USA
2.
O’Connor J et al 2017 Durability of Viral Suppression with first line anti-retroviral therapy in patients with 
HIV in the UK: an observational cohort study; Lancet HIV. 2017 Jul; 4(7): e295–e302.
3.
Bennett DE, Camacho RJ, Otelea D, Kuritzkes DR, Fleury H, et al. 2009 Drug Resistance Mutations for 
Surveillance of Transmitted HIV-1 Drug-Resistance: 2009 Update. PLoS ONE 4(3): e4724. 
doi:10.1371/journal.pone.000472
4.
Ulm K: A simple method to calculate the confidence interval of a standardized mortality ratio (SMR); Am J 
Epidemiol 1990; 131(2): 373-5.


14
APPENDIX 1: ADVERSE EVENTS OF INTEREST
AEDECOD
Category
Subcategory
17-HYDROXYPROGESTERONE INCREASED
ENDOCRINE
ACTH STIMULATION TEST ABNORMAL
ENDOCRINE
ADRENAL ADENOMA
ENDOCRINE
ADRENOCORTICAL INSUFFICIENCY CHRONIC
ENDOCRINE
AMENORRHOEA
ENDOCRINE
BLOOD ALDOSTERONE DECREASED
ENDOCRINE
BLOOD CORTISOL ABNORMAL
ENDOCRINE
BLOOD CORTISOL DECREASED
ENDOCRINE
BLOOD CORTISOL INCREASED
ENDOCRINE
DEHYDROEPIANDROSTERONE DECREASED
ENDOCRINE
DYSFUNCTIONAL UTERINE BLEEDING
ENDOCRINE
HAIR GROWTH ABNORMAL
ENDOCRINE
HYPERTRICHOSIS
ENDOCRINE
HYPOGONADISM
ENDOCRINE
HYPOTRICHOSIS
ENDOCRINE
MENOMETRORRHAGIA
ENDOCRINE
MENORRHAGIA
ENDOCRINE
MENSTRUAL DISORDER
ENDOCRINE
MENSTRUATION DELAYED
ENDOCRINE
MENSTRUATION IRREGULAR
ENDOCRINE
METRORRHAGIA
ENDOCRINE
OVARIAN CYST
ENDOCRINE
PAROVARIAN CYST
ENDOCRINE
PIGMENTATION DISORDER
ENDOCRINE
POLYMENORRHOEA
ENDOCRINE
POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME
ENDOCRINE
PROGESTERONE ABNORMAL
ENDOCRINE
PROGESTERONE INCREASED
ENDOCRINE
SKIN DISCOLOURATION
ENDOCRINE
SKIN HYPERPIGMENTATION
ENDOCRINE
SKIN HYPOPIGMENTATION
ENDOCRINE
ACUTE HEPATIC FAILURE
HEPATOBILIARY
ALANINE AMINOTRANSFERASE ABNORMAL
HEPATOBILIARY
ALANINE AMINOTRANSFERASE INCREASED
HEPATOBILIARY
ASPARTATE AMINOTRANSFERASE ABNORMAL
HEPATOBILIARY
ASPARTATE AMINOTRANSFERASE INCREASED
HEPATOBILIARY
BILIRUBIN CONJUGATED INCREASED
HEPATOBILIARY
BILIRUBINURIA
HEPATOBILIARY
BIOPSY LIVER
HEPATOBILIARY
BLOOD ALKALINE PHOSPHATASE INCREASED
HEPATOBILIARY
BLOOD BILIRUBIN INCREASED
HEPATOBILIARY
BLOOD BILIRUBIN UNCONJUGATED INCREASED
HEPATOBILIARY


TMC278  (Rilpivirine)
Statistical Analysis Plan TMC278-C222 (Week 240)
