Clinical trial NCT01504841
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2013-03-14; Completion date: 2020-08-26
Enrollment: 26 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used as part of combination antiretroviral therapy (ART) for infants and children, but NNRTI resistance is increasing, leading to treatment failure. This study tested the safety, tolerability, and dosing levels of etravirine (ETR), a new NNRTI.

Detailed description:
Use of NNRTI-based regimens as initial therapy for HIV-infected children is increasing, especially in areas where newborns exposed to HIV-1 receive single-dose nevirapine (NVP) as part of prevention of mother-to-child transmission (PMTCT) regimens and/or daily NVP for prevention of transmission through breastfeeding. First-generation NNRTIs have a low genetic barrier to the development of resistance; in two of the most widely used NNRTIs, NVP and efavirenz (EFV), even a single amino acid mutation in the virus can lead to a reduction in the drug's effectiveness. Even short-term use of these NNRTIs, including only a single dose of NVP, can cause NNRTI resistance. Second-generation NNRTIs are needed as part of ARV regimens for newly diagnosed infants and children who have been exposed to single-dose NVP or who have failed their current antiretroviral (ARV) regimens. In this study, the second-generation NNRTI ETR was tested for safety, tolerability, and appropriate dosing.

Children were assigned to one of three cohorts based on age:

* Cohort I: At least 2 but younger than 6 years of age
* Cohort II: At least 1 but younger than 2 years of age
* Cohort III: At least 2 months but younger than 1 year of age

Children in all three cohorts were treatment experienced, defined as being on a failing combination ARV regimen (containing at least 3 ARVs) for at least 8 weeks or having a treatment interruption of at least 4 weeks with a history of virologic failure while on a combination ARV regimen (containing at least 3 ARVs).

Children received ETR together with an optimized background regimen (OBR) consisting of at least 2 active agents (a boosted protease inhibitor \[PI\] and at least 1 additional active ARV drug). OBR were based on clinical status, treatment history, resistance data, and availability of appropriate pediatric dosing and formulations. The children received an oral dose of ETR twice daily.

Most children had 11 visits: at screening, entry (Day 0), Day 14 (intensive pharmacokinetic \[PK\] visit), and at Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Most visits included a physical exam, giving a medical history, discussion of adherence, and blood and urine collection. The screening and intensive PK visits also included an electrocardiogram (ECG). During the intensive PK visit, the child had blood drawn approximately 7 times over 12 hours. After the Week 48 visit, children entered the long-term follow-up phase of the study and have a visit every 12 weeks for up to 5 years. These follow-up visits included giving a medical history and undergoing a physical exam and blood draw.

Arms: arm 1: Children in this arm were at least 2 but younger than 6 years of age; they received the study drug etravirine (ETR) together with an optimized background regimen (OBR) consisting of one active boosted protease inhibitor (PI) and at least one other active antiretroviral (ARV) drug. arm 2: Children in this arm were at least 1 but younger than 2 years of age; they received ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug. arm 3: Children in this arm were at least 2 months but younger than 1 year of age; they received ETR together with an OBR consisting of one active boosted PI and at least one other active ARV drug.
Interventions: intervention 1: Etravirine (ETR)
Intervention descriptions: intervention 1: ETR was administered as 25-mg scored tablets and/or 100-mg tablets swallowed whole or dispersed in an appropriate liquid vehicle following a meal. Children took the specified dose orally twice daily within 30 minutes following a meal. Dose was decided according to dosing tables in protocol.

Protocol documents:
Prot_001.pdf: 
IMPAACT P1090 
 
 
 
A PHASE I/II, OPEN-LABEL TRIAL TO EVALUATE THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND ANTIVIRAL ACTIVITY OF 
ETRAVIRINE (ETR) IN ANTIRETROVIRAL (ARV) TREATMENT-EXPERIENCED 
HIV-1 INFECTED INFANTS AND CHILDREN, AGED ≥2 MONTHS TO <6 YEARS 
 
A Multicenter, Domestic & International Trial of 
the International Maternal Pediatric Adolescent 
AIDS Clinical Trials Group (IMPAACT) 
 
Sponsored by: 
The National Institute of Allergy and Infectious Diseases 
(NIAID) 
and 
The Eunice Kennedy Shriver National Institute of Child Health and Human 
Development 
(NICHD) 
 
Pharmaceutical Support Provided by Janssen 
R&D IND # 113,895 Held by DAIDS 
 
The IMPAACT HIV Treatment Scientific Committee Chair: Elaine Abrams, MD  
Protocol Chair: 
Richard Rutstein, MD 
Protocol Co Chairs: 
Andrew Wiznia, MD  
 
Ram Yogev, MD 
NIAID Medical Officer: 
Ellen Townley, MSN 
NICHD Medical Officer: 
Jack Moye, MD  
 
Clinical Trials Specialists: 
 Megan E. Valentine, MPA
 
Kathryn Lypen, MPH 
 
 
 
 
 
 
 
 
Version 5.0 
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P1090 PROTOCOL TEAM ROSTER 
 
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All questions concerning this protocol should be sent via e-mail to 
impaact.teamp1090@fstrf.org. Questions concerning clinical management of study subjects 
and all communication regarding adverse experiences should be addressed to the P1090 core 
protocol team at impaact.p1090cmc@fstrf.org. Remember to include the subject’s PID when 
applicable. 
 
A response should generally be received within 24 hours (Monday - Friday). For protocol 
registration questions, e-mail protocol@tech-res.com or call 301-897-1707.  Protocol 
registration material can be sent electronically to epr@tech-res.com or via fax at 1-800-418-
3544 or 301-897-1701.For EAE questions, e-mail RSCSafetyOffice@tech-res.com or call 1-
800-537-9979 or 1-301-537-9979 or fax 1-800-275-7619 or 1-301-897-1710.To order study 
agent, call the Clinical Research Products Management Center at (301) 294-0741. For 
randomization or enrollment questions, contact the Data Management Center at 716-834-0900 
or by email at sdac.random.desk@fstrf.org. 
 
Protocol Chair 
Richard Rutstein, M.D. 
Children's Hospital of Philadelphia 
34th & Civic Center Boulevard 
Philadelphia, PA  19104 
Phone: (215) 590-1466 
Email: rutstein@email.chop.edu 
 
Protocol Vice Chairs 
Andrew Wiznia, M.D. 
Jacobi Medical Center 
1400 Pelham Parkway South 
Bronx, NY  10461 
Phone: (718) 918-4664 
Email: awiznia@aecom.yu.edu 
 
Ram Yogev, M.D. 
CMRC Children's Memorial Hospital 
Northwestern University Medical School 
225 E. Chicago Ave, Box 155 
Chicago, IL 60611-2605 
  Phone: (312) 227-6280 
  Email: ryogev@luriechildrens.org 
 
NIAID Medical Officer 
Ellen Townley, MSN 
NIAID Maternal, Adolescent & Pediatric 
Research Branch 
BG 5601FL RM 8B37 
5601 Fishers Lane 
Rockville, MD 20852 
Phone: (240) 292-4784 
Email: ellen.townley@nih.gov 
NICHD Medical Officer 
Jack Moye, Jr., MD 
National Children’s Study 
Eunice Kennedy Shriver 
National Institute of Child Health & Human 
Development 
National Institutes of Health, DHHS 
Bldg. 6100 Rm. 3A01 MSC 7510 
9000 Rockville Pike 
Bethesda, MD  20892-7510 
Phone: (301-594-8624 
Email: john.moye@nih.hhs.gov 
 
Clinical Trials Specialists 
Megan E. Valentine, MPA 
IMPAACT Operations 
FHI 360 
359 Blackwell St 
Durham, NC 27701 
Phone: (919) 544-7040, Ext. 11186 
Fax: (919) 544-0207 
Email: mvalentine@fhi360.org 
 
Kathryn Lypen, MPH 
IMPAACT Operations FHI 360 
359 Blackwell St 
Durham, NC 27701 
Phone: (919) 544-7040, Ext. 11684 
Fax: (919) 544-0207 
Email: klypen@fhi360.org 
 
 
 


 
 
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Protocol Virologist 
Paul Palumbo, M.D. 
Dartmouth-Hitchcock Medical Center 
One Medical Center Drive 
Lebanon, NH 03756 
Phone: (603) 650-8840 
Email: paul.palumbo@dartmouth.edu 
 
Protocol Statisticians 
Terence Fenton, Ed.D. 
Statistical & Data Analysis Center 
Harvard School of Public Health 
651 Huntington Avenue 
Boston, MA  02115 
Phone: (617) 432-3027 
Email: fenton@sdac.harvard.edu 
 
Carmelita Alvero, M.S. 
Harvard School of Public Health 
FXB Building, Room 501 
651 Huntington Ave 
Boston, MA  02115 
Phone: (617) 582-7265Email: 
calvero@sdac.harvard.edu 
 
Protocol Data Manager 
Bobbie Graham, B.S. 
Frontier Science and Technology 
Research Foundation 
4033 Maple Road 
Buffalo, NY  14226-1056 
Phone: (716) 834-0900, ext. 7265 
Email: graham.bobbie@fstrf.org 
 
Aaron Atlas, B.S. 
Protocol Data Manager 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7422 
Fax: 716-834-8675 
E-mail: atlas@fstrf.org 
 
Protocol Pharmacist 
Katherine Shin, Pharm.D. Pharmaceutical 
Affairs Branch (PAB) DAIDS, NIAID 
5601 Fishers Lane, Room 9D30A 
Rockville, MD 20852 
Phone: (240) 627-3047 
Email: KaShin@niaid.nih.gov 
 
Protocol Pharmacologists 
Jennifer Kiser, Pharm.D. 
University of Colorado Denver 
Skaggs School of Pharmacy and 
Pharmaceutical Sciences 
12850 E Montview Blvd, V20-C238 
Aurora, CO  80045 
Phone: (303) 724-6131 
Lab: (303) 724-6132 
Email: jennifer.kiser@ucdenver.edu 
 
Laboratory Technologist 
Bill Kabat 
Infectious Disease Laboratory 
Deming Room 3012 Mailbox 82 
Ann & Robert H Lurie Children's Hospital 
of Chicago 
Chicago, IL 60611 
Phone: (312) 227-6290 
Email: bkabat@luriechildrens.org 
 
Laboratory Data Manager 
Oswald Dadson, M.S. 
Frontier Science and Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: (716) 834-0900, ext. 7238 
Email: dadson@fstrf.org 
 
Westat Clinical Research Associate 
Kathryn Myers, B.A., CCRP 
Westat 
1441 West Montgomery Ave. #215 
Rockville, MD 20850 
Phone: 301-610-8803 
Fax: 301-279-4545 
Email: kathrynmyers@westat.com 
 


 
 
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Investigators 
Cristina Hofer, M.D. Ph.D. 
Universidade Federal dos Rio de Janeiro 
Rua Lopes Quintas, 340/106 
JardimBotanico - Rio de Janeiro/RJ 
22460-010 
Brazil 
Phone: (+55 21) 2562 2555 
Email: cbhofer@hucff.ufrj.br 
 
Lee Fairlie, M.D. 
Shandukani Research Centre 
Wits Reproductive Health & HIV Institute 
(WRHI), University of the Witwatersrand, 
22 Esselen Street 
Hillbrow 2001 Johannesburg 
South Africa 
Phone: +27 11 358 5317 
Email: lfairlie@wrhi.ac.za 
 
Janssen R&D Representatives 
Herta Crauwels, Ph.D. 
Associate Director, Clinical Pharmacology 
Janssen Infectious Diseases, BVBA 
Turnhoutseweg 30 
2340 Beerse 
Belgium 
Phone: (+32) 14 641-054 
Email: hcrauwel@its.jnj.com 
 
Sophie Dedrie, Pharm. D 
Clinical Project Management Lead 
Janssen Pharmaceutica NV 
Turnhoutseweg 30 
2340 Beerse 
Belgium 
Office phone: +32-14-641751 
Email: sdedrie1@its.jnj.com 
 
Ludo Lavreys, M.D., Ph.D., M.Sc. 
Senior Trial Physician 
Janssen Infectious Diseases 
BVBA 
ID&V Medical Department 
Turnhoutseweg 30 
2340 Beerse 
Belgium 
Office phone: +32-14-607767 
Cell phone: +32-473-554739 
Email: llavrey1@its.jnj.com 
 
Simon Vanveggel 
Statistical Leader Intelence 
Janssen Infectious Diseases, BVBA 
Turnhoutseweg 30 
2340 Beerse  
Belgium 
Phone: (+32) 14 641 347 
Email: svanvegg@its.jnj.com 
 
Lotke Tambuyzer, M.Sc. Clinical Virologist 
Janssen Infectious Diseases, BVBA 
Turnhoutseweg 30 
2340 Beerse 
Belgium 
Phone: (+32) 14 641744 
Email: ltambuyz@its.jnj.com 
 
 
 


 
 
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GLOSSARY 
 
3TC 
Lamivudine 
ABC 
Abacavir 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine aminotransferase 
ART 
Antiretroviral therapy  
ARV 
Antiretroviral 
AST 
Aspartate aminotransferase 
ATV 
Atazanavir 
AUC12h 
Area under the drug plasma concentration-time profile over 12 
hours 
BID 
bis in die (twice daily) 
C0h 
plasma concentration immediately prior to dosing 
C12h 
plasma concentration at the end of the 12 hour dosing interval  
Cmax 
Maximal observed plasma concentration during a dosing interval 
Cmin 
Minimal observed plasma concentration during a dosing interval 
CAP 
College of American Pathologists 
CART 
Combination anti-retroviral therapy 
cDNA 
complementary DNA 
CL/F 
Apparent oral clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CPK 
Creatinine phosphokinase 
CRPMC 
Clinical Research Products Management Center 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS (United States) 
DHHS 
Department of Health & Human Services 
DMC 
Data Management Center 
DNA 
Deoxyribonucleic acid  
DRV 
Darunavir 
DSMB 
Data Safety and Monitoring Board 
EAE 
Expedited Adverse Event 
EC                                   Ethics Committee  
ECG                                Electrocardiogram  
EFV                                 Efavirenz 
EIA 
Enzyme immunoassay 
EMA 
European Medicines Agency 
ETR 
Etravirine 
EU 
European Union 
FDA 
Food and Drug Administration 
FPV 
Fosamprenavir  
FTC 
 Emtricitabine  
GI                                    Gastrointestinal 
GM 
Geometric mean 
GMR 
Geometric mean ratio 
HIV 
Human Immunodeficiency Virus 


 
 
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IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical 
Trials Network 
IgM 
Immunoglobulin M  
ICF 
Informed consent form  
IQ 
Inhibitory quotient 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISRP 
Independent Safety Review Panel 
IUD 
Intrauterine device 
LAR 
Legally authorized representative 
LDH 
Lactate dehydrogenase 
LPV 
Lopinavir 
NIAID 
National Institute of Allergy and Infectious Diseases  
NICHD 
National Institute of Child Health and Human Development  
NIH 
National Institutes of Health 
NNRTI 
Non-nucleoside reverse transcriptase inhibitors 
NVP 
Nevirapine 
OBR 
Optimized background regimen 
OHRP 
Office of Human Research Protections 
PCR 
Polymerase Chain Reaction 
PI 
Protease inhibitor  
PID 
Patient identifier  
PK 
Pharmacokinetic 
PMTCT 
Prevention of Mother to Child Transmission 
PRO 
Protocol Registration Office  
QD 
Quaque die (Once a day)  
RAL 
Raltegravir 
RAM 
Resistance associated mutations 
RSC 
Regulatory Support Center 
RE                                 Regulatory entity 
RNA                               Ribonucleic acid 
RTV                                Ritonavir 
SADR 
Suspected adverse drug reaction 
SAE 
Serious adverse event 
SDMC 
Statistical and Data Management Center 
sdNVP 
Single dose nevirapine 
SMC 
Study Monitoring Committee 
SUSAR 
Suspected, unexpected serious adverse reaction 
Tmax 
time at which Cmax occurs 
T1/2 
terminal elimination half-life 
TB 
Tuberculosis 
TDF 
Tenofovir disoproxil fumarate 
TID 
Ter in die (three times a day) 
TPV 
Tipranavir 
ULN 
Upper limit of normal 


 
 
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US 
United States 
WB 
Western blot 
Vd 
Apparent volume of distribution 
ZDV 
Zidovudine 
 
 


 
 
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TABLE OF CONTENTS 
GLOSSARY ..................................................................................................................................................... 5 
SCHEMA ....................................................................................................................................................... 11 
IMPAACT P1090 .......................................................................................................................................... 11 
1.0 
INTRODUCTION ............................................................................................................................ 13 
1.1 
Background ........................................................................................................................................ 13 
1.2 
Etravirine Background ....................................................................................................................... 13 
1.3 
Clinical Studies .................................................................................................................................. 14 
1.4 
Rationale ............................................................................................................................................ 26 
2.0 
STUDY OBJECTIVES .................................................................................................................... 26 
2.1 
Primary Objectives ............................................................................................................................. 26 
2.2 
Secondary Objectives ......................................................................................................................... 27 
3.0 
STUDY DESIGN .............................................................................................................................. 27 
3.1 
Description of Cohorts ....................................................................................................................... 28 
3.2 
Optimized Background Regimen ....................................................................................................... 28 
3.3 
Mini-Cohorts ...................................................................................................................................... 31 
3.4 
Full Cohorts........................................................................................................................................ 32 
3.5 
Cohort III............................................................................................................................................ 33 
3.6 
Long Term Safety Follow-Up ............................................................................................................ 34 
3.7 
Early Discontinuation ......................................................................................................................... 34 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS ................................................................. 34 
4.1 
Inclusion Criteria ................................................................................................................................ 34 
4.2 
Exclusion Criteria ............................................................................................................................... 36 
4.3 
Concomitant Medication Guidelines .................................................................................................. 37 
4.4 
Enrollment Procedures ....................................................................................................................... 38 
4.5 
Co-enrollment Procedures .................................................................................................................. 39 
5.0 
STUDY TREATMENT ................................................................................................................... 39 
5.1 
Drug Regimens, Administration and Duration ................................................................................... 39 
5.2 
Dosing and Administration ................................................................................................................ 40 
5.3 
Drug Formulation ............................................................................................................................... 41 
5.4 
Drug Supply, Distribution and Pharmacy ........................................................................................... 41 
5.5 
Long Term Safety Follow-up ............................................................................................................. 42 
6.0 
SUBJECT MANAGEMENT........................................................................................................... 42 
6.1 
Toxicity Management ........................................................................................................................ 42 
6.2 
Subject Management .......................................................................................................................... 48 
6.3 
Definition of Virologic Failure for Subject Management ................................................................... 48 
6.4 
Viral Resistance Testing ..................................................................................................................... 49 
6.5 
Permitted Changes to the ARV Optimized Background Therapy During the Study .......................... 49 
6.6 
Concerns Regarding Non-Adherence ................................................................................................. 50 
6.7 
Etravirine Dose Changes Due to Increases in Body Weight .............................................................. 50 
6.8 
Criteria for Etravirine (Study Drug) Discontinuation ......................................................................... 51 
6.9 
Criteria for Study Discontinuation ..................................................................................................... 51 
7.0 
EXPEDITED ADVERSE EVENT REPORTING ........................................................................ 52 
7.1 
Adverse Event Reporting to DAIDS .................................................................................................. 52 


