Conditions: HIV-1 Infections
Keywords: TMC114IFD3001 TMC114 HIV Darunavir PREZISTA
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 145
Healthy volunteers: no

Brief summary:
The primary objective of this trial is to continue the provision of darunavir/ low-dose ritonavir (DRV/rtv) to adult and pediatric patients who previously received DRV/rtv in the clinical trials TMC114-C211, TMC114-C214, TMC114-TiDP31-C229 or in the pediatric trial TMC114-TiDP29-C232 who continue to benefit from the use of darunavir in combination with low-dose ritonavir (DRV/rtv), in countries where DRV is not commercially available for the subject, is not reimbursed, or cannot be accessed through another source (e.g., access program, governmental program) and to provide DRV through this trial until the participants can switched to locally available DRV-based treatment regimens (that is commercially available and reimbursed, or accessible through another source \[for example, access program or government program\]) or to local standard of care, as appropriate.

Detailed description:
This is a continued access trial for adult and pediatric patients who have completed treatment with darunavir in combination with low-dose ritonavir (DRV/rtv) in the parent clinical trials TMC114-C211, TMC114-C214, TMC114-TiDP31-C229 or in the parent pediatric trial TMC114-TiDP29-C232 who continue to benefit from the use of DRV/rtv, and who live in a country where DRV is not accessible. At the baseline visit, inclusion and exclusion criteria will be checked to confirm eligibility. Once the eligibility criteria are met, patients will continue treatment as follows: HIV-1-infected patients participating in the TMC114-C211 trial and some HIV-1 infected patients from the pediatric trial TMC114-TiDP29-C232 will continue on the selected DRV/rtv once daily dosing regimen as administered in the original trial, or (for pediatric patients) on an adjusted dose if necessary due to a change in body weight. Some HIV-infected patients from the pediatric trial TMC114-TiDP29-C232 will continue on the selected twice daily DRV/rtv dosing regimen as administered in the original trial, or (for pediatric patients) on an adjusted dose if necessary due to a change in body weight. HIV-1-infected patients having participated in the TMC114-C214 or TMC114-TiDP31-C229 trial will continue on the DRV/rtv 600/100 mg twice daily dosing regimen as administered in the original trial. Visits and assessment are performed according to local standard of care, but desirable every 3 months for pediatric patients and not less frequently than every 6 months for adult patients. The interval between 2 consecutive visits should not exceed 6 months for pediatric patients. Adverse events (AEs) considered at least possibly related to DRV/rtv, AEs leading to discontinuation or treatment interruption, serious AEs (SAEs), and pregnancies (or all AEs if applicable per local regulation) will be recorded at each visit. Patients will be instructed to report any AEs to the investigator, who will report SAEs within 24 hours to the Sponsor. In addition to the assessments in the flowchart, the following assessments are recommended to be performed locally every 3 months or according to local, generally accepted standards of care: efficacy assessments (immunology and plasma viral load) and laboratory safety assessments (hematology and biochemistry, including pancreatic amylase \[if available\] or lipase and lipid analyses). Treatment will be continued until one of the following criteria is met (whichever occurs first): virologic failure; treatment-limiting toxicity; loss to follow-up; withdrawal of consent/assent by the patient; withdrawal of consent by the parent(s)/legal representative(s); pregnancy; termination of the trial by the sponsor; DRV based treatment regimen becomes commercially available for the patients and is reimbursed, or can be accessed through another source (for example, access program, government program) in the region the patient is living in or patients can be switched to local standard of care, as appropriate. A post-treatment follow-up contact is to be performed 4 weeks after the last dose of trial medication for patients with an ongoing adverse event, that discontinue the trial. This is consistent with the primary objective of the study to provide continued access to DRV/rtv for adult patients who previously received DR/rtv in the clinical trials sponsored by Tibotec Pharmaceuticals. This study is not set up to address any specific hypothesis. Depending on the previous trial the patients were in, they will continue to take either : DRV/rtv 800/100 mg once a day as 2 tablets of 400 mg DRV and 100 mg ritonavir; or DRV/rtv 600/100 mg twice a day as 1 tablet of 600 mg DRV and 100 mg ritonavir twice a day; DRV/rtv 375/100 mg twice a day as 1 tablet of 375 mg DRV and 100 mg ritonavir; DRV/rtv selected dose twice daily , or on an adjusted dose if necessary due to a change in body weight. For most of the patients, their next visit will be the final visit with data collection thereafter visits and assessments will be performed per local standard of care and documented in the patient's medical records only. Investigators will continue to report serious adverse events (SAEs) possibly related to DRV/rtv and pregnancies to the sponsor using regular reporting.

Arms:
arm 1: HIV-1 infected children participants (aged less than \[\<\] 12 years) will continue to receive darunavir (DRV) 200 to 600 milligrams (mg) as oral suspension twice daily (BID) along with ritonavir (rtv) 32 to 100 mg as oral solution/suspension BID. HIV-1 infected adolescent participants (aged 12-17 years) will continue to receive DRV 200 to 600 mg as oral suspension BID along with rtv 32 to 100 mg as oral solution/suspension BID. Dosing for children and adolescent participants will be based on body weight (per parent study TMC114-TiDP29-C232). HIV-1 infected adult participants (aged greater than or equal to \[\>=\] 18 years) will continue to receive DRV 800 mg (2 tablets of 400 mg) orally every day (qd) along with rtv 100 mg tablet (per parent study TMC114-C211) or DRV 600 mg tablet orally BID along with rtv 100 mg tablet (per parent study TMC114-C214 or TMC114-TiDP31-C229).

Interventions: intervention 1: Darunavir intervention 2: Ritonavir
Intervention descriptions: intervention 1: Participants will receive darunavir (per parent study) as oral suspension. intervention 2: Participants will receive ritonavir (per parent study) as oral solution/suspension.

Protocol document:
Prot_000.pdf: 
TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
1
GCP STATEMENT
This trial will be conducted in compliance with this protocol, Good Clinical Practices and applicable regulatory requirements.
CONFIDENTIALITY STATEMENT
The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be 
disclosed unless such disclosure is required by law. In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply to all future 
information supplied to you which is indicated as privileged or confidential.
Approved; Issued Date: 20 June 2019
Clinical Trial Protocol Amendment 
GEN-2
TMC114
Department:
Clinical R&D
Nonproprietary name:
darunavir
Version:
3.0
Date:
20-June-2019
Status:
Approved
Title:
Continued access to darunavir/ritonavir (DRV/rtv) in HIV-1 infected 
adults, adolescents and children aged 3 years and above.
Trial No:
TMC114IFD3001
Clinical phase:
IIIb
Summary:
This is a continued access trial for adult and pediatric subjects who have 
completed treatment with darunavir in combination with low-dose 
ritonavir (DRV/rtv) in the clinical (parent) trials TMC114-C211, 
TMC114-C214, TMC114-TiDP31-C229 or in the pediatric (parent) trial 
TMC114-TiDP29-C232, who continue to benefit from the use of 
DRV/rtv, and who live in a country where DRV is not accessible.
At the baseline visit, inclusion and exclusion criteria will be checked to 
confirm eligibility. Once the eligibility criteria are met, subjects will 
continue treatment as follows: 
HIV-1 infected subjects having participated in the TMC114-C211(parent)
trial and some HIV-1 infected subjects from the pediatric (parent) trial 
TMC114-TiDP29-C232 will continue on the DRV/rtv 800/100 mg once 
daily (q.d.) dosing regimen as administered in the original (parent) trial.
Some HIV-infected subjects from the pediatric (parent) trial 
TMC114-TiDP29-C232 will continue on the selected b.i.d. DRV/rtv 
dosing regimen as administered in the original (parent) trial, or on an 
adjusted dose if necessary due to a change in body weight.
HIV-1 infected subjects having participated in the TMC114-C214 or 
TMC114-TiDP31-C229 (parent) trial will continue on the DRV/rtv 
600/100 mg twice daily (b.i.d.) dosing regimen as administered in the 
original (parent) trial.
Visits and assessments are performed, according to local generally 
accepted standard of care, but desirable every 3 months for pediatric 
subjects and not less frequent than every 6 months for adult subjects. The 
interval between 2 consecutive visits should not exceed 6 months for 
pediatric subjects. Adverse events (AEs) considered at least possibly 
related to DRV/rtv, AEs leading to discontinuation or treatment 
NCT01281813


TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
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Approved; Issued Date: 20 June 2019
interruption, serious AEs (SAEs), and pregnancies (or all AEs if 
applicable per local regulation) will be recorded at each visit.
As per Protocol Amendment 2, the next planned visit will be a
Final/Withdrawal Visit, which will be the last visit with data collection. 
Thereafter, visits and assessments will be performed per local standard of 
care and documented in the subject’s medical records only. Investigators 
will continue to report SAEs possibly related to DRV/rtv and pregnancies 
to the sponsor using regular pharmacovigilance reporting. This 
information will only be entered in the company safety repository.
If the subject exits the trial, the last visit will be a local standard of care 
visit but without dispensation of investigational medication.
Treatment will be continued until 1 of the following criteria is met 
(whichever occurs first): virologic failure; treatment-limiting toxicity; loss 
to follow-up; withdrawal of consent/assent by the subject, withdrawal of 
consent by the parent(s)/legal representative(s); pregnancy; termination of 
the trial by the sponsor; a DRV-based treatment regimen becomes 
commercially available for the subject and is reimbursed, or can be 
accessed through another source (e.g., access program, government 
program) in the region the subject is living in or subjects can be switched 
to local standard of care, as appropriate.
Investigator:
See local Informed Consent/Assent Form
Site address:
See local Informed Consent/Assent Form
Sponsor:
Janssen Research & Development*
Treatment: 
Subjects will either continue on the DRV/rtv dose they received in the 
original (parent) trial or on an adjusted dose if necessary due to a change 
in body weight for pediatric subjects until the subjects can be switched to 
locally available DRV-based treatment regimens (ie, commercially 
available and reimbursed, or accessible through another source [eg, access 
program or government program]) or to local standard of care, as 
appropriate.
*Janssen Research & Development is a global organization that operates through different legal
entities in various countries. Therefore, the legal entity acting as the sponsor for Janssen
Research & Development studies may vary, such as, but not limited to Janssen Biotech, Inc.;
Janssen Products, LP; Janssen Biologics, BV; Janssen Cilag International NV; Janssen, Inc;
Janssen Pharmaceutica NV; Janssen Sciences Ireland Unlimited Company (which includes
former Tibotec Pharmaceuticals); Janssen Biopharma Inc; or Janssen Research & Development,
LLC. The term “sponsor” is used throughout the protocol to represent these various legal
entities; the sponsor is identified on the Contact Information page that accompanies the protocol.


TMC114 IFD3001
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Approved; Issued Date: 20 June 2019
PROTOCOL HISTORY
Protocol History
TMC114IFD3001
Document Type and
File Name
Document Identification
Amendment
Type
Comments
Initial Clinical Trial Protocol
TMC114IFD3001-CTP
8 July 2010
-
-
CTP Amendment I
TMC114IFD3001-CTPA-GEN-I
6 February 2017
Substantial
For details, refer to Amendment GEN-I 
CTP Amendment 2
TMC114IFD3001-CTPA-GEN-II
This document
Substantial
For details, refer to Amendment GEN-II


TMC114IFD3001
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TABLE OF CONTENTS
Protocol History...............................................................................................................................3
Table of Contents.............................................................................................................................4
Protocol Amendments......................................................................................................................7
PART I: Clinical Trial Protocol.....................................................................................................15
1
List of Abbreviations ......................................................................................................15
2
Flowchart ........................................................................................................................17
2.1
Flowchart 1: Trial Follow-up..............................................................................17
2.2
Flowchart 2: Simplified Trial Follow-up............................................................18
3
Introduction.....................................................................................................................19
4
Trial Objectives...............................................................................................................20
4.1
Primary Objective...............................................................................................20
5
Methods...........................................................................................................................20
5.1
Trial Design ........................................................................................................20
5.1.1
Overview of Trial.................................................................................20
5.1.2
Discussion of Trial Design...................................................................22
5.1.3
Selection of Dose(s) in the Trial..........................................................22
5.2
Trial Population ..................................................................................................22
5.2.1
Sample Size..........................................................................................22
5.2.2
Inclusion Criteria .................................................................................22
5.2.3
Exclusion Criteria ................................................................................23
5.2.4
Prohibitions and Restrictions...............................................................24
5.2.5
Removal of Subjects From Therapy or Assessment............................24
5.3
Treatment ............................................................................................................25
5.3.1
Identity of Investigational Product.......................................................25
5.3.2
Other Medication Administered in the Trial........................................26
5.3.3
Dosage(s) and Treatment Overview per Subject .................................26
5.3.4
Timing of Dosing.................................................................................28
5.3.5
Individually Optimized Background Regimen/Underlying 
Antiretroviral Therapy.........................................................................28
5.3.6
Packaging and Labeling.......................................................................29
5.3.7
Randomization.....................................................................................30
5.3.8
Blinding and Unblinding......................................................................30
5.3.9
Drug Accountability.............................................................................30
5.3.10
Storage .................................................................................................30
5.3.11
Adherence ............................................................................................31
5.3.12
Prior and Concomitant Therapy...........................................................31
5.4
Assessments........................................................................................................32
5.4.1
Timing of Assessments........................................................................32
5.4.2
Subject and Disease Characteristics.....................................................32
5.4.3
Efficacy................................................................................................32
5.4.4
Safety ...................................................................................................33
5.5
Safety Monitoring and Toxicity Management....................................................34
5.5.1
Cutaneous Reaction/Rash ....................................................................34
5.5.2
Acute Systemic Allergic Reaction.......................................................36


TMC114IFD3001
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5.5.3
AST and ALT Elevations.....................................................................37
5.5.4
Clinical Hepatitis .................................................................................39
5.5.5
Renal Complications............................................................................39
5.5.6
Nausea (With or Without Vomiting) ...................................................40
5.5.7
Diarrhea................................................................................................40
5.5.8
Other Toxicities ...................................................................................41
5.6
Toxicity Management for Specific Adverse Events with Concomitant 
Antiretroviral Agents ..........................................................................................42
5.6.1
Hyperglycemia.....................................................................................42
5.6.2
Hypertriglyceridemia, Hypercholesterolemia and LDL Cholesterol 
increase ................................................................................................42
5.6.3
Lactic Acidosis.....................................................................................43
5.6.4
Lipodystrophy/Fat Redistribution/Body Changes ...............................44
5.6.5
Pancreatitis...........................................................................................44
5.6.6
Hypersensitivity Reactions ..................................................................45
5.7
Statistical Methods Planned and Determination of the Sample Size..................47
5.7.1
Sample Size Calculation ......................................................................47
5.7.2
Statistical Analyses ..............................................................................47
5.8
Data Quality Assurance ......................................................................................48
6
References.......................................................................................................................49
7
Addenda ..........................................................................................................................51
7.1
Addendum 1: Trial Contact Persons...................................................................51
7.2
Addendum 2: DAIDS Grading Table .................................................................52
7.3
Addendum 3: Visit Schedule for Cutaneous Reaction/Rash Follow-up for 
pediatric subjects.................................................................................................71
7.4
Addendum 4: Revised WHO Clinical Staging of HIV/AIDS ............................73
7.4.1
Revised WHO Clinical Staging of HIV/AIDS ....................................73
7.5
Addendum 5: Lipid Abnormalities (Dyslipidemia)............................................75
PART II: Procedures......................................................................................................................81
1
Adverse Events ...............................................................................................................81
1.1
Definitions...........................................................................................................81
1.2
Attribution Definitions........................................................................................82
1.3
HIV-Related Events or Outcomes ......................................................................82
1.4
Reporting of Adverse Events and HIV-Related Events......................................83
2
Trial Closure Considerations ..........................................................................................84
3
Trial Materials.................................................................................................................85
3.1
Investigational Products......................................................................................85
3.2
Trial Documents..................................................................................................85
3.3
Participation Cards..............................................................................................86
3.4
Source Data.........................................................................................................86
3.5
Case Report Forms..............................................................................................87
3.6
Subject Identification Code List & Subject Screening and Enrollment Log......88
3.7
Archiving ............................................................................................................88
4
Confidentiality ................................................................................................................89
5
Reporting And Publication .............................................................................................89
5.1
Reporting.............................................................................................................89


TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
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5.2
Publication ..........................................................................................................89
6
Authorities/Ethics ...........................................................................................................90
6.1
Regulatory Authorities........................................................................................90
6.2
Independent Ethics Committee/Institutional Review Board...............................90
6.3
ICH-GCP Guidelines ..........................................................................................90
6.4
Subject Information and Informed Consent/Assent............................................90
6.5
Privacy of Personal Data.....................................................................................92
7
Financing and Insurance .................................................................................................92
7.1
Financial Disclosure............................................................................................92
7.2
Indemnification...................................................................................................92
7.3
Insurance.............................................................................................................93
8
Data Quality Control/Assurance.....................................................................................93
Signature Page ...............................................................................................................................94


TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
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Approved; Issued Date: 20 June 2019
PROTOCOL AMENDMENTS
Amendment GEN-II (This document)
The overall reason for the amendment: The aim of this roll-over study is to provide continued 
access to darunavir (DRV) in combination with low dose ritonavir (rtv) for adult and pediatric
subjects who continue to benefit from the use of DRV/rtv and who live in a country where DRV 
is either not commercially available, not reimbursed, or cannot be accessed through another 
source. As of this amendment, the follow-up in this study will be simplified for the reasons 
outlined below.
DRV is approved since 2006 in adults and since 2011 in children as of the age of 3 years and has 
a well-established safety profile. The collection of additional data in Study TMC114IFD3001 is 
unlikely to provide substantial additional information on DRV or to impact the risk-benefit 
assessment. The TMC114IFD3001 is a roll-over study that has been ongoing since August 2011
and provides already substantial long-term safety information on DRV. The parent adult trials 
TMC114-C211 and TMC114-TiDP31-C229 ended respectively in March 2010 and August 2009, 
after which the subjects entered an extension phase until they could rollover into this study. The 
parent adult trial TMC114-C214 ended in March 2012 and the parent pediatric trial 
TMC114-TiDP29-C232 ended in November 2017. Hence, the subjects from Study
TMC114IFD3001 have been on DRV for a significant amount of time. Therefore, the long-term 
safety of DRV has been properly assessed in these subjects, thereby allowing the study follow-up 
to be simplified for all subjects in this roll-over study.
As of this amendment, DRV will continue to be provided through this study until the subjects 
can be switched to locally available DRV-based treatment regimens (ie, commercially available 
and reimbursed, or accessible through another source [eg, access program or government 
program]) or to local standard of care, as appropriate.
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/202EC of the European Parliament and the Council of the European Union.
The table below gives an overview of the rationale of all changes in the GEN-II amendment 
and all applicable sections.
Rationale: The long-term safety of DRV has been established in patients aged 3 years or more, 
and the collection of additional data in this study is unlikely to impact the risk-benefit 
assessment. Therefore, the study follow-up will be simplified, and study-related data will no 
longer be collected in the CRF. The information that will continue to be collected consists of 
serious adverse events (SAEs) possibly related to DRV/rtv and information on pregnancies. 
These are to be reported to the sponsor using regular pharmacovigilance reporting and will only 
be entered in the company safety repository. Medical records should be maintained according to 
the local standard of care and should continue to include details on the use of DRV/rtv.
PART I:2 Flowchart
PART I:4.1 Primary Objective
PART I:5.1.1 Overview of Trial
PART I:5.1.2 Discussion of Trial Design
PART I:5.2.5 Removal of Subjects From Therapy or Assessment


TMC114IFD3001
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PART I:5.3.3 Dosage(s) and Treatment Overview per Subject
PART I:5.3.11 Adherence
PART I:5.4.1 Timing of Assessments
PART I:5.4.3 Efficacy
PART I:5.4.4 Safety
PART I:5.5 Safety Monitoring and Toxicity Management
PART I:5.6 Toxicity Management for Specific Adverse Events with Concomitant Antiretroviral 
Agents
PART II:1.3 HIV-Related Events or Outcomes
PART II:1.4 Reporting of Adverse Events and HIV-Related Events
PART II:3.4 Source Data
PART II:3.5 Case Report Forms
PART II:5.1 Reporting
PART II:8 Data Quality Control/Assurance
Rationale: To allow continuation of viral suppression, DRV will continue to be provided 
through this roll-over study until the subjects can be switched to locally available DRV-based 
treatment regimens (ie, commercially available and reimbursed, or accessible through another 
source [eg, access program or government program]) or to local standard of care, as appropriate.
PART I:3 Introduction
PART I:4 Trial Objectives
PART I:5.1.1 Overview of Trial
PART I:5.1.2 Discussion of Trial Design
PART I:5.2.5 Removal of Subjects From Therapy or Assessment
PART II:2 Trial Closure Considerations
Rationale: Instructions have been added for investigators to follow the guidance in the most 
recent Investigator's Brochure
regarding any contraindications, precautions, and other 
restrictions.
PART I:5.2.4 Prohibitions and Restrictions
Rationale: The list of allowed and disallowed antiretroviral agents was updated to align with the 
most recent Investigator's Brochure and Summary of Product Characteristic.
PART I:5.3.5 Individually Optimized Background Regimen/Underlying Antiretroviral Therapy


TMC114IFD3001
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Rationale: In line with the simplified study setting, information on the provision and destruction 
of study drug supplies was updated.
PART I:5.3.9 Drug Accountability
PART I:5.3.10 Storage
PART II:3.1 Investigational Products
Rationale: Information was added to clarify that the final analysis will be done once all subjects 
have completed the Final/Withdrawal Visit. After termination of data collection, no data will be 
collected in the CRF and no additional statistical analysis will be performed. The Clinical Study 
Report will contain CRF data from all study sites that participated in the study.
PART I:5.7.2 Statistical Analyses
PART II:5.1 Reporting
Rationale: A reference was added in the DAIDS grading table to provide guidance on the charts 
to be used to assess severity grade of abnormal blood pressure values in pediatric subjects.
PART I:7.2 Addendum 2: DAIDS Grading Table
Rationale: The legal entity Janssen, Inc was replaced by Janssen Pharmaceutica NV, Janssen, 
Inc and the abbreviation in Janssen Sciences Ireland UC was written in full. Furthermore, the 
legal entity Janssen Biopharma Inc was added.
Title page: Sponsor Footer
Rationale: Minor edits and corrections were made.
Throughout the document
Amendment GEN-I (06 February 2017)
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/202EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The main reason of this amendment is to integrate the 
clinical trial protocol TMC114-TiDP-C232 into protocol TMC114IFD3001, to allow 
participation of subjects currently enrolled in the pediatric roll-over trial TMC114-TiDP-C232. 
In addition, the name of the sponsor of the trial is updated from 'Tibotec Pharmaceuticals' to 
'Janssen Research & Development' because of the transition of the Johnson & Johnson 
Pharmaceutical Research & Development companies to a unified Janssen identity, as of 2 
February 2012. Finally, the informed consent section was updated to the most recently available 
version.
The table below gives an overview of the rationale of all changes in the GEN-I amendment 
and all applicable sections.
Rationale: The Sponsor amends this adult roll-over trial to allow inclusion of the subjects from 
the pediatric roll-over trial TMC114-TiDP29-C232. The requirements of the two separate 
protocols have been kept mainly unchanged in this revised protocol. For a few items, integration 
of the protocols has led to changes in either the adult or the pediatric safety monitoring. These 