15
BLOOD LACTATE DEHYDROGENASE INCREASED
HEPATOBILIARY
CHOLELITHIASIS
HEPATOBILIARY
CYTOLYTIC HEPATITIS
HEPATOBILIARY
GAMMA-GLUTAMYLTRANSFERASE INCREASED
HEPATOBILIARY
HEPATIC CIRRHOSIS
HEPATOBILIARY
HEPATIC ENZYME ABNORMAL
HEPATOBILIARY
HEPATIC ENZYME INCREASED
HEPATOBILIARY
HEPATIC FAILURE
HEPATOBILIARY
HEPATIC FUNCTION ABNORMAL
HEPATOBILIARY
HEPATIC FUNCTION ABNORMAL NOS
HEPATOBILIARY
HEPATIC STEATOSIS
HEPATOBILIARY
HEPATITIS
HEPATOBILIARY
HEPATITIS ACUTE
HEPATOBILIARY
HEPATITIS B
HEPATOBILIARY
HEPATITIS C
HEPATOBILIARY
HEPATOBILIARY DISEASE
HEPATOBILIARY
HEPATOMEGALY
HEPATOBILIARY
HEPATOSPLENOMEGALY
HEPATOBILIARY
HEPATOSPLENOMEGALY NOS
HEPATOBILIARY
HEPATOTOXICITY
HEPATOBILIARY
HEPATOTOXICITY NOS
HEPATOBILIARY
HYDROCHOLECYSTIS
HEPATOBILIARY
HYPERBILIRUBINAEMIA
HEPATOBILIARY
HYPERBILIRUBINEMIA
HEPATOBILIARY
HYPERTRANSAMINASAEMIA
HEPATOBILIARY
JAUNDICE
HEPATOBILIARY
JAUNDICE NOS
HEPATOBILIARY
LIVER DISORDER
HEPATOBILIARY
LIVER FATTY
HEPATOBILIARY
LIVER FUNCTION TEST ABNORMAL
HEPATOBILIARY
LIVER PALPABLE SUBCOSTAL
HEPATOBILIARY
TRANSAMINASES INCREASED
HEPATOBILIARY
URINE BILIRUBIN INCREASED
HEPATOBILIARY
YELLOW SKIN
HEPATOBILIARY
ABNORMAL BEHAVIOUR
NEUROPSYCH
ABNORMAL DREAMS
NEUROPSYCH
ACUTE PSYCHOSIS
NEUROPSYCH
ADJUSTMENT DISORDER
NEUROPSYCH
ADJUSTMENT DISORDER NOS
NEUROPSYCH
ADJUSTMENT DISORDER WITH ANXIETY
NEUROPSYCH
ADJUSTMENT DISORDER WITH DEPRESSED MOOD
NEUROPSYCH
ADJUSTMENT DISORDER WITH MIXED ANXIETY AND DEPRESSED 
MOOD
NEUROPSYCH
AFFECT LABILITY
NEUROPSYCH
AFFECTIVE DISORDER
NEUROPSYCH


16
AGGRESSION
NEUROPSYCH
AGITATION
NEUROPSYCH
AGORAPHOBIA
NEUROPSYCH
ALCOHOL ABUSE
NEUROPSYCH
ALCOHOL POISONING
NEUROPSYCH
ALCOHOL WITHDRAWAL SYNDROME
NEUROPSYCH
ALCOHOLISM
NEUROPSYCH
AMNESIA
NEUROPSYCH
ANGER
NEUROPSYCH
ANHEDONIA
NEUROPSYCH
ANXIETY
NEUROPSYCH
ANXIETY DISORDER
NEUROPSYCH
APATHY
NEUROPSYCH
ATTENTION DEFICIT/HYPERACTIVITY DISORDER
NEUROPSYCH
AUTONOMIC NERVOUS SYSTEM IMBALANCE
NEUROPSYCH
BALANCE DISORDER
NEUROPSYCH
BALANCE IMPAIRED
NEUROPSYCH
BALANCE IMPAIRED NOS
NEUROPSYCH
BIPOLAR DISORDER
NEUROPSYCH
BIPOLAR I DISORDER
NEUROPSYCH
BOREDOM
NEUROPSYCH
BRADYPHRENIA
NEUROPSYCH
BRUXISM
NEUROPSYCH
CATATONIA
NEUROPSYCH
CLAUSTROPHOBIA