 
 
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7.2 
Reporting Requirements for this Study .............................................................................................. 52 
7.3 
Grading Severity of Events ................................................................................................................ 52 
7.4  
Expedited AE Reporting Period ......................................................................................................... 53 
8.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 53 
8.1 
General Design Issues ........................................................................................................................ 53 
8.2 
Endpoints and Outcome Measures ..................................................................................................... 55 
8.3 
Randomization and Stratification ....................................................................................................... 56 
8.4 
Sample Size and Accrual .................................................................................................................... 56 
8.5 
Monitoring ......................................................................................................................................... 57 
8.6 
Analyses ............................................................................................................................................. 62 
9.0 
CLINICAL PHARMACOLOGY PLAN........................................................................................ 65 
9.1 
Pharmacology Objectives ................................................................................................................... 65 
9.2 
Primary and Secondary Data .............................................................................................................. 65 
9.3 
Study Design, Modeling and Data Analysis ....................................................................................... 65 
9.4 
Population Pharmacokinetic Study Design, Modeling and Data Analysis ......................................... 69 
9.5 
Anticipated Outcomes ........................................................................................................................ 70 
10.0 
HUMAN SUBJECTS ....................................................................................................................... 70 
10.1 
Institutional Review Board and Informed Consent ............................................................................ 70 
10.2 
Subject Confidentiality ....................................................................................................................... 71 
10.3 
Study Discontinuation ........................................................................................................................ 71 
11.0 
PUBLICATION OF RESEARCH FINDINGS ............................................................................. 71 
12.0 
BIOHAZARD CONTAINMENT ................................................................................................... 71 
13.0 
REFERENCES ................................................................................................................................. 73 
APPENDIX IA: SCHEDULE OF EVALUATIONS - Cohort I ................................................................ 76 
APPENDIX IB: SCHEDULE OF EVALUATIONS – Cohort II .............................................................. 79 
APPENDIX IC: SCHEDULE OF EVALUATIONS – Cohort III ............................................................ 82 
APPENDIX ID: SCHEDULE OF EVALUATIONS FOR FOLLOW UP OF SUBJECTS WHO 
DISCONTINUE ETRAVIRINE (OFF STUDY DRUG – ON STUDY) ...................................... 85 
APPENDIX IE: SCHEDULE OF EVALUATIONS FOR LONG-TERM SAFETY FOLLOW-UP OF 
SUBJECTS RECEIVING STUDY-PROVIDED ETRAVIRINE ................................................ 87 
APPENDIX II: PLANNED LABORATORY TESTING ON COLLECTED SPECIMENS ................. 89 
APPENDIX III: ETRAVIRINE DRUG DOSING TABLE FOR ORAL TABLET ................................ 90 
APPENDIX IV: VISIT SCHEDULE FOR RASH MANAGEMENT IN PEDIATRIC SUBJECTS .... 92 
APPENDIX V: GRADING FOR PR AND QTc INTERVALS................................................................. 93 
APPENDIX VI: SUPPLEMENTAL TOXICITY TABLE FOR GRADING SEVERITY OF 
NEUROLOGIC ADVERSE EVENTS ........................................................................................... 94 
APPENDIX VII-A: SUPPLEMENTAL TOXICITY TABLE FOR GRADING SEVERITY AND 
MANAGEMENT OF ADULT AND PEDIATRIC CUTANEOUS ADVERSE EXPERIENCES
 ............................................................................................................................................................ 95 
APPENDIX VII-B: SUPPLEMENTAL TOXICITY TABLE FOR GRADING SEVERITY AND 
MANAGEMENT OF ADULT AND PEDIATRIC ACUTE SYSTEMIC ALLERGIC 
ADVERSE EXPERIENCES ............................................................................................................ 97 


 
 
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APPENDIX VIII: SAMPLE INFORMED CONSENT ............................................................................. 98 
APPENDIX IX: FACT SHEET and TEMPLATE CONSENT FORM for SPECIMEN STORAGE AT 
REPOSITORIES FUNDED BY THE NATIONAL INSTITUE OF CHILD HEALTH AND 
HUMAN DEVELOPMENT (NICHD) ......................................................................................... 110 
 
 
 


 
 
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SCHEMA  
 
IMPAACT P1090 
 
 
A PHASE I/II, OPEN-LABEL TRIAL TO EVALUATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS AND ANTIVIRAL ACTIVITY OF ETRAVIRINE (ETR) IN 
ANTIRETROVIRAL (ARV) TREATMENT-EXPERIENCED HIV-1 INFECTED 
INFANTS AND CHILDREN, AGED ≥2 MONTHS TO <6 YEARS 
 
 
 
DESIGN: 
Phase I/II, multi-center, open-label, pharmacokinetic and safety study. 
 
SAMPLE SIZE: 
It is expected that approximately 50 subjects will be accrued, to yield a 
minimum of 36 evaluable subjects (a minimum of 12 subjects in each 
cohort). Up to 18 subjects may be enrolled into Cohort I. 
*See section 8.1 for definition of evaluable subjects 
 
The total sample size will depend upon the number needed to complete the 
dose finding stage of the study, the number of subjects who discontinue 
the study and the number of subjects required for regulatory approval of 
etravirine in these populations. 
 
POPULATION: 
HIV-infected treatment-experienced infants and children aged ≥ 2 months 
to < 6 years of age. 
 
STRATIFICATION:  This is a sequential study which started accrual with the oldest age cohort 
and will progress down to the youngest age cohort. Cohort III will open 
with the activation of Version 5.0. 
 
Children will be stratified by age, as follows: 
 
 Cohort I: ≥ 2 year to < 6 years who are treatment experienced* 
 Cohort II:  ≥ 1 year to < 2 years who are treatment experienced* 
 Cohort III: ≥ 2 months to < 1 year who are treatment experienced*, † 
 
*Treatment experienced children on a failing combination antiretroviral regimen 
(containing at least 3 ARVs) for at least 8 weeks OR Treatment experienced children on a 
treatment interruption of at least 4 weeks with a history of virologic failure while on a 
combination antiretroviral regimen (containing at least 3 ARVs) 
 
† subjects below 6 months of age will only be enrolled upon availability of initial safety 
and PK data from subjects between 6 months and 1 year of age. 
 
REGIMEN: 
Etravirine (ETR) will be administered as 25 mg scored tablets and/or 100 
mg tablets swallowed as a whole or dispersed in an appropriate liquid 
vehicle (see Section 5.2). ETR will be started concurrently with an 
optimized background regimen (OBR), while OBR will be based on 
clinical status, treatment history, resistance data and availability of 
appropriate pediatric dosing and formulations. Refer to Section 3.1 and 
Table 6 for further information on regimen design per cohort. 
 


 
 
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STUDY DURATION: Minimum of 48 weeks 
 
Long Term Safety Follow-up: 
Subjects who successfully complete 48 weeks of ETR treatment 
will continue to receive ETR throughout the study, and be followed 
(see Appendix IE) for up to 5 years as part of long-term safety 
follow-up. 
 
 
PRIMARY OBJECTIVES: 
 
1.   To evaluate the steady state pharmacokinetics of ETR in combination with an OBR in 
HIV-infected children aged ≥ 2 months to < 6 years. 
 
2.   To determine the safety and tolerability of ETR in combination with an OBR in children 
aged ≥ 2 months to < 6 years, through 48 weeks of therapy. 
 
3.   To determine the appropriate dose of ETR in combination with an OBR for children aged 
≥ 2 months to < 6 years. 
 
 
 
SECONDARY OBJECTIVES: 
 
1. To assess the antiretroviral activity of ETR containing regimens through 48 weeks 
of therapy. 
2.   To determine the immunological changes (change in CD4 percent and absolute count; 
CD4/CD8 ratio and percent) through 48 weeks of ETR therapy in combination with an 
OBR. 
3.   To determine changes in viral drug resistance during 48 weeks of ETR therapy 
in combination with an OBR. 
4.   To assess the relationship between ETR pharmacokinetics and the antiviral activity and 
safety of ETR containing regimens. 
5.   To explore the relationship between subject-specific gene CYP profile, 
sex, age, weight, race, HIV regimen (e.g., boosted PI) and HIV response 
markers and pharmacokinetics of ETR. 
 
 


 
 
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1.0 
INTRODUCTION 
 
 
1.1 
Background 
 
Nevirapine (NVP) and efavirenz (EFV), the two most widely used NNRTI drugs, have a low 
genetic barrier for the development of drug resistance mutations, so that a single amino acid 
substitution in the viral reverse transcriptase (RT), such as K103N, leads to profound reduction in 
viral susceptibility to both drugs, conferring cross resistance with other agents in this class. Among 
HIV-infected Thai children failing a non-nucleoside reverse transcriptase inhibitor 
(NNRTI) based regimen, 97% had NNRTI-related resistance. The most common NNRTI related 
mutations were Y181C/I, in 58% of subjects, and 34% of subjects had the K103N mutation (1). 
 
Short term use of these NNRTIs can select for NNRTI resistance mutations even after a single dose, 
as has been documented for NVP when used to prevent maternal to child transmission (PMTCT). A 
meta-analysis estimated NVP resistance in 52.5% of infants exposed only to single dose (sd) NVP 
and in 16.5% of infants receiving sdNVP with other postnatal antiretrovirals (2). 
 
Early detection of NNRTI resistance mutations among infants at 6 to 8 weeks of life who had 
perinatal exposure to sdNVP has been reported at 46% for a Ugandan cohort (3) and 87% for a 
Malawian cohort (4). Similar confirmatory reports have emerged from South Africa (5) and India 
(6).  In the P1060 IMPAACT treatment study, 12% of PMTCT-exposed infants who were 6 to 36 
months of age at enrollment had baseline resistance to first generation NNRTIs (15/18 carried 
the Y181C mutation, and 3/18 the K103N) (7). The trial demonstrated superiority of a 
lopinavir/ritonavir-based first line treatment regimen in infants when compared with a NVP- based 
regimen in the setting of prior sdNVP-exposure and led to changes in the WHO pediatric treatment 
guidelines (8).  The duration of persistence of these NNRTI mutations in individuals receiving 
MTCT prophylaxis regimens is not known and is the subject of ongoing studies. 
 
With the widespread use of first generation NNRTIs (NVP and EFV) as components of 
combination antiretroviral therapy (cART), NVP as a component of neonatal PMTCT treatment 
regimens, and infant exposure to NVP during breastfeeding, the number of children harboring virus 
with one or two NNRTI-resistance mutations will continue to increase. Thus, there is an urgent 
need to develop alternative therapeutic options for newly diagnosed neonates and infants exposed to 
sdNVP containing regimens, as well as for infants and children failing their present cART 
regimens. 
 
 
1.2 
Etravirine Background 
 
1.21 
General 
 
ETR (TMC125 from Janssen R&D) is a second generation NNRTI and has a diarylpyrimidine- 
based structure providing molecular flexibility relative to other NNRTIs, allowing ETR to maintain 
its binding affinity for HIV-1 reverse transcriptase despite binding site changes induced by the 
presence of common NNRTI resistance mutations. ETR exhibits potent in vitro anti-HIV activity 
against wild type and against HIV isolates with NNRTI resistance mutations such as K103N, 
Y181C and Y188L (9) (10). 
 


 
 
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1.22 
Preclinical Studies 
 
 
Preclinical studies noted EC50 values for wild-type laboratory and primary HIV-1 isolates of 0.9 to 
5.5 nM (0.4 to 2.4 ng/mL) with little or no loss of activity against HIV-1 variants with the most 
common NNRTI-related mutations. During in vitro testing, ETR showed potent antiviral 
activity against a panel of > 6000 recombinant clinical isolates resistant to at least one of the first 
generation NNRTIs, with EC50 values below 10nM for 83% of isolates and below 100nM for 
98% of isolates (9).  In addition, ETR was noted to have an increased genetic barrier to the 
development of resistance compared to first generation NNRTIs. Non-clinical safety evaluations 
demonstrated that ETR was safe for use in clinical testing. 
 
 
1.23 
Pharmacokinetics 
 
ETR absorption is increased 50% when taken with a meal (11); peak plasma concentrations occur 2 
to 4 hours post dose. The absorption is not affected when the drug is taken with proton pump 
inhibitors or H2 blockers (12).  ETR is a weak inducer of CYP3A4 and a weak inhibitor of P-
glycoprotein, CYP2C9 and CYP2C19.  Therefore it is subject to drug-drug interactions that may 
result in lower serum concentrations of drugs metabolized by CYP3A4 such as HIV protease 
inhibitors, if not boosted with ritonavir, and higher concentrations of drugs metabolized by 
CYP2C9 and/or CYP2C19 and/or transported by P-glycoprotein (13-16). 
 
 
 
1.3 
Clinical Studies 
 
 
1.31 
Adult Studies 
 
Trial TMC125-C228 established PK parameters for ETR administered as formulation F060, 200 mg 
BID in treatment experienced HIV-1 infected adults who were currently receiving a boosted PI 
(primarily LPV/rtv) (17).  Formulation F060 is the commercial 100-mg tablet formulation. 
 
In January of 2008 ETR was approved by the US Food and Drug Administration (FDA) for 
antiretroviral treatment-experienced adults at a dose of 200 mg BID, with similar European Union 
approval in August 2008. The approvals were based on the results of the DUET-1 and 
DUET-2 studies in treatment experienced HIV-1-infected adults (18). The DUET studies consist of 
two Phase III double- blind, placebo-controlled randomized trials of ETR, with an OBR that 
included darunavir/ritonavir (600/100 mg BID) plus other antiretrovirals in treatment 
experienced adults. In an intent to treat (ITT) pooled 24 week analysis (N = 1203), ETR was 
superior to placebo with respect to the following endpoints: viral load reduction to < 50 copies/mL 
(60% vs. 40%), viral load < 400 copies/mL (74% vs. 53%) and mean viral load reduction (2.4 vs. 
1.7 log10 copies/mL). The 48-week efficacy results were consistent in the demonstration of a 
statistically significant superior efficacy for ETR versus placebo (19).  The proportion of subjects 
with viral load < 50 copies/mL at week 96 was 57.4% in the ETR group and 36.3% in the placebo 
group (19).  Genotypic analyses identified seventeen ETR resistance associated mutations (RAMs) 
predictive for decreased virologic response to ETR and a weighted genotypic score has been 
developed (20). 
 


 
 
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Population pharmacokinetic analysis of week 48 data from DUET-1 and DUET-2 revealed an ETR 
mean AUC12h and C0h of 5506ng•h/mL and 393 ng/mL respectively, at a dose of 200 mg BID (21).  
Neither AUC12h nor C0h were correlated with virologic suppression or adverse events (AEs). Other 
factors, including baseline viral load, CD4 cell count, number of active agents in the background 
regimen, fold change in EC50 to ETR and adherence were more important determinants of virologic 
success (18, 22). The adult dose is 200 mg BID. The formulation used for the clinical trials, and for 
commercial use, is a tablet containing 100 mg of ETR. The tablets may be dispersed in water or 
other liquid to facilitate administration (see Section 5.2) (23). 
 
 
1.32 
Pediatric Studies 
 
Phase I trial (TMC125-C126) 
 
A Phase I, open-label, dose-ranging trial (TMC125-C126) to evaluate the pharmacokinetics and 
short-term safety and tolerability of ETR at steady-state in HIV-1 infected children who were 
virologically suppressed has been completed. The objective of this trial was to obtain dose 
recommendations of ETR per body weight in treatment-experienced HIV-1 infected children  6 
years old and weighing  20 kg (24). 
 
ETR was administered as a 100 mg tablet and/or as a scored 25 mg tablet developed for pediatric 
use. The trial population was comprised of subjects taking a stable ARV regimen that included 
lopinavir/ritonavir (LPV/rtv) and a minimum of 2 NRTIs, with or without enfuvirtide. Trial 
TMC125-C126 was conducted in two sequential stages: in Stage I the dose of ETR was 4 mg/kg 
BID (dose derived from allometric scaling) and in Stage II the dose of ETR was 5.2 mg/kg BID 
(representing a 30% increase from 4 mg/kg BID). In each Stage, at least 20 virologically suppressed 
(VL < 50 copies/mL) children on a LPV/rtv-containing regimen received ETR for 7 days followed 
by an intensive 12-hour pharmacokinetic assessment of ETR on Day 8 (24). 
 
Table 1. Summary of Adverse Events in TMC125-C126 
Severity of AE 
Number of subjects (%) 
Stage I 
4 mg/kg 
Stage II 
5.2 mg/kg 
Grades 1 or 2 
14 subjects (66.7%)1 
9 subjects (42.9%)4 
Grade 3 
1 subject2 
0 
Grade 4 
1 subject3 
SAEs 
Grade 1 influenza during follow-up 
1 Five subjects (23.8%) had an AE that was considered at least possibly related to ETR. One subject was reported 
with Grade 2 maculo-papular rash, which was considered very likely related to ETR. 
2 Grade 3 increased blood creatinine 
3 Grade 4 increased blood triglycerides 
4 Six subjects (28.6%) had an AE that was considered at least possibly related to ETR.  One subject was reported with 
Grade 1 rash, which was considered probably likely related to ETR. 
 
Safety analysis from Stage I showed that ETR at 4 mg/kg and 5.2 mg/kg BID was generally safe 
and well tolerated (Table 1). The majority of adverse events were Grade 1 (mild) or Grade 2 
(moderate) in severity. No deaths were reported. No relevant difference was observed between the 
age groups. 
 


 
 
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Pharmacokinetic 
parameters 
Mean (SD) 
tmax: median (range) 
TMC125-C126 
Stage I 
4 mg/kg BID 
TMC125-C126 
Stage II 
5.2 mg/kg BID 
TMC125-C228 
200 mg BID 
DUET trialsa 
200 mg BID 
N 
19c 
20 
27 
574 
tmax (h) 
4 (2-8) 
4 (2-6) 
4 (3-8) 
- 
Cmax (ng/mL) 
495 ± 453 
757 ± 680 
451 ± 232 
- 
Cmin (ng/mL) 
184 ± 151 
294 ± 278 
185 ± 128 
393 ± 391d 
AUC12h (ng·h/mL) 
4050 ± 3602 
6141 ± 5586 
3713 ± 2069 
5506 ± 4710 
GMRb 
1.02 
1.58 
Table 2 displays a comparison of the PK parameters for both stages of the pediatric dose-ranging 
studies with those from the adult study of ETR 200 mg BID with LPV/rtv (TMC125-C228) and the 
adult studies of ETR 200 mg BID with DRV/rtv (DUET). 
 