TMC114IFD3001
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are motivated by the standardization across protocols and the absence of safety concerns and are 
described below:
- Section 2 Flowchart - change for the adults: 
The adherence counseling was missing in the flowchart and is now added;
- Section 5.2.5 Must withdraw criteria for glucose levels G3/4 and Section 5.6.1 Toxicity 
Manangement/ Hyperglycemia - change for the adults:
The must withdraw criteria for adults are now extended to the subjects experiencing a persistent
grade 3 or 4 glucose elevation despite appropriate antihyperglycemic treatment (except if the 
subject has pre-existing diabetes) while previously the subjects with glucose grade 3 elevation or 
asymptomatic glucose grade 4 elevation did not require per se trial discontinuation;
- Section 5.2.5 Must withdraw criteria and Section 5.5.3 Safety Monitoring/AST and ALT 
elevations - change for the pediatric subjects:
In the pediatric protocol, language was provided in these sections to require withdrawal of the 
subjects in following circumstances: "The subject meets Hy’s Law criteria for drug-induced liver 
injury (DILI); i.e., alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 ´ the 
upper limit of laboratory normal range (ULN) in combination with total bilirubin elevation > 2 ´ 
ULN or international normalized ratio (INR) > 1.5 without evidence of obstructive disease and 
no other reason* can be found to explain the combination of aminotransferase and total bilirubin 
elevation."
* E.g.: viral hepatitis A, B, or C, pre-existing or acute liver disease, or another drug capable of 
causing the observed injury.
This wording is no longer provided in the current protocol since DILI occurs usually early after 
treatment start and the the pediatric patients entering in this trial have already been treated with 
DRV for a long time. Additionally, adequate safety monitoring rules and withdrawal criteria 
pertaining to the liver enzymes are in place in the same sections, to guarantee the safety of the 
patients in this trial.
- Section 5.5.1 Safety Monitoring/Cutaneous Reaction/Rash - change for the adults:
The use of anesthesia in case of skin biopsy is offered now as well to the adults. In addition, the 
local laboratory assessments are no longer systematic and are now left at the discretion of the 
investigator and after approval of the sponsor. Clarification is also provided that the referral to a 
dermatologist should preferably occur within 24 hours;
- Section 5.5.3 Safety Monitoring/AST and ALT elevations - change for the adults:
A warning on severe acute exacerbation of hepatitis B infection when discontinuing 
emtricitabine (FTC) or lamivudine (3TC) is present in the pediatric protocol as some patients 
might be treated with emtricitabine (FTC) or lamivudine (3TC); as adult patients may also be 
treated by FTC or 3TC, this warning now also applies to the adult population;
- Section 5.6.2 Toxicity Manangement/ Lipids - change for the adults:
The monitoring of low-density lipoprotein (LDL) cholesterol levels, performed for the pediatric 
patients, has now been added for the adult patients as well;


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PART I:2 Flowchart
PART I:5.2.5 Removal of Subjects From Therapy or Assessment
PART I:5.6.1 Hyperglycemia
PART I:5.5.1 Cutaneous Reaction/Rash
PART I:5.5.3 AST and ALT Elevations
PART I:5.6.2 Hypertriglyceridemia, Hypercholesterolemia and LDL Cholesterol increase
Rationale: The Sponsor amends this adult roll-over trial to allow inclusion of the subjects from 
the pediatric roll-over trial TMC114-TiDP29-C232. Therefore in most sections, specific wording 
applying to the pediatric patients was added. The most important additions and adjustments are:
- Section 5.3.3 Body weight: For pediatric subjects, body weight will be recorded at the baseline 
visit and at every visit during the treatment period. Tables for dosage regimens per body weight 
were added: PART I:5.3.3 Dosage(s) and Treatment Overview per Subject;
- Section 5.3.11 Adherence: Adherence counseling of the pediatric patients, the parents or legal 
representative is added as well as the requirement to have that documented in the source 
documents/charts: PART I:5.2.4 Prohibitions and Restrictions, PART I:5.3.11 Adherence;
- Section 5.5.6 Nausea (With or Without Vomiting): Grade 1 and grade 2 nausea were 
updated: PART I:5.5.6 Nausea (With or Without Vomiting);
- Section 5.5.7 Diarrhea: Grade 1 and grade 2 diarrhea were updated: PART I:5.5.7 Diarrhea;
- Section 5.6.4 Fat redistribution: Assessment of fat redistribution in HIV-infected children and 
adolescents is complicated by the normal, dynamic alterations in body composition that occur 
during childhood and adolescence: PART I:5.6.4 Lipodystrophy/Fat Redistribution/Body 
Changes;
- Section 6.4 Informed consent/assent process: The special vulnerability of children and 
adolescents requires specific measures in the informed consent/assent process in order to 
safeguard their best interests and to protect them from harm: PART II:6.4 Subject Information 
and Informed Consent/Assent;
- Section 5.3.5 Allowed and Disallowed Antiretroviral Agents After Baseline: The allowed 
and disallowed ARV agents were added for pediatric subjects: PART I:5.3.5 Individually 
Optimized Background Regimen/Underlying Antiretroviral Therapy.
Rationale: The Sponsor amends this adult roll-over trial to allow inclusion of the subjects from 
the pediatric roll-over trial TMC114-TiDP29-C232. Specific wording applying to the pediatric 
patients and some further clarifications, for consistency reasons, were added to the following 
sections:
Title Page: Title
Title Page: Treatment


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PART I:3 Introduction
PART I:4.1 Primary Objective
PART I:5.1.1 Overview of Trial
PART I:5.1.2 Discussion of Trial Design
PART I:5.1.3 Selection of Dose(s) in the Trial
PART I:5.2.1 Sample Size
PART I:5.2.2 Inclusion Criteria
PART I:5.2.4 Prohibitions and Restrictions
PART I:5.3.1 Identity of Investigational Product
PART I:5.3.2 Other Medication Administered in the Trial
PART I:5.3.4 Timing of Dosing
PART I:5.3.5 Individually Optimized Background Regimen/Underlying Antiretroviral Therapy
PART I:5.3.6 Packaging and Labeling
PART I:5.4.1 Timing of Assessments
PART I:5.4.4.1 Adverse Events/HIV-Related Events
PART I:5.4.4.2 Clinical Laboratory Tests
PART I:5.6.2 Hypertriglyceridemia, Hypercholesterolemia and LDL Cholesterol increase
PART I:5.6.3 Lactic Acidosis
PART I:5.7.1 Sample Size Calculation
PART I:6 References
PART I:7.3 Addendum 3: Visit Schedule for Cutaneous Reaction/Rash Follow-up for pediatric 
subjects
PART I:7.5 Addendum 5: Lipid Abnormalities (Dyslipidemia)
PART II:1.4 Reporting of Adverse Events and HIV-Related Events
PART II:3.2 Trial Documents
PART II:3.4 Source Data
PART II:3.7 Archiving
PART II:6.2 Independent Ethics Committee/Institutional Review Board
PART II:6.4 Subject Information and Informed Consent/Assent
PART II:7.3 Insurance
Rationale: Allowed and Disallowed Antiretroviral Agents After Baseline - changes for the 
adults: Dolutegravir is no longer an investigational but an approved integrase inhibitor;
PART I:5.3.5 Individually Optimized Background Regimen/Underlying Antiretroviral Therapy


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Rationale: The section on informed consent/assent was updated to reflect the latest language in 
the Janssen protocol template, taking into account that both adult and pediatric subjects will be 
included in this study.
PART II:6.4 Subject Information and Informed Consent/Assent
Rationale: A list of clinical trials with specific populations for which darunavir (DRV) is 
approved is added. For detailed and updated information on the clinical trial data, reference is 
made to the most recent Investigator's Brochure (IB) of DRV2.
PART I:3 Introduction
Rationale: Replacement of the Annual Safety Report by the Development Safety Update Report.
PART II:5.1 Reporting
Rationale: Minor editorial changes for clarity and consistency. 
List of Abbreviations
Signature Page
Rationale: The name of the sponsor of the trial is updated from 'Tibotec Pharmaceuticals' to 
'Janssen Research & Development' because of the transition of the Johnson & Johnson 
Pharmaceutical Research & Development companies to a unified Janssen identity, as of 2 
February 2012.
Title Page: Sponsor
PART I:3 Introduction
PART I:4.1 Primary Objective
PART I:5.1.1 Overview of Trial
PART I:5.1.2 Discussion of Trial Design
PART I:5.2.1 Sample Size
PART I:5.3.1 Identity of Investigational Product
PART I:5.3.2 Other Medication Administered in the Trial
PART I:5.3.6 Packaging and Labeling
PART I:5.3.10 Storage
PART I:5.4.1 Timing of Assessments
PART I:5.5 Safety Monitoring and Toxicity Management
PART I:5.5.1 Cutaneous Reaction/Rash
PART I:5.6 Toxicity Management for Specific Adverse Events with Concomitant Antiretroviral 
Agents
PART I:5.7.1 Sample Size Calculation
PART I:7.2 Addendum 2: DAIDS Grading Table


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PART I:7.5 Addendum 5: Lipid Abnormalities (Dyslipidemia)
PART II:1.4 Reporting of Adverse Events and HIV-Related Events
PART II:5.1 Reporting
Signature Page
Rationale: The sponsor has decided to harmonize the procedures for emergency medical 
questions and product complaints. Therefore, the telephone number mentioned on the title page 
has been removed. Appropriate information about who should be contacted regarding safety 
issues or questions regarding the clinical trial is provided on the contact information page. 
Title Page: Summary


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PART I: CLINICAL TRIAL PROTOCOL
1
LIST OF ABBREVIATIONS
3TC
lamivudine
ABC
abacavir
ACTG
Adult AIDS Clinical Trial Group
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ARV
antiretroviral
ASR
Annual Safety Report
AST
aspartate aminotransferase
BRAT
bananas, rice, applesauce and toast
b.i.d.
twice daily (bis in die)
CDC
U.S. Centers for Disease Control and Prevention
CRF
Case Report Form
DAIDS
Division of AIDS
DCF
Data Correction Form
DILI
Drug-induced liver injury
ddI
didanosine
DRV
darunavir (formerly known as TMC114)
FTC
emtricitabine
GCP
Good Clinical Practice
HDL
high-density lipoprotein
HIV
human immunodeficiency virus
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
IUD
intra-uterine device
LDL
low-density lipoprotein
NCEP
National Cholesterol Education Program
NCR
non-carbon required
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
OBR
optimized background regimen
PI
protease inhibitor
QA
Quality Assurance
QC
Quality Control
q.d.
once daily (quaque die)
RAM
resistance-associated mutation
RBC
red blood cell
rtv 
low-dose ritonavir
SAE
serious adverse event


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SJS
Stevens-Johnson syndrome
TDF
tenofovir disoproxil fumarate
TEN
toxic epidermal necrolysis
TMC114
darunavir
TMC125
etravirine
ULN
upper limit of laboratory normal range
WBC
white blood cell


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2
FLOWCHART
2.1
Flowchart 1: Trial Follow-up
Up to and including Protocol Amendment 1:
Type of Visit
Baseline 
Treatment Period
Post-treatment 
Period
Time of Visit
Day 1a
Visits and 
assessments are 
performed, according 
to Local Standard of 
Care, but desirable 
every 3 months for 
pediatric subjects and 
not Less Frequent 
Than Every 6 Months 
for adult subjects. 
The interval between 
2 consecutive visits 
should not exceed 6 
months for pediatric 
subjects.
Final / 
Withdrawal 
Visitg
Follow-up 
Contact Week 4b
Informed consent/assent
X
Xh
Inclusion/exclusion criteria
X
Demographic data
X
Pregnancy test, if applicablec
X
X
X
Weightf
X
X
Dispensation of investigational 
medication
X
X
Xh
Drug accountability
X
X
Adherence Counseling
X
X
Xh
Collection of the following AEsd:
X
X
X
X
-
AEs considered to be at least 
possibly related to DRV/rtv;
-
AEs leading to discontinuation or 
treatment interruption;
-
SAEs and pregnancies.
Treatments related to (S)AEse
X
X
X
a
Subjects will rollover from another (parent) trial. The baseline visit will coincide with the last visit of the 
previous (parent) trial. Assessments and results from the last visit of the previous (parent) trial will be used for 
the baseline visit of this trial; overlapping assessments only need to be conducted once. Demographic 
information will be copied from the previous (parent) trial, if needed.
b
The Week 4 follow-up contact is only needed for subjects with an ongoing AE as specified in this flowchart.
c
Urine pregnancy test for the females of childbearing potential only.
d
Other AEs will only be collected if required per local regulations.
e
Collection of data on treatments related to (S)AEs for which information is collected.
f
Only applicable for pediatric subjects.
g
The next planned visit will be a Final/Withdrawal Visit for all subjects when discontinuing the trial or switching 
to simplified data collection as per Protocol Amendment 2. For subjects continuing the trial under Protocol 
Amendment 2, all subsequent visits and assessments will be performed per local standard of care and 
documented in the subject's medical records only, as described in Flowchart 2: Simplified Trial Follow-up.
h
Only applicable for subjects continuing the trial under Protocol Amendment 2.


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2.2
Flowchart 2: Simplified Trial Follow-up
As of Protocol Amendment 2:
The next planned visit after approval of Protocol Amendment 2 will be a Final/Withdrawal Visit.
During this Final/Withdrawal Visit, the informed consent will be signed, final assessments will 
be carried out and recorded in the CRF, and the study medication will be dispensed as described 
in Flowchart 1: Trial Follow-up. All subsequent visits and assessments will be performed per 
local standard of care and documented in the subject’s medical records only. Investigators will
continue to report SAEs possibly related to DRV/rtv and pregnancies to the sponsor using 
regular pharmacovigilance reporting. This information will only be entered in the company 
safety repository.
If the subject exits the trial, the last visit will be a local standard of care visit but without 
dispensation of investigational medication.
Type of Visit
Local Standard of Care Visita
Informed consent/assent
Refer to the Final/Withdrawal Visit 
in Flowchart 1: Trial Follow-up
Dispensation of investigational medication
Xd
Collection of SAEs possibly related to DRV/rtv and pregnanciesb
X
Study terminationc
X
Note: Assessments are to be performed per local standard of care and documented in the subject's medical 
records only.
a The next planned visit before switching to simplified data collection as per Protocol Amendment 2 will be a 
Final/Withdrawal Visit. During this Final/Withdrawal Visit, the informed consent will be signed, final assessments 
will be carried out and recorded in the CRF, and the study medication will be dispensed as described in Flowchart 1: 
Trial Follow-up.
b Investigators will continue to report SAEs possibly related to DRV/rtv and pregnancies to the sponsor using regular 
pharmacovigilance reporting.
c Study termination will be documented in the subject’s medical records and recorded on a separate, paper 
termination disposition form to be shared with the sponsor.
d If the subject exits the trial, the last visit will be a local standard of care visit but without dispensation of 
investigational medication.


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3
INTRODUCTION
Inhibitors of human immunodeficiency virus (HIV) protease have become cornerstones in the 
treatment of HIV disease, particularly in HIV-1 infected subjects with a long history of 
antiretroviral (ARV) therapy. Current options for the treatment of HIV-1 infected adult subjects 
consist of nucleoside/nucleotide reverse transcriptase inhibitor (NRTIs), non-nucleoside reverse 
transcriptase inhibitor (NNRTIs), protease inhibitors (PIs), entry inhibitors, and an integrase 
inhibitor. A triple regimen is considered standard of care1 and when effective, results in 
suppression of the virus below the detection limits of the current tests, thereby strongly reducing 
the emergence of resistance.
Darunavir (DRV, formerly known as TMC114) is an HIV PI with potent in vitro activity against 
wild-type HIV-1, and, as a result of the drug-screening program aimed at activity against 
resistant strains of HIV-1, also active against a large panel of viruses resistant to currently 
licensed PIs.
DRV, co-administered with low dose ritonavir is indicated in combination with other 
antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) 
infection in adult and pediatric patients from the age of 3 years. DRV was first registered in the 
United States (June 2006) and has obtained marketing authorization in Europe in February 2007. 
The approved indications and registered tablet strengths for DRV vary per country where 
registered.
DRV has been approved based on the below mentioned clinical trials in the following 
populations:
ADULT HIV-Infected subjects:
In ARV-experienced: Studies TMC114-C202, TMC114-C213, TMC114-C215, TMC114-C214
In ARV-experienced without DRV resistance-associated mutations (RAMs): Trial
TMC114-TiDP31-C229
In ARV-naive subjects: Trial TMC114-C211
The adult patients could roll-over to trial TMC114IFD3001 for access to DRV if not yet 
accessible by other means in their country.
PEDIATRIC HIV-Infected subjects:
In ARV-experienced adolescents: Trial TMC114-C212 
In ARV-naive adolescents: Trial TMC114-C230
In ARV-experienced subjects aged 3 years to 6 years: Trial TMC114-C228
The pediatric patients could roll-over to trial TMC114-TiDP29-C232 for access to DRV if not 
yet accessible by other means in their country.
For detailed and updated information on the clinical trial data, refer to the most recent 
Investigator's Brochure (IB) of DRV.2


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The aim of the present amended trial TMC114IFD3001 is to provide continued access to 
DRV/rtv for adult and pediatric subjects who previously received DRV/rtv in the 
above-mentioned clinical (parent) trials, who continue to benefit from treatment with DRV and 
cannot have access to DRV in their country by other means.
4
TRIAL OBJECTIVES
4.1
Primary Objective
The primary objective of this trial is to continue the provision of DRV/rtv for adult and pediatric
subjects who previously received DRV/rtv in the clinical (parent) trials TMC114-C211,
TMC114-C214, TMC114-TiDP31-C229 or in the pediatric (parent) trial
TMC114-TiDP29-C232, who continue to benefit from the use of DRV/rtv, in countries where 
DRV is not commercially available for the subject, is not reimbursed, or cannot be accessed 
through another source (e.g., access program, governmental program).
In addition, the long-term safety and tolerability of DRV/rtv in combination with other ARVs 
will be assessed.
Protocol Amendment 2 Objective:
As of Protocol Amendment 2, the objective of the trial is to provide DRV through this trial until 
the subjects can be switched to locally available DRV-based treatment regimens (ie, 
commercially available and reimbursed, or accessible through another source [eg, access 
program or government program]) or to local standard of care, as appropriate.
5
METHODS
5.1
Trial Design
5.1.1
OVERVIEW OF TRIAL
This is a continued access trial for adult and pediatric subjects who have completed treatment 
with DRV/rtv in the adult clinical (parent) trials TMC114-C211, TMC114-C214, 
TMC114-TiDP31-C229 or in the pediatric (parent) trial TMC114-TiDP29-C232, who continue 
to benefit from the use of DRV/rtv, and who live in a country where DRV is not accessible.
At the baseline visit, inclusion and exclusion criteria will be checked to confirm eligibility. Once 
the eligibility criteria are met, subjects will continue treatment as follows: 
-
HIV-1 infected subjects participating in the TMC114-C211(parent) trial or in the pediatric 
(parent) trial TMC114-TiDP29-C232, after original participation in TMC114-TiDP29-C230
trial will continue on the DRV/rtv 800/100 mg q.d. dosing regimen as administered in the 
original (parent) trial.
-
HIV-1 infected subjects participating in the pediatric (parent) trial TMC114-TiDP29-C232, 
after original participation in TMC114-C212 or TMC114-TiDP29-C228 trial will continue 
on the selected b.i.d. DRV/rtv dosing regimen as administered in the original (parent) trial, or 
on an adjusted dose if necessary due to a change in body weight.


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HIV-1 infected subjects participating in the TMC114-C214 or TMC114-TiDP31-C229 (parent) 
trials will continue on the DRV/rtv 600/100 mg b.i.d. dosing regimen as administered in the 
original (parent) trial. 
Visits and assessments are performed, according to local generally accepted standard of care, 
but desirable every 3 months for pediatric subjects and not less frequent than every 6 months for 
adult subjects. The interval between 2 consecutive visits should not exceed 6 months for 
pediatric subjects. Adverse events (AEs) considered at least possibly related to DRV/rtv, AEs 
leading to discontinuation or treatment interruption, serious AEs (SAEs), and pregnancies (or all 
AEs if applicable per local regulation) will be recorded at each visit. Subjects will be instructed 
to report any AEs to the investigator, who reports SAEs within 24 hours to the sponsor (see Part 
II, Section 1.4 ‘Reporting of Adverse Events and HIV-Related Events’).
Details on the timing of treatment and assessments are provided in the flowchart in Section 2.
In addition to the assessments in this flowchart, the following assessments are recommended to 
be performed locally every 3 months or according to local generally accepted standard of care:
-
Efficacy assessments (immunology and plasma viral load); and 
-
Laboratory safety assessments (hematology and biochemistry, including pancreatic amylase 
[if available] or lipase and lipid analyses).
As per Protocol Amendment 2, the next planned visit will be a Final/Withdrawal Visit, which 
will be the last visit with data collection. Thereafter, visits and assessments will be performed per 
local standard of care and documented in the subject’s medical records only. Investigators will
continue to report SAEs possibly related to DRV/rtv and pregnancies to the sponsor using 
regular pharmacovigilance reporting. This information will only be entered in the company 
safety repository.
If the subject exits the trial, the last visit will be a local standard of care visit but without 
dispensation of investigational medication.
Treatment will be continued until one of the following criteria is met (whichever occurs first): 
-
Virologic failure;
-
Treatment-limiting toxicity;
-
Loss to follow-up;
-
Withdrawal of consent/assent by the subject or withdrawal of consent by the parent(s)/legal 
representative(s);
-
Pregnancy;
-
Termination of the trial by the sponsor;
-
A DRV-based treatment regimen becomes commercially available for the subject and is 
reimbursed, or can be accessed through another source (e.g., access program, government 
program) in the region the subject is living in or subjects can be switched to local standard of 
care, as appropriate.
A post-treatment follow-up contact is to be performed 4 weeks after the last dose of trial 
medication for subjects with an ongoing adverse event, that discontinue the trial under Protocol 
Amendment 1, as specified in the flowchart in Section 2.