NEUROPSYCH
CLUSTER HEADACHE
NEUROPSYCH
COGNITIVE DISORDER
NEUROPSYCH
COMPLETED SUICIDE
NEUROPSYCH
CONCENTRATION IMPAIRED
NEUROPSYCH
CONFUSIONAL STATE
NEUROPSYCH
CONVERSION DISORDER
NEUROPSYCH
COORDINATION ABNORMAL
NEUROPSYCH
CRANIAL NEUROPATHY
NEUROPSYCH
DECREASED ACTIVITY
NEUROPSYCH
DELIRIUM
NEUROPSYCH
DELUSION
NEUROPSYCH
DEPRESSED LEVEL OF CONSCIOUSNESS
NEUROPSYCH
DEPRESSED MOOD
NEUROPSYCH
DEPRESSION
NEUROPSYCH
DEPRESSION AGGRAVATED
NEUROPSYCH
DEPRESSIVE SYMPTOM
NEUROPSYCH
DISORIENTATION
NEUROPSYCH
DISSOCIATION
NEUROPSYCH
DISTRACTIBILITY
NEUROPSYCH
DISTURBANCE IN ATTENTION
NEUROPSYCH


TMC278  (Rilpivirine)
Statistical Analysis Plan TMC278-C222 (Week 240)
17
DIZZINESS
NEUROPSYCH
DRUG DEPENDENCE
NEUROPSYCH
DYSPHORIA
NEUROPSYCH
DYSSOMNIA
NEUROPSYCH
DYSTHYMIC DISORDER
NEUROPSYCH
EARLY MORNING AWAKENING
NEUROPSYCH
EMOTIONAL DISORDER
NEUROPSYCH
EMOTIONAL DISTRESS
NEUROPSYCH
EUPHORIC MOOD
NEUROPSYCH
HALLUCINATION
NEUROPSYCH
HALLUCINATION, AUDITORY
NEUROPSYCH
HALLUCINATION, VISUAL
NEUROPSYCH
HALLUCINATIONS, MIXED
NEUROPSYCH
HEAD DISCOMFORT
NEUROPSYCH
HEADACHE
NEUROPSYCH
HEADACHE NOS AGGRAVATED
NEUROPSYCH
HEMICEPHALALGIA
NEUROPSYCH
HOMICIDAL IDEATION
NEUROPSYCH
HYPERKINESIA
NEUROPSYCH
HYPERSOMNIA
NEUROPSYCH
HYPOMANIA
NEUROPSYCH
INITIAL INSOMNIA
NEUROPSYCH
INSOMNIA
NEUROPSYCH
INSOMNIA EXACERBATED
NEUROPSYCH
IRRITABILITY
NEUROPSYCH
LETHARGY
NEUROPSYCH
LIBIDO DECREASED
NEUROPSYCH
LIBIDO DISORDER
NEUROPSYCH
LIBIDO INCREASED
NEUROPSYCH
LISTLESS
NEUROPSYCH
LOSS OF LIBIDO
NEUROPSYCH
MAJOR DEPRESSION
NEUROPSYCH
MALE ORGASMIC DISORDER
NEUROPSYCH
MANIA
NEUROPSYCH
MEMORY IMPAIRMENT
NEUROPSYCH
MENTAL DISORDER
NEUROPSYCH
MENTAL IMPAIRMENT
NEUROPSYCH
MENTAL STATUS CHANGES
NEUROPSYCH
MIDDLE INSOMNIA
NEUROPSYCH
MONONEUROPATHY
NEUROPSYCH
MOOD ALTERED
NEUROPSYCH
MOOD SWINGS
NEUROPSYCH
NEGATIVE THOUGHTS
NEUROPSYCH
NERVOUSNESS
NEUROPSYCH
NIGHTMARE
NEUROPSYCH


18
NIGHTMARES
NEUROPSYCH
ORGASM ABNORMAL
NEUROPSYCH
PANIC ATTACK
NEUROPSYCH
PANIC DISORDER
NEUROPSYCH
PARAESTHESIA CIRCUMORAL
NEUROPSYCH
PARANOIA
NEUROPSYCH
PERSONALITY DISORDER
NEUROPSYCH
PHOBIA
NEUROPSYCH
PHOTOPHOBIA
NEUROPSYCH
POOR QUALITY SLEEP
NEUROPSYCH
POST-TRAUMATIC STRESS DISORDER
NEUROPSYCH