Table 2:  Pharmacokinetic Parameters of ETR at two Doses in HIV-1 Infected Subjects between the 
Ages of 6 and 17 years, Inclusive, at Day 8 (TMC125-C126), and in HIV-1 Infected Adult Subjects 
(TMC125-C228; Day 8 and DUET Trials population PK). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Population PK at Week 48. 
b Relative to TMC125-C228 (protocol-specified comparison). 
c N=18 for AUC12h d C0h (ng/mL) 
 
The exposure of ETR, expressed as Cmin and AUC12h, after administration of ETR 4 mg/kg BID to 
children and adolescents on a LPV/rtv containing regimen was comparable with the exposure of ETR 
administered as 200 mg BID in adults on a LPV/rtv containing regimen, although the 
90% CIs were outside 80 to 125% for both Cmin and AUC12h. No age or weight difference was 
noticed within this dosing group. When ETR was administered as 5.2 mg/kg BID in children and 
adolescents, higher Cmin and AUC12hvalues were observed compared to administration of ETR as 
200 mg BID in adults. Only the upper limit of the 90% CI was outside 80 to 125% for both Cmin and 
AUC12h. Furthermore, the exposure was higher for the younger children (6 to 12 years) in 
comparison to the adolescents (12 to 17 years), although the range in the exposure was large in both 
groups. The higher exposure in younger children was related to 1 outlier; no apparent cause could 
be established for this higher exposure. When compared to adults receiving DRV/rtv with ETR, the 
ETR exposures achieved in children and adolescents on LPV/rtv with 5.2 mg/kg BID ETR dose 
were comparable (pooled DUET results). 
 
Based on the general concern for under dosing of ARVs in the pediatric population (25-28), the 
higher exposures of ETR achieved with ETR 5.2 mg/kg BID and the overall safety and tolerability 
during Stage II, the selected dose of ETR in children aged 6 to 17 is 5.2 mg/kg BID,which was also 
confirmed in a further trial (PIANO). 
 
Phase I/II trial (TMC125-C213, PIANO) 
 
Further long-term safety, tolerability, antiviral activity and pharmacokinetics of the selected dose 
was collected in trial TMC125-C213 (Pediatric Trial with Intelence as an Active NNRTI Option, 
PIANO). This was an open-label trial in 101 treatment-experienced HIV-1 infected children and 
adolescents 6 to 17 years of age, who were receiving ETR 5.2 mg/kg BID (up to a maximum of 
200mg BID) in combination with an investigator-selected OBR comprising of select boosted PI 


 
 
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in combination with NRTIs over 48 weeks (29). 
 
The 48 week safety and tolerability data with ETR in PIANO further confirm the favorable 
benefit/risk analysis in treatment-experienced pediatric patients. ETR was generally safe and 
well tolerated in the studied treatment-experienced HIV-1 infected pediatric population up to 
Week 48 with a safety profile comparable to that observed in the adult HIV 1 infected population 
and no new safety findings were identified. The Week 48 pharmacokinetic results re-confirm that 
pharmacokinetic exposure achieved in the pediatric population (6 – 17 years) with etravirine 5.2 
mg/kg BID is comparable to that in the adult population. The Week 48 analysis also provides 
further confirmatory evidence of an effective viral suppression in treatment-experienced 
pediatric patients taking ETR. 
 
A population pharmacokinetic model of ETR for the pediatric population was developed based on 
a previously developed population pharmacokinetic model of ETR used in adults, supplemented 
with rich and sparsely sampled pharmacokinetic data from pediatric subjects (6 to 
< 18 years). This model consisted of a sequential zero- and first-order absorption process with a 
lag-time and one-compartment disposition. A covariate effect of weight on volume of distribution 
(Vc/F) and clearance (CL/F) is included in the model. 
 
Using the population pharmacokinetic model and sparse sampling data from study TMC125- 
C213, ETR pharmacokinetic parameters for all subjects were derived using Bayesian feedback. A 
total of 313 sparsely sampled ETR plasma concentration-time data were available from 78 
subjects. ETR plasma concentrations were assumed to be at steady-state. Data for 4 subjects were 
excluded from analysis due to lack of dosing information (2 subjects) or ETR plasma 
concentrations below the lower limit of quantitation at all time-points (2 subjects). Therefore, 
pharmacokinetic parameters of ETR were available in 74 subjects. Table 3 summarizes the ETR 
AUC12h and C0h from the ISRP analysis, overall and by age cohort, with pediatric and adult 
historical controls for comparison (TMC125-C126 and pooled DUET, respectively). 
 
In general, the pharmacokinetics of ETR when administered at 5.2 mg/kg BID (i.e., 100 mg BID 
for 16 to < 20 kg; 125 mg BID for 20 to < 25 kg; 150 mg BID for 25 to < 30 kg and 200 mg BID 
for ≥ 30 kg) were comparable in children (≥ 6 to < 12 years) and adults. In the adolescents (≥ 12 to 
≤ 17 years), slightly lower ETR exposures were observed relative to adults. Of note, most of these 
adolescents (91%, 43 out of 47 adolescents) were on the adult dose of ETR (200 mg BID). 


 
 
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Table 3: Population Pharmacokinetics of ETR (AUC12h and C0h) by Age Cohort when ETR is Dosed 
at 5.2 mg/kg BID 
 
N 
AUC12h (ng•h/mL) 
Mean (SD) 
Median (Min - Max) 
PIANO (TMC125-C213)1 
≥6 to <12 years 
27 
5260 (2845) 
5090 (1722 - 13628) 
≥12 to ≤17 years 
47 
4568 (4761) 
3622 (113 - 29039) 
All subjects 
74 
4820 (4157) 
3990 (113 - 29039) 
Pediatric dose finding 
(TMC125-C126) 
≥6 to <12 years 
11 
7713 (7160) 
4559 (2967 – 27060) 
≥12 to ≤17 years 
9 
4219 (1575) 
4300 (1924 – 7142) 
All subjects 
20 
6141 (5586) 
4407 (1924 – 27060) 
Adults (Pooled DUET) 
575 
5506 (4710) 
4380 (458 – 59084) 
N 
C0h (ng/mL) 
Mean (SD) 
Median (Min - Max) 
PIANO (TMC125-C213)1 
≥6 to <12 years 
27 
334 (222) 
332 (38 - 996) 
≥12 to ≤17 years 
47 
299 (378.2) 
195 (2 - 2291) 
All subjects 
74 
312 (328.7) 
246 (2 - 2291) 
Pediatric dose finding 
(TMC125-C126) 
≥6 to <12 years 
11 
453 (442) 
273 (88 – 1620) 
≥12 to ≤17 years 
9 
247 (155) 
204 (115 – 627) 
All subjects 
20 
360 (352) 
241 (88 – 1620) 
Adults (Pooled DUET) 
575 
393 (391) 
298 (2 – 4852) 
1 ISRP analysis 
 
The median baseline viral load was 3.9 log10 copies/mL, and the median baseline CD4+ cell count 
was 385x106 cells/L. 
 
The virologic response rate was evaluated in pediatric subjects receiving ETR in combination with 
other ARVs. Virologic response was defined as achieving a confirmed undetectable viral load (<50 
copies/mL). 
 
The primary analysis was performed at Week 24, when all subjects had completed the 24-week 
assessment or discontinued earlier. The final analysis was performed when all subjects had 
completed the Week 48 assessment or discontinued earlier. An overview of the key efficacy 
findings at 48 weeks in the PIANO study is given in Table 4. 
 
 
 
 
 


 
 
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Table 4: Virologic Response to ETR at Week 48 in Treatment-experienced HIV-1 Infected Pediatric 
Subjects (PIANO Final Analysis) 
 
 
 
Efficacy Outcome Measure 
 
Children 
≥6-<12 years 
N=41 
 
Adolescents 
≥12-<18 years 
N=60 
 
All subjects 
 
N=101 
<50 copies/mL (NC=F), n (%) 
28 (68.3) 
29 (48.3) 
57 (56.4) 
<50 copies/mL (TLOVR), n (%) 
28 (68.3) 
26 (43.3) 
54 (53.5) 
<400 copies/mL (TLOVR), n (%) 
 28 (68.3) 
   36 (60.0) 
 64 (63.4) 
Decrease in VL vs BL of ≥1.0 log10, n (%) 
   27 (65.9) 
   34 (56.7) 
   61 (60.4) 
Change in log10 VL, Mean (SE) 
-1.67 (0.219) 
-1.44 (0.163) 
-1.53 (0.132) 
CD4+ Cell Count 
Change in CD4+ cell count, Mean (SE) 
+178 (39.7) 
+141 (27.0) 
+156 (22.7) 
BL: Baseline; VL: Viral Load; NC=F: non-completer equals failure; TLOVR: time to loss of virologic response; SE: 
standard error, vs: versus, CD4+: Cluster of differentiation 4 positive 
 
At  Week  24,  51.5%  of  all  pediatric  subjects  had  a  confirmed  undetectable  viral  load 
<50 copies/mL. The proportion of pediatric subjects with viral load <400 copies/mL was 65.3%. 
The mean change in viral load from Baseline to Week 24 was -1.51 log10 copies/mL, and the mean 
CD4+ cell count increase from Baseline was 112x106 cells/L. 
 
At  Week  48,  53.5%  of  all  pediatric  subjects  had  a  confirmed  undetectable  viral  load 
<50 copies/mL. The proportion of pediatric subjects with viral load <400 HIV-1 RNA copies/mL 
was 63.4%. The mean change in HIV-1 RNA from Baseline to Week 48 was -1.53 log10 copies/mL, 
and the mean CD4+ cell count increase from Baseline was 156x106 cells/L.By age group, virologic 
response at Week 48 was 68.3% in children and 48.3% in adolescents. Sensitivity analyses 
(including observed case, TLOVR and TLOVR non-VF censored analyses, and snapshot approach) 
showed that these results were robust and not driven by the imputation method. 
 
Eighty-three percent of the children and 92% of adolescents experienced at least 1 adverse event 
(AE). By preferred term, the most commonly reported AEs (in at least 10.0% of all subjects) were 
upper respiratory tract infection (24.4% in children and 28.3% in adolescents), diarrhea (12.2% and 
18.3%), cough (12.2% and 13.3%), vomiting (9.8% and 11.7%) and rash (individual preferred term; 
4.9% and 15.0%). 
 
Most AEs were grade 1 or 2 in severity. Grade 3 or 4 AEs occurred in 6 (14.6%) children and 
8 (13.3%) adolescents. Each of the grade 3 or 4 AE preferred terms, except thrombocytopenia and 
hypertriglyceridemia (both in 2 subjects), were reported in only 1 subject. Only 2 subjects (both 
children) were reported with a grade 4 AE (both thrombocytopenia). Both grade 4 AEs were 
considered not related to ETR 
 
No fatalities were reported. Five subjects, all adolescents, reported at least one SAE (abnormal 
lymphocyte morphology and oligoclonal immunoglobulins at electrophoresis; carbamazepine 
toxicity; ETR overdose; treatment noncompliance, drug resistance and weight decreased; ulcerative 
keratitis). The subject with the overdose was inadvertently treated with ETR 250 mg instead of 200 
mg bid for 50 days without safety consequences. All SAEs, except the overdose (considered very 
likely related to ETR), were considered not related to ETR. A limited number of subjects in each age 
group had AEs leading to permanent discontinuation of treatment with ETR: 


 
 
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2 (4.9%) children and 6 (10.0%) adolescents. One adolescent permanently discontinued treatment 
because of an SAE (drug resistance). 
 
Skin events were the most frequently reported events of interest. ‘Rash cases’, referring to a 
grouped term combining all rash-related AEs except events considered ‘severe cutaneous 
reactions’, were reported in 6 (14.6%) children and 17 (28.3%) adolescents. Consistent with other 
drug-related rashes, rashes with ETR occurred early during treatment, with a median time to first 
onset of 10 days; were self-limiting, with a median duration of 7 days; and were usually grade 1 or 
2 in severity. One subject in each age group developed a grade 3 rash. Four subjects (1 child and 
3 adolescents) discontinued treatment because of rash. No grade 4 rashes or rash related SAEs were 
reported. Other relevant skin events of interest included 1 case of erythema multiforme 
(grouped under severe cutaneous reactions) and 1 case each of hypersensitivity and urticaria 
papular (grouped under angioedema). The incidence of neuropsychiatric events of interest, 
pancreatic events, lipid-related events and neoplasms was low (≤ 2%). There were no hepatic, 
cardiac and bleeding events of interest reported in this study. 
 
A slightly higher frequency of rash was observed in the PIANO study compared to the DUET 
studies in adults and therefore, a multivariate analysis was performed on the pooled data of the 
Week 48 data of the DUET studies and the Week 24 data of the PIANO study to investigate risk 
factors for developing rash when treated with ETR. The results of this analysis consistently showed 
that being female, but not age or participation in the PIANO study (a partial surrogate for age), is a 
risk factor for developing rash. No other risk factors could be firmly identified. This is also seen in 
the Week 48 PIANO data: Rash ≥ grade 2 was reported in 13/64 (20.3%) of females vs 2/37 
(5.4%) of males; discontinuations due to rash were reported in 4/64 (6.3%) of females vs 0/37 
(0%) of males. Most often, rash was mild to moderate, of macular/papular type, and occurred in 
the second week of therapy. Rash was mostly self-limiting and generally resolved within 1 week 
on continued therapy. 
 
Mean changes over time in the clinical laboratory parameters were small in either age group and 
were generally not considered clinically relevant. There was an increase over time in total 
cholesterol, low-density lipoprotein (LDL) and triglycerides, as seen with many other ARV 
regimens. The majority of treatment-emergent laboratory abnormalities were grade 1 or 2 in 
severity. The most common treatment-emergent graded laboratory abnormalities were related to 
lipid related parameters, and mainly included increases in total cholesterol (50.0% in children and 
38.8% in adolescents) and LDL calculated (31.6% and 25.0%). All abnormalities in total 
cholesterol and LDL were grade 1 or 2 in severity with the exception of 1 adolescent who had a 
grade 3 increase in LDL cholesterol. 
 
There were no clinically significant changes over time in vital signs, nor findings suggestive of 
delayed sexual maturation. The mean age-adjusted z-scores for height, weight and body mass 
index remained stable over time. 
 
Taken together, the administration of ETR at a weight-based dose revealed no new findings 
compared with the known ETR safety profile in HIV-1 infected adults. 
In conclusion, the safety analysis shows that ETR is generally safe and well tolerated in treatment-
experienced HIV-1 infected children and adolescents aged 6 to 17 years. There were no clinically 
relevant differences with the safety profile in adults. No new safety signals or consistent patterns in 


 
 
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the incidence of adverse events (AEs) were detected in the pediatric population studied. These safety 
results represent the clinical basis to start the clinical trial in children below the age of six years. 
 
Data from the initial P1090 mini-cohort and rationale for revised ETR dose 
 
At the start of the P1090 trial, the ETR starting dose for the first (mini)-cohort was 5.2 mg/kg BID, 
based on data from the TMC125-C213 trial in children aged 6 to 17 years. The first 6 children 
enrolled in P1090 received this dose, and the ETR exposure was assessed at an intensive PK visit 
performed between 1-2 weeks after initiating ETR. The aim was to achieve similar exposures 
compared to those in adults (geometric mean AUC12h of the cohort between 3618- 
5879 ng.h/mL corresponding to 80% -130% of the geometric mean AUC12h observed in adults). 
 
The observed geometric mean ETR AUC12h for the first six children was 2576 ng.h/mL. Two of the 
six children had an individual AUC12h below 2350 ng.h/mL and had dose increases per protocol 
(see Section 9.34). Short-term safety and antiviral activity data did not reveal any concerns. 
 
Based on the combined pharmacokinetic data, even though the mini-cohort had passed the 
applicable criteria at that time of no more than 2 subjects with AUC12h <2350 ng.h/mL, and no 
safety or efficacy concerns, it was evident that with the 5.2 mg/kg dose, the probability of meeting 
the necessary criteria for the overall cohort (n=12, geometric mean AUC12h 3618-5879 ng.h/mL) 
would be very low. Therefore, it was decided to modify the ETR dosing regimen for the cohort, 
prior to recruiting additional subjects. 
 
To determine the most appropriate dosing regimen, a modeling and simulation approach was 
applied. For this, a population pharmacokinetic model of ETR for the pediatric population was used 
which is structurally based on a previously developed ETR population pharmacokinetic model in 
adults, using all rich and sparsely sampled pharmacokinetic data from pediatric subjects (6 to 17 
years from studies TMC125-C126 and TMC125-C213 [PIANO]; 2 to 6 years from the first mini-
cohort in P1090 [all doses, all samples]). The model consists of a sequential zero- and first-order 
absorption process with a lag-time and one-compartment disposition, includes a covariate effect of 
body weight on volume of distribution (Vc/F) and clearance (CL/F), and an allometric exponent for 
CL/F and Vc/F of 0.75 and 1.00, respectively. 
 
Standard graphical and numerical evaluation techniques (goodness-of-fit plots, including observed 
versus population and individual predicted ETR plasma concentrations, and conditional weighted 
residuals versus time since first dose and time since last dose), showed that the model 
fit the data with high precision and minimal bias. So far, no impact of age on the ETR CL/F has 
been observed. It was also shown specifically for the 6 subjects already enrolled in P1090 that their 
ETR pharmacokinetic parameters were well estimated with the model. Therefore, the final model 
was considered suitable for further simulations to evaluate potential dosing regimens for the 
pediatric population of interest for P1090. 
 
The model was used to evaluate several potential weight-based dosing regimens, with the intent to 
achieve ETR exposures similar to those observed in adults. From these simulations, the weight-
based ETR dosing regimens likely to result in similar ETR exposures as those observed in adults 
were selected for each weight band. This is presented in Figure 1, which shows the median 
simulated ETR AUC12h (with 80% prediction interval) by weight, for different ETR mg/kg doses 
across different weight bands. This dosing regimen is also in line with the currently approved ETR 


 
 
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dosing regimen for children aged 6 years and above, as of 16 kg of body weight (reference: US 
Package Insert revised 08/2014). 
 
Figure 1: Simulated ETR Exposures (AUC12h) By Body Weight for Different ETR BID Doses, Aimed 
at Achieving a Geometric Mean ETR AUC12h Similar to That in Adults. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The solid colored lines represent the median simulated AUC12h and the shaded areas represent the 
80% prediction interval. The two solid horizontal lines represent 80% and 130% of the geometric 
mean AUC12h in adults; the two dashed horizontal lines represent 60% and 150% of the geometric mean AUC12h in 
adults; the lower dotted line represents the 10th percentile of the adult AUC12h. 
 
Based on the above described approach, the revised ETR dosing regimen is presented in 
Appendix III. 
 
To evaluate the probability of success for this regimen, 10000 virtual trials with 12 pediatric 
subjects each were simulated. The virtual pediatric subjects were randomly sampled from a 
database built based on WHO’s age-gender-body weight distributions, assuming equal probabilities 
for gender and a uniform age distribution. With this, it was determined that for this dosing regimen 
(Appendix III), there is a very high probability to achieve a geometric mean exposure (AUC12h) 
across the age cohort that is similar to that observed in adults (i.e., 80% probability for a geometric 
mean AUC12h within 80-130% of adult geometric mean exposure; 96% probability for a geometric 
mean AUC12h within 60-150%). 
The inter-individual variability for apparent clearance in the population PK model is 62%. Given 
this rather high value, exposures in the study are expected to be as variable. Increasing the target 
band for the AUC12h from 80-130% to 60-150% of the geometric mean AUC12h in adult would 
provide a more suitable criterion. Also, individual exposures are anticipated to fall in range of the 
exposures observed in adults, which have been shown to be safe and efficacious. Across previous 
trials of ETR in HIV-infected adults and children, there was no observation of a PK/PD relationship 
for adverse events of interest, nor was ETR exposure found to be a significant prognostic factor for 
virologic response. 
 