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5.1.2
DISCUSSION OF TRIAL DESIGN
The primary objective of this trial is to continue the provision of DRV/rtv to subjects who have 
completed treatment with DRV/rtv in the adult clinical (parent) trials TMC114-C211, 
TMC114-C214, TMC114-TiDP31-C229 or in the pediatric (parent) trial
TMC114-TiDP29-C232, who continue to benefit from the use of DRV/rtv, and who live in a 
country where DRV is not commercially available, is not reimbursed, or cannot be accessed 
through another source (e.g., access program, government program).
Selected safety data are to be collected during DRV/rtv treatment (see Section 5.4.4). Additional 
assessments not included in this protocol can be done locally as per local standard of care.
As per Protocol Amendment 2, the next planned visit will be a Final/Withdrawal Visit, which 
will be the last visit with data collection. Thereafter, visits and assessments will be performed per 
local standard of care and documented in the subject’s medical records only. SAEs possibly 
related to DRV/rtv and information on pregnancies will continue to be reported to the sponsor
using regular pharmacovigilance reporting. This information will only be entered in the company 
safety repository.
If the subject exits the trial, the last visit will be a local standard of care visit but without 
dispensation of investigational medication.
5.1.3
SELECTION OF DOSE(S) IN THE TRIAL
Subjects will continue on the DRV/rtv dosing regimen as administered in the original (parent) 
trial i.e., DRV/rtv 800/100 mg q.d. for HIV-infected subjects from the TMC114-C211 (parent) 
trial or from the pediatric (parent) trial TMC114-TiDP29-C232; the selected b.i.d. DRV/rtv 
dosing regimen for HIV-infected subjects from the pediatric (parent) trial
TMC114-TiDP29-C232 with weight-based dose adjustment if necessary (see Section 5.3.3); and 
DRV/rtv 600/100 mg b.i.d. for HIV-infected subjects from the TMC114-C214 or 
TMC114-TiDP31-C229 (parent) trial.
5.2
Trial Population
5.2.1
SAMPLE SIZE
Not applicable.
Subjects who previously received treatment with DRV/rtv in the clinical (parent) trials 
TMC114-C211, TMC114-C214, TMC114-TiDP31-C229 or in the pediatric (parent) trial
TMC114-TiDP29-C232, who continue to benefit from the use of DRV/rtv, and who live in a 
country where DRV is not accessible may be eligible to continue treatment with DRV/rtv via this 
trial.
5.2.2
INCLUSION CRITERIA
Subjects who meet all of the following criteria are eligible for this trial:
1. "Criterion modified per Amendment 1"
1.1 Male or female subjects, aged 3 years and above.
2. "Criterion modified per Amendment 1"


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2.1 Subjects treated with DRV/rtv who have successfully completed the TMC114-C211, 
TMC114-C214, TMC114-TiDP31-C229 (parent) trial or the pediatric (parent) trial 
TMC114-TiDP29-C232 and in the opinion of the investigator continue to receive benefit from 
using DRV/rtv.
3. DRV is not commercially available for the subjects, is not reimbursed, or cannot be accessed 
through another source (e.g. access program, government program) in the region the subject is 
living in.
4. "Criterion modified per Amendment 1"
4.1 Subject (where appropriate, depending on age) and the parent(s) or legal representative(s) 
have signed the Informed Consent/Assent Form voluntarily. Children will be informed about the 
program and asked to give assent (where appropriate, depending on age).
5.2.3
EXCLUSION CRITERIA
Subjects meeting 1 or more of the following criteria cannot be selected:
1.
Any condition (including but not limited to alcohol and drug use) which, in the opinion of 
the investigator, could compromise the subject’s safety or adherence to treatment with 
DRV/rtv.
2.
Any active clinically significant disease (e.g., pancreatitis, cardiac dysfunction) or findings 
of medical history, laboratory or physical examination that, in the investigator’s opinion, 
would compromise the subject’s safety during treatment with DRV/rtv.
3.
Previously demonstrated clinically significant allergy or hypersensitivity to any of the 
excipients of the investigational medication (DRV) or ritonavir.
4.
Pregnant or breastfeeding female subjects.
5.
Female subject of childbearing potential without use of effective non-hormonal birth control 
methods or not willing to continue practicing these birth control methods for at least 
30 days after the end of the treatment period.
Note: Estrogen hormonal based contraception may not be reliable when taking DRV/rtv, 
therefore to be eligible for this trial female subjects of childbearing potential should either:
a. Use a double-barrier method to prevent pregnancy (i.e., use a male condom with either 
diaphragm or cervical cap)*; or
b. Use non-estrogen hormonal based contraceptives in combination with a barrier 
contraceptive (i.e., male condom, diaphragm or cervical cap, or female condom); or
c. Use an intra-uterine device (IUD) in combination with a barrier contraceptive (i.e., male 
condom, diaphragm or cervical cap, or female condom); or
d. Be non-heterosexually active, practice heterosexual abstinence, or have a vasectomized 
partner (confirmed sterile).
*A male and female condom should not be used together due to the risk of breakage 
or damage caused by latex friction.
Women who are postmenopausal for at least 2 years, women with total hysterectomy, 
and women with tubal ligation are considered of non-childbearing potential.


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6.
Heterosexually active male subject not using effective birth control methods or not willing 
to continue practicing these birth control methods during the trial and until 30 days after the
end of the trial (or after last intake of investigational medication).
5.2.4
PROHIBITIONS AND RESTRICTIONS
It is the investigator’s responsibility to provide appropriate counseling to HIV-1 infected subjects 
about taking the necessary precautions to reduce the risk of transmitting HIV.
Since the effects of DRV/rtv on gestation are unknown, heterosexually, non-vasectomized male 
subjects, who are sexually active and/or female subjects of child-bearing potential having 
heterosexual intercourse should receive counseling about birth control methods7 and be advised 
to use one of the following birth control methods as outlined above in the exclusion criteria 
(Section 5.2.3). Girls having their first menses during the trial should receive counseling as well.
Female subjects should not breastfeed when taking DRV/rtv, since the effects to the newborn 
child are unknown. Female subjects who have a newborn child should talk to their physician 
about the best way to feed their child. They should be aware that HIV could be transmitted 
through breastfeeding.
The above precautions and restrictions apply from baseline onwards, until at least 30 days after 
the last intake of investigational medication.
Investigators should follow the guidance in the most recent Investigator’s Brochure2 regarding 
any contraindications, precautions for use, and other restrictions.
For detailed and updated information on the clinical trial data with regard to the reproductive 
toxicity of DRV, refer to the most recent Investigator's Brochure (IB) of DRV2.
5.2.5
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT 
A subject may be withdrawn from the trial if:
1. An SAE occurs.
2. The subject fails to comply with the protocol requirements or to cooperate with the 
investigator.
3. The subject starts disallowed treatment (see Section 5.3.12). The sponsor should be contacted 
to evaluate the need for withdrawal.
4. The subject demonstrates lack or loss of treatment response during the trial.
A subject must be withdrawn from the trial if:
1. The parent(s) or legal representative(s) withdraw(s) consent, or the subject withdraws 
consent or assent.
2. The investigator considers it, for safety reasons, in the best interest of the subject that he or 
she be withdrawn.
3. Pregnancy has been determined.
4. The subject is diagnosed with acute hepatitis A, B, or C infection after baseline. For details 
on monitoring and management of hepatitis, see Section 5.5.4.


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5. The subject experiences a grade 3 or 4 cutaneous reaction/rash (according to the DAIDS 
scale; see Section 7.2, Addendum 2: DAIDS Grading Table). For details on monitoring and 
management of cutaneous reaction/rash, see Section 5.5.1.
6. The subject experiences a grade 4 AE considered at least possibly related to DRV/rtv or a 
confirmed grade 4 laboratory abnormality (according to the Division of AIDS [DAIDS] 
scale; see Section 7.2, Addendum 2: DAIDS Grading Table) considered at least possibly 
related to DRV/rtv. Exceptions are, unless clinical assessment foresees an immediate health 
risk to the subject:
7. Subjects with asymptomatic triglyceride grade 4 elevations (see Section 5.6.2).The subject 
experiences a persistent grade 3 or 4 glucose elevation despite appropriate 
anti-hyperglycemic treatment (except if the subject has pre-existing diabetes; see Section
5.6.1)
8. The subject experiences a confirmed grade 4 pancreatic amylase elevation or a confirmed 
grade 3 or grade 4 lipase elevation, which persists after 14 days after the interruption of the 
trial medication, or if the toxicity recurs more than twice (see also Section 5.6.5.2).The 
subject experiences, after trial medication interruption because of a confirmed grade 3 
increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST), a confirmed 
recurrence of grade 3 or 4 increase in ALT or AST. For subjects with hepatitis B or C 
coinfection present at baseline, refer to Section 5.5.3 for toxicity management plans.
9. The subject experiences a grade 3 or 4 acute systemic allergic reaction (according to the 
DAIDS scale; see Section 7.2, Addendum 2: DAIDS Grading Table). For details on 
monitoring and management of acute systemic allergic reactions, refer to Section 5.5.2.
10. A DRV-based treatment regimen becomes commercially available for the subject and is 
reimbursed, or can be accessed through another source (e.g., access program, government 
program) in the region the subject is living in or subjects can be switched to local standard of 
care, as appropriate.
The date and reason for discontinuation must be noted on the Case Report Form (CRF). Unless 
the parent(s)/legal representative(s) or subject withdraw(s) consent/assent, each subject 
prematurely discontinuing the trial must be seen for a final evaluation (withdrawal visit). A 
post-treatment follow-up contact is to be performed 4 weeks after the last dose of trial 
medication for subjects with an ongoing adverse event, that discontinue the trial under Protocol 
Amendment 1, as specified in the flowchart in Section 2. After the last visit, the Trial 
Termination page and Investigator’s Signature page of the CRF is to be completed.
As per Protocol Amendment 2, study termination will be documented in the subject’s medical 
records and recorded on a separate, paper termination disposition form to be shared with the 
sponsor.
5.3
Treatment
5.3.1
IDENTITY OF INVESTIGATIONAL PRODUCT
The investigational medication DRV will be manufactured under the responsibility of the 
sponsor and will be formulated as follows:


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Formulation F029: oral tablet composed of DRV ethanolate eq. 75 mg, microcrystalline 
cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate, and OPADRY®
white.
-
Formulation F050: oral tablet composed of DRV ethanolate eq. 150 mg, microcrystalline 
cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate, and OPADRY®
white.
-
Formulation F030: oral tablet composed of DRV ethanolate eq. 400 mg, microcrystalline 
cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate, and OPADRY®
light orange.
-
Formulation F032: oral tablet composed of DRV ethanolate eq. 600 mg, microcrystalline 
cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate, and OPADRY®
orange.
-
Formulation F052: oral suspension composed of DRV ethanolate eq. 100 mg per ml, 
hydroxypropylcellulose, microcrystalline cellulose and sodium carboxymethylcellulose, 
sodium methyl parahydroxybenzoate, citric acid monohydrate, sucralose, masking flavor, 
strawberry cream flavor, concentrated hydrochloric acid and purified water.
Note: The oral tablets should not be crushed but be swallowed as whole tablets. The oral 
suspension should be shaken immediately before administration.
5.3.2
OTHER MEDICATION ADMINISTERED IN THE TRIAL
The sponsor provides commercial ritonavir (Norvir®) which is formulated as a capsule or tablet, 
depending on availability, containing 100 mg ritonavir, as a sachet of 100 mg ritonavir powder 
for oral suspension (at a ritonavir concentration of 10 mg/mL), or as a liquid solution containing 
80 mg/mL ritonavir. Refer to Section 5.3.6 and the current package inserts for further details.
The sponsor will not provide the medication of the optimized background regimen (OBR). The 
subject will receive the investigator-selected OBR medications according to the locally 
applicable procedures. Refer to the current package inserts for further details.
5.3.3
DOSAGE(S) AND TREATMENT OVERVIEW PER SUBJECT 
Adult Patients
Once eligibility criteria are met, subjects will continue on the DRV/rtv dose they received in the 
original (parent) trial.
HIV-1 infected subjects participating in the TMC114-C211 (parent) trial continue on DRV/rtv 
800/100 mg q.d (i.e., 2 tablets of 400 mg DRV and 100 mg ritonavir q.d.).HIV-1 infected 
subjects participating in the TMC114-C214 or TMC114-TiDP31-C229 (parent) trial continue 
on DRV/rtv 600/100 mg b.i.d. (i.e., 1 tablet of 600 mg DRV and 100 mg ritonavir b.i.d.).
Pediatric Patients
The dosing regimen for subjects participating in the pediatric (parent) trial
TMC114-TiDP29-C232 is identical to the dosing regimen in the trials that subjects originated 
from before rolling over into TMC114-TiDP29-C232 (adjusted for weight if applicable).


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Table 1 and Table 2 provide an overview of the exact volume of trial medication to be 
administered per body weight and per intake.
Table 1: Exact volume of trial medication (DRV [oral suspension] and ritonavir [oral 
solution, 80 mg/mL]) to be administered per body weight and per intake.
Body Weight, kg
DRV dose, 
mg b.i.d.
DRV volume,
mL b.i.d.
Ritonavir dose,
mg b.i.d.
Ritonavir volume,
mL b.i.d.
10 – 10.9
200
2.0
32
0.4
11 – 11.9
220
2.2
32
0.4
12 – 12.9
240
2.4
40
0.5
13 – 13.9
260
2.6
40
0.5
14 – 14.9
280
2.8
48
0.6
≥ 15 – 29.9
375
3.8
50
0.6
≥ 30 – 39.9
450
4.6
60
0.7
≥ 40*
600
6.0
100
1.25
* It is expected that these subjects are able to swallow the tablets. Therefore, most subjects will be taking the solid 
formulation only.
Table 2: Exact volume of trial medication (DRV [oral suspension] and ritonavir [powder 
for oral suspension (prepared as 100 mg/10 mL)*]) to be administered per body 
weight and per intake.
Body Weight, kg
DRV dose, 
mg b.i.d.
DRV volume,
mL b.i.d.
Ritonavir dose,
mg b.i.d.
Ritonavir volume,
mL b.i.d.*
10 – 10.9
200
2.0
32
3.2
11 – 11.9
220
2.2
32
3.2
12 – 12.9
240
2.4
40
4.0
13 – 13.9
260
2.6
40
4.0
14 – 14.9
280
2.8
48
4.8
≥ 15 – 29.9
375
3.8
50
5.0
≥ 30 – 39.9
450
4.6
60
6.0
≥ 40**
600
6.0
100
10.0
* When mixed with 9.4 mL of liquid (water, chocolate milk, or infant formula) the concentration of the suspension is 
10 mg/mL.
** It is expected that these subjects are able to swallow the tablets. Therefore, most subjects will be taking the solid 
formulation only.
As the dose recommendations for pediatric subjects changed during the trial, it is recommended 
to check the subject’s viral load after dose adjustment based on the new dosing. 
Note: This approach is consistent with the standard practice, whenever a change in ARV therapy 
is made.
Note: Subjects who experience tolerability issues with the ritonavir liquid or powder (for oral 
suspension) formulation and/or are at risk of discontinuing DRV/rtv based on investigator 
assessment will be allowed to switch to one 100-mg capsule or tablet ritonavir b.i.d..
For pediatric subjects, body weight is recorded at the baseline visit and at every visit during the 
treatment period (Up until the Final/Withdrawal Visit as of Protocol Amendment 2). Subjects 
will be weighed in underwear, wearing no shoes. The same calibrated weighing scale should be 
used at each visit.


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In case the subject has a relevant change in body weight, the dose of DRV/rtv should be adapted 
accordingly:
- Increase of weight: no confirmation of the weight required;
- Decrease of weight: confirmed weight is required at the next consecutive visit or at an 
additional visit, at the investigator’s discretion, in case of intended dose decrease.
5.3.4
TIMING OF DOSING
Subjects will be required to take the trial medication (DRV/rtv) orally within 30 minutes after 
completion of a meal, approximately every 12 hours (in case of b.i.d. dosing) or every 24 hours 
(in case of q.d. dosing). The bitter taste for ritonavir solution may be lessened if mixed with 
another fluid as suggested in the product information (do not dilute with water). The bitter 
aftertaste of Norvir® powder for oral suspension may be lessened if peanut butter, hazelnut 
chocolate spread, or black currant syrup are taken immediately after dose administration.
The type of meal does not need to be considered.
For subjects who miss a dose of DRV/rtv:
If a caregiver (parent or legal representative) or a subject notices that he/she has missed the 
combined dose, or simply one of its components (DRV or ritonavir) and it is still within 6 hours 
(in case of b.i.d. dosing) or 12 hours (in case of q.d. dosing) of the time it is usually taken, the 
subject should always take the combined dose of DRV and ritonavir as soon as possible with 
food (i.e., when DRV or ritonavir are not taken, both compounds [DRV and ritonavir] should be 
taken if still within the 6 or 12 hours, respectively). The subject may then continue his/her usual 
dosing schedule.
If a caregiver (parent or legal representative) or subject notices that he/she has missed the dose 
more than 6 hours (in case of b.i.d. dosing) or 12 hours (in case of q.d. dosing) after the time it is 
usually taken, the subject must be instructed not to take it, but simply to resume the usual dosing 
schedule. Subjects should not double the dose to make up for a missed dose.
If a subject vomits immediately after intake of the trial medication, the correct dose of DRV/rtv 
may be re-taken. Re-dosing is not allowed if the subject vomits more than 15 minutes after 
intake of the trial medication.
5.3.5
INDIVIDUALLY OPTIMIZED BACKGROUND REGIMEN/UNDERLYING 
ANTIRETROVIRAL THERAPY
The OBR will be composed at the discretion of the investigator, according to the local standard 
of care and based on experience with previous therapies. It is strongly recommended that the 
OBR consists of at least 2 active ARV agents. If abacavir (ABC) is selected as an NRTI in the 
OBR, documentation should be available showing that a HLA-B*5701 test has been performed 
with a negative result.
Allowed and disallowed ARV agents after baseline for adult and pediatric subjects are 
summarized below in Table 3 and Table 4 respectively. All subjects can have their OBR changed 
or optimized at any time if medically considered, including at trial entry.


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Table 3:
Allowed and Disallowed Antiretroviral Agents After Baseline for adults
Class
Allowed
Disallowed a
PIs
DRV/rtv
All other PIs
NRTIs
All approved NRTIs
Investigational NRTIs
NNRTIs
Efavirenz
Etravirine (TMC125)
Nevirapine
Rilpivirine
Delavirdine
Investigational NNRTI
Fusion Inhibitors
Enfuvirtide
-
Entry inhibitors
Maraviroc b
-
Integrase inhibitors
Raltegravir (MK-0518)
Dolutegravir
Elvitegravir
Investigational integrase inhibitors
a
Note: Investigational ARVs in general are disallowed.
b
Refer to local product information of maraviroc for dose adjustment when combined with DRV/rtv.
Table 4: Allowed and Disallowed Antiretroviral Agents After Baseline for pediatric
subjects
Class
Allowed
Disallowed
PIs
DRV/rtv
All other HIV PIs
NRTIs
All NRTIs with dose 
recommendations for pediatric use
All NRTIs without approved dose 
recommendations for pediatric use
NNRTIs
Nevirapine
Efavirenz
Investigational NNRTI;
Etravirine a
Delavirdine
Rilpivirine a
Fusion Inhibitors
-
Enfuvirtide a
Entry inhibitors
-
Maraviroc a
Integrase inhibitors
-
Elvitegravir
Raltegravir (MK-0518) a
a
This agent can only be used as part of the OBR if in the country of the patient there is an approved dose 
recommendation for the age category of the patient.
Special considerations may be warranted for the discontinuation of certain antiretroviral 
agents1, 14:
-
Discontinuation of emtricitabine, lamivudine, or tenofovir in patients with hepatitis B 
coinfection:
Subjects with hepatitis B coinfection (hepatitis B surface antigen and/or HBe antigen 
positive) and receiving one or a combination of the above NRTIs may experience an 
exacerbation of their hepatitis upon discontinuation of these drugs. If any of the above agents 
is to be discontinued, the subjects should be closely monitored for exacerbation of hepatitis 
or hepatic flare.
5.3.6
PACKAGING AND LABELING
DRV tablets will be provided by the sponsor and will be packaged under the responsibility of the 
sponsor. The tablets will be labeled with a trial-specific label according to the local regulatory 
requirements.
Ritonavir capsules, tablets, and powder will be provided by the sponsor as the commercially 
available package to which a trial-specific label according to the local regulatory requirements 


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will be added. Local sourcing of ritonavir oral solution is recommended. The sponsor will 
provide the oral solution only if local sourcing is not possible.
For medication provided by the sponsor, the labels will contain the protocol number, batch 
number, storage caution statements, dispensing instructions and ‘Keep out of reach of children’.
For the DRV oral suspension and ritonavir liquid or powder (for oral suspension) formulation, a 
syringe with a 2 mL graduation will be provided to ensure accurate dosing.
5.3.7
RANDOMIZATION
Randomization is not applicable.
5.3.8
BLINDING AND UNBLINDING
Since this is an open-label trial, blinding procedures are not applicable.
5.3.9
DRUG ACCOUNTABILITY
The investigator, his/her designee, or the hospital pharmacist must maintain an adequate record 
of the receipt of the trial medication. Dispensation and return, or destruction (if applicable) of the 
trial medication must be documented on an individual patient level by using the appropriate 
forms. All these records must be available for inspection at any time. Drug accountability will be 
performed at each visit (see Part II, Section 3.1 ‘Investigational Products’).
After termination of data collection, compliance check on unused and used trial medication 
returned by the subject will still be performed by the investigator or designee and will not be 
verified by the sponsor, however, drug accountability will be reviewed during the on-site 
monitoring visits.
5.3.10
STORAGE
All trial medication must be strictly handled in accordance with the protocol and the container 
labels. Storage and dispensing instructions and an expiry date are supplied with the trial material 
on delivery. Access to the trial medication should be restricted to designated trial personnel.
All storage conditions and specific administration instructions for DRV and ritonavir will be 
provided to the investigator prior to drug delivery at the investigational site. Storage conditions 
will be mentioned on the label.
The trial medication must be stored in a limited access area or in a locked cabinet under 
appropriate environmental conditions. All supplies of trial medication must be stored as specified 
on the label. Supplies should be stored in the original, childproof container delivered under the 
responsibility of the sponsor.
The ARVs for the background regimen must be stored according to locally applicable procedures 
and conditions as stipulated on the package insert.
Temperature logging at the investigational site should be performed. Should a deviation in 
storage conditions occur, the site must not further dispense the affected drug and must provide 
the monitor immediately with the following information:
-
Date and duration of the deviation;


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Minimum temperature below the range and/or maximum temperature above the range that 
the product was exposed to.
Deviations in storage conditions will be evaluated by the sponsor. The monitor periodically 
checks the supplies of trial medication held by the investigator or pharmacist to ensure 
accountability and appropriate storage conditions of all trial medication used. After termination 
of data collection, storage conditions will still be checked by the investigator or designee and 
will not be verified by the sponsor, however, storage conditions will be reviewed during the 
on-site monitoring visits.  At the end of the trial all unused medication will be passed over for 
destruction on site (conform local regulations), or by an authorized destruction unit after 
authorization by the sponsor.
5.3.11
ADHERENCE
Medication adherence is critical to successful ARV therapy. In addition to compromising the 
efficacy of the current treatment regimen, suboptimal adherence has implications for limiting 
future effective regimens for patients with resistant strains.
Evidence indicates that adherence problems occur frequently in children and adolescents. Studies 
have reported that fewer than 50% of children and/or their caretakers reported full adherence to 
ARV regimens7. Although a variety of factors have been associated with treatment adherence, no
clear predictors of either good or poor adherence have been consistently identified in children.
The investigator should discuss the importance of good compliance to the entire treatment 
regimen, including DRV taken in combination with low-dose ritonavir and other ARVs. It is 
highly desirable that the investigator assesses the individual adherence to DRV/rtv, as well as all 
to the other ARVs used in combination, at each visit. If a subject’s medication intake is 
suggestive of inadequate compliance, the investigator should address the issue and help provide 
solutions 
to 
maximize 
adherence 
to 
the 
therapy.
Adherence 
counseling 
of 
the 
subject/parent(s)/legal representative(s) by the investigator should be documented in the 
subject’s source document/chart.
After termination of data collection, treatment adherence counseling should be performed per 
local standard of care and documented in the subject’s medical records only. Data will no longer 
be recorded in the CRF.
5.3.12
PRIOR AND CONCOMITANT THERAPY
5.3.12.1
Disallowed Non-Antiretroviral Medication
Refer to the current Investigator’s Brochure of DRV for an up-to-date overview of disallowed 
medications during clinical trials with DRV/rtv.
Please consult the prescribing information/package inserts and the most current Investigator’s 
Brochures for the individual medications as other medications may also not be allowed or 
cautioned for use given an individual subject’s specific situation.
5.3.12.2
Disallowed Antiretroviral Medication
Refer to Section 5.3.5 for an overview of disallowed ARVs during this trial.
Please consult the prescribing information/package inserts of the individual ARVs and most 
recent DRV Investigator’s Brochure for an up-to-date overview of contraindications as other 