PSYCHIATRIC INVESTIGATION
NEUROPSYCH
PSYCHOGENIC ERECTILE DYSFUNCTION
NEUROPSYCH
PSYCHOLOGICAL FACTOR AFFECTING MEDICAL CONDITION
NEUROPSYCH
PSYCHOMOTOR HYPERACTIVITY
NEUROPSYCH
PSYCHOTIC DISORDER
NEUROPSYCH
PSYCHOTIC DISORDER DUE TO A GENERAL MEDICAL CONDITION
NEUROPSYCH
RESTLESS LEGS SYNDROME
NEUROPSYCH
RESTLESSNESS
NEUROPSYCH
SEASONAL AFFECTIVE DISORDER
NEUROPSYCH
SEDATION
NEUROPSYCH
SENSATION OF PRESSURE IN EAR
NEUROPSYCH
SENSE OF OPPRESSION
NEUROPSYCH
SLEEP DISORDER
NEUROPSYCH
SLEEP DISORDER NOS
NEUROPSYCH
SLEEP PHASE RHYTHM DISTURBANCE
NEUROPSYCH
SLUGGISHNESS
NEUROPSYCH
SOCIAL PHOBIA
NEUROPSYCH
SOMATOFORM DISORDER
NEUROPSYCH
SOMNOLENCE
NEUROPSYCH
SOPOR
NEUROPSYCH
STRESS
NEUROPSYCH
STRESS SYMPTOMS
NEUROPSYCH
SUBSTANCE ABUSE
NEUROPSYCH
SUICIDAL IDEATION
NEUROPSYCH
SUICIDE ATTEMPT
NEUROPSYCH
TENSION
NEUROPSYCH
UVEITIS
NEUROPSYCH
VERTIGO
NEUROPSYCH
VISION BLURRED
NEUROPSYCH
VISUAL DISTURBANCE
NEUROPSYCH
CARDIAC ARREST
QT PROLONGING EFF
CARDIAC DEATH
QT PROLONGING EFF
CARDIAC FIBRILLATION
QT PROLONGING EFF
CARDIO-RESPIRATORY ARREST
QT PROLONGING EFF


TMC278  (Rilpivirine)
Statistical Analysis Plan TMC278-C222 (Week 240)
19
ELECTROCARDIOGRAM QT INTERVAL ABNORMAL
QT PROLONGING EFF
ELECTROCARDIOGRAM QT PROLONGED
QT PROLONGING EFF
ELECTROCARDIOGRAM REPOLARISATION ABNORMALITY
QT PROLONGING EFF
ELECTROCARDIOGRAM U-WAVE ABNORMALITY
QT PROLONGING EFF
ELECTROCARDIOGRAM U-WAVE BIPHASIC
QT PROLONGING EFF
LONG QT SYNDROME
QT PROLONGING EFF
LONG QT SYNDROME CONGENITAL
QT PROLONGING EFF
LOSS OF CONSCIOUSNESS
QT PROLONGING EFF
SUDDEN CARDIAC DEATH
QT PROLONGING EFF
SUDDEN DEATH
QT PROLONGING EFF
SYNCOPE
QT PROLONGING EFF
TORSADE DE POINTES
QT PROLONGING EFF
VENTRICULAR ARRHYTHMIA
QT PROLONGING EFF
VENTRICULAR FIBRILLATION
QT PROLONGING EFF
VENTRICULAR FLUTTER
QT PROLONGING EFF
VENTRICULAR TACHYARRHYTHMIA
QT PROLONGING EFF
VENTRICULAR TACHYCARDIA
QT PROLONGING EFF
DERMATITIS CONTACT
SKIN
Dermatitis contact
URTICARIA CONTACT
SKIN
Dermatitis contact
DERMATITIS
SKIN
Dermatitis/Eczema
DERMATITIS ATOPIC
SKIN
Dermatitis/Eczema
DERMATITIS EXFOLIATIVE
SKIN
Dermatitis/Eczema
DERMATITIS NOS
SKIN
Dermatitis/Eczema
ECZEMA
SKIN
Dermatitis/Eczema
ECZEMA NUMMULAR
SKIN
Dermatitis/Eczema