 
 
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Also in the currently enrolled pediatric subjects in the P1090 study, there have been no significant 
safety concerns. There was one case of virologic failure, which was first noted approximately 32 
weeks after start of dosing (and confirmed at Week 40). The reason for the virologic failure is not 
clear, but it is unlikely to be related to ETR exposure and there was no evidence of ETR resistance. 
The observed ETR AUC12h for this subject at the intensive PK visit (6165 ng.h/mL) was above the 
mean exposure in adults, and also based on the sparse sampling at later visits, there was no 
indication of low ETR exposures. All other subjects in the trial have had a good virologic response. 
 
Data from the second P1090 mini-cohort and a) rationale for opening Cohort III and b) dose 
selection for Cohort III 
 
As described in the section above, modelling of the initial mini-cohort led to a revision in the 
dosing for study participants and adoption of weight based dosing.  Results from the second mini-
cohort of Cohort I suggest that this approach is appropriate and that the weight-based population 
PK model used for dose selection can thus be assumed to be adequate. Estimation of the allometric 
exponents in the model revealed no significant improvement of the model compared to fixed 
theoretical values (3/4 for CL/F and 1 for V/F). This suggests that the standard theoretical model 
for pharmacokinetics in pediatric populations is applicable to ETR. 
[http://www.ncbi.nlm.nih.gov/pubmed/18336053  / ; 
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2010.03802.x/pdf] 
 
Introduction of a maturation function did not show any significant improvement in the model 
based on the current data. As maturation is known to exist, these results suggest that the available 
data are insufficient to estimate the effect of age on the PK of ETR.  Therefore, additional data in 
younger patients is needed (Cohorts II and III). 
 
Given the uncertainties around maturation of CYP metabolism in subjects aged <1 year, some 
additional precautions are taken for Cohort III: 
 6 months to < 1 year: the dose (in mg/kg) is reduced by 25% compared to what the model 
suggests to adjust for possible ongoing maturation of enzymatic metabolism  (30) 
 2 months to < 6 months: subjects in this age group will only be included once there are 
available data on subjects aged 6 months to 1 year 
 
Safety of the weight-based dosing in the younger participants is anticipated to be acceptable based 
on the safety data collected so far among subjects in Cohorts I and II.  The latter was opened 30 
October 2015 and, based on input from participating sites in late 2015, the expectation is that there 
will be at least 2 and likely 6 participants already enrolled in Cohort II by the time of release of 
Version 5.0.  There are adequate safeguards included in the protocol, which include: 
 Intensive PK evaluation with individual dose adjustment if needed and continuous safety 
monitoring on an individual level,   
 Close monitoring of PK data and continuous safety monitoring on a cohort level;  
 Additional safety monitoring rules for first 6 patients entering cohorts II and III combined. 
 
In conclusion, the added scientific value of the collected data -and the precautions taken to ensure 
safety and efficacy of the compound in this age group- justifies an early enrollment of Cohort III.   
 
 


 
 
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Other Available Data 
 
In a Spanish cohort of five children (5 to 12 years old) and 18 adolescents (13 to 18 years old) of 
whom 22 had a history of NNRTI-based CART failure with proven genotypic NNRTI resistance 
mutations, salvage regimens including ETR at 5.2 mg/kg BID (for children) and 200 mg BID 
(for adolescents) and (in 21 of the patients) OBR with at least 2 active agents, 87% achieved 
HIV-1 RNA< 400 copies/mL and 78% achieved HIV-1 RNA< 50 copies/mL by 8 months. Mild (3 
adolescents) or moderate (2 adolescents) rash was observed only in adolescents but not in children, 
and therapy was otherwise well tolerated (31). 
 
Table 5. Adverse Events Summary (Adult Studies Phase IIb /III Pooled Analysis) 
 
AEs during treatment period 
n (%) 
Week 48 
Placebo DUET 
N = 604 
Week 48 
ETR DUET 
N = 599 
ETR Selected 
Dose 
N = 1043 
All ETR 
N = 1223 
Treatment duration (weeks), 
Median (range) 
51.0 
(3 - 80) 
52.3 
(2 - 85) 
51.7 
(0 - 271) 
52.3 
(0 - 271) 
Subject years of exposure 
556.8 
583.4 
1125.1 
1476.2 
Any AE 
580 (96.0) 
575 (96.0) 
990 (94.9) 
1164 (95.2) 
Any Grade 1 or 2 AE 
Grade 1 
Grade 2 
573 (94.9) 
512 (84.8) 
425 (70.4) 
564 (94.2) 
511 (85.3) 
445 (74.3) 
973 (93.3) 
877 (84.1) 
751 (72.0) 
1143 (93.5) 
1040 (85.0) 
888 (72.6) 
Any Grade 3 or 4 AE 
Grade 3 
Grade 4 
211 (34.9) 
190 (31.5) 
64 (10.6) 
199 (33.2) 
177 (29.5) 
59 (9.8) 
347 (33.3) 
311 (29.8) 
106 (10.2) 
434 (35.5) 
387 (31.6) 
135 (11.0) 
Treatment-related AEa 
285 (47.2) 
320 (53.4) 
557 (53.4) 
671 (54.9) 
Death 
20 (3.3) 
12 (2.0) 
21 (2.0) 
26 (2.1) 
Any SAE 
141 (23.3) 
118 (19.7) 
205 (19.7) 
254 (20.8) 
AE leading to temporary stop 
57 (9.4) 
64 (10.7) 
131 (12.6) 
161 (13.2) 
AE leading to permanent stop 
34 (5.6) 
43 (7.2) 
101 (9.7) 
127 (10.4) 
Most Common AEsb 
Diarrhea 
Nausea 
Headache 
Injection site reaction 
Fatigue 
Nasopharyngitis 
Upper respiratory tract 
infection 
142 (23.5) 
77 (12.7) 
77 (12.7) 
75 (12.4) 
57 (9.4) 
63 (10.4) 
56 (9.3) 
108 (18.0) 
89 (14.9) 
65 (10.9) 
63 (10.5) 
48 (8.0) 
66 (11.0) 
44 (7.3) 
202 (19.4) 
175 (16.8) 
127 (12.2) 
109 (10.5) 
107 (10.3) 
111 (10.6) 
94 (9.0) 
266 (21.7) 
214 (17.5) 
168 (13.7) 
144 (11.8) 
140 (11.4) 
133 (10.9) 
123 (10.1) 
AEs of interest 
Any skin event of interest 
Rash (any type) 
110 (18.2) 
66 (10.9) 
159 (26.5) 
115 (19.2) 
288 (27.6) 
207 (19.8) 
353 (28.9)c 
249 (20.4) 
Any neuropsychiatric event of 
interest 
Nervous system events of 
interest 
Psychiatric events 
205 (33.9) 
119 (19.7) 
118 (19.5) 
181 (30.2) 
103 (17.2) 
100 (16.7) 
338 (32.4) 
191 (18.3) 
196 (18.8) 
427 (34.9)d 
249 (20.4) 
248 (20.3) 
Any hepatic event 
37 (6.1) 
39 (6.5) 
86 (8.2) 
103 (8.4) 


 
 
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Any cardiac event 
Coronary artery disorders 
44 (7.3) 
8 (1.3) 
42 (7.0) 
11 (1.8) 
92 (8.8) 
16 (1.5) 
124 (10.1) 
28 (2.3) 
Any pancreatic event 
27 (4.5) 
24 (4.0) 
38 (3.6) 
51 (4.2) 
Any bleeding event 
39 (6.5) 
33 (5.5) 
59 (5.7) 
76 (6.2) 
N: number of subjects; n: number of subjects with observations 
a   defined as possibly, probably or very likely related to treatment in the opinion of the investigator 
b   > 10% of subjects in the All ETR group 
c      Of the total skin rashes, 1.5 % were Grade 3;there were no Grade 4 skin rashes 
d      Of neuropsychiatric events, 0.7% were Grade 3; 0.2% (1 patient had a Grade 4, and it was a suicide). 
 
Additional Safety Data 
 
Safety data derived from pooling of the results of 1,043 adult HIV-1-infected treatment- 
experienced subjects enrolled in the Phase III trial indicated that ETR is generally safe and well 
tolerated. The most common AEs reported during ETR treatment with the selected dose were rash 
(any type, 16.9%; Grade 2 to 4 rash 9%), diarrhea (any Grade 1: 9.4%; Grade 2 to 4: 5.2%), nausea 
(any Grade, 13.9%), and headache (Grade 1: 2.2%; Grade 2 to 4: 2.7%). 
 
With the exception of rash, the incidence of AEs and laboratory abnormalities were generally 
comparable to placebo. Table 5 describes these results. 
 
A recent double-blind placebo-controlled trial of ETR 400 mg QD versus EFV in HIV-infected 
adults, naïve to ART, compared neuropsychiatric side effects in the two arms. At week 12, 
16.5% of ETR treated subjects reported at least one grade 1 to 4 treatment related neuropsychiatric 
AE, compared to 46.2% in the EFV treated subjects; for grade 2 to 4 AEs, the incidence was 5.1% 
in the ETR arm and 16.7% in the EFV arm (32). 
 
Twenty-six subjects (2.1%) died during the study while on ETR; 25 of which were judged not, or 
unlikely, related to ETR therapy. One death, due to myocardial infarction with cardio respiratory 
failure, in a subject with risk factors for premature coronary artery disease, was considered possibly 
related to ETR therapy (18). 
 
The rashes tended to be mild to moderate; they usually occurred in the second week of therapy, and 
resolved within 1 to 2 weeks on continued therapy. In the adult phase III trials, the cumulative 
incidence of Grade 3 and 4 rashes was 1.3% for subjects on ETR and 0.2% for those on placebo. A 
total of 2% of subjects discontinued study due to rash. There were no cases of Stevens Johnson 
Syndrome (SJS) or toxic epidermal necrolysis (TEN) reported due to ETR in any of the Phase 
IIb/III studies (18). 
 
In August of 2009, the FDA issued a warning to physicians, related to the occurrence of severe, 
potentially life threatening, and fatal skin rashes (erythema multiforme, SJS and TEN) linked to 
ETR use during the post marketing period. Prescribing information has been updated to reflect this 
information. The rate of SJS and TEN was < 0.01% each. The hypersensitivity reactions manifested 
as rash along with constitutional findings. At times, evidence of impending organ failure existed. 
The current recommendation is to stop ETR at the onset of severe skin rash, with careful clinical 
monitoring (13). 
 
As of February 12th, 2016, fourteen participants between the ages of 2 to 6 years have been 


 
 
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enrolled into P1090.  To date, adverse events have been primarily unrelated to study product; none 
raised concerns regarding the safety of ETR in this population. Specifically, there has been no 
reported skin rashes related to study med, nor any safety events related to EKGs obtained on the 
day of pharmacokinetic testing. 
 
 
1.4 
Rationale 
 
There is increasing use of NNRTI-based regimens as initial therapy for HIV-1 infected children, 
especially in areas where HIV-1 exposed newborns receive NVP as part of PMTCT regimens 
and/or daily NVP for prevention of breastfeeding transmission (33).  Though NNRTI-based CART 
regimens are effective, first generation NNRTI agents have a low genetic barrier to the 
development of resistance. 
As a result, there are an increasing number of treatment-experienced infected infants and children 
who have failed, or will fail, their initial regimen. The majority of these infants, at the time of 
virologic failure to a NNRTI based regimen, will have mutations associated with resistance to first 
generation NNRTIs (7).  Similarly, a high percentage of infected infants exposed to NVP as a 
component of PMTCT regimens will harbor virus with NNRTI related resistance mutations.(3-7). 
Failure or intolerance of LPV/rtv based regimens, especially among infants and children with prior 
NNRTI exposure (as treatment or for PMTCT), leaves few or no alternative treatment options (7). 
 
ETR, a second generation NNRTI, approved for adult use, has a higher genetic barrier to HIV drug 
resistance than EFV or NVP and retains activity against EFV and NVP drug resistant HIV-1 
isolates harboring the K103N and Y181C mutations (9, 10). The drug dosing and tolerability have 
been established in adult registration studies. Skin rash was the main treatment-limiting significant 
adverse event. It was seen in up to 20% of subjects, with 1 to 2% of subjects showing Grade 3 or 4 
severity (18).  Phase I/II trials of ETR in children aged 6 to 17 years of age demonstrated acceptable 
safety and tolerability, and established suggested dosing for this age group (24). See Section 1.32. 
 
We propose to investigate ETR, in combination with at least 2 active ARVs, one of which must be 
a boosted PI, for treatment experienced HIV-1 infected infants and children aged 2 months to 
< 6 years. 
 
2.0 
STUDY OBJECTIVES 
 
 
2.1 
Primary Objectives 
 
2.11 
To evaluate the steady state pharmacokinetics of ETR in combination with an OBR in 
HIV-infected children aged ≥ 2 months to < 6 years. 
 
2.12 
To determine the safety and tolerability of ETR in combination with an OBR in children 
aged ≥ 2 months to < 6 years, through 48 weeks of therapy. 
 
2.13 
To determine the appropriate dose of ETR in combination of an OBR for children aged ≥ 
2 months to < 6 years. 
 
 


 
 
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2.2 
Secondary Objectives 
 
2.21 
To assess the antiretroviral activity of ETR containing regimens through 48 weeks of 
therapy. 
 
2.22 
To determine the immunological changes (change in CD4 percent and absolute count; 
CD4/CD8 ratio and percent) through 48 weeks of ETR therapy in combination with an 
OBR. 
 
2.23 
To determine changes in viral drug resistance during 48 weeks of ETR therapy in 
combination with an OBR. 
 
2.24 
To assess the relationship between ETR pharmacokinetics and the antiviral activity and 
safety of ETR containing regimens. 
 
2.25 
To explore the relationship between subject-specific gene CYP profile, sex, 
age, weight, race, HIV regimen (e.g., boosted PI) and HIV response 
markers and pharmacokinetics of ETR. 
 
3.0 
STUDY DESIGN 
 
This is a Phase I/II, multicenter, open label 48 week study of ETR in combination with at least 2 
active agents (a boosted PI and at least one additional active drug), for treatment experienced HIV-
1-infected infants and children ≥ 2 months to < 6 years separated by age into three cohorts. 
 
The study will, in a sequential manner, accrue subjects for an initial dose finding intensive PK 
component for age related cohorts. It is expected that up to 50 subjects will be accrued, to yield 
data from at least 36 evaluable1 subjects with a minimum of 12 subjects for each of the three 
cohorts, who were started on the final approved dose for that cohort. The total sample size will 
depend upon the number needed to complete the dose finding stage of the study, the number of 
subjects who discontinue the study and the number of subjects required for regulatory approval of 
ETR in these populations. Up to 18 subjects may be enrolled into Cohort I. 
 
The P1090 core protocol team will be responsible for reviewing the PK and safety data and 
approving the dose selection for each full and mini-cohort. The P1090 core protocol team will 
consist of the protocol chair and co-chairs, clinical trials specialist, NIAID and NICHD Medical 
Officers, data manager, pharmacologists, pharmacist, statisticians and Janssen R&D 
representatives. 
 
 
 
 
1NOTE: For the Week 24 (or Week 48) analysis, evaluable will be defined as having been treated exclusively on the 
dose determined to be optimal for a given age cohort and having either completed 24 (or 48) weeks of exposure to the 
study drug or having been classified as a safety failure, due to a study drug related adverse event occurring during the 
first 24 (or 48) weeks of treatment. 
 
 


 
 
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This study is designed to determine the appropriate ETR dose for HIV-1-infected infants and 
children and to evaluate the PK, safety and tolerability of ETR in this population. ETR will be 
administered as 25 mg scored tablets and/or 100 mg tablets swallowed as a whole or dispersed in an 
appropriate liquid vehicle (see Section 5.2). 
 
3.1 
Description of Cohorts 
 
Subjects will be stratified by age and will undergo viral phenotype and genotype evaluations as 
described in Table 6 below. 
 
 
3.2 
Optimized Background Regimen 
 
As described in Table 6, OBR for treatment experienced subjects must consist of at least two active 
agents, a boosted PI and at least one additional active drug, in addition to ETR. 
 
Prior to the enrollment visit (entry), the protocol team must be notified and approve the proposed 
OBR regimen. OBR should be based on clinical status, treatment history, resistance data as well as 
availability of dosing guidelines and appropriate pediatric formulations. 
 


 
 
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Table 6. Description of Cohorts 
Cohort 
Description of Subject 
Drug Regimen 
Phenotyping / 
Genotyping Information 
Comments 
Anticipated Accrual 
Mini 
Cohort 
To 
complete a 
full cohort 
Total 
cohort 
size 
I 
≥ 2 year to < 6 years who are 
treatment experienced 
ETR 
+ OBR 
(1 active 
boosted 
PI+ at least 1 
other active 
drug) 
HIV genotype and 
phenotype assays should 
be performed in real time 
and results available prior 
to starting study drug 
Subjects will be enrolled providing the 
phenotypic assay results indicate a <  10 
fold change in sensitivity to ETR 
6 
6 
Up 
to  
18 
II 
≥ 1 year to < 2 years who are 
treatment experienced 
ETR 
+ OBR 
(1 active 
boosted 
PI+ at least 1 
other active 
drug) 
HIV genotype and 
phenotype assays should 
be performed in real time 
and results available prior 
to starting study drug 
Subjects will be enrolled providing the 
phenotypic assay results indicate a <  10 
fold change in sensitivity to ETR 
6 
6 
12 
III 
≥ 2 months to < 1 year who 
are treatment experienced1 
ETR 
+ OBR 
(1 active 
boosted 
PI+ at least 1 
other active 
drug) 
HIV genotype and 
phenotype assays should 
be performed in real time 
and results available prior 
to starting study drug 
Subjects will be enrolled providing the 
phenotypic assay results indicate a <  10 
fold change in sensitivity to ETR 
6 
6 
12 
 
1.  Subjects below 6 months of age will only be enrolled upon availability of initial safety and PK data from subjects between 6 months and 1 year of age.


 
 
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Figure 2: Algorithm for Cohort Management as of Version 5.0  
 
 
 


 
 
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The investigator-selected ARVs in the OBR will be used in doses that are specified in the individual 
package inserts. Brand name ARVs and generics with tentative approval from the US FDA may be 
prescribed. For a list of tentatively approved generics, please consult 
http://www.fda.gov/InternationalPrograms/FDABeyondOurBordersForeignOffices/AsiaandAfric 
a/ucm119231.htm 
 
If the site intends to use study products not marketed in the United States, sites should consult the DAIDS 
SOP on “Use of Study Products Not Marketed in the United States” (Jun 24, 2011). It is the sites 
responsibility to ensure that they are in compliance with this policy. Please refer to 
http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/NonFDAa 
pprovedProducts.pdf 
 
Applicable procedures and treatment guidance based on package inserts of the selected ARVs should be 
respected. Proposed OBR regimens for individual subjects will need to be approved by the protocol team 
prior to the enrollment (entry) visit. 
 