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medications may also not be allowed or cautioned for use given an individual subject’s specific 
situation.
5.4
Assessments
5.4.1
TIMING OF ASSESSMENTS
Subjects will rollover after completion of 1 of the following clinical (parent) trials
TMC114-C211, TMC114-C214, TMC114-TiDP31-C229 and the pediatric (parent) trial
TMC114-TiDP-C232, which was a roll-over trial for the original trials TMC114-C212, 
TMC114-TiDP-C228 or TMC114-TiDP-C230. The baseline visit will coincide with the last visit 
of the treatment phase of the previous (parent) trial. Assessments and results from the last visit of 
the previous (parent) trial will be used for the baseline visit of the present trial; overlapping 
assessments only need to be conducted once. Additional assessments not included in this 
protocol can be done locally as per local standard of care.
If a subject is considered eligible after signing informed consent/assent (see Part II, Section 6.4
‘Subject Information and Informed Consent/Assent’), completion of the Baseline Form, and 
evaluation by the sponsor or its designee, the subject receives the trial medication (DRV/rtv) at 
the baseline visit.
Visits and assessments are performed, according to local generally accepted standard of care, but 
desirable every 3 months for pediatric subjects and not less frequent than every 6 months for 
adult subjects. The interval between 2 consecutive visits should not exceed 6 months for 
pediatric subjects. An additional visit may also be scheduled at the investigator’s discretion to 
follow up on clinically relevant adverse events or laboratory abnormalities and in case of weight 
decrease for pediatric subjects (see Section 5.3.3). A final/withdrawal visit will be performed. 
The exact timing of the assessments is presented in the flowchart in Section 2.
As per Protocol Amendment 2, the next planned visit will be a Final/Withdrawal Visit, which 
will be the last visit with data collection. Thereafter, visits and assessments will be performed per 
local standard of care and documented in the subject’s medical records only. Investigators will 
continue to report SAEs possibly related to DRV/rtv and pregnancies to the sponsor using 
regular pharmacovigilance reporting. This information will only be entered in the company 
safety repository.
If the subject exits the trial, the last visit will be a local standard of care visit but without 
dispensation of investigational medication.
5.4.2
SUBJECT AND DISEASE CHARACTERISTICS
At the baseline visit, information from the previous (parent) trial will be confirmed, including the 
original subject ID. The overall eligibility of the subject to participate in the trial will be 
assessed.
5.4.3
EFFICACY
In addition to the assessments described in the flowchart in Section 2, it is desirable to perform 
the following efficacy assessments locally every 3 months or according to the local generally 
accepted standard of care:


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Immunology; and
-
Plasma viral load (HIV-1 RNA copies/mL).
After termination of data collection, efficacy assessments will be performed per local standard of 
care and documented in the subject’s medical records only.
5.4.4
SAFETY 
5.4.4.1
Adverse Events/HIV-Related Events
For detailed definitions and reporting procedures of adverse events, refer to Part II, Section 1
‘Adverse Events’. For reported HIV-related events, further details will be recorded if these 
events are AIDS-defining illnesses (U.S. Centers for Disease Control and Prevention [CDC] 
Category C conditions; see Section 7.4, Addendum 4: Revised WHO Clinical Staging of 
HIV/AIDS).
For subjects experiencing specific adverse events, toxicity management should be performed as 
described in Section 5.5 (cutaneous reactions/rash, acute systemic allergic reactions, AST and 
ALT elevations, clinical hepatitis, renal complications, nausea (with or without vomiting), 
diarrhea, and other toxicities) and Section 5.6 (hyperglycemia, hypertriglyceridemia and 
hypercholesterolemia, low-density lipoprotein (LDL) cholesterol increase, lactic acidosis, 
lipodystrophy/fat distribution/body changes, pancreatitis, and hypersensitivity reactions).
A post-treatment follow-up contact is to be performed 4 weeks after the last dose of trial 
medication for subjects with an ongoing adverse event, that discontinue the trial under Protocol 
Amendment 1, as specified in the flowchart in Section 2.
After termination of data collection, safety assessments will be performed per local standard of 
care and documented in the subject’s medical records only. Investigators must continue to report 
SAEs possibly related to DRV/rtv and pregnancies to the sponsor using regular 
pharmacovigilance reporting. This information will only be entered in the company safety 
repository.
5.4.4.2
Clinical Laboratory Tests
Urine pregnancy tests are to be performed at the baseline visit (female subjects of childbearing 
potential only) and every visit thereafter. The first test for girls having their first menses during 
the course of the trial can be performed on serum or urine, according to local practice. For girls 
who have had their first menses, urine tests can be performed at all visits.
In addition to the assessments described in the flowchart in Section 2, it is desirable to perform 
the following laboratory safety assessments locally every 3 months or according to the local 
generally accepted standard of care:
-
Hematology; and
-
Biochemistry, including pancreatic amylase (if available) or lipase and lipid analyses.
After termination of data collection, laboratory safety assessments will be performed per local 
standard of care and documented in the subject’s medical records only.


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5.5
Safety Monitoring and Toxicity Management
Toxicity management is at the discretion of the investigator, and is to take into account the 
protocol-defined procedures defined under 5.5.1, 5.5.2, 5.5.3, 5.5.4, 5.5.5, 5.5.6, 5.5.7, and 5.5.8, 
and the local standard clinical practice.
After termination of data collection, toxicity management will be performed per local standard of 
care and documented in the subject’s medical records only.
The following guidelines are present in the Clinical Trial Protocols for ongoing HIV-1 trials 
of DRV. Participating investigators are strongly encouraged to follow these guidelines and to 
apply the same safety measures for subjects participating in this trial.
Note:For grade 3 or 4 laboratory toxicities, a confirmatory measurement within 48 hours after 
the laboratory results become available is mandatory. This management scheme is for confirmed 
laboratory abnormalities and not for isolated events.
The following laboratory abnormalities do not warrant mandatory confirmation within 48 hours:
-
Subjects with asymptomatic triglyceride or cholesterol elevations of grade 3 or 4.
All adverse events occurring at any time during the trial will be followed until satisfactory 
clinical resolution (i.e., value back to baseline value) or stabilization or until final database lock. 
All grade 3 and grade 4 laboratory abnormalities and laboratory abnormalities resulting in an 
increase of 2 DAIDS grades from baseline will be followed until return to baseline or within 1 
grade from baseline. Certain long-term adverse events of ARV therapy cannot be followed to 
resolution within the setting of this protocol; in these cases follow-up will be the responsibility 
of the treating physician, which will be agreed upon with the sponsor.
5.5.1
CUTANEOUS REACTION/RASH
DRV is a sulfonamide. Subjects who previously experienced a sulfonamide allergy will be 
allowed to enter the trial. To date, no potential for cross sensitivity between drugs in the 
sulfonamide class and DRV has been identified in subjects participating in Phase II/III adult 
trials as well as Phase II pediatric trials with HIV-1 infected subjects aged > 6 years.
Management will be at the discretion of the investigator, taking into account the following 
protocol-defined procedures, and should follow generally accepted medical standards. Cetirizine, 
levocetirizine, topical corticosteroids, and antipruritic agents will be allowed at the investigator’s 
discretion for all grades of rashes.
Grade 1 and 2 Cutaneous Reaction/Rash
A grade 1 cutaneous reaction/rash is defined as localized macular rash.
A grade 2 cutaneous reaction/rash is defined as diffuse macular, maculopapular or morbilliform 
rash, or target lesions.


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Subjects experiencing a grade 1 or grade 2 rash or cutaneous reaction may continue treatment or 
have their trial medication interrupted at the investigator’s discretion. Local safety sampling at 
the time of the rash and clinical follow-up for these adverse events will be at the discretion of the 
investigator, however, close clinical follow-up is recommended to monitor for any progression of 
the adverse event.
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.
Grade 3 and 4 Cutaneous Reaction/Rash
A grade 3 cutaneous reaction/rash is defined as:
-
Diffuse macular, maculopapular or morbilliform rash with vesicles or limited number of bullae
-
Superficial ulcerations of mucous membrane limited to 1 site*
-
Cutaneous reaction/rash with at least 1 of the following*:
1. Elevations of ALT and/or AST > 2 baseline but at least 5 ULN;
2. Fever 38°C or 100° F;
3. Serum sickness-like reaction;
4. Eosinophil count > 1000/mm³.
* Revised by the sponsor.
A grade 4 cutaneous reaction/rash is defined as:
-
Extensive or generalized bullous lesions;
-
Stevens-Johnson syndrome (SJS);
-
Ulceration of mucous membrane involving 2 or more distinct mucosal sites;
-
Toxic epidermal necrolysis (TEN).
A visit schedule for cutaneous reaction/rash follow-up is provided in Table 5 below.
Subjects experiencing a grade 3 or 4 rash or cutaneous event must have their study medication 
discontinued and be withdrawn from the trial (see Section 5.2.5 and see Section 7.3, 
Addendum 3: Visit Schedule for Cutaneous Reaction/Rash Follow-up for pediatric subjects). 
Referral to a dermatologist and biopsy are required for these events. To minimize distress of skin 
biopsies, the skin should be anesthetized by application of an anesthetic cream and/or an 
intradermal injection of 1-2% lidocaine. At the discretion of the investigator and after approval 
of the sponsor, local safety testing of the following parameters is required to determine possible 
liver or systemic abnormalities: ALT, AST, bilirubin (total, direct and indirect), creatinine and a 
complete blood cell count (including hemoglobin, hematocrit, red blood cell (RBC) and white 
blood cell (WBC) count, neutrophils, lymphocytes, monocytes, eosinophils, basophils and 
platelet count). Close clinical follow-up and appropriate medical intervention should be instituted 
for these events; daily follow-up is recommended for 5 days from the onset of the event to 
monitor for progression of the event and weekly afterwards.
Subjects should be advised to contact the investigator immediately if they notice any 
worsening of the rash.


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Table 5: 
Visit Schedule for Cutaneous Reaction/Rash Follow-up
DAIDS 
Toxicity Grade
Definitions
Investigator Action
Grade 1
Localized macular rash
May continue trial medication or have their 
trial medication interrupted at the 
investigator’s discretion.
Grade 2
Diffuse macular, maculopapular or morbilliform 
rash
Target lesions
May continue trial medication or have their 
trial medication interrupted at the 
investigator’s discretion.
Grade 3
Diffuse macular, maculopapular or morbilliform 
rash with vesicles or limited number of bullae
Superficial ulcerations of mucous membrane 
limited to 1 site*
Cutaneous reaction/rash with at least 1 of the 
following*:
- Elevations in ALT and/or AST (> 2 baseline 
but at least 5 ULN)
- Fever 38°C or 100°F
- Serum sickness-like reaction
- Eosinophils > 1000/mm³
* Revised by the sponsor
Permanently discontinue trial medication 
(see Section 5.2.5).
Referral to a dermatologist and biopsy are 
required for these events (preferably within 
24 hours).
Local laboratory assessments can be 
performed at the discretion of the 
investigator and after approval of the 
sponsor.
Daily follow-up visits for the first 5 days and 
weekly afterwards.
Grade 4
Extensive or generalized bullous lesions
Stevens-Johnson syndrome (SJS)
Ulceration of mucous membrane involving 2 or 
more distinct mucosal sites 
Toxic epidermal necrolysis (TEN)
Permanently discontinue trial medication 
(see Section 5.2.5).
Referral to a dermatologist and biopsy are 
required for these events (preferably within 
24 hours).
Local laboratory assessments can be 
performed at the discretion of the 
investigator and after approval of the 
sponsor.
Daily follow-up visits for the first 5 days and 
weekly afterwards.
5.5.2
ACUTE SYSTEMIC ALLERGIC REACTION
A summary of allergic reactions is provided in Table 6 below.
Subjects should be followed until resolution of the AE.
Grade 1 (localized urticaria [wheals] with no medical intervention indicated):
Subjects may continue medication for a grade 1 acute systemic allergic reaction. The subject 
should be advised to contact the investigator immediately if there is any worsening of the allergic 
reaction, or if any systemic signs or symptoms develop. Antihistamines or topical corticosteroids 
or antipruritic agents may be prescribed as long as these are in line with the package inserts of 
the ARVs (including DRV/rtv and background regimen) and with (dis)allowed medication for 
DRV indicated in Section 5.3.5.
Grade 2 (localized urticaria with medical intervention indicated or mild angioedema with 
no medical intervention indicated):
Subjects may continue medication for a grade 2 acute systemic allergic reaction. The subject 
should be advised to contact the investigator immediately if there is any worsening of the allergic 


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reaction; the subject should discontinue the trial medication and be withdrawn from the trial.
Antihistamines or topical corticosteroids or antipruritic agents may be prescribed as supportive 
care as long as these are in line with the package inserts of the ARVs (including DRV/rtv and 
background regimen) and with (dis)allowed medication for DRV indicated in Section 5.3.5.
Grade 3 (generalized urticaria, angioedema with medical intervention indicated, or 
symptomatic mild bronchospasm):
Subjects will permanently discontinue medication (including DRV/rtv and background regimen) 
and will be withdrawn from the trial. Subjects will be treated as clinically appropriate. Standard 
management should be undertaken.
Grade 4 (acute anaphylaxis, life-threatening bronchospasm, or laryngeal edema):
Subjects will permanently discontinue medication (including DRV/rtv and background regimen)
and will be withdrawn from the trial. Subjects will be treated as clinically appropriate. Standard 
management should be undertaken.
Table 6:
Summary of Allergic Reaction
DAIDS Toxicity Grade
Definitions
Investigator Action
Grade 1
Localized urticaria (wheals) with no 
medical intervention indicated
May continue trial medication 
or have their trial medication 
interrupted at the investigator’s 
discretion
Grade 2
Localized urticaria with medical 
intervention indicated, or
mild angioedema with no medical 
intervention indicated
May continue trial medication 
or have their trial medication 
interrupted at the investigator’s 
discretion
Grade 3
Generalized urticaria, or
angioedema with medical intervention 
indicated, or
symptomatic mild bronchospasm
Permanently discontinue trial 
medication
Grade 4
Acute anaphylaxis, or 
life-threatening bronchospasm, or
laryngeal edema
Permanently discontinue trial 
medication
5.5.3
AST AND ALT ELEVATIONS
A summary of AST and ALT elevations is provided in Table 7 below.
Note: For grade 3 or 4 laboratory toxicities, subjects should have a confirmatory measurement 
within 48 hours after the laboratory results become available. This management scheme 
is for confirmed laboratory abnormalities and not for isolated events.


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Grade 3 AST or ALT elevations (> 5.0 - ≤10.0 ULN):
Subjects are to interrupt all medication (including DRV/rtv and background regimen) except if 
they are coinfected with hepatitis B or C (see below). Upon resolution of the laboratory 
abnormality to within 1 grade level (grade 2), the subject may resume all trial medication under 
the guidance of the investigator and after discussion with a sponsor physician.
If after a grade 3 elevation, the subject has a recurrence of a grade 3 or 4 increase in AST or ALT 
after restarting trial medications, he/she will permanently discontinue the medication (including 
DRV/rtv and background regimen) and will be withdrawn from the trial.
Subjects with concomitant hepatitis B and with emtricitabine (FTC) or lamivudine (3TC) as a 
component of the background regimen:
Warning: Severe acute exacerbations of hepatitis B have been reported in subjects who are 
co-infected with hepatitis B virus and HIV and have discontinued FTC or 3TC. 
Hepatic function should be monitored closely with both clinical and laboratory 
follow-up for at least several months in subjects who discontinue FTC or 3TC 
and are co-infected with hepatitis B virus and HIV. If appropriate, initiation of 
anti-hepatitis B therapy may be warranted.
Subjects with concomitant hepatitis A, B, C, or E:
Subjects with concomitant acute hepatitis A infection diagnosed at or after baseline have to be 
excluded. If acute viral hepatitis is diagnosed while on trial, the subject must be withdrawn 
immediately and the necessary follow-up visits performed.
Subjects with chronic hepatitis B or C coinfection are allowed to participate. These subjects will 
be allowed to continue treatment (including DRV/rtv and background regimen) if they develop a 
grade 3 elevation in AST or ALT provided alkaline phosphatase (ALP) is not elevated to grade 2 
or higher and total bilirubin is not elevated to grade 3 or higher or subjects do not have signs and 
symptoms of clinically active hepatitis. Signs and symptoms of active hepatitis include, but are 
not limited to fatigue, malaise, anorexia, nausea, dark urine and clay-colored stools, bilirubinuria, 
jaundice, and liver tenderness. If signs or symptoms of clinically active hepatitis occur, or if AST 
or ALT increases to grade 4 elevations, then all treatment (including DRV/rtv and background 
regimen) will be permanently discontinued and the subject will be withdrawn from the trial.
In regions where hepatitis E is endemic, it is recommended that hepatitis E serologies be tested 
for the evaluation of unexplained increases of AST or ALT. Subjects diagnosed with acute 
hepatitis E at or after screening must be withdrawn immediately.
However, if subjects with chronic hepatitis B or C co-infection and with grade 3 elevation in 
AST or ALT elect to interrupt treatment (including DRV/rtv and background regimen) and have 
a recurrence of grade 3 increase in AST or ALT they may continue provided ALP is not elevated 
to grade 2 or higher and total bilirubin is not elevated to grade 3 or greater or subjects do not 
have signs and symptoms of clinically active hepatitis. If signs or symptoms of clinically active 
hepatitis occur or if AST or ALT increases to grade 4 elevations, then all treatment (including 
DRV/rtv and background regimen) will be permanently discontinued and the subject will be 
withdrawn from the trial.


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Grade 4 AST or ALT elevations (> 10.0 ULN):
Subjects will permanently discontinue treatment (including DRV/rtv and background regimen) 
and will be withdrawn from the trial.
Table 7: 
Summary of AST and ALT Elevations
Revised DAIDS Table 
for Grading Severity 
Ranges
Investigator Action
Rechallenge 
Instructions
Grade 1
1.25 – 2.5 ULN
May continue therapy
Not applicable
Grade 2
> 2.5 – 5.0 ULN
May continue therapy
Not applicable
Grade 3
> 5.0 – 10.0 ULN
Interrupt HIV therapy until toxicity 
≤grade 2;
if coinfected with hepatitis B or C: 
may continue if ALP is grade 2 or below, 
bilirubin grade 3 or below, and 
asymptomatic
Allowed once
Grade 4
> 10.0 ULN
Discontinue therapy
No
5.5.4
CLINICAL HEPATITIS
Subjects should be followed until resolution of the AE.
5.5.4.1
Non-viral Hepatitis
Subjects should be monitored for the development of signs and symptoms of hepatitis, which 
include fatigue, malaise, anorexia, nausea, dark urine and clay-colored stools, bilirubinuria, 
jaundice and liver tenderness, with or without initially abnormal serum transaminase levels.
Subjects with these signs and symptoms should seek medical attention immediately and have 
liver function tests performed.
5.5.4.2
Viral Hepatitis
If acute viral hepatitis is diagnosed while on trial, the subject should be permanently withdrawn 
from the trial.
5.5.5
RENAL COMPLICATIONS
Investigators should closely monitor trial subjects for disturbances in serum creatinine, urine 
electrolytes and for abnormalities in urinalysis (e.g., proteinuria). If renal complications develop, 
subjects must be treated as clinically appropriate. The trial medication may be continued if the 
renal complication is considered not related to the treatment (including DRV/rtv and OBR) in the 
opinion of the investigator.
Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been 
reported in association with the use of Viread® (tenofovir). The majority of these cases occurred 
in subjects with underlying systemic or renal disease, or in subjects taking nephrotoxic agents, 
however, some cases occurred in subjects without identified risk factors (please refer to the 
package insert of tenofovir for details).


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5.5.6
NAUSEA (WITH OR WITHOUT VOMITING)
Although common, nausea after the initiation of ARV therapy usually subsides or resolves 
during the first few weeks of treatment.
Grade 1 nausea (transient [< 24 hours] or intermittent nausea with no or minimal 
interference with oral intake):
Subjects may continue with the trial medication and may be treated as needed with anti-emetics 
given orally or by suppository. If vomiting occurs in pediatric subjects, they should wait 15 to 30 
minutes and then start hydration in frequently small amounts. Once vomiting has stopped for at 
least a few hours, solid food can be reintroduced.
Grade 2 nausea (persistent nausea resulting in decreased oral intake for 24-48 hours):
Subjects may continue with the trial medication and may be treated as needed with anti-emetics 
given orally or by suppository. If vomiting occurs in pediatric subjects, they should wait 15 to 30 
minutes and then start hydration in frequently small amounts. Oral rehydration solution should 
not be used for more than 24 hours, other liquids with salt and sugars should be given. Once 
vomiting has stopped for at least a few hours, solid food can be reintroduced.
Grade 3 nausea (persistent nausea resulting in minimal oral intake for > 48 hours or 
aggressive rehydration indicated [e.g., intravenous fluids]):
Subjects developing grade 3 nausea will have all treatment (including DRV/rtv and background 
regimen) interrupted. The subject will be treated as needed with anti-emetics given orally or by 
suppository. All medication may be resumed when the nausea resolves to grade 2.
Grade 4 nausea (life-threatening consequences [e.g., hypotensive shock]):
Subjects developing grade 4 nausea will discontinue treatment (including DRV/rtv and 
background regimen) and will be withdrawn from the trial.
5.5.7
DIARRHEA
Grade 1 diarrhea (transient or intermittent episodes of unformed stools or increase of 
≤3 stools over baseline per 24-hour period):
Subjects may continue the trial medication. Loperamide and diphenoxylate can be administered.
Pediatric subjects should start with the BRAT (bananas, rice, applesauce and toast) diet.
Grade 2 diarrhea (persistent episodes of unformed to watery stools or increase of 4-6 stools 
over baseline per 24-hour period):
Subjects may continue the trial medication. Loperamide and diphenoxylate can be administered.
Pediatric subjects should start with the BRAT diet and increase the amount of fluids.
Grade 3 diarrhea (bloody diarrhea, increase of ≥ 7 stools per 24-hour period, or 
intravenous fluid replacement indicated):
Subjects with grade 3 diarrhea will have all treatment (including DRV/rtv and background 
regimen) interrupted. All medication (including DRV/rtv and background regimen) may be 
resumed when the diarrhea resolves to grade 2.
Grade 4 diarrhea (life-threatening consequences [e.g., hypotensive shock]):
Subjects will permanently discontinue treatment (including DRV/rtv and background regimen) 
and will be withdrawn from the trial.