SEBORRHOEIC DERMATITIS
SKIN
Dermatitis/Eczema
SKIN INFLAMATION
SKIN
Dermatitis/Eczema
SKIN INFLAMMATION
SKIN
Dermatitis/Eczema
SKIN INFLAMMATION NOS
SKIN
Dermatitis/Eczema
EYE SWELLING
SKIN
Oedema
LARYNGEAL OEDEMA
SKIN
Oedema
PHARYNGEAL OEDEMA
SKIN
Oedema
BLISTER
SKIN
Other
CHLOASMA
SKIN
Other
DESQUAMATION
SKIN
Other
EOSINOPHILIC PUSTULAR FOLLICULITIS
SKIN
Other
ERYTHEMA NODOSUM
SKIN
Other
INFECTED SKIN ULCER
SKIN
Other
LIP BLISTER
SKIN
Other
LIP ULCERATION
SKIN
Other
NEURODERMATITIS
SKIN
Other
PENILE ULCERATION
SKIN
Other
PHOTOSENSITIVITY REACTION
SKIN
Other
PHOTOSENSITIVITY REACTION NOS
SKIN
Other
POLYMORPHIC LIGHT ERUPTION
SKIN
Other


20
SCROTAL ULCER
SKIN
Other
SEBORRHOEA
SKIN
Other
SKIN DESQUAMATION
SKIN
Other
SKIN DESQUAMATION NOS
SKIN
Other
SKIN EXFOLIATION
SKIN
Other
SKIN ULCER
SKIN
Other
SKIN ULCERATION
SKIN
Other
ANGIONEUROTIC OEDEMA
SKIN
Rash
DERMATITIS ALLERGIC
SKIN
Rash
DERMATITIS MEDICAMENTOSA
SKIN
Rash
DRUG ERUPTION
SKIN
Rash
DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS
SKIN
Rash
ERYTHEMA
SKIN
Rash
ERYTHEMA GENERALISED
SKIN
Rash
ERYTHEMA INDURATUM
SKIN
Rash
ERYTHEMA OF EYELID
SKIN
Rash
EXANTHEM
SKIN
Rash
EXFOLIATIVE RASH
SKIN
Rash
EYELID OEDEMA
SKIN
Rash
FACE OEDEMA
SKIN
Rash
GENERALISED ERYTHEMA
SKIN
Rash
GENITAL ERYTHEMA
SKIN
Rash
GENITAL RASH
SKIN
Rash
PERIORBITAL OEDEMA
SKIN
Rash
PRURIGO
SKIN
Rash
PRURITUS
SKIN
Rash
RASH
SKIN
Rash
RASH ERYTHEMATOUS
SKIN
Rash
RASH FOLLICULAR
SKIN
Rash
RASH GENERALISED
SKIN
Rash
RASH MACULAR
SKIN
Rash
RASH MACULO-PAPULAR
SKIN
Rash
RASH MORBILLIFORM
SKIN
Rash
RASH NOS
SKIN
Rash
RASH PAPULAR
SKIN
Rash
RASH PRURITIC
SKIN
Rash
RASH PUSTULAR
SKIN
Rash
RASH SCALY
SKIN
Rash
RASH URTICARIA-LIKE
SKIN
Rash
SKIN REACTION
SKIN
Rash
SKIN TOXICITY
SKIN
Rash
SWELLING FACE
SKIN
Rash
TOXIC SKIN ERUPTION
SKIN
Rash
URTICARIA
SKIN
Rash
URTICARIA CHRONIC
SKIN
Rash


TMC278  (Rilpivirine)
Statistical Analysis Plan TMC278-C222 (Week 240)
21
URTICARIA GENERALISED
SKIN
Rash
URTICARIA LOCALISED
SKIN
Rash
URTICARIA NOS
SKIN
Rash
URTICARIA PAPULAR
SKIN
Rash
DERMATITIS BULLOUS
SKIN
Rash vesicular
ERYTHEMA MULTIFORME
SKIN
Rash vesicular
RASH VESICULAR
SKIN
Rash vesicular
STEVENS-JOHNSON SYNDROME
SKIN
Rash vesicular