 
3.3 
Mini-Cohorts 
 
Under prior versions of the protocol, enrollment moved in a sequential manner, from the oldest cohort to 
the next youngest cohort (Cohort I Cohort II).  Upon release of Version 5.0, the team will consider 
opening Cohort III while the first mini-cohort of Cohort II may still be enrolling based on available PK 
and safety data to ongoing participants. Subjects below 6 months of age will only be enrolled upon 
availability of initial safety and PK data from subjects of at least 6 months of age and less than 1 year of 
age (see Figure 2 and Section 3.5). 
 
All cohorts will begin with enrollment into an initial mini-cohort of 6 subjects. Intensive PK on initial dose 
will be performed on Day 14 (± 4 days) (to allow ETR levels to reach steady-state) and the mini-cohort 
will be followed for 4 weeks to assess safety. 
 
For all cohorts, plasma concentrations of ETR will be assayed in real time (within two weeks of sample 
receipt) by the protocol specified IMPAACT pharmacology laboratory. After the sixth subject is enrolled, 
enrollment into that cohort will pause so that the pharmacokinetics (PK) and safety data can be analyzed. 
The safety criteria are described in Section 8.52 and PK criteria are described in Section 9.0. 
 
The P1090 core protocol team will review the PK and safety results of each mini-cohort, and if acceptable, 
enrollment will resume, at that dose, to complete enrollment of the remaining 6 slots.   
 
Subjects who pass screening but cannot enroll because the mini-cohort is filled, will join a waiting list and 
will be given first priority to enroll when the remaining six slots are opened for that cohort.  NOTE:  
Screening labs must be repeated if the subject is on the waiting list for ≥ 60 days. 
 
In the rare event where the results of a single subject’s intensive PK are extremely low, AND the site 
clinician/protocol team strongly suspect non-adherence, an additional subject may be enrolled into the 
mini-cohort to replace the non-adherent subject. The non-adherent subject may remain on study and on 
study drug (ETR), if the site investigator agrees it is in the best interest of the subject, but this subject will 
not be considered for dose-finding or safety final analysis. 


 
 
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If the PK or safety monitoring results of the mini-cohort suggest that a higher or lower dose is needed, the 
new dose will be agreed upon by the P1090 core protocol team (upwards for inadequate PK values; 
downwards for safety failure, or high PK values). Up to 6 new subjects will be enrolled as a new mini-
cohort, for PK and safety evaluation of the new dose. 
 
Those enrolled in a failed mini-cohort, who had acceptable PK parameters, antiviral activity and safety can 
remain on the same dose without dose adjustment and will be followed on study. Subjects from the failed 
mini-cohort may be dose adjusted to the new dose, if feasible and the site investigator and/or protocol team 
believe this is in the best interest of the patient. Such subjects will have truncated intensive PK evaluation 
(3 samples: pre-dose and samples 2h and 3-5h after dosing) 7-14 days after the dose change, for safety 
considerations, but will not be considered towards the cohort pass/fail criteria. 
 
Two out of six of the children from the mini-cohort who passed the safety criteria in Version 3.0 would be 
on the same dose chosen for the new weight-banding dosing strategy in Version 4.0. Consequently, the 
team agreed that those two participants could be included in considering the Cohort I mini-cohort under 
V4.0; only four additional participants would be needed to complete enrollment into that mini-cohort. In 
future mini-cohorts, if dose adjustments need to be made but subjects in the prior failed cohorts were on the 
same dose that will be evaluated in the new cohort, the PK and safety data for these subjects will be carried 
forward and counted towards the number of evaluable subjects on the final dose. 
 
Those who need an individual dose adjustment (see Section 9.34 for management of individual dose 
adjustments), will have a repeat 12 hour intensive PK performed between Day 7 to 14 following their dose 
adjustment. Subjects who require a dose adjustment but decline to undergo repeat intensive PK (see 
Section 9.34 for management of individual dose adjustments) will have ETR therapy discontinued and best 
available therapy by their clinician will be initiated. 
 
If a subject discontinues therapy for a non-ETR related toxicity reason (e.g., drug intolerance to an OBR 
agent) the subject will be replaced. Subjects discontinued due to ETR toxicity will NOT be replaced; rather, 
they will continue to be counted as failures. However, the safety data from the subjects who replace them for 
PK purposes will also be used when applying the safety guidelines  
 
3.4 
Full Cohorts 
 
Once PK and safety criteria have been met for a full cohort, subjects will continue their treatment in the 
specific cohort at the selected dose. The safety criteria are described in Section 8.52. In order to meet the 
PK criteria, the geometric mean AUC12h in the cohort must be within 60 to 150% of the geometric mean 
AUC12h in adults (i.e. between 2713 and 6783 ng•h/mL). The recommended dose must be approved by the 
P1090 core protocol team. If, however, the selected dose for a full cohort does not meet the PK and safety 
criteria, the dose may be adjusted for the subjects already in the cohort (as described above) and 
additionally new subjects will be enrolled, if needed, to have (at least) 12 subjects in total on the new 
starting dose. The evaluation of PK and safety will then be repeated. If the starting dose is still not 
acceptable, the dose selection process will be repeated. 
 
Subjects from the failed cohort may be dose-adjusted to the new dose if the site investigator and protocol 
team believes this is in the best interest of the subject. These subjects will have a truncated intensive PK 
evaluation (sampling at pre-dose and 2hr and 3-5h after dose). 
Those subjects that require an individual dose adjustment for high or low AUCs (see Section 


 
 
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9.34 for management of individual dose adjustments), will have a repeat intensive PK evaluation 
7-14 days following their dose adjustment. 
 
Those subjects from a failed cohort who are not dose-adjusted to the new dose, but had acceptable PK 
parameters and antiviral activity and safety can remain on the same dose and will be followed on study. 
 
Subjects who require a dose adjustment but refuse to undergo repeat intensive PK (see Section 
9.34 for management of individual dose adjustments) will have ETR therapy discontinued and will be 
replaced (but will be followed on study but off study drug). 
 
If full cohort data are inconclusive, the protocol team may decide to enroll additional subjects at the starting 
dose, and/or the P1090 Study Monitoring Committee (SMC) may be asked to review the data and advise the 
team. 
 
As enrollment into each cohort continues, the study team will review the data via conference call at least 
monthly, to ensure that the stated PK and safety targets are acceptable. 
 
3.5 
Cohort III 
 
Upon release of Version 5.0, the P1090 core protocol team will review the available PK and safety results 
of Cohort II to determine whether Cohort III may be opened to enrollment of infants > 6 months and < 1 
year of age. 
 
3.5.1 Available Cohort II PK and safety data are acceptable 
 
If the available PK and safety data are acceptable, enrollment into Cohort III will commence starting with 
infants > 6 months and < 1 year of age.  
 
In the event that Cohort III is open to accrual at the time that Cohort II completes accrual of a mini-cohort 
(N=6), accrual into both cohorts will be paused as per Section 3.3. 
 
3.5.2  Available Cohort II PK and safety data are not acceptable 
 
If available safety and/or PK data from Cohort II are unacceptable at this time, Cohort III will remain 
closed to enrollment; Cohort II will continue to enroll to complete the mini-cohort of six subjects.  At that 
point, the team will evaluate the mini-cohort as described in Section 3.3.   
 
If the 4-week safety data from the six subjects in the Cohort II mini-cohort are deemed appropriate, and 
sufficient PK data are available to confirm the starting weight-based dose for the older infants in Cohort III 
as per Dosing Table 2, Cohort III will open to enrollment of infants > 6 months and < 1 year of age.  
 
If the 4-week safety data from the six subjects in the Cohort II mini-cohort are not deemed appropriate, 
and/or PK data confirm the starting weight-based dose for the older infants in Cohort III as per Dosing 
Table 2, Cohort III will remain closed to enrollment and a new mini-cohort will be enrolled into Cohort II 
as per Section 3.3. 
 
 


 
 
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3.5.3 Enrollment of Cohort II is paused at time of release of Version 5.0 
 
If enrollment of Cohort II is paused for review of mini-cohort data at the time of release of Version 5.0, 
opening of Cohort III will be held until Cohort II is re-opened. 
 
Once there are sufficient data of infants > 6 months and < 1 year of age to assess the impact of age on the 
pharmacokinetics, enrollment of the youngest group of infants in Cohort III (> 2 months and < 6 months 
of age) will commence. 
 
3.6 
Long Term Safety Follow-Up 
 
Long term safety follow-up is described in Section 5.5. 
 
3.7 
Early Discontinuation 
 
Subjects who are withdrawn from study drug within the first 48 weeks of study will not enter long term 
follow-up but will be followed for safety for 4 weeks, as per Appendix ID.  Additionally, any AEs will be 
followed until satisfactory clinical resolution (i.e. value returns back to subjects baseline value) or 
stabilization (to be agreed upon with the sponsor).  All grade 3 and grade 4 laboratory abnormalities as 
well as any laboratory abnormalities resulting in an increase of 2 DAIDS Grades from baseline, will be 
followed until they return to baseline or within 1 Grade from baseline. 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 
Inclusion Criteria 
 
4.11 
Confirmed HIV-1 infection 
 
NOTE: Results can be abstracted from the medical record to meet this criterion for HIV diagnosis. 
 
Tests Performed at < 2 years of age 
 
An infant will be considered to be infected with HIV if TWO separate peripheral blood 
specimens from different days are drawn and each specimen is positive by at least one of the 
following assays: 
 HIV DNA PCR 
 Plasma HIV RNA (quantitative or qualitative) 
 HIV total nucleic acid tests 
 
At least one of the above tests must be done in a VQA-certified laboratory that is approved to 
perform the assay for protocol testing. If the mother or infant is receiving antiretroviral drugs, 
then an HIV DNA assay may be more sensitive. 
 
Tests Performed at ≥ 2 years of age 
 
Documentation of HIV-1 infection is defined as positive results from two samples collected at 
different time points. All samples tested must be whole blood, serum or plasma. For studies 


 
 
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conducted under an IND, all test methods should be FDA-approved if available. If FDA- approved 
methods are not available, test methods should be verified according to GCLP and approved by the 
IMPAACT central laboratory. 
 
 Sample #1 may be tested by non-study public or PEPFAR programs. However, both the 
result and the assay date must be recorded in subject’s charts. Source documentation 
[patient’s medical record/chart, Ministry of Health (MOH) registers, laboratory results, 
etc.] must be available if requested. 
 Sample #2 must be performed in a CAP/CLIA-approved laboratory (for U.S. sites) or in a 
laboratory that operates according to GCLP guidelines and participates in appropriate 
external quality assurance program (for international sites). 
 
Acceptable Tests 
 
Sample #1 may be tested using any of the following: 
 Two rapid antibody tests from different manufacturers or based on different principles and 
epitopes. 
 One EIA OR Western Blot OR immunofluorescence OR chemiluminescence 
 One HIV DNA PCR 
 One quantitative HIV RNA PCR (above the limit of detection) 
 One qualitative HIV RNA PCR 
 One HIV culture (prior to August 2009) 
 One total HIV nucleic acid test 
 
If Sample #1 is positive, then collect and test Sample #2. Sample #2 may be tested using any of the 
following: 
 Rapid antibody test. If this option is used in combination with two rapid tests for Sample 
 #1, at least one of the three rapid tests must be FDA-approved and the third rapid test must 
be from a third manufacturer or based on a third principle or epitope. 
 One EIA OR Western Blot OR immunofluorescence OR chemiluminescence 
 One HIV DNA PCR 
 One quantitative HIV RNA PCR (above the limit of detection) 
 One qualitative HIV RNA PCR 
 One HIV culture (prior to August 2009) 
 One total HIV nucleic acid test 
 
4.12 
Age ≥ 2 months to < 6 years old at study entry. NOTE: For subjects who were born at ≤ 
37 weeks gestational age, the subject must be at least 12 weeks of age, AND ≥ 46 weeks post-
conceptual age at study entry. 
 
4.13 
HIV-1 RNA viral load > 1,000 copies/mL (within the previous 90 days prior to screening) AND an 
HIV-1 RNA viral load > 1,000 copies/mL at screening. 
 
4.14 
Treatment experienced children on a failing combination antiretroviral regimen (containing at least 
3 ARVs) for at least 8 weeks OR Treatment experienced children on a treatment interruption of at 
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(containing at least 3 ARVs). 
 
4.15 
Ability to swallow ETR whole or dispersed in an appropriate liquid (see Section 5.2). 
 
4.16 
Parent or legal guardian able and willing to provide signed informed consent and to have the 
subject followed at the clinic site. 
 
4.17 
Availability of sufficient active ARV drugs to create an OBR consistent with protocol requirements 
(as outlined in Table 6). 
 
 
4.2 
Exclusion Criteria 
 
4.21 
Evidence of phenotypic resistance to ETR at screening. Phenotypic cutoffs of > 10 for loss of 
sensitivity for cohorts I, II, III. 
 
4.22 
Known history of HIV-2 infection in subject or subject’s mother. 
4.23 
Diagnosis of a new CDC Stage C (per 1994 Revised Classification System for Human 
Immunodeficiency Virus Infection in Children Less than 13 Years of Age) criteria or opportunistic 
or bacterial infection diagnosed within 30 days prior to screening and not considered clinically 
stable. 
 
4.24 
Prior history of malignancy. 
 
4.25 
Any clinically significant diseases (other than HIV infection) or clinically significant findings 
during the screening medical history or physical examination that, in the investigator’s opinion, 
would place the subject at an unacceptable risk of injury; render the subject unable to meet the 
requirements of the protocol; compromise the outcome of this study; or lead to the child being 
ineligible for participation. 
 
4.26 
Current ≥ Grade 3 of any of the following laboratory toxicities at screening: neutrophil count, 
hemoglobin, platelets, AST, ALT, lipase, serum creatinine. 
 
4.27 
Current or anticipated use of any disallowed medications (see Section 4.32). 
 
4.28 
Subject’s family is unlikely to adhere to the study procedures, keep appointments, or is planning to 
relocate to a non-IMPAACT study site during the study. 
 
4.29 
History of non-adherence with ARV medications that in the investigator’s opinion could affect the 
ability of the subject to comply with the protocol/procedures. 
 
4.210   Subject is currently participating, or has participated within the previous 30 days prior to screening, 
in a study with a compound or device that is not commercially available. 
 
4.211   Grade 3 or higher QTc or PR interval prolongation from the ECG at screening (see Appendix V). 
 
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ECG reading indicates Grade 3 or higher QTc or PR interval on the screening ECG that was not 
recognized by the site investigator, the Team will inform the site investigator, and the subject will 
be taken off study treatment. 
 
 
4.3 
Concomitant Medication Guidelines 
 
4.31 
Precautionary Medications 
 
The following medications should be avoided, if possible, and alternative treatments sought. Please contact 
the protocol team at impaact.teamp1090@fstrf.org if treatment with any of these medications is necessary 
for clinical care. 
 
 Clopidogrel 
 Clarithromycin when used for the treatment of Mycobacterium avian complex (MAC) - other 
indications are acceptable 
 ≥ 14 days of all inhaled/intranasal corticosteroids, except for fluticasone (see disallowed meds 
below), for subjects taking ritonavir-boosted PIs 
 Rifabutin, when combined with a boosted protease inhibitor 
 Any drugs not recommended in the package insert under concomitant medications. 
 
4.32 
Disallowed Medications 
 
Anticonvulsants: 
 Carbamazepine 
 Oxcarbazapine 
 Phenytoin 
 Fosphenytoin 
 Phenobarbital 
 
Anti-infectives: 
 Rifampin 
 Rifapentine 
 
Antiretrovirals: 
 Darunavir use in subjects < 3 years old 
 Fosamprenavir/ritonavir (etravirine increases fosamprenavir exposure posing a potential safety 
issue) 
 Maraviroc 
 Saquinavir/ritonavir 
 Tipranavir/ritonavir (tipranavir/ritonavir significantly decreases etravirine) 
 Ritonavir, used as sole PI therapy 
 Unboosted PIs including nelfinavir (drug interaction unknown – etravirine may increase nelfinavir) 
 Other NNRTIs 
 
 
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 ≥ 14 days of continuous use of inhaled fluticasone (for subjects taking ritonavir-boosted 
PIs) 
 ≥ 7 days of oral or IV steroids 
 
Other: 
 Products containing St. John’s wort (Hypericumperforatum) 
 Any drugs contraindicated in the package insert under concomitant medications 
 
 
4.4 
Enrollment Procedures 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site must have 
the protocol and the protocol informed consent form(s) approved, as appropriate, by their local institutional 
review board (IRB)/ethics committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the DAIDS Protocol 
Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC).  The DAIDS PRO will review 
the submitted protocol registration packet to ensure that all of the required documents have been received. 
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by the DAIDS PRO and 
sites will receive an Initial Registration Notification from the DAIDS PRO that indicates successful 
completion of the protocol registration process. A copy of the Initial Registration Notification should be 
retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, sites should 
implement the amendment immediately. Sites are required to submit an amendment registration packet to 
the DAIDS PRO at the RSC.  The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site- specific ICF(s) WILL NOT be reviewed 
and approved by the DAIDS PRO and sites will receive an Amendment Registration Notification when the 
DAIDS PRO receives a complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents required for initial 
and amendment registrations, refer to the current version of the DAIDS Protocol Registration Manual. 
 
Sites interested in screening or enrolling subjects in IMPAACT P1090 must send an email to the team at 
impaact.teamp1090@fstrf.org  indicating the candidate’s PID# (if no PID is assigned, the age of the 
subject is sufficient), cohort number and prior ART experience. If the participant has a milestone birthday 
that will change cohort assignment, it is the site's responsibility to notify the 
DMC data manager to request a cohort assignment change. 
 
Sites should refer to subjects medical charts to ensure potential eligibility. Slots will be granted based on 
the date a slot was requested. Sites must receive authorization from the protocol team before proceeding 
with screening. 
 
Enrollment slots will be granted only for a study candidate who: 
 Receives permission to proceed with the screening visit 


 
 
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 Accepts the slot and completes the screening visit within two weeks of receipt of the slot (Sites 
MUST email the protocol team to accept the slot and to complete the Screening visit) 
 Meets the study inclusion criteria 
 
Sites should contact the protocol team at impaact.teamp1090@fstrf.org with any screening timeline 
deviations. A slot may be recalled if deviations from the timeline are not approved by the protocol team. 
Sites need to inform the protocol team of the proposed optimized background regimen (OBR) at least 24 
hours prior to enrollment. Enrollment is contingent upon the protocol team and site agreeing on the OBR. 
Sites with study candidates who are granted a slot but fail to enroll will be required to complete an 
enrollment failure form which will collect general failure-to-enroll information. 
 
 
4.5 
Co-enrollment Procedures 
 
Co-enrollment is permitted except for protocols that would violate the exclusion criteria. Co- enrollment in 
P1074 is strongly encouraged. With the exception of P1074, all co-enrollments in protocols require the 
prior approval of the P1090 protocol team and the co-enrollment protocol teams. 
 