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Note: Rare cases of acute renal insufficiency have been reported in patients receiving DRV/rtv 
and tenofovir as part of a combination HIV therapy, more specifically in cases where
moderate to severe diarrhea resulted in dehydration. Special attention should be given to 
the appropriate clinical management of diarrhea, dehydration and electrolyte losses, if 
applicable. In certain cases, temporary interruption of HIV therapy may be appropriate
until the condition has improved.
5.5.8
OTHER TOXICITIES
Grade 1
Subjects who develop a grade 1 AE or toxicity may continue intake of the trial medication.
Grade 2
Subjects who develop a grade 2 AE or toxicity may continue intake of the trial medication based 
on the investigator’s clinical judgment.
Note: For grade 3 or 4 laboratory toxicities, subjects should have a confirmatory measurement 
within 48 hours after the laboratory results become available. This management scheme 
is for confirmed laboratory abnormalities and not for isolated events.
Grade 3
Subjects who develop a grade 3 AE or toxicity should interrupt all medications (including 
DRV/rtv and OBR) and may resume all therapy when the AE or laboratory abnormality resolved 
to within one grade level (grade 2) of the subject’s baseline. 
The following exceptions apply:
-
subjects who experience an asymptomatic glucose elevation of grade 3 (See Section 5.6.1);
-
subjects who experience asymptomatic triglyceride or cholesterol elevations of grade 3 (See 
Section 5.6.2);
-
subjects who experience asymptomatic pancreatic amylase elevations of grade 3 with no past 
or active history of pancreatitis (provided lipase is within normal limits) (See Section 5.6.5);
-
subjects who experience an AE that is considered not related or doubtfully related to the 
study medication.
Grade 4
Subjects experiencing a grade 4 AE or toxicity will permanently discontinue medication 
(including DRV/rtv and OBR).
The following exceptions apply:
-
subjects who experience asymptomatic triglycerides elevations of grade 4 (see also 
Section 5.2.5);
-
subjects who experience an AE that is considered not related or doubtfully related to the trial 
medication.


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5.6
Toxicity Management for Specific Adverse Events with Concomitant 
Antiretroviral Agents 
Participating investigators are strongly encouraged to follow the guidelines and to apply the 
same safety measures for subjects participating in this trial.
Toxicity management is at the discretion of the investigator, and is to take into account the 
protocol-defined procedures defined under 5.6.1, 5.6.2, 5.6.3, 5.6.4, 5.6.5, and 5.6.6, and the 
local standard clinical practice.
After termination of data collection, toxicity management will be performed per local standard of 
care and documented in the subject’s medical records only.
The information below does not imply that the respective adverse events are only related to the 
concomitant ARV therapy, since a contribution of DRV cannot be excluded.
5.6.1
HYPERGLYCEMIA
Grade 3: 13.89-27.75 mmol/L (251-500 mg/dL);
Grade 4: > 27.75 mmol/L (> 500 mg/dL).
Management decisions should be based on fasted results. Subjects with persistent grade 3 or 4 
glucose elevations despite appropriate anti-hyperglycemic treatment should be permanently 
discontinued with the exception of subjects with pre-existing diabetes. Appropriate clinical 
management of hyperglycemia must be started in a timely fashion, if applicable.
5.6.2
HYPERTRIGLYCERIDEMIA, HYPERCHOLESTEROLEMIA AND LDL CHOLESTEROL 
INCREASE
Hypertriglyceridemia grade 3: 8.49-13.56 mmol/L (751-1200 mg/dL);
grade 4: > 13.56 mmol/L (> 1200 mg/dL).
Hypercholesterolemia grade 3: > 7.77 mmol/L (> 300 mg/dL);
grade 4: not applicable.
LDL cholesterol increase grade 3: 4.91 mmol/L (190 mg/dL); 
grade 4: not applicable.
Management decisions should be based on fasted results. Subjects who experience grade 3 or 4 
asymptomatic triglyceride or cholesterol elevations may continue to receive the trial medication 
unless clinical assessment foresees an immediate health risk to the subject.
Hypertriglyceridemia, hypercholesterolemia and LDL cholesterol increase should be treated 
according to the specific guidelines for treating HIV-positive subjects (see Section 7.5Addendum 
5: Lipid Abnormalities)13. Current treatment guidelines (eg, The National Cholesterol Education 
Program [NCEP] guidelines) specify different lipid thresholds for intervention for different 
degrees of cardiovascular risk. The presence or absence of other significant cardiovascular risk 
factors, which include smoking, age, family history of premature cardiovascular disease, 
diabetes, hypertension, low high density lipoprotein (HDL) cholesterol, and prior history of 
cardiovascular disease should be taken into account. Appropriate clinical management of 
hyperlipidemia in the setting of HIV disease should be started in a timely fashion, if applicable.


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For the OBR, the respective package inserts should be consulted for contraindicated medications 
or medications that are not recommended for concomitant use.
For an overview of allowed and disallowed medication, please refer to Section 5.3.5, and the 
respective sections in the IB of DRV.
5.6.3
LACTIC ACIDOSIS
The relevance of asymptomatic lactic acid elevations is unclear, and lactates are not part of the 
routine safety evaluations for this trial. Routine lactate monitoring is not currently recommended. 
However, lactate monitoring should be performed if there is a clinical suspicion of lactic acidosis 
(see description below).
A sometimes-fatal syndrome of lactic acidosis, often associated with evidence of hepatic 
steatosis, is a recognized but rare complication of NRTI therapy. This syndrome is felt to be 
secondary to mitochondrial toxicity induced by the inhibitory effect of NRTIs on DNA 
polymerase gamma, a key enzyme needed for mitochondrial DNA synthesis. Current knowledge 
regarding this syndrome is incomplete. Obesity and prolonged NRTI exposure may be risk 
factors. Females are also at increased risk. Symptoms of lactic acidosis are frequently non-
specific (e.g., fatigue, weakness, hyperventilation and fever), but in the majority of cases also 
involve symptoms suggestive of hepatic dysfunction such as nausea, vomiting, abdominal or 
epigastric discomfort, abdominal distension, hepatomegaly, and new-onset elevated liver 
enzymes. A high index of suspicion may be required to diagnose this condition. Alternatively, 
it is possible that unwarranted concern may be raised by over-interpretation of lactic acid levels.
NRTI toxicity is only one cause of lactic acidosis. Type “B” lactic acid elevations or those 
without clinically apparent tissue hypoxia are also seen in the context of diabetes, uremia, liver 
disease, infections, malignancies, alkaloses, and drug and toxin ingestion of substances such as 
ethanol, methanol, ethylene glycol, and salicylates.
The following case definition of lactic acidosis will be used in this protocol:
Symptomatic Hyperlactatemia
New, otherwise unexplained, and persistent (2 weeks) occurrence of 1 or more of the following 
symptoms:
-
Nausea and vomiting
-
Abdominal pain or gastric discomfort
-
Abdominal distention
-
Increased liver function tests
-
Unexplained fatigue
-
Dyspnea 
and
-
Lactate level > 2 ULN, confirmed by repeat lactate level analysis
Note: All lactates > 2 ULN should be repeated as soon as possible, generally within 1 week. 
Lactate levels should not be assessed following physical exertion as this causes elevated 
lactate levels and may confound assessment of the clinical significance of these findings. 
If the second result confirms hyperlactatemia (> 2 ULN) in subjects with symptoms as 
described above, the subjects should immediately discontinue their medication (DRV/rtv 


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and background regimen). Standard management should be initiated with follow-up to 
resolution. If causality is related to the background regimen only and not to DRV/rtv, the 
NRTIs must be changed (see Section 5.3.5) and subjects should continue DRV/rtv if 
treatment is re-initiated. If causality is (also) related to DRV/rtv, subjects must be 
withdrawn.
Processing of the lactate needs to be done according to strict guidelines both in the 
preparation of the patient (ideally, fasting and with no recent exercise) and in the 
blood drawing/processing procedure (ideally, blood drawn without a tourniquet, no 
hand clenching, blood drawn into a chilled tube and processed immediately) to 
minimize false elevations of lactates.
5.6.4
LIPODYSTROPHY/FAT REDISTRIBUTION/BODY CHANGES
Investigators should avoid using the term “lipodystrophy acquired” to describe and report fat 
redistribution abnormalities associated with ARV therapy as this term is not very descriptive. 
The different symptoms and gradings are listed in the DAIDS scale under ‘Endocrine/Metabolic’ 
(see Section 7.2, Addendum 2: DAIDS Grading Table). The relevant terms include: abnormal 
fat accumulation, lipoatrophy and gynecomastia.
Although metabolic abnormalities such as hyperlipidemia or hyperglycemia are often associated 
with body changes, these events should be reported separately for the purpose of AE reporting.
Assessment of fat redistribution in HIV-infected children and adolescents is complicated by the 
normal, dynamic alterations in body composition that occur during childhood and adolescence.
Children and adolescents can be considered to have abnormal fat accumulation if they have 1 or 
more of the following signs:
-
Trunk with increased abdominal girth
-
Dorso-cervix with fat accumulation ‘buffalo hump’
-
Breast enlargement
Children and adolescents can be considered to have lipoatrophy if they have 1 or more of the 
following signs:
-
Face with sunken cheeks, sunken eyes with prominent zygomatic arch
-
Skinny arms with prominent veins; muscularity and bones
-
Skinny legs with prominent veins; muscularity and bones
-
Buttocks with loose of skin folds, prominent muscles, loss of contour and fat
5.6.5
PANCREATITIS
Pancreatitis must be considered whenever a subject develops abdominal pain, nausea, vomiting, 
and/or elevated amylase or lipase. Temporary treatment interruption is allowed (including 
DRV/rtv and background regimen) in case of clinical suspicion and until the diagnosis of 
pancreatitis can be excluded.
It is not recommended to co-administer tenofovir disoproxil fumarate (TDF) and didanosine 
(ddI) in the OBR (if applicable) due to an increased risk of pancreatitis14.


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5.6.5.1
Clinical Pancreatitis
Grade 1: not applicable.
Grade 2: symptomatic and hospitalization not indicated (other than emergency room visit).
Grade 3: symptomatic and hospitalization indicated (other than emergency room visit).
Grade 4: life-threatening consequences (e.g., circulatory failure, hemorrhage, sepsis).
5.6.5.2
Laboratory Abnormalities
For asymptomatic grade 1 and grade 2 pancreatic amylase and/or lipase elevations, and 
confirmed asymptomatic grade 3 pancreatic amylase elevations with no past or active history 
of pancreatitis, subjects should be carefully evaluated and followed closely.
For confirmed grade 4 elevations of pancreatic amylase and/or confirmed grade 3 or 4 elevations 
of lipase, subjects should interrupt therapy (including DRV/rtv and background regimen) until 
amylase returns to grade ≤ 2, at which time therapy could be reintroduced. The NRTI(s) most 
likely related to the elevated lipase will be switched to another NRTI (see Section 5.3.5). If 
grade 4 elevations of pancreatic amylase and/or grade 3 or 4 lipase levels persist 14 days 
following interruption of therapy, or if the toxicity recurs more than twice, therapy (including 
DRV/rtv and background regimen) should be discontinued.
5.6.6
HYPERSENSITIVITY REACTIONS
In clinical studies approximately 5% of subjects receiving an ABC-containing product developed 
a hypersensitivity reaction, which in rare cases has been proven fatal11.
At baseline, it is recommended to test subjects without prior documented HLA-B*5701 negative 
results in whom the investigator considers ABC/3TC as background regimen to avoid 
hypersensitivity reactions. In those subjects where HLA-B*5701 is tested positive, ABC should 
not be administered12. In this case, the investigator must select another background regimen 
(without ABC) consisting of at least 2 NRTIs (see Section 5.3.5 for more details about the 
background regimen).
It should also be noted that HLA screening and exclusion of HLA-B*5701 positive subjects does 
not completely eliminate the risk of hypersensitivity reactions.
5.6.6.1
Description of the Hypersensitivity Reaction
The ABC hypersensitivity reaction is characterized by the appearance of symptoms indicating 
multi-organ involvement. The majority of subjects have fever and/or rash as part of the 
syndrome, however reactions have occurred without rash or fever.
Other signs and symptoms may include respiratory signs and symptoms such as dyspnea, sore 
throat, cough and abnormal chest x-ray findings (predominantly infiltrates, which can be 
localized), gastrointestinal symptoms, such as nausea, vomiting, diarrhea, or abdominal pain, and 
may lead to misdiagnosis of hypersensitivity as respiratory disease (pneumonia, bronchitis, 
pharyngitis), or gastroenteritis. Other frequently observed signs or symptoms of the 
hypersensitivity reaction may include lethargy or malaise and musculoskeletal symptoms 
(myalgia, rarely myolysis, arthralgia). 


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The symptoms related to this hypersensitivity reaction worsen with continued therapy and can be 
life-threatening. These symptoms usually resolve upon discontinuation of ABC.
5.6.6.2
Management of Hypersensitivity Reactions
Subjects developing signs or symptoms of hypersensitivity must contact their doctor 
immediately for advice.
If a hypersensitivity reaction is diagnosed, the subject must discontinue ABC treatment 
immediately. The background regimen will be replaced by an alternative background regimen 
(see Section 5.3.5).
The subject should be asked to return all unused supplies of the ABC-containing product for 
disposal to prevent an accidental re-challenge.
An ABC-containing medicinal product (Ziagen®, Trizivir®, or Epzicom®/Kivexa®) must 
never be administered following a hypersensitivity reaction, as more severe symptoms will 
recur within hours and may include life-threatening hypotension and death.
To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity 
reaction, the ABC-containing product should be permanently discontinued if hypersensitivity 
cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, 
gastroenteritis, or reactions to other medications).
Symptomatic support for ABC hypersensitivity may be indicated. This should include, for 
example, administration of intravenous fluids to subjects who develop hypotension. 
Antihistamines or corticosteroids have been used in cases of ABC hypersensitivity, however, 
there are no clinical data demonstrating the benefit of these in the management of the reaction.
Laboratory and other investigations which may be useful in the evaluation and treatment of ABC 
hypersensitivity include, but may not be limited to, measurement of ALT, AST, creatine 
phosphokinase, serum creatinine, and WBC differential count and chest x-ray, if respiratory 
symptoms are present.
5.6.6.3
Special Considerations Following an Interruption of ABC Therapy
If therapy with ABC has been discontinued and restarting therapy is under consideration, the 
reason for discontinuation should be evaluated to ensure that the subject did not have symptoms 
of a hypersensitivity reaction. If a hypersensitivity reaction cannot be ruled out, no medicinal 
product containing ABC should be restarted.
There have been infrequent reports of hypersensitivity reaction following reintroduction of an 
ABC-containing product where the interruption was preceded by a single key symptom of 
hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal symptoms, or a respiratory 
symptom). If a decision is made to restart any ABC-containing product in these subjects, this 
should be done only under direct medical supervision.
On very rare occasions hypersensitivity reactions have been reported in subjects who have 
restarted therapy, and who had no preceding symptoms of a hypersensitivity reaction. If a 
decision is made to restart an ABC-containing product, this must be done only if the subject or 
others can access medical care readily.


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5.6.6.4
Essential Subject Information
An Alert Card is available in the commercial medication pack containing ABC to remind the 
subject and the medical staff about ABC hypersensitivity. This card should be removed and kept 
with the subject at all times.
Investigators must ensure that subjects are fully informed regarding the following information on 
the hypersensitivity reaction:
-
Subjects must be made aware of the possibility of a hypersensitivity reaction to ABC that 
may result in a life-threatening reaction or death.
-
All subjects without prior documented HLA-B*5701 negative results in whom the 
investigator considers ABC/3TC as background regimen should be tested for HLA-B*5701 
(refer to ABC prescribing information/package inserts). In those subjects where 
HLA-B*5701 is tested positive, ABC should not be administered12.
-
Subjects developing signs or symptoms possibly linked with a hypersensitivity reaction must 
contact their doctor immediately.
-
Subjects who are hypersensitive to ABC should be reminded that they must never take any 
ABC-containing medicinal product (Ziagen®, Trizivir®, or Epzicom®/Kivexa®) again.
-
In order to avoid restarting the ABC-containing product, subjects who have experienced a 
hypersensitivity reaction should be asked to return the remaining tablets to the site.
-
Subjects who have stopped taking an ABC-containing product for any reason, and 
particularly due to possible adverse events or illness, must be advised to contact their doctor 
before restarting.
5.6.6.5
Reporting of Hypersensitivity Reaction
All cases of potential ABC hypersensitivity should be reported as a serious adverse event (see 
Part II, Section 1.4 ‘Reporting of Adverse Events and HIV-Related Events’).
5.7
Statistical Methods Planned and Determination of the Sample Size
5.7.1
SAMPLE SIZE CALCULATION
Since the objective of the trial is only to provide continued access to DRV/rtv for HIV-1 infected
adult or pediatric subjects who previously received DRV/rtv in a clinical (parent) trial, who 
continue to benefit from using it, and who live in a country where DRV is not commercially 
available for the subject, is not reimbursed, or is not accessible through another source (e.g., 
access program, government program), and since the trial is not set up to show a specific 
statistical hypothesis, a sample size calculation is not applicable.
Data from this trial may be included in safety updates.
5.7.2
STATISTICAL ANALYSES
Final analysis will be done once all subjects have completed the Final/Withdrawal Visit. After 
termination of data collection in the CRF, no additional statistical analysis will be performed. 


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5.7.2.1
Initial Subject and Disease Characteristics
The demographic and baseline disease characteristics of the subjects included in this trial, such 
as gender and race, will be tabulated when deemed necessary for submissions or safety updates.
5.7.2.2
Efficacy
There will be no formal efficacy analysis.
5.7.2.3
Safety
The safety and tolerability of DRV/rtv in combination with other ARVs will be summarized in 
terms of:
-
Mortality;
-
All serious adverse events;
-
Adverse events leading to discontinuation;
-
Adverse events considered at least possibly related to DRV/rtv treatment.
The number and causes of deaths will be summarized.
The number of subjects who terminate treatment will be tabulated, and the reasons for drug 
discontinuation will be summarized.
5.8
Data Quality Assurance
See Data Quality Control/Assurance (Part II, Section 8).


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6
REFERENCES
1. 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 (DHHS). July 14, 2016; 1-161.
2. Investigator’s Brochure, DRV, Janssen Research & Development, Version17, January 2019.
3. Sekar V, Van Baelen B, Vangeneugden T, Guzman S. A phase II, open-label trial, to 
investigate pharmacokinetics, safety, tolerability and antiviral activity of DRV/rtv b.i.d. in 
treatment-experienced HIV-1 infected children and adolescents. Tibotec Pharmaceuticals 
Ltd, Topline Results Report, TMC114-C212-Topline-Part I, January 2007.
4. Spinosa-Guzman S, Vangeneugden T, Sekar V, Dierynck I. A Phase II, open-label trial, to 
investigate pharmacokinetics, safety, tolerability and antiviral activity of TMC114/rtv b.i.d. 
in treatment-experienced HIV-1 infected children and adolescents – Week 24 analysis. 
Tibotec Pharmaceuticals Ltd, Clinical Research Report, TMC114-C212-W24-CRR, 
March 2008.
5. Spinosa-Guzman S, Vangeneugden T, Sekar V, Dierynck I. A Phase II, open-label trial, to 
investigate pharmacokinetics, safety, tolerability and antiviral activity of TMC114/rtv b.i.d. 
in treatment-experienced HIV-1 infected children and adolescents – Analysis with cut-off 
date of 10 April 2008, at which time all subjects had reached Week 48 or discontinued 
before. Tibotec Pharmaceuticals Ltd, Clinical Research Report, TMC114-C212-W48-CRR, 
January 2009.
6. Spinosa-Guzman S, Vangeneugden T, Sekar V. A Phase I, open-label, randomized, crossover 
trial in healthy subjects to compare the oral bioavailability of a suspension formulation of 
darunavir (DRV) to that of the commercial 300 mg tablet formulation in the presence of low-
dose ritonavir, under fasted and fed conditions, and to assess multiple dose pharmacokinetics 
of the suspension formulation of DRV in the presence of low dose ritonavir. Tibotec 
Pharmaceuticals Ltd, Clinical Research Report, TMC114-TiDP29-C169, February 2009.
7. Rimsza ME. Counseling the adolescent about contraception. Pediatr Rev 2003; 24: 162-170.
8. Sulkowski MS. Drug-induced liver injury associated with antiretroviral therapy that includes 
HIV-1 protease inhibitors. Clin Infect Dis 2004; 38 (Suppl 2): S90-S97.
9. Soriano V, Puoti M, Garcia-Gascó P, et al. Antiretroviral drugs and liver injury. AIDS 
2008; 22: 1-13.
10. FDA/CDER/CBER draft guidance. Guidance for Industry. Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation. October 2007. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM072278.pdf (accessed 12 November 2009).
11. Sabin CA, Worm S, Weber R, et al. Recent use of abacavir and didanosine, but not of 
thymidine analogeus, is associated with risk of myocardial infarction. [Poster # 957c]. 
15th Conference on Retroviruses and Opportunistic Infections, Boston, February 2008.
12. Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S. Prospective genetic 
screening decreases the incidence of abacavir hypersensitivity reactions in the Western 
Australian HIV cohort study. Clin Infect Dis 2006; 43: 99-102.


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13. Fletcher B, Berra K, Ades P, et al. AHA Scientific Statement. Managing abnormal blood 
lipids. A collaborative approach. Circulation 2005; 112: 3184-3209.
14. BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 
2015 (2016 interim update).


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ADDENDA
7.1
Addendum 1: Trial Contact Persons 
An up-to-date version of the contact details of sponsor and third parties is available in the 
investigator site file. 


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7.2
Addendum 2: DAIDS Grading Table
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND 
PEDIATRIC ADVERSE EVENTS - PUBLISH DATE: DECEMBER 2004
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(“DAIDS grading table”) is a descriptive terminology to be utilized for adverse event reporting 
in this trial. A grading (severity) scale is provided for each adverse event term.
General Instructions
Estimating Severity Grade
If the need arises to grade a clinical adverse event that is not identified in the DAIDS grading 
table, use the category “Estimating Severity Grade” located at the top of the table on the 
following page.
Grading Adult and Pediatric Adverse Events
The DAIDS grading table includes parameters for grading both adult and pediatric adverse 
events. When a single set of parameters is not appropriate for grading specific types of adverse 
events for both adult and pediatric populations, separate sets of parameters for adult and/or 
pediatric populations (with specified respective age ranges) are provided. If there is no 
distinction in the table between adult and pediatric values for a type of adverse event, then the 
single set of parameters listed is to be used for grading the severity of both adult and pediatric 
events of that type.
Determining Severity Grade
If the severity of an 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 
(social interactions, play activities, learning tasks, etc.).
Medical intervention
Use of pharmacologic or biologic agent(s) for treatment of an 
adverse event.
Operative intervention
Surgical OR other invasive mechanical procedures.


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


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


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


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CLINICAL
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 non-urgent 
intervention indicated
Life-threatening 
consequences 
(e.g., tamponade) OR 
Urgent intervention 
indicated
Prolonged PR interval
Adult > 16 years
PR interval 
0.21 – 0.25 s
PR interval > 0.25 s
Type II 2nd degree AV 
block OR Ventricular 
pause > 3.0 s
Complete AV block
Pediatric 
16 years
1st degree AV block (PR 
> normal for age and rate)
Type I 2nd degree AV 
block
Type II 2nd degree AV 
block
Complete AV block
a
Revised by the sponsor.
Use as a reference: Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 
14, 2011; DOI: 10.1542/peds.2009-2107C.
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement).
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.).


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


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


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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.)


TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
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Approved; Issued Date: 20 June 2019
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and attention 
deficit disorder)
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater 
than minimal interference 
with usual social & 
functional activities OR 
Specialized resources on 
part-time basis indicated
Disability causing 
inability to perform usual 
social & functional 
activities OR Specialized 
resources on a full-time 
basis indicated
Disability causing 
inability to perform basic 
self-care functions OR 
Institutionalization 
Indicated
CNS ischemia (acute)
NA
NA
Transient ischemic Attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit
Developmental delay
Pediatric 16 years
Mild developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting
Moderate developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting
Severe developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting
Developmental 
regression, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting
Headache
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
Symptoms causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
(other than emergency 
room visit) OR Headache 
with significant 
impairment of alertness or 
other neurologic function
Insomnia
NA
Difficulty sleeping 
causing greater than 
minimal interference with 
usual social & functional 
activities
Difficulty sleeping 
causing inability to 
perform usual social & 
functional activities
Disabling insomnia 
causing inability to 
perform basic self-care 
functions
Neuromuscular weakness 
(including myopathy & 
neuropathy)
Asymptomatic with 
decreased strength on 
exam OR Minimal muscle 
weakness causing no or 
minimal interference with 
usual social & functional 
activities
Muscle weakness causing 
greater than minimal 
interference with usual 
social & functional 
activities
Muscle weakness causing 
inability to perform usual 
social & functional 
activities
Disabling muscle 
weakness causing 
inability to perform basic 
self-care functions OR 
Respiratory muscle 
weakness impairing 
ventilation
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement).
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play 
activities, learning tasks, etc.)


TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
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Approved; Issued Date: 20 June 2019
xCLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Neurosensory alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with 
sensory alteration on 
exam or minimal 
paresthesia causing no or 
minimal interference with 
usual social & functional 
activities
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with usual 
social & functional 
activities
Sensory alteration or 
paresthesia causing 
inability to perform usual 
social & functional 
activities
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions
Seizure: (new onset) 
Adult 18 years
See also Seizure: (known 
pre-existing seizure 
disorder)
NA
1 seizure
2 – 4 seizures
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult to 
control (e.g., refractory 
epilepsy)
Seizure: (known 
pre-existing seizure 
disorder)
Adult 18 years
For worsening of existing 
epilepsy the grades should 
be based on an increase 
from previous level of 
control to any of these 
levels.
NA
Increased frequency of 
pre-existing seizures 
(nonrepetitive) without 
change in seizure 
character OR Infrequent 
breakthrough seizures 
while on stable 
medication in a previously 
controlled seizure 
disorder
Change in seizure 
character from baseline 
either in duration or 
quality (e.g., severity or 
focality)
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult to 
control (e.g., refractory 
epilepsy)
Seizure
Pediatric < 18 years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with 
< 24 hours post-ictal 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.)


TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
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Approved; Issued Date: 20 June 2019
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.)


TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
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Approved; Issued Date: 20 June 2019
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Myalgia 
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing 
greater than minimal 
interference with usual 
social & functional 
activities
Muscle pain causing 
inability to perform usual 
social & functional 
activities
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions
Osteonecrosis
NA
Asymptomatic with 
radiographic findings 
AND No operative 
intervention indicated
Symptomatic bone pain 
with radiographic findings 
OR Operative intervention 
indicated
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions
GENITO-URINARY
Cervicitis (symptoms)
(For use in studies 
evaluating topical study 
agents)
For other cervicitis see 
Infection: Infection (any 
other than HIV infection)
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Symptoms causing 
inability to perform usual 
social & functional 
activities
Symptoms causing 
inability to perform basic 
self-care functions
Cervicitis (clinical exam) 
(For use in studies 
evaluating topical study 
agents)
For other cervicitis, 
see Infection: Infection 
(any other than HIV 
infection)
Minimal cervical 
abnormalities on 
examination (erythema, 
mucopurulent discharge, 
or friability) OR 
Epithelial disruption 
< 25% of total surface
Moderate cervical 
abnormalities on 
examination (erythema, 
mucopurulent discharge, 
or friability) OR 
Epithelial disruption of 
25% – 49% total surface
Severe cervical 
abnormalities on 
examination (erythema, 
mucopurulent discharge, 
or friability) OR 
Epithelial disruption 
50% – 75% total surface
Epithelial disruption 
> 75% total surface
Intermenstrual bleeding 
(IMB)
Spotting observed by 
participant OR Minimal 
blood observed during 
clinical or colposcopic 
examination
Inter-menstrual bleeding 
not greater in duration or 
amount than usual 
menstrual cycle
Inter-menstrual bleeding 
greater in duration or 
amount than usual 
menstrual cycle
Hemorrhage with life-
threatening 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 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.)


TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
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Approved; Issued Date: 20 June 2019
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.)


TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
65
Approved; Issued Date: 20 June 2019
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.)


TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
66
Approved; Issued Date: 20 June 2019
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.
Revised by the sponsor; monomer conversion factor used for conversion from g/dL to mmol/L


TMC114IFD3001
Clinical Trial Protocol Amendment GEN-II
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Approved; Issued Date: 20 June 2019
LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Infanta,b
22 – 35 days
(HIV positive or 
negative)
9.5 – 10.5 g/dL
5.8 – 6.4 mmol/L
8.0 – 9.4 g/dL
4.8 – 5.7 mmol/L
7.0 – 7.9 g/dL
4.2 – 4.7 mmol/L
< 7.00 g/dL
< 4.2 mmol/L
Infanta,b
1 – 21 days
(HIV positive or 
negative)
12.0 – 13.0 g/dL
7.3 – 7.9 mmol/L
10.0 – 11.9 g/dL
6.1 – 7.2 mmol/L
9.0 – 9.9 g/dL
5.5 – 6.0 mmol/L
< 9.0 g/dL
< 5.5 mmol/L
International normalized 
ratio of prothrombin time
(INR)c
≥1.1 to ≤1.5 x ULN
> 1.5 to ≤ 2.0 x ULN
> 2.0 to ≤ 3.0 x ULN
> 3.0 x ULN
Methemoglobin
5.0% – 10.0%
10.1% – 15.0%
15.1% – 20.0%
> 20.0%
Prothrombin time (PT) d, c
≥1.1 to ≤1.25 x ULN
> 1.25 to ≤1.50 x ULN
> 1.50 to ≤3.00 x ULN
> 3.00 x ULN
Partial thromboplastin
time (PTT)d
≥ 1.1 to ≤1.66 x ULN
> 1.66 to ≤2.33 x ULN
> 2.33 to ≤3.00 x ULN
> 3.00 x ULN
Platelets, decreased
100,000 –
124,999/mm³
100.000 x 109 –
124.999 x 109/L
50,000 –
99,999/mm³
50.000 x 109–
99.999 x 109/L
25,000 –
49,999/mm³
25.000 x 109–
49.999 x 109/L
< 25,000/mm³
< 25.000 x 109/L
WBC, decreased
2,000 – 2,500/mm³
2.000 x 109 –
2.500 x 109/L
1,500 – 1,999/mm³
1.500 x 109–
1.999 x 109/L
1,000 – 1,499/mm³
1.000 x 109–
1.499 x 109/L
< 1,000/mm³
< 1.000 x 109/L
CHEMISTRIES Standard International Units are listed in italics
Acidosis
NA
pH < normal, but 7.3
pH < 7.3 without 
life-threatening 
consequences
pH < 7.3 with 
life-threatening 
consequences
Albumin, serum, low
3.0 g/dL – < LLN
30 g/L – < LLN
2.0 – 2.9 g/dL
20 – 29 g/L
< 2.0 g/dL
< 20 g/L
NA
Alkaline phosphatasec
≥1.25 to ≤2.5 x ULNb
> 2.5 to ≤5.0 x ULNb
> 5.0 to ≤10.0 x ULNb
> 10.0 x ULNb
Alkalosis
NA
pH > normal, but 7.5
pH > 7.5 without 
life-threatening 
consequences
pH > 7.5 with 
life-threatening 
consequences
ALT (SGPT) c
≥1.25 to ≤2.5 x ULN
> 2.5 to ≤5.0 x ULN
> 5.0 to ≤10.0 x ULN
> 10.0 x ULN
AST (SGOT) c
≥1.25 to ≤2.5 x ULN
> 2.5 to ≤5.0 x ULN
> 5.0 to ≤10.0 x ULN
> 10.0 x ULN
Bicarbonate, serum, low
16.0 mEq/L – < LLN
16.0 mmol/L – < LLN
11.0 – 15.9 mEq/L
11.0 – 15.9 mmol/L
8.0 – 10.9 mEq/L
8.0 – 10.9 mmol/L
< 8.0 mEq/L
< 8.0 mmol/L
a
Values are for term infants.
b
Use age- and sex-appropriate values (e.g., bilirubin), including preterm infants.
c
Revised by the sponsor.
d
If the local laboratory is reporting PT as percentage, only INR value will be considered for reporting PT related abnormalities and adverse events.


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


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


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


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7.3
Addendum 3: Visit Schedule for Cutaneous Reaction/Rash Follow-
up for pediatric subjects
This visit schedule summarizes the visits and assessments to be performed in case of Cutaneous 
Reaction/Rash. At the investigator’s discretion, additional visits and assessments can be 
performed.
Grade 1 
Grade 2 
Grade 3 or 4 
Day 0a
Unscheduled trial visit for initial 
cutaneous reaction/rash 
evaluation and local lab 
assessment.
Referral to dermatologist.
Biopsy.
Trial medication may be 
continued.
Unscheduled trial visit for 
initial cutaneous 
reaction/rash evaluation and 
local lab assessment.
Referral to dermatologist, 
preferably within 24 hours.
Biopsy.
Trial medication MAY be 
continued at the 
investigator’s discretion.
Unscheduled trial visit for 
initial rash evaluation and 
local lab assessment.
Referral to dermatologist 
and biopsy, preferably 
within 24 hours.
Trial medication MUST be 
discontinued.
Day 1
Follow-up visit, including local 
lab assessment.
Follow-up visit, including 
local lab assessment.
Follow-up visit, including 
local lab assessment.
Day 2
No cutaneous reaction/rash 
follow-up visit requiredb.
No cutaneous reaction/rash 
follow-up visit requiredb.
Follow-up visit. Local lab 
AST/ALT assessment only 
if AST/ALT on Days 0 and 
1 are 2 x baseline value 
and/or 5 x ULN, and/or in 
case of cutaneous 
reaction/rash progression.
Day 3
No cutaneous reaction/rash 
follow-up visit requiredb.
No cutaneous reaction/rash 
follow-up visit requiredb.
Follow-up visit. Local lab 
AST/ALT assessment only 
if AST/ALT on Days 0 and 
1 are 2 x baseline value 
and/or 5 x ULN, and/or in 
case of cutaneous 
reaction/rash progression.
a
Note that Day 0 of the cutaneous reaction/rash follow-up is the first day of investigator assessment and not the 
first day of cutaneous reaction/rash as reported by the subject.
b
In case cutaneous reaction/rash progresses to grade 3 or 4, start follow-up schedule for grade 3 or 4 cutaneous 
reaction/rash as of Day 1 and conduct biopsy/refer to dermatologist as appropriate. (Even if the subject was 
already referred to dermatologist in scope of grade 1 or 2 cutaneous reaction/rash.)


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Grade 1 
Grade 2 
Grade 3 or 4 
Day 4 
No cutaneous reaction/rash 
follow-up visit requiredc.
No cutaneous 
reaction/rash follow-up 
visit requiredc.
Follow-up visit. Local lab 
AST/ALT assessment 
only if AST/ALT on Days 
0 and 1 are 2 x baseline 
value and/or 5 x ULN, 
and/or in case of 
cutaneous reaction/rash 
Day 5
No cutaneous reaction/rash 
follow-up visit requiredc.
No cutaneous 
reaction/rash follow-up 
visit requiredc.
Follow-up visit, including 
local lab assessment.
Day 7
Follow-up visit, including 
local lab assessmentc.
Follow-up visit, including 
local lab assessmentc.
No cutaneous 
reaction/rash follow-up 
visit required.
Further Visits
If cutaneous reaction/rash 
unresolved after second 
follow-up visit, further visits 
(including local lab 
assessments) at investigator’s 
discretion.
If cutaneous reaction/rash 
unresolved after second 
follow-up visit:
- without AST/ALT 
increase: further visits 
(including local lab 
assessments) at 
investigator’s 
discretionc;
- with AST/ALT 
increase < 2 x baseline: 
weekly visits 
(including local lab 
assessments)c.
- with AST/ALT 
increase 2 x baseline 
but not reaching the 
criteria for grade 3 
rash: weekly visits 
(including local lab 
assessments)a.
Weekly visits until 
resolution/stabilization of 
cutaneous reaction and 
AST/ALT elevation, or 
more frequently at 
investigator’s discretion. 
Local lab assessments if 
AST/ALT on Day 5 are 
2 x baseline value and 
5 x ULN.
Upon Rash 
Resolution/Stabilizationd
Complete Final Cutaneous 
Reaction/Rash Evaluation 
form.
Complete Final 
Cutaneous Reaction/Rash 
Evaluation form.
Complete Final 
Cutaneous Reaction/Rash 
Evaluation form.
c
In case cutaneous reaction/rash progresses to grade 3 or 4, start follow-up schedule for grade 3 or 4 cutaneous 
reaction/rash as of Day 1 and conduct biopsy/referral to dermatologist as appropriate. (Even if the subject was 
already referred to dermatologist in scope of grade 1 or 2 cutaneous reaction/rash.)
d
Stabilization: to be agreed upon in collaboration with the sponsor.


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7.4
Addendum 4: Revised WHO Clinical Staging of HIV/AIDS
7.4.1
REVISED WHO CLINICAL STAGING OF HIV/AIDS
7.4.1.1
The clinical stages of HIV infection for adults and adolescents are defined as 
follows (refer to the 1993 revised classification system for HIV infection and expanded 
surveillance case definition for AIDS among adolescents and adults. MMWR 1992; 41 (RR-
17): 1-19; and WHO 2007, Table 3 of: WHO case definitions of HIV for surveillance and 
revised clinical staging and immunological classification of HIV-related disease in adults 
and children, available at http://www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf).
Clinical Stage 1
Clinical Stage 1 consists of 1 or more of the conditions listed below in an adolescent or adult 
(13 years) with documented HIV infection. Conditions listed in Clinical Stages 2, 3 or 4 must 
not have occurred.
-
Asymptomatic HIV infection;
-
Persistent generalized lymphadenopathy.
7.4.1.2
Clinical Stage 2
Clinical Stage 2 consists of symptomatic conditions in an HIV-infected adolescent or adult that 
are not included among conditions listed in Clinical Stage 3, and that meet at least 1 of the 
following criteria: a) the conditions are attributed to HIV infection or are indicative of a defect in 
cell-mediated immunity; or b) the conditions are considered by physicians to have a clinical 
course or to require management that is complicated by HIV infection. Examples of conditions 
in Clinical Stage 2 include, but are not limited to the following.
-
Moderate unexplained weight loss (< 10% of presumed or measured body weight);
-
Recurrent respiratory tract infections sinusitis, tonsillitis, otitis media and pharyngitis);
-
Herpes zoster;
-
Angular cheilitis;
-
Recurrent oral ulceration;
-
Papular pruritic eruptions;
-
Seborrhoeic dermatitis;
-
Fungal nail infections.
7.4.1.3
Clinical Stage 3
Clinical Stage 3 includes the clinical conditions listed in the AIDS surveillance case definition. 
For classification purposes, once a Clinical Stage 3 condition has occurred, the person will 
remain in Clinical Stage 3. Conditions in Clinical Stage 3 include the following.
-
Unexplained§ severe weight loss (> 10% of presumed or measured body weight);
-Unexplained chronic diarrhoea for longer than one month; 
                                                
§ Unexplained refers to where the condition is not explained by other causes.


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-Unexplained persistent fever (above 37.6°C intermittent or constant, for longer than one 
month);
-Persistent oral candidiasis;
-Oral hairy leukoplakia;
-Pulmonary tuberculosis (current);
-Severe bacterial infections (such as pneumonia, empyema, pyomyositis, bone or joint 
infection, meningitis or bacteraemia);
-Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis;
-Unexplained anaemia (< 8 g/dl), neutropaenia (< 0.5 × 109 per litre) or chronic 
thrombocytopaenia (< 50 × 109 per litre).
7.4.1.4
Clinical Stage 4‡
HIV wasting syndrome;
-Pneumocystis pneumonia;
-Recurrent severe bacterial pneumonia;
-Chronic herpes simplex infection (orolabial, genital or anorectal of more than one month’s 
duration or visceral at any site);
-Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs);
-Extrapulmonary tuberculosis;
-Kaposi’s sarcoma;
-Cytomegalovirus infection (retinitis or infection of other organs);
-Central nervous system toxoplasmosis;
-HIV encephalopathy;
-Extrapulmonary cryptococcosis including meningitis;
-Disseminated non-tuberculous mycobacterial infection;
-Progressive multifocal leukoencephalopathy;
-Chronic cryptosporidiosis (with diarrhoed);
-Chronic isosporiasis;
-Disseminated mycosis (coccidiomycosis or histoplasmosis);
-Recurrent non-typhoidal Salmonella bacteraemia;
-Lymphoma (cerebral or B-cell non-Hodgkin) or other solid HIV-associated tumours;
-Invasive cervical carcinoma;
-Atypical disseminated leishmaniasis;
-Symptomatic HIV-associated nephropathy or symptomatic HIV-associated cardiomyopathy.
                                                
‡ Some additional specific conditions can also be included in regional classifications (such as reactivation of 
American trypanosomiasis [meningoencephalitis and/or myocarditis]) in the WHO Region of the Americas and 
disseminated penicilliosis in Asia).


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7.5
Addendum 5: Lipid Abnormalities (Dyslipidemia)a
(Adapted by the sponsor)
Background
Dyslipidemia is only one part of the array of factors that increase cardiovascular risk. At present, 
there are only limited data linking HIV- and treatment-induced alterations in lipid levels with an 
increase in cardiovascular disease events. Nonetheless, these abnormalities are reason for serious 
concern among subjects with improved life expectancy as a result of potent ARV therapy.
Cardiovascular disease risk assessment and intervention must include evaluation of not only 
lipids, but also other modifiable risk factors such as cigarette smoking, hypertension, diabetes, 
obesity, and physical inactivity.
Definitions
Increases of triglycerides and LDL cholesterol and decreases in high-density lipoprotein (HDL)-
cholesterol have been observed in subjects with HIV infection receiving HIV therapy. A variety 
of lipid disturbances have been reported due to HIV and its therapies. Briefly, both HIV infection 
(low HDL-cholesterol, elevation in triglycerides) and PIs (elevation in total and LDL cholesterol 
and additional elevation in triglycerides) are important underlying causes of dyslipidemia in HIV 
infected subjects. With NNRTIs, increases in total cholesterol and LDL cholesterol also occur, 
but these may be offset by increases in HDL-cholesterol. Subjects with fat redistribution (central 
obesity, loss of peripheral fat) are at increased risk of lipid abnormalities; however, a causal 
relationship has not been established.
ADULT SUBJECTS:
Recommendations
Clinicians should monitor patients receiving ARV therapy for dyslipidemia by obtaining a 
fasting lipid profile before and after starting ARV therapy. Frequent monitoring may be indicated 
by the presence of persistent lipid elevation, cardiovascular risk factors, or cardiovascular 
symptoms.
Clinicians should recommend lifestyle modifications, such as increased exercise, weight loss, 
nutrition therapy, smoking cessation, and drug addiction treatment.
Pharmacologic treatment of dyslipidemia should be guided by currently available clinical 
guidelines.
When a statin is indicated, clinicians should avoid using simvastatin and lovastatin in patients 
who are receiving PI based regimens.
                                                
aTaylor P, Worrell C, Steinberg SM, et al. Natural history of lipid abnormalities and fat 
redistribution among human immunodeficiency virus-infected children receiving long-term, 
protease inhibitor-containing, highly active antiretroviral therapy regimens. Pediatrics 2004; 
114: e235-e242.


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Lipid abnormalities in HIV-infected patients, specifically hypocholesterolemia and 
hypertriglyceridemia, were described before the advent of ARV therapy; however, the number of 
patients with lipid abnormalities appears to be increasing in the HAART era. Patients often 
develop lipid abnormalities within 3 months of initiation of ARV therapy. The full clinical 
significance of these laboratory abnormalities is not yet clear, although the abnormalities may be 
associated with premature coronary artery disease in some patients, especially those with other 
risk factors for coronary heart disease or the metabolic syndrome previously referred to as 
syndrome X.
Table 8:
Major Risk Factors (Exclusive of LDL Cholesterol increase) that Modify LDL 
Goals*
cigarette smoking;
hypertension (blood pressure 140/90 mmHg or on antihypertensive medication);
low HDL cholesterol (<40 mg/dL)†;
family history of premature CHD
(coronary heart disease [CHD] in male first-degree relative <55 years; CHD in female first-
degree relative <65 years)
age (men 45 years; women 55 years)
* All the risk factors listed above are captured in the CRF
† HDL cholesterol 60 mg/dL counts as a “negative” risk factor; its presence removes one risk factor from the total 
count
Hypertriglyceridemia, low HDL-cholesterol levels, and elevated low-density lipoprotein (LDL)-
cholesterol levels have been described in patients receiving ARV therapy, especially PIs. NNRTI 
use has been associated with hypercholesterolemia. The mechanism by which PIs cause 
dyslipidemia is unclear. Hypertriglyceridemia seems to be most significant in patients with 
regimens that include low-dose ritonavir. Significant hypertriglyceridemia (>500 mg/dL) is 
associated with an increased risk of pancreatitis, particularly in patients with other risk factors 
for pancreatitis (e.g., alcohol or didanosine use).
Lipid abnormalities in HIV-infected patients receiving ARV therapy may occur in conjunction 
with body fat changes. Secondary causes of dyslipidemia, including diabetes, hypothyroidism, 
liver disease, chronic renal failure, and other medications, such as progestins, anabolic steroids, 
and corticosteroids, should be considered in patients with new onset dyslipidemia.
A fasting lipid profile (total cholesterol, LDL, HDL, triglycerides) should be obtained prior to 
starting ARV treatment (ideally at baseline visit). A fasting lipid profile should be obtained 3 to 
6 months after starting or changing ARV therapy (ideally at each visit of the study protocol).
Alternatively, if collection of a fasting sample is not feasible, a non-fasting total cholesterol and 
HDL may be obtained. The clinician should proceed with a fasting lipoprotein profile when the 
non-fasting TC is >200 mg/dL or the HDL is <40 mg/dL.
The management of lipid disorders in HIV-infected patients parallels management in non-HIV 
infected patients (see Table 8 to Table 10). Individual risk assessments for an acute coronary 
event and management of lipid disorders can be accomplished by following current guidelines 
for assessment and management, such as those published by the National Cholesterol Education 
Program (NCEP) and the Adult AIDS Clinical Trial Group (ACTG) Cardiovascular Disease 