5.0 
STUDY TREATMENT 
 
Study treatment is defined as etravirine (ETR) 25 mg and 100 mg tablets. Both will be provided by the 
study. Darunavir 100 mg/mL suspension, darunavir 75 mg tablets, and darunavir 150 mg tablets, will be 
provided through the study if not reasonably available locally. (NOTE: Darunavir may only be used in 
children ≥ 3 years.). Other antiretrovirals (ARVs) will not be provided through the study. 
 
The subjects will be accrued into the study for an initial dose finding intensive PK component for age 
related cohorts. It is anticipated that approximately 50 subjects will be accrued, to yield at least 36 
evaluable subjects with a minimum of 12 subjects for each of the three cohorts, whose initial dose was the 
final optimal dose determined for their age cohort. The total sample size will depend upon the number of 
subjects needed to complete the dose finding stage of the study and the number of subjects who 
discontinue the study. 
 
Subjects enrolled into the study will be stratified by age, as described in Section 3.1 and Table 6. In all 
cohorts, ETR will be started concurrently with an optimized ARV background regimen (OBR). 
 
This study is designed to determine the appropriate ETR dose for HIV-1 infected infants and children and 
to evaluate the PK, safety and tolerability of ETR in this population. 
 
5.1 
Drug Regimens, Administration and Duration 
All subjects enrolled into the study will be stratified by age into one of three cohorts.  
Cohort I: ≥ 2 year to < 6 years who are treatment experienced 
 ETR 25 mg and/or 100 mg tablet(s) 
 Subjects will take the specified dose of ETR tablet(s) orally twice daily within 30 minutes 
following a meal per Dosing Table 1 in Appendix III 
 


 
 
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Cohort II: ≥ 1 year to < 2 years who are treatment experienced 
 ETR 25 mg and/or 100 mg tablet(s) 
 Subjects will take the specified starting dose of ETR tablet(s) orally twice daily within 30 minutes 
following a meal, per Dosing Table 1 in Appendix III 
 
Cohort III: ≥ 2 months to < 1 year who are treatment experienced 
 ETR 25 mg and/or 100 mg tablet(s) 
 Subjects will take the specified starting dose of ETR tablet(s) orally twice daily within 30 minutes 
following a meal, per Dosing Table 2 in Appendix III 
 
ETR will be administered as 25 mg scored tablets and/or 100 mg tablets swallowed as a whole or dispersed 
in an appropriate liquid vehicle following a meal. Refer to Section 3.1 and Table 6 for further information 
on regimen design per cohort. 
 
Study Duration: Minimum of 48 weeks 
Long Term Safety Follow-up: See Section 5.5 
 
 
5.2 
Dosing and Administration 
 
ETR will be dosed orally according to the dosing table in Appendix III. The investigator will be notified by 
the P1090 Protocol Team in case there would be any change in the dosing table (see Appendix III). 
 
ETR tablets should be swallowed whole with a sufficient amount of water or other liquid within 
30 minutes following a meal. Subjects unable to swallow the tablets whole may disperse the tablets in a 
container with a minimum of 5 mL (1 teaspoon) of water. One minute should be allowed for the tablet(s) to 
be dispersed, stirring will aid in the dispersion. The dispersed tablet(s) in water may be further diluted with 
a beverage (see list below) not to exceed 30 mL (2 tablespoons) total volume. The recommendation for 
administration to infants is to disperse the tablet in approximately 10 mL of liquid (e.g. formula or milk). 
Once dispersed, subjects should drink the dispersion immediately. 
 
The container should be rinsed with a minimum of 5 mL (1 teaspoon) of water or other beverage and the 
rinse completely swallowed to ensure the entire dose is consumed. This step may be repeated as needed. 
The dispersion should be consumed completely and immediately; it is not allowed to administer a portion. 
 
Subjects must avoid the use of warm or hot (> 40°C) beverages and carbonated drinks when swallowing 
study drug. ETR can be dispersed in the following beverages without compromising drug stability: 
 Water that is safe to drink (sterile water will be provided by the study staff, as appropriate) 
 Mineral water that is safe to drink 
 Orange juice 
 Milk (whole milk, skim milk or chocolate milk) 
 Various infant formula 
 
5.21 
Missed Doses 
 
Any missed ETR study drug dose should be taken by the subject if it is within 6 hours of the scheduled 
missed dosing time. 
 


 
 
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5.22 
Vomited Doses 
 
If the subject vomits the ETR study drug dose within 15 minutes of taking the dose, then another full dose 
should be taken by the subject. 
 
5.3 
Drug Formulation 
 
ETR 100 mg tablet and 25 mg scored tablet: store at 25°C (77°F); with excursions permitted to 
15°to 30°C (59° to 86°F) [see USP controlled room temperature]. Store in the original bottle. Keep the bottle 
tightly closed in order to protect from moisture. Do not remove the desiccant pouches. 
 
Darunavir (Prezista®) 100 mg/mL oral suspension: store at 25°C (77°F); with excursions permitted to 15° 
to 30°C (59°-86°F). Do not refrigerate or freeze. Avoid exposure to excessive heat. Store in the original 
container. Shake well before each use. 
 
Darunavir (Prezista®) 75 mg and 150 mg tablets: Store at 25°C (77°F); with excursions permitted to 15° 
to 30°C (59°-86°F). 
 
 
5.4 
Drug Supply, Distribution and Pharmacy 
 
ETR 100 mg tablet and 25mg scored tablet are provided by Janssen R&D and supplied through the study. 
 
Darunavir 100 mg/mL suspension, and darunavir 75 mg and 150 mg tablets are provided by Janssen R&D 
and supplied through the study for OBR purposes if not reasonably available locally. 
 
Study Product Acquisition 
 
ETR 100 mg tablets and ETR 25 mg scored tablets will be available through the NIAID Clinical 
Research Products Management Center (CRPMC).  Darunavir 100 mg/mL suspension, darunavir 
75 mg tablets, and darunavir 150 mg tablets will be available through the NIAID Clinical Research 
Products Management Center (CRPMC) for OBR purposes if not reasonably available locally. 
 
The IMPAACT pharmacist can obtain the study product by following the instructions in the manual 
"Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks" in the section Study Product 
Control. 
 
The optimized background regimen to be used in this study (with the exception of darunavir, as noted) will 
not be provided by the study and must be obtained by non-study prescription (see Section 3.2). 
 
5.41 
Study Product Accountability 
 
The IMPAACT site pharmacist is required to maintain complete records of all study products received from 
the CRPMC and dispensed. All unused study products must be returned to the CRPMC after the study is 
completed or terminated at U.S. sites. 
 
Non-U.S. sites will receive instructions regarding the final disposition of any remaining study products. 
The procedures to follow for accountability can be found in the manual, “Pharmacy Guidelines and 


 
 
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Instructions for DAIDS Clinical Trials Networks” in the section entitled “Study Product Management 
Responsibilities.” 
 
 
5.5 
Long Term Safety Follow-up 
 
Provided that the overall data for this drug appear to be generally favorable, each subject who successfully 
completes 48 weeks of ETR treatment will continue to receive study drug through the study, and be 
followed on study for long-term safety follow-up (see Appendix IE) for up to 5 years or until any one or 
more of the following events occur within the 5 years: 
 
The age-appropriate formulations provided by the study are available locally from another source; 
OR 
 
The subject is no longer deriving benefit; OR 
 
The subject meets a protocol-defined reason for discontinuation; OR 
 
Pharmaceutical development of ETR for that age cohort is terminated 
 
Subjects in countries where ETR, darunavir 100 mg/mL suspension, darunavir 75 mg tablets, and 
darunavir 150 mg tablets continue to be unavailable locally at the end of the planned 5 year long- term 
safety follow-up program will be provided the drug either through a P1090 protocol amendment or through 
other sources, such as another Janssen R&D-sponsored program, government programs, and aid and 
assistance programs. It is also expected that such programs will be in place in all countries where study 
sites are located within the planned 5 year duration of long-term safety follow-up phase. 
 
Once subjects enter the Long Term Safety Follow-up phase, they will be seen in clinic every 12 weeks for 
safety visits and laboratory evaluations until one of the above criteria are fulfilled, as per Appendix IE.  
Sites should record any laboratory results, diagnoses etc. that are recorded as part of standard of care as 
well as perform the study mandated HIV-1 RNA assay (See Appendix IE). 
 
6.0 
SUBJECT MANAGEMENT 
 
 
6.1 
Toxicity Management 
 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, (DAIDS AE Grading 
Table), Version 1.0, December 2004, Clarification August 2009, must be used and is available on the RSC 
website at (http://rsc.tech-res.com/safetyandpharmacovigilance/). 
 
Management of adverse experiences will be according to the best clinical practice and the judgment of the 
site investigator. Alternate explanations for clinical and laboratory abnormalities must be sought. 
Laboratory normal ranges will be the institutional values. However, if a site does not have an age-specific 
normal range/value for a particular laboratory, the site should use the latest edition of the Harriet Lane 
Handbook for normal ranges/values and document this for monitoring purposes. Abnormal clinical and 
laboratory findings should be followed until resolution to < Grade 2. 
 
The toxicity management guidelines are for events for which a relationship to study drugs cannot be 
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result in study drug interruption. General guidelines for study drug suspected adverse drug reactions 
(SADRs) are provided below: 
 
6.11 
Reporting 
 
 Grade 1: All study drug SADRs should be recorded on Case Report Forms (CRFs) at each visit. 
 
 Grade 2: All study drug SADRs should be recorded on CRFs at each visit. Inform team monthly 
whether toxicity has resolved or not. 
 
 Grade 3 or 4: 
o The protocol team must be notified of study drug SADRs within 24 hours at 
impaact.p1090cmc@fstrf.org 
o The investigator should attempt to confirm any unexpected laboratory test results as soon as 
possible but always within 72 hours to determine if the result was spurious. 
o Expedited Adverse Event (EAE) reporting must be done within 72 hours of the initial result. 
Reporting will occur whether the value is confirmed or if confirmatory results are not available 
within 72 hours. 
 
6.12 
General Management Guidelines 
 
NOTES: 
 All antiretroviral therapy including study drug should be started or stopped together whenever 
possible, except for when one antiretroviral agent can be substituted for another within the same 
class, when the etiology of the toxicity can be determined. 
 If a subject is pending a safety event analyses or resolution, additional safety tests may be required 
by the team. 
Grade 1 
Continue study drug; routine monitoring.  
Grade 2 
 
Continue study drug; monitor closely with more frequent visits; as per site investigator, work-up to exclude 
other causes. 
 
Grade 3 
 
NOTE: Grade 3 triglycerides and cholesterol events will NOT require the subject to stop study drug or 
OBR. 
 The protocol team should be notified of a Grade 3 event at impaact.p1090cmc@fstrf.org. 
 Study drugs can be continued at the discretion of the site investigator/clinician while awaiting a 
repeat assessment/confirmation of an abnormal laboratory test as soon as possible (within 72 
hours). 
 If the repeat assessment confirms Grade 3 toxicity, AND if the investigator considers the event to 
be at least possibly related to study drug, ETR should be withheld and any abnormal laboratory 
values should be followed weekly (Except in Grade 3 cholesterol and triglycerides). 


 
 
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 OBR should be held at the discretion of the site investigator. 
 If the toxicity resolves to ≤ Grade 2 within 21 days, ETR (and OBR if applicable) can be restarted. 
 If the Grade 3 toxicity persists for > 21 days, or recurs at a ≥ Grade 3 after re-introduction of ETR; 
ETR must be permanently discontinued. 
 
Grade 4: Non-Life-Threatening Toxicity 
 
 Study drug (ETR) and concomitant antiretrovirals (OBR) should be discontinued immediately 
unless the clinician and P1090 core protocol team, believe that withholding OBR and/or ETR 
would be harmful to the subject and that continuing the drugs would pose little additional risk. 
 Sites should attempt to confirm any unexpected laboratory results as soon as possible, but always 
within 72 hours of the event to determine if these results were spurious. 
 The protocol team should be notified of a Grade 4 event at impaact.p1090cmc@fstrf.org. 
 If the repeat assessment confirms Grade 4 toxicity, ETR should be permanently discontinued, 
HOWEVER, for Grade 4 adverse events that are determined to be unrelated to study drug, the 
investigator should contact the team to determine when study drug may be safely resumed. 
 If the repeat assessment shows Grade 3 toxicity, continue to hold ETR and follow abnormal 
laboratory values weekly. 
 If the toxicity resolves to ≤ Grade 2 within 21 days, all study drugs can be restarted. 
 If ≥ Grade 3 toxicity recurs after re-introduction of ETR, the study drug (ETR) must be 
permanently discontinued. 
 
Grade 4: Life-Threatening Toxicity 
 
 Study drug (ETR) and concomitant antiretrovirals (OBR) should be discontinued immediately. 
 Sites should attempt to confirm any unexpected laboratory results as soon as possible, but always 
within 72 hours of the event to determine if these results were spurious. 
 The protocol team should be notified of a Grade 4 event at impaact.p1090cmc@fstrf.org. 
 If the repeat assessment confirms Grade 4 toxicity, ETR should be permanently discontinued, 
HOWEVER, for Grade 4 adverse events that are determined to be unrelated to study drug, the 
investigator should contact the team to determine when study drug may be safely resumed. 
 
6.13 
Management of Cutaneous Adverse Events 
 
Since cutaneous adverse events are of particular interest for this drug, the following guidelines on 
monitoring and management should be followed. The table in Appendix VII-A illustrates these grading 
and management guidelines. Additionally, please refer to Appendix IV which describes the visit schedule 
for management of cutaneous adverse events. 
 
NOTE: These management guidelines are NOT applicable to rashes with clear alternative etiology, such as 
chicken pox, impetigo and cutaneous HSV. 
 
Grade 1 cutaneous reaction/rash is defined as localized macular rash. 
 
Grade 2 cutaneous reaction/rash is defined as diffuse macular, maculopapular or morbilliform rash or 
target lesions. 
 


 
 
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Subjects with Grade 1 or Grade 2 rash may continue ETR or temporarily interrupt therapy at the 
investigator’s discretion. Close clinical follow up is recommended to monitor progression of rash. All 
subjects with Grade 2 rash must be seen by a dermatologist within 24 to 48 hours. 
 
Grade 3 cutaneous reaction/rash is defined as: 
 
 Diffuse macular, maculopapular or morbilliform rash with vesicles or limited number of bullae 
 Cutaneous reaction/rash with superficial ulceration of mucous membrane limited to 1 mucosal site 
 Cutaneous reaction/rash with at least 1 of the following: 
o Elevations of ALT/AST > 2 x baseline but at least 5 x upper limit of laboratory normal 
range (ULN) 
o Fever ≥ 38°C or 100.4oF 
o Serum sickness-like reaction 
o Eosinophil count > 1000/mm³ 
 Subjects experiencing a Grade 3 rash or cutaneous event must have ETR discontinued permanently; 
but should remain on study for safety follow-up. 
 OBR should be held at the discretion of the site investigator. 
 Subjects must also be evaluated by a dermatologist within 24 to 48 hours. 
 The protocol team should be notified of a Grade 3 event at impaact.p1090cmc@fstrf.org. 
 
Grade 4 cutaneous reaction/rash is defined as: 
 
 Extensive or generalized bullous lesions 
 Stevens-Johnson syndrome (SJS) 
 Ulceration of mucous membrane involving 2 or more distinct mucosal sites 
 Toxic epidermal necrolysis (TEN) 
 Subjects experiencing a Grade 4 rash or cutaneous event must have ETR discontinued permanently; 
but should remain on study for safety follow-up. 
 OBR should be held at the discretion of the site investigator. 
 Subjects must also be evaluated by a dermatologist within 24 to 48 hours. 
 The protocol team should be notified of a Grade 4 event at impaact.p1090cmc@fstrf.org. 
 
NOTE: Topical corticosteroids, topical anti-pruritic agents, and oral H1-antihistamines (such as cetirizine, 
diphenhydramine, hydroxyzine and levocetirizine but excluding astemizole and terfenadine) will be 
allowed at the investigator’s discretion for all grades of rashes. 
 
6.14 
Management of Acute Systemic Allergic Reaction 
 
The table in Appendix VII-B illustrates these grading and management guidelines. Grade 1 
Localized urticaria with no medical intervention indicated. Subject may continue intake of ETR. 
 
Grade 2 
 
Localized urticaria with medical intervention needed, or mild angioedema with no medical intervention 
indicated. Subject may continue intake of ETR. 


 
 
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Grade 3 
 
Generalized urticaria or angioedema with medical intervention indicated; or symptomatic mild 
bronchospasm. 
 Subjects with Grade 3 acute systemic allergic reactions will be permanently discontinued from the 
investigational medication (ETR) and background regimen but will be followed on study on a 
modified schedule (Appendix ID) for safety outcomes. 
 Subjects will be treated as clinically appropriate per the local physician. 
 
Grade 4 
 
Acute anaphylaxis; life-threatening bronchospasm; laryngeal edema. 
 Subjects with Grade 4 acute systemic allergic reactions will be permanently discontinued from the 
investigational medication (ETR) AND background regimen (OBR) but will be followed on study 
on a modified schedule (Appendix ID) for safety outcomes. 
 Subjects will be treated as clinically appropriate per the local physician. 
 The protocol team should be notified of a Grade 4 event at impaact.p1090cmc@fstrf.org. 
 
6.15 
Management of Abnormal QTc or PR intervals noted onECG 
 
NOTE: Please refer to Appendix V for grading of abnormal QTc or PR intervals by ECG.  Any subject 
who is permanently discontinued from the investigational medication (ETR) because of toxicity will be 
followed on study on a modified schedule (Appendix IE) for safety outcomes. Subjects will be treated as 
clinically appropriate per the local physician. 
 
Grade 1 
Continue study drug; routine monitoring. Grade 2 
 
Continue study drug; work-up to exclude other causes according to judgment of site investigator. Grade 3 
 Study drugs may be continued at the discretion of the site investigator/clinician. 
 Based on the local investigator reading of the ECG, sites should request a turnaround time of 24 
hours for the ECG from the centralized reading service. 
 If the central ECG reader confirms a Grade 3 ECG abnormality (QTc and/or PR interval), ETR 
must be permanently discontinued. 
 For Grade 3ECG abnormalities that are determined to be unrelated to study drug, the investigator 
should contact the team to determine whether study drug may be safely resumed. 
 
Grade 4: Non-Life-Threatening Toxicity 
 
 Subjects experiencing a Grade 4toxicity must have ETR discontinued. 
 OBR should be held at the discretion of the site investigator. 
 Based on the local investigator reading of the ECG, sites should request a turnaround time of 24 
hours for the ECG from the centralized reading service. 


 
 
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 The protocol team should be notified of a Grade 4 event at impaact.p1090cmc@fstrf.org. 
 If the central ECG assessment confirms Grade 4 ECG abnormalities (QTc and/or PR interval), ETR 
must be permanently discontinued. OBR should be held at the discretion of the site investigator. 
 For Grade 4ECG abnormalities that are determined to be unrelated to study drug, the investigator 
should contact the team to determine whether study drug may be safely resumed. 
 If subjects are discontinued from ETR, they will still be followed on study on a modified schedule 
(Appendix ID) for safety outcomes. Subjects will be treated as clinically appropriate per the local 
physician. 
 