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Focus Group (see Table 8 to Table 10). Treatment of dyslipidemia should include lifestyle and 
risk modification with or without pharmacological therapies.
For patients without known coronary artery disease (CAD), therapeutic lifestyle changes should 
be the first intervention for the treatment of lipid disorders. These changes include increased 
physical exercise, weight reduction when indicated, smoking cessation and dietary changes. 
Consultation with a registered dietitian may be helpful in achieving dietary goals [restriction of 
total fat to 25%-30% of total caloric intake, and dietary cholesterol to <200 mg/day; use of plant 
sterols (2 gm/d) found in commercial margarines (e.g., Benecol or Basikol), and increased 
soluble fiber (10-25 g/d)].
Lipid-lowering agents should be considered for hyperlipidemias that do not respond to changes 
in ARV therapy or therapeutic lifestyle changes, or for patients in whom such modifications are 
not appropriate. The first-line pharmacological treatment for patients with isolated elevation of 
LDL is statin therapy. Pravastatin is the safest drug for treating hyperlipidemia during concurrent 
therapy with currently FDA approved PIs. Atorvastatin can be used cautiously at lower doses (5-
10 mg) with careful titration. Rosuvastatin will not likely interact with PIs and NNRTIs. Use of 
other statins, particularly lovastatin and simvastatin, is contraindicated.
Fibric acid derivatives, such as gemfibrozil and fenofibrate, are the first-line treatment for
isolated elevation of fasting triglyceride levels. The threshold suggested for intervention is 
500 mg/dL.
Gemfibrozil and fenofibrate are not metabolized via the cytochrome P450 system and are 
generally safe to use in patients receiving ARV therapy. For patients with high triglycerides in 
whom LDL cholesterol increases cannot be measured, the non-HDL cholesterol level may be 
calculated to guide initiation of therapy (total cholesterol – HDL). 
Patients with persistent high-grade hypertriglyceridemia (>1000 mg/dL) may benefit from a very 
low-fat diet, even if they are not overweight.
Table 9:
LDL and non-HDL Cholesterol Goals and Thresholds for Therapeutic Lifestyle 
Changes and Drug Therapy in Different Risk Categories
Risk Category
LDL Goal 
(mg/dL)
LDL Level at 
Which to Initiate 
Lifestyle Changes 
(mg/dL)
LDL Level at 
Which to 
Consider Drug 
Therapy (mg/dL)
Non-HDL Goal 
(mg/dL)*
CHD or CHD risk 
equivalents: diabetes 
mellitus, 
atherosclerotic disease 
(CAD or stroke), or 
multiple risk factors 
(10-year risk >20%)
<100
≥100
<130 (100-129: 
drug optional)†
≥130
2+ risk factors: HDL 
<40, strong
family history, age >45 
<130
≥130
10-year risk
10%-20%: ≥130
10-year risk 
<160


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years, and
smoking (10-year risk 
>20%)
<10%: ≥160
0-1 risk factor‡
<160
≥160
≥190 (160-189: 
LDL-lowering 
drug optional)
<190
* Non-HDL cholesterol = (total cholesterol – HDL). When LDL cannot be measured because the triglyceride level 
is >200 mg/dL, non-HDL cholesterol may be used as a secondary goal. The non-HDL cholesterol goal is 
30 mg/dL higher than the LDL cholesterol goal.
† Some authorities recommend use of LDL-lowering drugs in this category if an LDL cholesterol level of 
<100 mg/dL cannot be achieved by therapeutic lifestyle changes (dietary and exercise intervention). Others prefer 
use of drugs that primarily modify triglycerides and HDL (e.g., nicotine acid or fibrate). Clinical judgment also 
may suggest deferring drug therapy in this subcategory.
‡ Almost all people with 0 or 1 risk factors have a 10-year risk <10%; thus, 10-year risk assessment in people with 
0 or 1 risk factors is not necessary.
For those with both elevated serum LDL and triglyceride levels, combination therapy with a 
statin and fibrate may be needed but should be used with extreme caution because of overlapping 
toxicity (rhabdomyolysis) profiles. Therapy should begin first with a statin, followed by the 
addition of the fibric acid derivative if response to the maximal statin dose is suboptimal after 3 
to 4 months of treatment. Routine monitoring for hepatic and muscle toxicity should be 
performed in these situations.
The use of additional drugs, such as nicotinic acid or bile sequestrants, may be necessary to 
manage dyslipidemia. Nicotinic acid may cause hepatotoxicity and elevated serum glucose
levels. Therefore, low-dose therapy with incremental dose increases is advisable for those 
patients who require this drug. Bile acid sequestrants (e.g., colesevelam 3 tablets b.i.d. or 
ezetimibe 10 mg q.d.) may also be used but may interfere with absorption of oral medications; 
therefore, proper timing of the dosing of this drug is important when used in conjunction with 
ARV medications (i.e., 1 hour before or 4 hours after).
Table 10:
Choice of Drug Therapy for Dyslipidemia in HIV-infected Individuals 
Receiving HAART
Lipid Abnormality
First Choice
Second Choice (or if 
additional treatment is 
needed)
Comments
Isolated high LDL
Statin*
Fibrate
Start with low doses 
of statins and titrate 
upward.
Patients receiving PIs 
may be at increased 
risk of statin-induced 
myopathy.


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Combined 
hyperlipidemia (high 
cholesterol and high 
triglycerides)
Fibrate or statin*
– If starting with fibrate, 
add statin*
– If starting with statin*, 
add fibrate
Combining statin and a 
fibrate may increase risk 
for myopathy
Isolated 
hypertriglyceridemia
Fibrate
Statin*
Combining statin and a 
fibrate may increase risk 
for myopathy.
Adapted from the Preliminary guidelines for the evaluation and management of dyslipidemia in 
adults infected with human immunodeficiency virus and receiving antiretroviral therapy: 
Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group.
* Statins should be dosed at bedtime. Simvastatin and lovastatin are not allowed in patients 
receiving DRV/rtv (the only allowed PI in this trial).
PEDIATRIC SUBJECTS:
Identifying Dyslipidemia in Children and Youth
The National Cholesterol Education Program (NCEP) and the American Heart Association 
(AHA) recommend an individualized/high-risk approach to identifying dyslipidemia in children 
and youth as describe belowa:
Primary Prevention in Children and Youth
Dietary modification
Limit foods with
-
Saturated fats to less than 10% calories per day
-
Cholesterol below 300 mg/day
-
Trans fatty acids
Physical activity
-
Increase moderate to rigorous more than 60 minutes per day
-
Limit sedentary activities less than 2 hours per day
Identification of dyslipidemia
Selective screening
-
Family history of coronary heart disease
-
One parent with blood cholesterol greater than 240 mg/dL
-
No parental history, but coronary heart disease risk factors present
-
More than 1 of the following risk factors present: high blood pressure, smoking, sedentary 
lifestyle, obesity, alcohol intake, use of drugs or diseases associated with dyslipidemia
                                                
a Fletcher B, Berra K, Ades P, et al. AHA Scientific Statement. Managing abnormal blood lipids. A collaborative 
approach. Circulation 2005; 112: 3184-3209.


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A fasting lipid profile allows for a comprehensive assessment that includes measurement of
elevations in total cholesterol and LDL cholesterol, triglycerides and HDL-cholesterol. The AHA 
recommends the averaged results of 3 fasting lipid profiles as the baseline for guiding treatment 
modalities.
The AHA endorses the guidelines established by the NCEP in setting the following definitions 
for acceptable, borderline, and high total cholesterol and LDL- cholesterol levels in children and 
adolescents between 2 and 19 years of age.
Cholesterol Levels for 2- to 19-Year-Olds
Levels               Total cholesterol, mg/dL           LDL cholesterol, mg/dL
Acceptable       < 170< 110
Borderline        170–199                                     110–129
High                 >200                                           > 130
Although these cut off points are recommended to guide treatment decisions, it is important to 
emphasize that no long-term longitudinal studies have been conducted to determine the absolute 
levels in childhood and adolescence that accelerate atherosclerotic processes and predict 
cardiovascular heart disease in adult life.
Lifestyle modification with an emphasis on normalization of body weight and heart-healthy 
patterns of dietary intake and physical activity is the cornerstone of treatment for children and 
youth who are identified as having dyslipidemia.
This approach should be supported through education as well as through community-based 
activities. In the pediatric clinics, the management of dyslipidemia is best accomplished via a 
multidisciplinary collaborative team approach. Nurses, nurse practitioners, and dietitians 
experienced in the treatment of dyslipidemia in children and youth are well positioned within 
these settings to facilitate lifestyle modification with children and families.
The AHA recommends an “adequate” trial (i.e., 6-12 months) of therapeutic lifestyle change 
before consideration of lipid-lowering medication. Three general classes of lipid-lowering agents 
are available and have been used in the treatment of dyslipidemia in children and adolescents. 
These include the bile acid sequestrants, niacin, and statins (refer to the current Investigator’s 
Brochure of DRV2 for the allowed and disallowed concomitant medication during clinical trials 
with DRV).


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PART II: PROCEDURES
1
ADVERSE EVENTS
1.1
Definitions
ADVERSE EVENT (AE)
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (International Conference on Harmonisation - ICH E6; 1.2).
SERIOUS ADVERSE EVENT (SAE)
Any untoward medical occurrence that at any dose:
-
results in death;
-
is life threatening;
-
requires inpatient hospitalization or prolongation of existing hospitalization;
-
results in persistent or significant disability/incapacity;
or 
-
is a congenital anomaly/birth defect (ICH E6; 1.50).
Additionally, any report containing an untoward medical occurrence considered medically 
significant which includes any suspected transmission of any infectious agent via a medicinal 
product is a serious adverse event.
Note 
-
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life threatening or result in death or hospitalization, but may jeopardize 
the subject or may require intervention to prevent one of the outcomes listed in the 
definition above.
-
Hospitalizations that were planned prior to the signing of informed consent/assent, and 
where the underlying condition for which the hospitalization was planned has not 
worsened, will not be considered serious adverse events. Any adverse event that results in 
a prolongation of the originally planned hospitalization is to be reported as a new serious 
adverse event.
-
For convenience the investigator may choose to hospitalize the subject for the duration of 
the treatment period; this will not be considered as a serious adverse event.


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UNLISTED (UNEXPECTED) ADVERSE EVENT
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g., Investigator’s Brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product).
LIFE THREATENING
Any event in which the subject was at risk of death at the time of the event; it does not refer to an 
event, which hypothetically might have caused death if it were more severe.
ASSOCIATED WITH THE USE OF THE DRUG
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable or very likely.
1.2
Attribution Definitions
NOT RELATED
An adverse event, which is not related to the use of the drug.
DOUBTFUL
An adverse event for which an alternative explanation is more likely, e.g., concomitant drug(s) or 
concomitant disease(s), and/or the relationship in time suggests that a causal relationship is 
unlikely.
POSSIBLE
An adverse event, which might be due to the use of the drug. An alternative explanation, 
e.g., concomitant drug(s) or concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore the causal relationship cannot be excluded.
PROBABLE
An adverse event, which might be due to the use of the drug. The relationship in time is 
suggestive, e.g., confirmed by dechallenge. An alternative explanation is less likely, 
e.g., concomitant drug(s) or concomitant disease(s).
VERY LIKELY
An adverse event, which is listed as a possible adverse reaction and cannot be reasonably 
explained by an alternative explanation, e.g., concomitant drug(s) or concomitant disease(s). 
The relationship in time is very suggestive (e.g., it is confirmed by dechallenge and rechallenge).
1.3
HIV-Related Events or Outcomes
The events or outcomes listed in the classification list (see PART I:7.4, Addendum 4: Revised 
WHO Clinical Staging of HIV/AIDS) are to be recorded as HIV-related events on the CRF. 
These events or outcomes, as well as any sign, symptom, diagnosis, illness, and/or clinical 
laboratory abnormalities that can be linked to any of these events or outcomes, are not to be 
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After termination of data collection, safety will continue to be assessed per local standard of care
and documented in the subject’s medical records only. Data will no longer be recorded in the 
CRF. Investigators will continue to report SAEs possibly related to DRV/rtv and pregnancies to 
the sponsor using regular pharmacovigilance reporting. This information will only be entered in 
the company safety repository.
1.4
Reporting of Adverse Events and HIV-Related Events 
Any new adverse event, serious adverse event, or worsening of a condition will be reported to 
the originating (parent) trial until the Week 4 follow-up contact in the originating protocol. 
After the Week 4 follow-up of the originating (parent) trial, adverse events leading to 
discontinuation or treatment interruption, adverse events considered at least possibly related to 
treatment with DRV/rtv, serious adverse events, and pregnancies are to be reported in the CRF of 
trial TMC114IFD3001. All other adverse events that do not meet criteria for seriousness are only 
to be collected if required per local regulations.
Occurrence of adverse events and HIV-related events are to be reported in the Adverse Event 
and HIV-Related Events sections of the CRF, respectively.
All reportable adverse events still ongoing at the end of the treatment are to be followed until 
satisfactory resolution (i.e., value back to baseline value) or stabilization (to be agreed upon in 
collaboration with the sponsor) at the investigator’s discretion, according to the local standard 
of care, or until final database lock.
New adverse events leading to discontinuation or treatment interruption, new adverse events 
considered at least possibly related to treatment with DRV/rtv, and new serious adverse events 
reported during the follow-up period of the trial are to be followed as agreed between the sponsor 
and investigator.
Certain long-term adverse events of antiretroviral therapy cannot be followed until resolution 
within the setting of this protocol; in these cases follow-up is the responsibility of the treating 
physician. However, this has to be agreed upon with the sponsor.
Serious adverse events occurring within the trial (between the signing of informed consent/assent
and last follow-up visit) are to be reported. Any serious adverse events with at least a possible 
relationship to the study medication occurring after the end of the trial must be reported, and are 
to be handled by the sponsor. 
The start date of the serious adverse event documented on the Serious Adverse Event Form must 
be the same as the start date of the corresponding adverse event documented on the CRF. If a 
change in severity is noted for the existing adverse event, it must be recorded as a new adverse 
event. If a worsened adverse event meets the criteria for a serious adverse event, the start date of 
the serious adverse event must be the same as the start date of the worsened adverse event.
The cause of death of a subject in a clinical trial, whether the event is expected or associated with 
the investigational agent, is a serious adverse event.
All serious adverse events and pregnancies occurring during clinical trials must be 
reported to the Drug Safety Officer as specified on the Serious Adverse Event Form 
immediately (i.e., within 24 hours) after the investigator becoming aware of the event. 


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For the names and phone numbers of the contact person(s) refer to Part I, Section 7.1, 
Addendum 1: Trial Contact Persons.
The first report of a serious adverse event may be made by telephone or facsimile (FAX). The 
investigator must provide the minimal information, i.e., trial number, subject’s initials and date 
of birth, medication code number, period of intake, nature of the adverse event, and 
investigator’s attribution.
This report of a serious adverse event by telephone must always be confirmed by a written, more 
detailed report. For this purpose, the monitor provides the investigator with a Serious Adverse 
Event Form, to be completed and signed by the latter. If initial reporting was done by telephone, 
the person answering the phone can complete the Serious Adverse Event Form according to the 
information provided by the investigator. This form needs to be reviewed, completed if 
applicable, signed, and dated for approval by the investigator.
Pregnancies occurring during clinical trials are considered immediately reportable events. They 
must be reported as soon as possible using the same Serious Adverse Event Form. The outcome 
of the pregnancy must also be reported to the Drug Safety Officer.
The sponsor or its representatives assumes responsibility for appropriate reporting of adverse 
events to Regulatory Authorities. Adverse Events reporting, including suspected unexpected 
serious adverse reactions, is to be carried out in accordance with applicable local regulations. 
For reported deaths, the investigator should supply the sponsor and the Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB) with any additional requested information 
(e.g., autopsy reports and terminal medical reports).
After termination of the clinical trial (last subject last visit in the trial), any unexpected safety 
issue that changes the risks benefit analysis and is likely to have an impact on the subjects who 
have participated in it, should be reported as soon as possible to the competent authority(ies) 
concerned together with proposed actions.
After termination of data collection, safety will continue to be assessed per local standard of care
and documented in the subject’s medical records only. Data will no longer be recorded in the 
CRF. Investigators will continue to report SAEs possibly related to DRV/rtv and pregnancies to 
the sponsor using regular pharmacovigilance reporting. This information will only be entered in 
the company safety repository.
2
TRIAL CLOSURE CONSIDERATIONS
The sponsor reserves the right to close an investigational site or terminate the trial at any time for 
any reason. In case of an early termination of the trial or temporary halt by the sponsor, the 
IEC/IRB should be notified within 15 calendar days, including a detailed written explanation of 
the reasons for the termination/halt.
When the trial ends in a particular country, the sponsor will submit an end of trial declaration, to 
both the IEC/IRB and regulatory authority for that particular country by using the “Declaration 
of the end of trial form” (EU member states only). 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.


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Reasons for the closure of an investigational site or termination of a trial by the sponsor may 
include but are not limited to:
-
discontinuation of the trial at the center;
-
failure of the investigator to comply with the protocol, ICH-Good Clinical Practice 
(GCP) guidelines or local requirements;
-
safety concerns;
-
switch of all subjects enrolled at the site to locally available DRV-based treatment 
regimens (ie, commercially available and reimbursed, or accessible through another 
source [eg, access program or government program]) or to local standard of care, as 
appropriate.
3
TRIAL MATERIALS
3.1
Investigational Products
The investigator acknowledges that the drug supplies are investigational and as such must be 
handled strictly in accordance with the protocol and the container label. Supplies must be 
retained in a limited access area and under the appropriate environmental conditions as specified 
on delivery. Supplies should be dispensed under the supervision of the investigator or 
subinvestigator, or by a hospital pharmacist. Local regulations should be adhered to.
It is the investigator’s responsibility to ensure that subjects or those held to be responsible for 
subjects, return their medication (including empty packages, e.g., empty blisters). Returned 
supplies must not be dispensed again, even not to the same subject. Each time medication is 
dispensed to or returned by the subject, this must be documented on the Drug Accountability 
Form. Unused medication and medication returned by the subject must be available for 
verification by the monitor.
After termination of data collection, compliance check on unused and used trial medication 
returned by the subject will still be performed by the investigator or designee and will not be 
verified by the sponsor, however, drug accountability will be reviewed during the on-site 
monitoring visits.
All used and unused trial medication will be passed over for destruction on site (conform local 
regulations), or by an authorized destruction unit after authorization by the sponsor. This will be 
documented on the Drug Return Form, and a destruction certificate, if applicable.
3.2
Trial Documents
The following documents must be provided to the sponsor or representatives before shipment of 
trial medication to the trial center. 
-
A signed and dated protocol and amendment(s), if any.
-
A copy of the signed and dated written IEC/IRB approval specifying the documents 
being approved: the protocol, amendments, Informed Consent/Assent Forms, any other 
written information provided to the subject, and subject recruitment materials. This 
approval must clearly identify the trial by protocol title and trial number.
-
Regulatory authority approval or notification, if required.


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Documentation on which the assessment of the principal investigator’s qualifications was 
based (e.g., curriculum vitae).
-
The FDA Form 1572, if applicable, and the FDA Waiver Letter provided to non-US 
investigators.
-
Completed Investigator Financial Disclosure Form from the principal investigator.
-
Signed and dated Clinical Trial Agreement, if applicable.
-
Signed and dated financial agreement.
-
Import License, if required.
The following documents must be provided to the sponsor or representatives prior to enrollment 
of the first subject.
-
Current list of the IEC/IRB members, their function and affiliation or equivalent, 
officially authorized assurance on the IEC/IRB composition.
-
Statement or equivalent documentation* that the IEC/IRB operation is in compliance 
with ICH-GCP, and local regulatory requirements.
* Equivalent documentation applies to countries where the IEC/IRB is certified through 
the Local Health Authorities.
-
Current license to prescribe and distribute controlled substances, if applicable.
-
Completed Investigator Financial Disclosure Form from all participating 
subinvestigators.
-
Documentation on which the assessment of the subinvestigators’ qualifications was based 
(e.g., curriculum vitae).
-
Signed and dated agreement between the investigator and Local Health Authority, if 
applicable.
3.3
Participation Cards
If the subjects are not under 24-hour supervision of the investigator or his/her staff (out-subjects), 
they must be provided with a Subject Participation Card indicating the name of the 
investigational product, the trial number, the investigator’s name and a 24-hour emergency 
contact number. The subject should be advised to keep the participation card in his/her wallet at 
all times.
3.4
Source Data
The nature and location of all source documents is to be identified in the Source Document 
Identification Form to ensure that all sources of original data required to complete the CRF are 
known and are accessible for verification by the monitor. If electronic records are maintained, 
the method of verification must be discussed and agreed upon between the investigational staff 
and the monitor.
The required source data are listed in the Source Data Verification Plan, and should include 
sequential notes containing at least the following information for each subject:


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subject identification (name, date of birth, gender);
-
documentation that subject meets eligibility criteria, i.e., history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria);
-
participation in trial (including trial number);
-
trial discussed and date of informed consent/assent;
-
dates of all visits;
-
documentation that protocol specific procedures were performed;
-
start and end date (including dose regimen) of trial medication (preferably drug 
dispensing and return should be documented as well);
-
record of all reportable adverse events (see Section 1.4 of Part II) and other safety 
parameters (start and end date, and preferably including causality and intensity);
-
concomitant medication;
-
date of trial completion and reason for early discontinuation, if applicable.
It is recommended that the author of an entry in the source documents is identifiable. Direct 
access to source documentation (medical records) must be allowed for the purpose of verifying 
that the data recorded on the CRF are consistent with the original source data.
After termination of data collection, visits and assessments will be performed per local standard 
of care and documented in the subject’s medical records only. Data will no longer be recorded in 
the CRF.
3.5
Case Report Forms 
CRFs are provided for each subject. All forms must be filled out legibly in durable black 
ballpoint pen.
Data Management may make changes to the entries made by the site (self-evident corrections or 
global rulings such as correction of obvious spelling errors). If global rulings (self-evident 
corrections) are applied to the clinical database by data management during the trial, the rules are
to be documented in a global rulings document and provided to the site for review and sign-off 
prior to applying the global rulings. If required, an investigator may request a detailed list of 
corrections applied to the data from his/her site through the trial monitor.
All data must be entered in English.
All data relating to the trial must be recorded on CRFs prepared by the sponsor. These CRFs 
should always reflect the latest observations on the subjects participating in the trial. Therefore, 
CRFs are to be completed as soon as possible after (or during) the subject’s visit. The 
investigator must verify that all data entries on the CRFs are accurate and correct. If some 
assessments are not done, or if certain information is not available, not applicable, or unknown, 
the investigator must enter “ND”, “NAV”, “NAP”, or “UN/UNK”, respectively, in the 
appropriate space.
Monitoring in this trial is to be done by means of telephone contacts and monitoring visits as per 
monitoring guidelines. During monitoring visits, the monitor reviews the CRFs and evaluate 
them for completeness, legibility and consistency. The CRF is to be compared with the source 
documents to ensure that there are no discrepancies between critical data. All entries, corrections, 


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and alterations are to be made by the responsible investigator or his/her designee. The monitor 
cannot write on the CRF pages, except for obvious data modifications. Corrections must be made 
in such a way that the original entry is not obscured. Correction fluid must NOT be used. The 
correct data must be inserted, dated, and initialed by the person making the correction. The 
persons entering data on the CRFs must be identified on the Signature Sheet. The investigational 
staff must not write on non-carbon required (NCR) copies of CRFs left at the site once the 
original is transmitted to the sponsor or representative.
A CRF must be completed and the original must be returned to the sponsor or representative. A 
copy must be archived by the investigator as specified in Section 3.7 (of Part II).
In case corrections to a CRF are needed after removal of the original CRF copy from the site, a 
Data Correction Form (DCF) is to be used. All DCFs sent to the investigator are to be answered 
by the appropriate investigational staff and signed and dated for approval.
After termination of data collection, visits and assessments will be performed per local standard 
of care and documented in the subject’s medical records only. Data will no longer be recorded in 
the CRF. Investigators will continue to report SAEs possibly related to DRV/rtv and pregnancies 
to the sponsor using regular pharmacovigilance reporting. This information will only be entered 
in the company safety repository.
3.6
Subject Identification Code List & Subject Screening and 
Enrollment Log
In order to permit easy identification of the individual subject during and after the trial, the 
investigator is responsible for keeping an updated Subject Identification Code List. The monitor 
will review this document for completeness. However, in order to ensure subject confidentiality, 
this document will remain at the center and no copy will be made.
A Subject Screening and Enrollment Log that report on all subjects who were seen to determine 
eligibility for inclusion in the trial have to be completed by the investigator also.
3.7
Archiving
The investigator shall maintain the trial documents as specified in “Essential Documents for the 
Conduct of a Clinical Trial” (ICH E6; 8.2 - 8.4) and as required by the applicable regulatory 
requirement(s). The investigator should take measures to prevent accidental or premature 
destruction of these documents.
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region, and until there are no pending or contemplated 
marketing applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period however, if required by the applicable regulatory requirements.
It is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained.
Under no circumstance shall the investigator relocate or dispose of any trial documents before 
having obtained a written approval of the sponsor.