Grade 4: Life-Threatening Toxicity 
 
 Subjects experiencing a life-threatening Grade 4toxicity must have ETR discontinued 
 OBR should be held at the discretion of the site investigator. 
 Sites should request a turnaround time of 24 hours for the ECG from the centralized reading 
service. 
 The protocol team should be notified of a Grade 4 event at impaact.p1090cmc@fstrf.org. 
 For confirmed drug-related, life-threatening Grade 4 QTc or PR interval SAEs, study medication 
must be permanently discontinued. 
 For life-threatening Grade 4 ECG abnormalities that are determined to be unrelated to study drug, 
the investigator should contact the team to determine whether study drug may be safely resumed. 
 If subjects are discontinued from ETR, they will still be followed on study on a modified schedule 
(Appendix ID) for safety outcomes. Subjects will be treated as clinically appropriate per the local 
physician. 
 
6.16 
Management of Neurologic Adverse Events 
 
NOTE: Please refer to Appendix VI for grading abnormal neurologic adverse events. Grade 1 
Continue study drug; routine monitoring. 
 
Grade 2 
 
Continue study drug; work-up to exclude other causes according to judgment of site investigator. Grade 3 
 Subjects experiencing a Grade 3toxicity must have ETR discontinued 
 OBR may be discontinued at the discretion of the site investigator. 
 The protocol team should be notified of a Grade 3 event at impaact.p1090cmc@fstrf.org. 
 For Grade 3 adverse events that are determined to be unrelated to study drug, the investigator 
should contact the team to determine if/when the study drug may be safely resumed 
 If the event is considered to be ‘definitely related,’ ‘probably related’ or ‘possibly related’ 
 to study drug, AND is resolved to grade 2 or less, AND the site physician feels it is in the subjects 
best interest to re-try the drug, the investigator should contact the team to determine if/when the 
study drug may be safely resumed 
 If subjects are permanently discontinued from ETR, they will still be followed on study on a 
modified schedule (Appendix IE) for safety outcomes. Subjects will be treated as clinically 
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Grade 4: Non-Life-Threatening Toxicity 
 
 Subjects experiencing a Grade 4 adverse event must have ETR discontinued temporarily 
 OBR should be held at the discretion of the site investigator. 
 The protocol team should be notified of a Grade 4 event at impaact.p1090cmc@fstrf.org. 
 For Grade 4 adverse events that are determined to be unrelated to study drug, the investigator 
should contact the team to determine when/if study drug may be safely resumed. 
 If the event is considered to be definitely related, probably related or possibly related to study drug, 
ETR should be permanently discontinued. 
 If subjects are discontinued from ETR, they will still be followed on study on a modified schedule 
(Appendix ID) for safety outcomes. Subjects will be treated as clinically appropriate per the local 
physician. 
 
Grade 4: Life-Threatening Toxicity 
 
 Subjects experiencing a Grade 4 toxicity must have ETR discontinued permanently; but should 
remain on study for safety follow-up. 
 OBR should be held at the discretion of the site investigator. 
 The protocol team should be notified of a Grade 4 event at impaact.p1090cmc@fstrf.org. 
 If subjects are discontinued from ETR, they will still be followed on study on a modified schedule 
(Appendix ID) for safety outcomes. Subjects will be treated as clinically 
 appropriate per the local physician. 
 
 
6.2 
Subject Management 
 
The DMC will maintain a web page informing sites as to the availability of enrollment slots per cohort. 
The protocol team, including the co-chairs, medical officers, pharmacist, and pharmacologist, will respond 
to sites who contact the team with questions regarding toxicity management, dose modifications, or other 
issues within 1 business day. Team responses will include, at a minimum, the study team. 
 
Sites will be given 7 days to respond to queries to allow the team to meet Janssen R&D data delivery 
requirements. Sites will be contacted by the protocol data manager or co-chairs regarding any query 
responses or data issues that are outstanding after 7 days.  All dose modifications will be recommended by 
the protocol team. See Section 3.0 for detailed information on the review process and dose modifications 
for a mini-cohort or full cohort. 
 
Information on permitted ARV changes can be found in Section 6.5. 
 
6.3 
Definition of Virologic Failure for Subject Management 
 
 
NOTE: A confirmatory (repeat) HIV-1 RNA measurement MUST be performed within 1 to 4 weeks of 
the initial suspected failure or rebound. 
 
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 
 A confirmed HIV-1 RNA at week 8 that is not at least 0.5 log lower than the HIV-1 RNA at entry 
(unless the viral load at week 8 or later is already ≤ 400 copies/mL) 
OR 
 
 
 A confirmed HIV-1 RNA at or after week 12 that is not at least 1 log lower than the HIV RNA at 
entry (unless the viral load at week 12 or later is already ≤ 400 copies/mL 
 
OR 
 
 
 A confirmed HIV-1 RNA ≥ 400 copies/mL at week 24 
Virologic REBOUND in this study is defined as: 
 
For subjects whose nadir was ≤ 400 copies/mL; a confirmed HIV-1 RNA >1000 copies/mL (on 2 
consecutive measurements at least 1 week but no more than 4 weeks apart). 
 
Subjects, who are confirmed as virologic failures (including virologic rebound) as defined above, should 
follow the schedule of evaluations for Virologic Failure as described in Appendix IA – 
IC. At the confirmed virologic failure visit, a specimen should be drawn that should be sent for resistance 
testing (genotyping and phenotyping), as described in Appendix IA – ID. 
 
Subjects will then, at the discretion of the subject’s clinician; with the approval of the protocol team and 
assuming the subject agrees to continue; be moved into one of the following three options: 
 
 Off Study Drug – On Study: Be taken off study drug and followed as per Appendix ID, 
‘Follow up for Subjects who Discontinue Study Provided Etravirine;’ 
 
OR 
 
 On Study Drug – re-optimize OBR: Have background therapy re-optimized, with the subject 
remaining on study drug; 
 
OR 
 
 On Study Drug:  Continue with no changes made to the current regimen. 
 
Any re-optimization of background therapy that includes experimental drugs must first be approved by the 
P1090 core team by emailing a request to impaact.p1090cmc@fstrf.org. 
 
6.4 
Viral Resistance Testing 
 
For all subjects, blood samples for viral resistance assays will be collected at screening. In addition, to 
evaluate development of resistance to ETR and to other antiretroviral therapies, used in the treatment 
regimen, blood samples will be collected at any confirmed virologic failure (including virologic rebound) 
and at any early discontinuation visit (if not already obtained at virologic failure) to assess development of 
resistance to ETR and or OBT.  (Refer to Appendix I for more information) 
 
6.5 
Permitted Changes to the ARV Optimized Background Therapy During the Study 
 


 
 
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Any changes in background ARV therapy after initial optimization must be approved by the P1090 core 
protocol team. Unless the change is specifically permitted, subjects who have one or more new agents 
added to the optimized background CART regimen will be considered virologic failures. 
The following changes to optimized background therapy are permitted during the study. However, the 
P1090 core protocol team requests that they be notified of any of these changes BEFORE they occur 
(impaact.p1090cmc@fstrf.org). 
 
 
Subjects may discontinue a background ARV (if approved by the P1090 team) and remain on study 
and on study drug 
 
Formulation substitutions for NRTI class (substituting single agents for fixed dose combinations and 
vice versa of the same ARV, or switching from liquid to pill/capsule form) are allowed. 
 
Formulation substitutions for PI class (capsule to tablet or liquid, or vice versa) are permitted only 
after discussion with the P1090 core protocol team, including the pharmacologists. In certain cases, 
repeat PK evaluations may be requested 
 
Substitution within the NRTI or PI class, for reasons of toxicity or intolerance will be considered. If 
approved, the subject will remain on study drug, with the new PI, but considered as a virologic failure 
if the change occurs after the week 4 visit. 
 
 
6.6 
Concerns Regarding Non-Adherence 
 
In the rare event where the results of a single subject’s intensive PK are extremely low, AND the site 
clinician/protocol team strongly suspect non-adherence, an additional subject may be enrolled into the 
mini-cohort to replace the non-adherent subject. The non-adherent subject may remain on study and on 
study drug (ETR) but will not be considered for dose-finding or safety final analysis. 
 
Medication adherence is critical to successful antiretroviral therapy. In addition to compromising the 
efficacy of the current regimen, suboptimal adherence has implications for limiting future effective 
regimens for subjects with resistant strains. 
 
Evidence indicates that adherence problems occur frequently in children. Studies have reported that fewer 
than 50% of children and/or their caretakers reported full adherence to the regimens. Although a variety of 
factors have been associated with adherence, no clear predictors of either good or poor adherence have been 
consistently identified in children. 
As a part of this trial, adherence to therapy should be stressed at each visit, along with continued 
exploration of strategies to maintain and/or improve adherence. 
 
Multiple methods of determining adherence to ARV therapy will be used simultaneously (e.g., quantitative 
self-report, pill counts). Pill counts will take place at each visit and will be recorded on the drug 
accountability form. Adherence to the study drug, OBR, and assessment of the palatability of the study 
drug, will also be monitored in the form of questionnaires/CRF administered by the site staff. 
 
 
 
6.7 
Etravirine Dose Changes Due to Increases in Body Weight 
 
Confirmed increases in subject's body weight will trigger an ETR dose increase as follows: 
 


 
 
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 If NO PK directed dose change was made following the day 14 (± 4 days) PK visit, i.e., the starting 
ETR dose from dosing tables provided an adequate AUC12h, then as the subject’s weight increases 
such that it crosses into a higher weight band, the dose will be changed to correspond with the new 
weight band, consistent with the Dosing Table provided in Appendix III. 
 If an individualized PK directed dose change was made following the day 14 (± 4 days) PK visit, a 
dose increase is triggered when the subject's weight has increased by 25% from the weight at the 
most recent AUC12h evaluation. Contact the protocol team at impaact.p1090cmc@fstrf.org for an 
individualized dosing recommendation based on the subject's pharmacokinetic parameters. 
 
There will be no 12-hour pharmacokinetic studies for dose adjustments due to increase in body weight. 
 
 
6.8 
Criteria for Etravirine (Study Drug) Discontinuation 
 
The following are criteria that will result in discontinuation of study treatment (ETR). Subjects who are 
withdrawn from study drug within the first 48 weeks of study will not enter long term follow-up, but will 
be followed for safety for 4 weeks, as per Appendix ID. 
 
Additionally, any AEs will be followed until satisfactory clinical resolution (i.e. value returns back to 
subjects baseline value) or stabilization (to be agreed upon with the sponsor).  All Grade 3 and Grade 4 
laboratory abnormalities as well as any laboratory abnormalities resulting in an increase of 2 DAIDS 
grades from baseline will be followed until they return to baseline or within 1 grade from baseline. 
 
 Grade 3 or higher events that are believed to be related, or possibly related, to study drug 
 Treatment with disallowed medications 
 Grade 3 or higher cutaneous reactions as outlined in section 6.13, that are not clearly related to a 
specific viral illness 
 Grade 3 or higher acute systemic allergic reactions as outlined in section 6.14, that are related to 
study drug 
 Other Grade 3 or higher toxicities that don’t resolve to < Grade 3 
 Grade 3 or higher ECG toxicities (QTc and/or PR interval) as outlined in Section 6.15, that are 
deemed related to study drug 
 Grade 3 or higher neurologic adverse events as outlined in Section 6.16 
 For subjects who have an AUC > 4380ng.h/mL, but who cannot be dose reduced 
 Non-adherence to study medication or study medication administration instructions 
 New data become available that indicate treatment should be discontinued 
 Subject declines further study visits, including PK visits 
 
 
6.9 
Criteria for Study Discontinuation 
 
Following are criteria for study discontinuation: 
 
 The parent or legal guardian refuses to allow the subject further treatment and/or follow-up 
evaluations. 
 The investigator determines that further participation would be detrimental to the subject’s health 
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 The subject fails to comply with the study requirements so as to cause harm to him/herself or 
seriously interfere with the validity of the study results. 
 
7.0 
EXPEDITED ADVERSE EVENT REPORTING 
 
7.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse Events (AEs) are outlined in 
Version 2.0 of the DAIDS EAE Manual, which is available on the RSC website at: http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 
The DAERS internet-based reporting system must be used for expedited AE reporting to DAIDS.  In the 
event of system outages or technical difficulties, expedited AEs may be submitted via the DAIDS EAE 
Form. For questions about DAERS, please contact  CRMSSupport@niaid.nih.gov or from within the 
DAERS application itself. 
 
Sites where DAERS has not been implemented will submit expedited AEs by documenting the information 
on the current DAIDS EAE Form. This form is available on the RSC website: http://rsc.tech-
res.com/safetyandpharmacovigilance/. For questions about EAE reporting, please contact the RSC 
(DAIDSRSCSafetyOffice@tech-res.com). 
 
7.2 
Reporting Requirements for this Study 
 
 
 The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used 
for this study. 
 
The study agent for which expedited reporting is required is Etravirine 
 
 In addition to the EAE Reporting Category identified above, other AEs that must be reported in an 
expedited manner are: 
 Erythema multiforme 
 Suspected transmission of an infectious agent by study product (as required by Vol. 9A, section 5.9 
of the Rules Governing Medicinal Products in the European Union – Guidelines on 
Pharmacovigilance for Medicinal Products for Human Use.  Such reporting is required irrespective 
of the presence of other seriousness criteria.) 
 
7.3 
Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table, Version 1.0, December 2004, Clarification August 2009) is used and is available on the 
RSC website at http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
To grade to the severity of any abnormal QTc or PR intervals, the DAIDS AE grading table for these 
events are described in Appendix V. 
 
To grade the severity of any neurologic events, sites should use the grading table in Appendix VI. 


 
 
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7.4  
Expedited AE Reporting Period 
 
 The expedited AE reporting period for this study is as per the EAE manual. 
 After the protocol-defined AE reporting period, unless otherwise noted, only SUSARs as defined in 
Version 2.0 of the EAE Manual will be reported to DAIDS if the study staff become aware of the 
events on a passive basis (from publicly available information). 
 
NOTE: For reporting of all adverse experiences the Investigator will determine the causality and relationship 
to study drug.  However, in regards to subject safety and PK evaluations which will support the selection of 
a dose for a given cohort, the protocol team will also have input as to the causality and drug relation of 
specific adverse experiences. 
 
8.0 
STATISTICAL CONSIDERATIONS 
 
 
8.1 
General Design Issues 
 
This is a Phase I/II multicenter, open label study with primary objectives of assessing the safety/tolerability 
and pharmacokinetics of ETR in combination with optimized background regimen (OBR) administered to 
HIV-infected treatment-experienced children within the age range of ≥ 2 months to < 6 years. 
 
Hypothesis: ETR will be safe, well tolerated, will have pharmacokinetics comparable to adults and will 
demonstrate antiviral activity when used with an optimized background therapy in HIV- 
1-infected, treatment experienced infants and children. 
 
The sample will be stratified into the following age groups: 
 
Cohort I 
≥ 2 years to < 6 years of age who are treatment experienced*  
Cohort II 
≥ 1 year to < 2 years of age who are treatment experienced*  
Cohort III: 
≥ 2 months to < 1 year who are treatment experienced* † 
 
*Treatment experienced children on a failing combination antiretroviral regimen (containing at least 3 ARVs) for at least 8 
weeks OR Treatment experienced children on a treatment interruption of at least 4 weeks with a history of virologic failure 
while on a combination antiretroviral regimen (containing at least 3 ARVs) 
†Subjects below 6 months of age will only be enrolled upon availability of initial safety and PK data from subjects between 6 
months and 1 year of age. 
 
A minimum of 12 subjects will be enrolled into each cohort of the study. Up to 18 subjects may be enrolled 
into Cohort 1. The total sample will include at least 36 evaluable subjects who have been treated exclusively 
at the doses judged to be optimal for their age cohorts.   
 
NOTE: For the Week 24 (or Week 48) analysis, evaluable will be defined as having been treated 
exclusively on the dose determined to be optimal for a given age cohort and having either completed 24 
(or 48) weeks of exposure to the study drug or having been classified as a safety failure, due to a study 
drug related adverse event occurring during the first 24 (or 48) weeks of treatment. 
 


 
 
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Accrual to the study will follow an algorithm in which younger children’s (Cohort II and Cohort III) exposure 
to the study medication is contingent upon the older age cohort (Cohort I) having passed the safety criteria. 
In addition, sufficient pharmacokinetic data will be required to determine the starting dose for the younger 
cohort (see Section 3.3-3.4 for details). 
 
Initial tests of safety and PK will examine data from the first 6 subjects (mini-cohort) of Cohort I to 
determine whether Cohort II and Cohort III will be allowed to open for its mini-cohort of 6 subjects. 
Subjects below 6 months of age will not be enrolled until there are initial safety and PK data from subjects between 
6 months and 1 year of age. These tests will proceed as follows: 
 
 
 The PK data for the first six subjects of the Cohort I will be evaluated on the basis of blood samples 
taken 14 days ±4 days after the start of therapy. 
 
 
 Safety will be evaluated on the basis of all available data collected through the 28th day on the dose 
that is being evaluated (see Section 8.51 for the safety guidelines to be used in the dose-finding 
algorithm). 
 
 
 For subjects failing to meet PK targets and requiring individual dose adjustments, safety will be 
evaluated on the basis of data gathered until the time of the visit at which the dose is adjusted. This 
will insure that, for subjects needing PK determined dose adjustment, adverse events attributed to 
the starting dose must have occurred while the subjects were still on that dose. However, this also 
means that for such subjects the safety of the starting dose may be assessed on the basis of less than 
28 days of study drug exposure. 
 
The overall safety and PK data of the first 6 subjects on a given cohort will be evaluated with respect to the 
guidelines specified in Section 8.512 and in Section 9.0 of the protocol. Once these subjects have passed 
both PK and safety criteria, 6 additional subjects will be accrued to complete each cohort (up to 12 
additional subjects may be accrued to Cohort I). The full cohort must also pass the PK and safety criteria 
(see Section 8.513 and Section 9.0). If the mini or full cohort fails either the safety or the PK guidelines, 
then the starting dose will be adjusted in the appropriate direction, (upwards for inadequate PK values; 
downwards for safety failure), if this is feasible. Subjects in a cohort that failed PK or safety but were 
receiving the same dose as that recommended in the new dosing cohort will be included in PK and safety 
analysis of the new dose and additional new subjects will be enrolled as appropriate at the new dose in 
order to have a mini-cohort of 6 subjects treated with the new dose.  An initial evaluation of safety and PK 
will be made on the basis of data from these subjects. The evaluation will proceed as described above. In 
the event that the mini- or full cohort fails the PK criteria before the cohort completes accrual, then safety 
will be evaluated on all available subjects to confirm that a dose increase is not contraindicated. 
 