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If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this trial, the investigator must permit access to such reports. The 
subject is granting access to his/her source data by signing the informed consent/assent.
Any difficulty in storing original documents must be discussed with the monitor prior to the 
initiation of the trial.
4
CONFIDENTIALITY
All information concerning the product and the sponsor’s operations (such as patent applications, 
formulae, manufacturing processes, basic scientific data, or formulation information supplied to 
the investigator by the sponsor and not previously published) is considered confidential by the 
sponsor and should not be disclosed by the investigator to any third party without the sponsor’s 
prior written approval. The investigator agrees to use this information only in accomplishing the 
trial and will not use it for other purposes.
5
REPORTING AND PUBLICATION
5.1
Reporting
The sponsor will create an Annual Safety Report (ASR) and Line Listings in accordance with the 
EU Clinical Trials Directive with a data-lock date of 23 June. This study TMC114IFD3001 will 
be included in the first ASR produced after approval of this protocol, which may be less than 
1-year’s time from this particular study approval date, and in all subsequent ASRs, as 
appropriate, until study closure. From January 2011, in accordance to the ICH guideline E2F, 
ASRs will be replaced by Development Safety Update Reports (DSURs) (data-lock of 23 
December). This trial will be included in the first DSUR, and in all subsequent DSURs, as 
appropriate, until trial closure.
The results of the trial will be reported in a Clinical Research Report and will contain CRF data 
from all study sites that participated in the study. A summary of the Clinical Study Report will be 
provided to the investigators, to the applicable regulatory authorities, and IECs/IRBs, if required 
by the applicable regulatory requirements, within 6 months after end of trial.
After termination of data collection, only limited safety data (SAEs possibly related to DRV/rtv
and pregnancies) will continue to be reported using regular pharmacovigilance reporting and will 
only be entered in the company safety repository. Appropriate safety reports will continue to be 
provided to IECs/IRBs and regulatory authorities, as required.
One investigator will be appointed for signing off the final Clinical Research Report. The 
selection of this investigator will be determined by the recruitment performance and specific 
expertise related to the nature and the key assessment parameter(s).
5.2
Publication
The sponsor will not unreasonably withhold consent to publish the data generated in this trial. 
However, it is the policy of the sponsor not to allow the investigators to publish their results or 
findings prior to the sponsor’s publication of the overall trial results. The investigator agrees that 
before he/she publishes any results of this trial, he/she shall allow at least 45 days for the sponsor 
to review the prepublication manuscript prior to submission of the manuscript to the publisher, as 


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specified in the Clinical Trial Agreement between Institution/investigator and sponsor. In 
accordance with generally recognized principles of scientific collaboration, co-authorship with 
any company personnel will be discussed and mutually agreed upon before submission of a 
manuscript to a publisher.
6
AUTHORITIES/ETHICS
6.1
Regulatory Authorities
This trial will be submitted to the local regulatory authority for approval or notification 
whichever is applicable. The trial will only be undertaken in compliance with the local 
regulatory requirements.
6.2
Independent Ethics Committee/Institutional Review Board
This trial can only be undertaken after full approval of the protocol, informed consent/assent, any 
other written information given to subjects, and subject recruitment materials has been obtained 
from the IEC/IRB. This document must be dated and clearly identify the trial and the documents 
being approved.
During the trial the following documents will be sent to the IEC/IRB for their review:
-
changes to the Investigator’s Brochure;
-
reports of adverse events that are serious, unlisted and associated with the investigational 
drug;
-
DSUR and Quarterly Line Listings (EU member states only).
Substantial amendments and applicable Informed Consent/Assent Form revisions must promptly 
be submitted to the IEC/IRB for review and approval prior to implementation of the change(s), 
except when necessary to eliminate an immediate hazard to the trial subjects.
The IEC/IRB is responsible for continuous review of the trial. At least once a year, the 
investigator will provide the IEC/IRB with a progress report to allow review of the trial. 
Additional progress reports should be provided if required by the IEC/IRB.
These requests and (re)approvals, if applicable, should be documented in writing.
6.3
ICH-GCP Guidelines
This trial will be conducted in accordance with the current ICH-GCP Guidelines. GCP is an 
international ethical and scientific quality standard for designing, conducting, recording, and 
reporting trials that involve the participation of human subjects. Compliance with this standard 
provides public assurance that the rights, safety and well being of trial subjects are protected, 
consistent with the principles that have their origin in the Declaration of Helsinki, and that the 
clinical trial data are credible.
6.4
Subject Information and Informed Consent/Assent
Each subject or a legally acceptable representative must give written consent/assent according to 
local requirements after the nature of the study has been fully explained. The ICF(s) must be 
signed before performance of any study-related activity. The ICF(s) and assent form that is/are 


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used must be approved by both the sponsor and by the reviewing IEC/IRB and be in a language 
that the subject can read and understand. The informed consent/assent should be in accordance 
with principles that originated in the Declaration of Helsinki, current ICH and GCP guidelines, 
applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent/assent to participate at any time. They will be 
informed that choosing not to participate will not affect the care the subject will receive. 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 personnel 
without violating the confidentiality of the subject, to the extent permitted by the applicable 
law(s) or regulations. By signing the ICF the subject or legally acceptable representative is 
authorizing such access. It also denotes that the subject agrees to allow his or her study physician 
to recontact the subject for the purpose of obtaining consent/assent for additional safety 
evaluations and subsequent disease-related treatments, if needed. The physician may also 
recontact the subject for the purpose of obtaining consent to collect information about his or her 
survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, 
consent/assent should be appropriately recorded by means of either the subject's or his or her 
legally acceptable representative's personally dated signature. After having obtained the 
consent/assent, a copy of the ICF must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent/assent
of the subject or legally acceptable representative] is obtained.
Children (minors) or subjects who are unable to comprehend the information provided can be 
enrolled only after obtaining consent/assent of a legally acceptable representative. Assent must 
be obtained from children (minors) capable of understanding the nature of the study, typically 
subjects 7 years of age and older, depending on the institutional policies. Written assent should 
be obtained from subjects who are able to write. A separate assent form written in language the 
subject can understand should be developed for adolescents. After having obtained the assent, a 
copy of the assent form must be given to the subject, and to the subject's parent or if applicable 
legally acceptable representative.


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When prior consent/assent of the subject is not possible and the subject's legally acceptable 
representative is not available, enrollment procedures should be described in the protocol with 
documented approval/favorable opinion by the IEC/IRB to protect the rights, safety, and 
well-being of the subject and to ensure compliance with applicable regulatory requirements. The 
subject or legally acceptable representative must be informed about the study as soon as possible 
and give consent/assent to continue.
6.5
Privacy of Personal Data
The processing of personal data in pursuit of this trial will be limited to those data that are 
reasonably necessary to investigate the efficacy, safety, quality, and utility of the investigational 
product(s) used in this trial. These data will be processed with adequate precautions to ensure 
confidentiality.
The sponsor ensures that the personal data are:
-
collected for a specified and legitimate purpose;
-
processed fairly and lawfully;
-
credible.
Explicit consent for the processing of personal data will be obtained from the participating 
subjects or their legally acceptable representative prior to any processing of personal data.
The sponsor or its representatives whose responsibilities require access to personal data are 
obliged to keep the identity of trial subjects confidential. This confidentiality will be maintained 
throughout the complete data processing. Trial subjects will be entitled to request confirmation 
of the existence of personal data held by the sponsor and will have the right to rectify erroneous 
or inaccurate data.
7
FINANCING AND INSURANCE
7.1
Financial Disclosure
The disclosed financial interest of the investigator must be collected before enrollment of the 
first subject. The investigator should promptly update this information if any relevant changes 
occur up to 1 year following trial completion.
Disclosable financial interests will be recorded on the Investigator Financial Disclosure Form.
Any investigator(s) added as investigational staff must complete the Investigator Financial 
Disclosure Form at the beginning of their participation in the trial. For any investigator(s) 
leaving the site prior to trial completion, an Investigator Financial Disclosure Form should be 
obtained at the end of their participation.
7.2
Indemnification
The sponsor undertakes to indemnify and hold harmless the investigator and his/her medical staff 
from any claim, demand or cost arising from the activities to be carried out in compliance with 
the protocol, as further specified in the Clinical Trial Agreement.


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7.3
Insurance
The sponsor ensures that appropriate liability insurance is available covering injuries arising 
from the participation of the trial subject in this trial, as further specified in the Informed 
Consent/Assent and the Clinical Trial Agreement.
8
DATA QUALITY CONTROL/ASSURANCE
The trial is to be monitored by the sponsor or representatives according to the current Standard 
Operating Procedure for the monitoring of clinical trials.
Shortly before the trial starts, the monitor meets with the investigator and all staff involved to 
review the procedures regarding trial conduct and recording the data on the CRF. During the 
trial, the investigator shall permit the monitor to verify the progress of the trial at the center as 
frequently as necessary. The investigator shall make the CRFs available, provide missing or 
corrected data and sign the CRFs. Key data transcribed onto the CRFs, such as the subject’s sex, 
date of birth, assessment dates, test results, etc., is to be reviewed against source documents. 
Personal information is to be treated as strictly confidential and is not to be made publicly 
available. Any inconsistency between source data and data recorded on the CRF is to be
corrected.
After termination of data collection, visits and assessments will be performed per local standard 
of care and documented in the subject’s medical records only. Data will no longer be recorded in 
the CRF.
The sponsor will ensure that appropriate Quality Control (QC) steps are included into the 
different clinical processes to guarantee adequate protection of the trial subjects and quality of 
the data.
An independent Quality Assurance (QA) department, regulatory authorities and/or IECs/IRBs 
may review this trial. This implies that auditors/inspectors will have the right to inspect the trial 
center(s) at any time during and/or after completion of the trial and will have access to source 
documents, including the subject’s file. By participating in this trial, investigators agree to this 
requirement.
For any data transfer, measures will be undertaken to protect subject data handed over against 
disclosure to unauthorized third parties and subject confidentiality will be maintained at all 
times.


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SIGNATURE PAGE
Global Medical Leader:
This Clinical Trial Protocol has been reviewed and approved by the sponsor in order to ensure 
compliance with Good Clinical Practices.
Name: Magda Opsomer, M.D. 
Affiliation: Janssen Research & Development
See appended electronic signature page
Investigator:
The trial will be performed in compliance with Good Clinical Practices, including the archiving 
of essential documents.
Name:
Affiliation:
Signature & Date:


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Magda Opsomer
21Jun2019, 07:48:07 AM, UTC
Document Approval

SAP_001.pdf: 
1
Approved, Date: 9 February 2022
Janssen Research & Development *
Statistical Analysis Plan
Continued access to darunavir/ritonavir (DRV/rtv) in HIV-1 infected adults, adolescents
and children aged 3 years and above
Protocol TMC114IFD3001; Phase N/A
Prezista®/TMC114  (darunavir)
Status:
Approved
Date:
9 February 2022
Prepared by:
Janssen Sciences Ireland UC
Document No.: EDMS-RIM-642655
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.
*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
Infectious Diseases BVBA; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC.
NCT01281813


Prezista®/TMC114  (darunavir)
Statistical Analysis Plan TMC114IFD3001
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Approved, Date: 9 February 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 3
ABBREVIATIONS ........................................................................................................................................ 3
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Objectives ................................................................................................................................ 5
1.2.
Trial Design ...................................................................................................................................... 5
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 6
1.4.
Sample Size Justification ................................................................................................................. 6
1.5.
Randomization and Blinding ............................................................................................................ 6
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 8
2.1.
Visit Windows................................................................................................................................... 8
2.1.1.
Trial Phases.................................................................................................................................. 8
2.1.2.
Analysis Time points..................................................................................................................... 8
2.2.
Analysis Sets.................................................................................................................................... 9
2.2.1.
Safety Analysis Set....................................................................................................................... 9
2.3.
Definition of Subgroups.................................................................................................................... 9
3.
SUBJECT INFORMATION.................................................................................................................. 9
3.1.
Demographics and Baseline Characteristics ................................................................................... 9
3.2.
Disposition Information..................................................................................................................... 9
3.3.
Treatment Adherence ...................................................................................................................... 9
3.4.
Extent of Exposure........................................................................................................................... 9
3.5.
Concomitant Medications............................................................................................................... 10
3.5.1.
Antiretroviral Therapy ................................................................................................................. 10
3.5.2.
Non-Antiretroviral Therapy.......................................................................................................... 10
3.6.
Protocol Deviations ........................................................................................................................ 10
4.
SAFETY............................................................................................................................................. 10
4.1.
Adverse Events .............................................................................................................................. 11
4.1.1.
Analysis Methods........................................................................................................................ 11
4.2.
Clinical Laboratory Tests................................................................................................................ 11
4.2.1.
Overall laboratory safety............................................................................................................. 11


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AMENDMENT HISTORY
Not applicable ; this is the initial version of this Statistical Analysis Plan
ABBREVIATIONS
3TC
lamivudine
ABC
abacavir
ADR
adverse drug reaction
AHA
American Heart Association
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ARV
antiretroviral
ASR
Annual Safety Report
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC12h
area under the plasma concentration-time curve from time of intake until 
12 hours after dosing 
AZT
zidovudine
b.i.d.
twice daily (bis in die)
BRAT
bananas, rice, applesauce and toast
CDC
US Centers for Disease Control and Prevention
C0h
predose plasma concentration 
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CRF
Case Report Form
DAIDS
Division of AIDS
DCF
Data Correction Form
DILI
drug-induced liver injury
DRV
darunavir (formerly known as TMC114)
DSUR
Development Safety Update Report
FTC
emtricitabine
GCP
Good Clinical Practice
HDL
high-density lipoprotein
HIV
human immunodeficiency virus 
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
IUD
intra-uterine device
LC-MS/MS
liquid chromatographic mass spectrometry/mass spectrometry
LDL
low-density lipoprotein
LPV
lopinavir
NCEP
National Cholesterol Education Program
NCR
non-carbon required
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
OBR
optimized background regimen
PI
protease inhibitor


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QA
Quality Assurance
QC
Quality Control
q.d.
once daily (quaque die)
RAM
resistance-associated mutation
RBC
red blood cell
rtv 
low-dose ritonavir
SJS
Stevens-Johnson syndrome
TEN
toxic epidermal necrolysis
ULN
upper limit of laboratory normal range
WBC
white blood cell


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for the CSR analysis (final analysis) of the continued access trial
TMC114IFD3001.
1.1.
Trial Objectives
Primary Objective
The primary objective of this trial was to continue the provision of DRV/rtv for adult and 
pediatric subjects who previously received DRV/rtv in the clinical (parent) trials TMC114-C211, 
TMC114-C214, TMC114-TiDP31-C229 or in the pediatric (parent) trial 
TMC114-TiDP29-C232, who continued to benefit from the use of DRV/rtv, in countries where 
DRV is not commercially available for the subject, is not reimbursed, or cannot be accessed 
through another source (e.g., access program, governmental program).
In addition, the long-term safety and tolerability of DRV/rtv in combination with other ARVs 
was to be assessed.
1.2.
Trial Design
This was a continued access trial for adult and pediatric subjects who have completed treatment 
with DRV/rtv in the adult clinical (parent) trials TMC114-C211, TMC114-C214, 
TMC114-TiDP31-C229 or in the pediatric (parent) trial TMC114-TiDP29-C232, who continued
to benefit from the use of DRV/rtv, and who lived in a country where DRV is not accessible.
At the baseline visit, inclusion and exclusion criteria were to be checked to confirm eligibility. 
Once the eligibility criteria were met, subjects were to continue treatment as follows: 
-
HIV-1 infected subjects participating in the TMC114-C211(parent) trial or in the pediatric 
(parent) trial TMC114-TiDP29-C232, after original participation in TMC114-TiDP29-C230 
trial were to continue on the DRV/rtv 800/100 mg q.d. dosing regimen as administered in the 
original (parent) trial.
-
HIV-1 infected subjects participating in the pediatric (parent) trial TMC114-TiDP29-C232, 
after original participation in TMC114-C212 or TMC114-TiDP29-C228 trial were to
continue on the selected b.i.d. DRV/rtv dosing regimen as administered in the original 
(parent) trial, or on an adjusted dose if necessary due to a change in body weight.
-
HIV-1 infected subjects participating in the TMC114-C214 or TMC114-TiDP31-C229 
(parent) trials were to continue on the DRV/rtv 600/100 mg b.i.d. dosing regimen as 
administered in the original (parent) trial. 
Treatment was to be continued until one of the following criteria was met (whichever occurs first):
-
Virologic failure;
-
Treatment-limiting toxicity;


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-
Loss to follow-up;
-
Withdrawal of consent/assent by the subject or withdrawal of consent by the parent(s)/ legal 
representative(s);
-
Pregnancy;
-
Termination of the trial by the sponsor;
-
A DRV-based treatment regimen became commercially available for the subject and was 
reimbursed, or could be accessed through another source (e.g., access program, government 
program) in the region the subject was living in or subjects could be switched to local 
standard of care, as appropriate.
A post-treatment follow-up contact was to be performed 4 weeks after the last dose of trial 
medication for subjects with an ongoing adverse event, that discontinue the trial under Protocol 
Amendment 1.
Adverse event reporting was restricted to the following (or all AEs if applicable per local 
regulation):

Adverse events considered at least possibly related to DRV/rtv;

Adverse events leading to discontinuation or treatment interruption;

Serious adverse events and pregnancies.
Efficacy and safety laboratory assessments were done locally, and were not transferred into the 
database for formal analysis purposes.
1.3.
Statistical Hypotheses for Trial Objectives
Not applicable.
1.4.
Sample Size Justification
Not applicable.
Subjects who previously received treatment with DRV/rtv in the clinical (parent) trials 
TMC114-C211, TMC114-C214, TMC114-TiDP31-C229 or in the pediatric (parent) trial 
TMC114-TiDP29-C232, who continued to benefit from the use of DRV/rtv, and who lived in a 
country where DRV was not accessible might have been eligible to continue treatment with 
DRV/rtv via this trial.
1.5.
Randomization and Blinding
Randomization
Since this was a continued access single arm trial, randomization procedures were not applicable.
Blinding


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Since this was an open label, continued access trial, blinding procedures were not applicable.


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2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
2.1.1.
Trial Phases
Analysis phases are constructed as per Table 1.
Table 1: Analysis Phases: 
Trial phase
Start date
End date
Treatment
Date of first DRV intake in 
trial
If the subject died: min (date of last DRV + 2 days ; 
date of death)
If the subject permanently stopped the trial 
medication: minimum of:

date of last DRV  intake + 2 days, if missing,
date of discontinuation + 2 days

date of last contact 
Follow-up (not defined 
when derived End date is 
before Start date of this 
phase )
End date of DRV Treatment 
phase + 1 day
If the subject died: date of death
Otherwise: date of last contact
2.1.2.
Analysis Time points
Visits and assessments were to be performed, according to local generally accepted standard of 
care, but desirable every 3 months for pediatric subjects and not less frequent than every 6 months 
for adult subjects. The interval between 2 consecutive visits was not to exceed 6 months for 
pediatric subjects.
Therefor, no time points for analysis purposes are used.


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2.2.
Analysis Sets
Full Analysis Set (FAS): the set of all subjects who have taken at least one dose of DRV, regardless 
of their compliance with the protocol and adherence to the dosing regimen.
2.2.1.
Safety Analysis Set
Safety results will be presented for the FAS population only.
2.3.
Definition of Subgroups
The following subgroups will be defined for all outputs:

Population: Pediatric (children <12y and adolescents 12-18y separately) and adults
For listings only, the corresponding DRV/rtv dose (ie. 600/100 mg b.i.d. or 800/100 mg q.d.) will 
be added; no distinction will be made in tables or figures.
3.
SUBJECT INFORMATION
3.1.
Demographics and Baseline Characteristics
The following parameters will be analyzed: 
Demographic Parameters:

sex (male, female)

age at baseline

country/site

weight at baseline (kg).
3.2.
Disposition Information
The following disposition information will be analyzed:

Subject disposition by visit, according to actual visits recorded.

Discontinuations, plus the reasons for discontinuation (from trial).
3.3.
Treatment Adherence
No analysis of treatment adherence (based on drug accountability) will be performed.
3.4.
Extent of Exposure
Exposure is defined as the duration of DRV treatment during the treatment phase (in days), up to 
the last DRV date. The extent of exposure will be summarized in years, and the total subject-years-
of-exposure will be provided. Treatment duration will be calculated as described below:
Treatment duration (years) = [End of phase – Start of phase +1 (days)]/365.25
The total subject-years-of-exposure will be calculated by taking the sum of the DRV treatment 
durations (years) over all subjects.


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In addition, the proportion of subjects in the study (exposed to DRV) using 24-week intervals will 
be tabulated, i.e. based on 1 x 24 weeks (=169 days), 2 x 24 weeks (=337 days), etc.
Rtv exposure will be calculated in the same manner.
3.5.
Concomitant Medications
Concomitant medications are allocated to each phase (see Section 2.1.1) during which they were 
actually 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.
The dictionaries used for concomitant medications are WHODRUG version 01Mar2011  
(enhanced ) at trial start, and WHODRUG version 01Sep2019 (enhanced) at trial end.
3.5.1.
Antiretroviral Therapy
Frequency (%) of subjects will be provided per class and per ARV, during treatment phase.
All ARV classes will be shown in the table and listing.
The dictionaries used for administration of Antiviral Therapy are the same as for concomitant 
medications.
3.5.2.
Non-Antiretroviral Therapy
All Conmed drug categories and actual medications will be shown in a listing.
The dictionaries used for administration of Antiviral Therapy are the same as for concomitant 
medications.
3.6.
Protocol Deviations
All major protocol deviations will be tabulated and listed.
A listing of major protocol deviations where interruptions of dose occurred will be provided, along 
with missing dose information.
4.
SAFETY
Safety results will be summarized for the Treatment phase; all safety data (including Follow-up 
phase) will be included in listings.


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4.1.
Adverse Events
4.1.1.
Analysis Methods
AE incidence (count and percentage) will be tabulated, overall and by preferred term/SOC. 
Overall AE Summary tables and tables by preferred term/SOC for serious events, AEs leading to 
discontinuation, AEs at least grade 3, HIV-related AEs, and AEs at least possibly related to DRV 
will be presented throughout the treatment phase only; any AEs in the Follow-up phase will be 
listed only.
The dictionary used for adverse events will be MedDRA version 23.0.
4.2.
Clinical Laboratory Tests
4.2.1.
Overall laboratory safety
Only the following 2 laboratory parameters were collected (pregnancy tests): 

General biochemistry : Creatinine Clearance

Urinalysis : Human Chorionic Gonadotropin.
These parameters will be listed.