If the P1090 core protocol team judges a given subject’s PK data to be unevaluable, the subject will be 
replaced for dose finding purposes. Note that the subject would be replaced for evaluating safety, as well 
as PK, criteria, since unevaluable PK data would reflect uncertainty about appropriate exposure to the 
study medication. 
The study accrual is designed to yield at least 36 evaluable subjects for the Week 24 (and 48) safety 
analyses, which analyses will occur when the last subject of the last cohort has reached week 24 (or Week 
48).  For these safety analyses, “evaluable” will be defined as having been treated exclusively on the dose 
determined to be optimal for a given age cohort and having either completed 24 (or 48) weeks of exposure 
to the study drug or having been classified as a safety failure, due to a study drug related adverse event 


 
 
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occurring during the first 24 (or 48) weeks of treatment. Although the primary safety analyses will focus 
on the effects of exposure to the optimal dose level for 24 and 48 weeks, secondary analyses will include 
all safety data collected from first subject exposure to 24 (or 48) weeks and until the end of the study. This 
will include data representing the final dose for each cohort, as well as data gathered during the dose 
finding stage which may represent exposure to doses which have failed. This will also include data from 
subjects whose individual doses have been adjusted, with results broken down by the times at which 
different dose levels were taken. 
 
 
8.2 
Endpoints and Outcome Measures 
8.21 
Primary Endpoints: 
Toxicity Endpoints: 
 
 Termination from treatment due to a suspected adverse drug reaction (SADR) 
 Adverse events of Grade 3 or higher severity 
 Death 
 
Pharmacokinetic Endpoint: 
 
 Failure to meet PK targets (specified in Section 9.0) 
 
8.22 
Secondary Endpoints: 
 
 Adverse events of Grade 3 or higher severity judged to be at least possibly attributable to the study 
medications 
 Confirmed failure to suppress plasma HIV-1 RNA to ≤ 400 copies 
 AND 
 Failure to achieve at least a 2 log reduction (from baseline) in HIV-1 RNA at weeks 24 and/or 48 
(confirmed in 1 to 4 weeks) 
 Treatment discontinued due to toxicity or virologic failure 
 Change in optimized background regimen due to virologic failure 
 New onset OI or AIDS diagnosis 
 Decline in absolute CD4 percent of > 5% any time after 12 weeks of therapy 
 
8.23 
Primary Response Variables: 
 
 Pharmacokinetic parameters - AUC12h 
 
8.24 
Secondary Response Variables: 
 
 Plasma HIV-1 RNA (copies/mL) 
 CD4 counts and percent 
 CD4/CD8 ratio and percent 
 Genotypic and phenotypic measures of resistance at virologic failure and at early discontinuation 


 
 
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 
Pharmacokinetic parameters - C12h and Cmax 
 
8.25 
Exploratory Response Variables: 
 
 Patient-specific CYP gene profiles. 
 
 
8.3 
Randomization and Stratification 
 
There will be no randomization. Subjects will be enrolled into one of the three cohorts described in the 
“General Design Issues” section above. 
 
 
8.4 
Sample Size and Accrual 
 
8.41   Pharmacokinetics 
 
Sample size for this study was estimated using a pharmacokinetic modeling and simulation approach. 
Details of this approach are provided in Supplemental Document I. Briefly, the objectives of this approach 
were to ensure that 1) the mean value of ETR apparent oral clearance (CL/F) has a standard error <20% on 
80% of occasions and 2) that the 95% confidence interval for CL/F is 60 to 140% or 60 to 166.6% of the 
point estimate of the geometric mean on 80% of occasions in each of the above age groups. A third 
approach was developed and consisted of simulation-estimation platform incorporating data from previous 
trials. It was used to determine the number of pediatric subjects required across the age range of 2 months 
to <6 years to ensure the median estimate for CL/F for a typical subject within each age group has a 
reported standard deviation <20%. Based on a pharmacokinetic model adapted for pediatric maturation and 
incorporating prior data, a minimum of 12 subjects in each age group is deemed sufficient to provide 
pharmacokinetic data for pediatric subjects treated with ETR. 
 
8.42  Safety 
 
Total accrual will depend upon the number of subjects who must be accrued to yield a minimum of 36 
evaluable subjects for purposes of the primary safety analyses. There is some uncertainty concerning the 
number needed to complete the dose finding procedures and the number who may be lost to follow-up for 
reasons other than treatment failure. Each successful age cohort will include at least 12 subjects. In total, it 
is anticipated that approximately 50 subjects may need to be enrolled in the protocol to yield 36 evaluable 
subjects for the weeks 24 and 48 safety analyses. 
 
Table 7. Percent of Subjects Experiencing Grade 3+ Adverse Events (or Grade 3+ Adverse Events 
Attributed to the Study Medication) with Exact 95% Confidence Intervals 
N 
No. of Subjects (% ) With Grade 
3+ Adverse Events 
95% C.I. 
12 
0 (0%) 
0% -- 26% 
24 
0 (0%) 
0% -- 14% 
36 
0 (0%) 
0% -- 10% 
12 
1 (8%) 
0.2% -- 38% 
24 
2 (8%) 
1% -- 27% 


 
 
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36 
4 (11%) 
3% -- 26% 
12 
3 (25%) 
5% -- 57% 
24 
6 (25%) 
10% -- 47% 
36 
9 (25%) 
12% -- 42% 
12 
4 (33%) 
10% -- 65% 
24 
8 (33%) 
16% -- 55% 
36 
11 (31%) 
16% -- 48% 
 
Table 7 presents exact 95% confidence intervals around various potential rates of Grade 3+ adverse events 
which might be observed in a total sample of 36 evaluable subjects, a sample of 12 subjects representing a 
minimal sample that might be accrued within any age stratum and potential sample size that might occur if 
a subgroup of N = 24  was analyzed. This table indicates that confidence intervals will be wide around the 
minimal sample size of 12 subjects within a given stratum, but would be reasonably precise around a 
sample size of 36 subjects. 
 
8.5 
Monitoring 
 
The study will be monitored intensively by the core protocol team which will review safety and 
pharmacokinetic data at least twice a month during the dose-finding stage with the aim of determining the 
optimal dose for each cohort while protecting patient safety. In addition, the IMPAACT Network will 
appoint a study monitoring committee (SMC) to provide independent reviews when necessary to ensure 
subject safety. In accordance with IMPAACT and DAIDS procedures, this committee will be composed of 
two individuals from the Primary Scientific Committee, one PDMC member and a statistician, independent 
of both the P1090 protocol team and drug manufacturer (Janssen R&D).  Members of said study 
monitoring committee will have: 
 
1) No financial interest in the study; 
2) No planned authorship in publication of study results; and 
3) No involvement in the conduct of the study. 
 
8.51 
Safety Guidelines 
 
8.511   Evaluation of the Starting Doses During the Dose-Finding Stage 
 
The attribution of relationship of serious adverse events to study drug for the purposes of employing the 
start, stop and pause rules specified below will be by consensus among the site investigator, the protocol 
team and the DAIDS medical officers. If unanimous agreement between them cannot be established, the 
relevant data will be reviewed by the independent Study Monitoring Committee as described above, which 
will make the final judgment concerning the relationship between study drug and the adverse event. Within 
this committee the decision will be determined by the majority opinion of this study’s independent Study 
Monitoring Committee clinicians. 
 


 
 
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Gradation of relationship will use the following terminology: 
 Not related 
 Probably not related 
 Possibly related 
 Probably related 
 Definitely related 
 
An event judged to be at least possibly related to the study treatment will be considered to be a Suspected 
Adverse Drug Reaction (SADR) for purposes of the dose finding algorithm which follows. 
 
8.512   First Six Subjects Started at a Given Dose Level in Each Cohort 
 
For each study cohort (Cohort I, Cohorts II & III combined), the frequency of adverse reactions to the 
starting dose of the study medication will be evaluated on the first 6 subjects. The data will extend to the 
week 4 visit for subjects not requiring dose adjustment or until the visit on which the dose is adjusted, as 
described above. Further accrual into this cohort will be contingent upon meeting the following safety 
guidelines: 
 
If any of the first 6 subjects has a life threatening SADR or any Grade 4 event or death that is probably or 
definitely attributable to the study medication or 3 or more subjects have terminated study drug due to a 
Grade 3+ at least possibly treatment related SADR, stop accrual into this study cohort (Cohort I, Cohorts II 
& III combined) until a safety review by the P1090 core protocol team is conducted. If none of the first 6 
subjects has experienced a life-threatening SADR or a Grade 4 event or death that is probably or definitely 
attributable to the study medication and at most 2 of these 6 subjects has terminated study drug due to a 
Grade 3+ at least possibly treatment related SADR, then this cohort has passed the initial safety guidelines. 
If these 6 subjects also meet the PK guidelines, accrue more subjects to this cohort and evaluate the safety 
and PK results of the overall cohort. 
 
In cases where the mini-cohort has failed either the safety or pharmacokinetic guidelines, the P1090 core 
protocol team will conduct a thorough review before proceeding with accrual to the study. All of the 
relevant safety and pharmacokinetic data will be examined to determine whether it is safe to continue the 
attempt to find an optimal dose for this cohort. If the P1090 study team determines that it is safe to 
proceed, it will make specific changes in dosing and monitoring procedures which may be indicated. If 
there are any concerns regarding safety, the study’s Study Monitoring Committee will then review all of 
the relevant safety and pharmacokinetic data, along with the recommendations of the core protocol team, 
and will determine whether and under what conditions further dose finding activities for this cohort may 
proceed. 
 
The protocol will only proceed if this review has led to a recommendation that it is safe to do so. The 
safety review may lead to a recommendation that the dose be de-escalated. Before implementing such a 
recommendation, the P1090 core protocol team will review the PK data to determine whether a lower dose 
is likely to achieve adequate drug exposure. 
 
Given the small sample sizes within each cohort, the information available for preliminary safety decisions 
will be imperfect. Two types of sampling errors are possible: 1) in a cohort where the true rate of toxicity 
is too high to warrant increased exposure to the current starting dose of the medication, the sample data 
may pass the safety guidelines; and 2) in a cohort where the true rate of toxicity is low enough that further 


 
 
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exposure to the current starting dose is warranted, the sample data may fail the guidelines. 
 
The extent to which the safety guidelines protect against the errors described above can be assessed by 
examining various hypothetical rates of "true toxicity" which could occur, if the study medication were 
used extensively among the patient population at the dose level under question.  The hypothetical 
situations presented in the immediately succeeding table range from conditions under which a given dose 
level would cause a high incidence of severe and life threatening SADRs to conditions under which severe 
SADRs would be relatively rare and would not be life threatening. For each of these hypothetical 
situations, we assume that a sample of 6 subjects is drawn from the patient population and that the safety 
guidelines, summarized above, are followed. 
 
Table 8 shows that there is a 78% chance of failing the safety guidelines under conditions in which the true 
rate of life-threatening toxicity is 5% and the rate of non-life threatening SADR is 50%.  Assuming that it 
would be undesirable to accrue additional subjects at a dose that had these true rates of adverse events, the 
22% chance of NOT failing the safety guidelines would represent the probability of error. The table also 
shows that there is a 0.2 % chance of failing, when the true rate of non-life threatening SADR is only 5% 
and the true rate of life threatening SADR is zero. Assuming that the potential benefits associated with 
exposing additional subjects to this dose of the drug would outweigh the risks associated with this 
relatively low rate of toxicity, failing the safety guidelines under these conditions would be an error. 
 
 


 
 
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Table 8. Probability of Failing Dose Escalation Guidelines under Potential Rates of True Toxicity 
True Toxicity Rates 
Probability of 
Failing Safety 
Guidelines 
Non-Life Threatening SADR 
that would result in treatment 
discontinuation, excluding Grade 
4 events probably or definitely 
attributable to study medication 
Life Threatening SADR or 
Grade 4 events probably or 
definitely attributable to study 
medication 
0.50 
0.00 
0.67 
0.50 
0.05 
0.78 
0.50 
0.25 
0.98 
0.25 
0.00 
0.17 
0.25 
0.05 
0.41 
0.25 
0.25 
0.88 
0.05 
0.00 
0.002 
0.05 
0.05 
0.27 
0.05 
0.25 
0.82 
0.00 
0.05 
0.26 
0.00 
0.25 
0.82 
 
 
 
8.513   Total Group of Subjects (Minimum of Twelve) Started at a Given Dose Level of Each Cohort 
 
The final safety guidelines applied to a given starting dose of the study medication within a cohort will 
make use of data from all subjects started at that dose. The data will extend to the week 4 visit for subjects 
in the cohort which do not require PK determined dose adjustments or until the visit on which the dose is 
adjusted, as described above. If none of these subjects has experienced a life-threatening SADR or a Grade 
4 event or death that is probably or definitely attributable to the study medication and no more than 25% 
terminated study treatment due to Grade 3+ at least possibly treatment related SADR, then this starting 
dose will pass the safety guidelines for the cohort under investigation. 
 
If any of these subjects has a life threatening SADR or any Grade 4 event or death that is probably or 
definitely attributable to the study medication or more than 25% terminated study treatment due to Grade 
3+ at least possibly treatment related SADR, this starting dose will fail the safety guidelines for the cohort 
under investigation. If this occurs, the core protocol team will review all of the relevant safety and 
pharmacokinetic data in an attempt to determine whether it is safe to continue the attempt to find an 
optimal dose for the said cohort. 
 
If the P1090 study team determines that it is safe to proceed, it will make specific changes in dosing and 
monitoring procedures which may be recommended. If there are any concerns resulting from an 
inconclusive safety/PK study team review, the study’s independent Study Monitoring Committee will then 
review all of the relevant safety and pharmacokinetic data and will determine whether and under what 
conditions further dose finding activities for this cohort may proceed. 
 


 
 
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8.52 
Study Safety Monitoring 
 
Since Phase I and Phase II studies are not routinely reviewed by a Data and Safety Monitoring Board 
(DSMB), it is the responsibility of the Protocol Team to interpret safety data, and make decisions regarding 
SADRs that are needed to protect subjects from undue risk. In addition, the Study Monitoring Committee 
described above is appointed to provide impartial reviews in situations where patient safety is in question. 
 
For safety monitoring, a drug related SAE is an SAE that is judged to be “definitely”, “probably” or 
“possibly related” to study drug (ETR). 
 
The safety and tolerability of the study agent will be monitored by means of adverse events reports and 
toxicity reports presenting laboratory and clinical events. It is required that the data required for the 
toxicity reports be entered into the database within 48 hours of the time at which the results of the 
laboratory tests or clinical examinations become available. 
 
Reports compiled by the Data Management Center (DMC) will be reviewed and discussed by the Protocol 
Team on conference calls held at least twice a month during the dose-finding stage and every month 
thereafter and by the study’s Study Monitoring Committee under conditions specified above. Data on 
accrual, pharmacokinetics and toxicity will be reviewed. 
 
Adverse events will be monitored from screening onwards throughout the follow-up period. If the protocol 
team identifies any potentially treatment-related toxicities, which may compromise subject safety, the study 
will be paused and the Study Monitoring Committee will review all relevant data and will determine 
whether, and under what conditions, the study would be allowed to proceed. 
 
8.521   Rules for Suspending Accrual to Assess Safety Following an Adverse Event 
 
Accrual will be temporarily suspended if any subject has a life threatening Suspected Adverse Drug 
Reaction (SADR), or death, or any Grade 4 event that may not be judged to be life- threatening but is 
judged to be probably or definitely attributable to the study medication. 
 
Following temporary suspension of accrual, the Study Monitoring Committee will be convened and will 
further review the safety data within 48 hours of notification of the event to determine if continuation of 
accrual is appropriate. If the Study Monitoring Committee agrees that the study drug is likely to be safe for 
additional subjects, they may allow accrual to resume. Regulatory agencies will be notified of the event 
and the team’s decision after this review of the safety data has taken place. 
 
8.522   Accrual Rate Evaluation 
 
Accrual to this study will be monitored by the IMPAACT leadership in accordance with standard operating 
procedures. The team will monitor feasibility quarterly, first based on site registration and then on accrual. 
Initially, the team will monitor site registration monthly to ensure that an adequate number of sites have 
registered to complete the protocol. If relatively few of the eligible sites have registered after the protocol 
has been approved for 6 months, the team will re- assess the feasibility of the protocol and the reasons why 
sites have not registered, and may amend the protocol accordingly. Once one-third of eligible sites have 
registered, the team will assess accrual on a quarterly basis.  If any cohort during the dose-finding stage has 


 
 
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not accrued half its subjects within 6 months of opening, the team will identify the reasons for lack of 
accrual and possibly amend the protocol accordingly.  
 
A trial go/no-go decision point will be set approximately 2 years after opening of Cohort 2. At that time, 
an analysis across all age cohorts (irrespective of the number of enrolled subjects or length of follow-up 
within each age group and across the age groups) will be performed, for the purpose of complying with 
regulatory requirements for Janssen R&D. In addition, accrual rate and all of the relevant safety and 
pharmacokinetic data will be examined to determine whether it is safe and worth to continue the trial in an 
attempt to find an optimal dose for Cohorts II and III. 
 
8.523   Long Term Follow-Up for Safety 
 
Subjects who successfully complete 48 weeks of ETR treatment will be followed for clinical long term 
safety follow up every 12 weeks.  Sites should refer to Section 5.5 and Appendix IE.  
 
8.6 
Analyses 
 
8.61  Summary of Dose Finding Data 
 
The analysis of dose finding data will consist of descriptive statistics summarizing the safety and PK data 
from the dose finding phase of the study. (See Section 9.0 for PK analysis). The safety data will be 
analyzed by cohort and will present the results of the safety evaluations applied to each starting dose 
regimen tested within each cohort, including information indicating which starting doses have passed or 
failed the safety guidelines. For each starting dose within each cohort, every adverse event of Grade 3 or 
higher will be listed, along with subject demographics, the dose prescribed to the patient at the time of the 
event and the protocol team’s assessment of the probability that this event was due to the study treatment 
(not related, probably not related, possibly related, probably related or definitely related). 
 
8.62 Analysis of Data Representing Exposure to the Doses Judged to be Optimal for Each Cohort 
 
These analyses will be stratified by cohort. The findings will be presented in both in aggregate and broken 
down by cohort, with estimates bounded by 95% confidence limits. Given that the small sample sizes 
within cohorts will provide limited power for statistical tests of differences across age cohorts, 
interpretation of the results will depend upon whether differences across cohorts are great enough to be 
considered to be clinically significant. If no such differences are observed, then the clearest interpretation 
of the findings will come from the aggregated data, where analyses will have the greatest statistical 
precision. However, if results vary across cohorts to a clinically important extent, interpretation of results 
should take into account the issues represented by the stratification factor. 
 
8.63 
Primary Analyses - performed on data through the Week 24 and Week 48 visit 
 
8.631   Safety 
 
The primary safety analysis will include only subjects whose total exposure to ETR has been at the dose 
judged to be optimal for their cohorts. Subjects whose doses have been adjusted for inadequate PK will be 
excluded. Subjects who have been removed from treatment or have had their doses reduced due to 
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analysis. Additional analyses will look at the combined data from subjects whose doses failed and those 
who have been treated solely at the optimal doses determined for their cohorts and without individual PK 
determined dose adjustments. Sensitivity analyses will be performed to determine whether the exclusion of 
subjects whose doses have been adjusted creates a selection bias which impacts upon any results. 
 
Each subject’s safety data will be summarized as: the worst grade of adverse event experienced during the 
first 24 weeks (and 48 weeks) of exposure to the optimal dose of the study treatment and the worst grade 
of adverse event judged to be at least possibly related to study treatment during this time period. Frequency 
distributions of these safety outcomes will be presented in the aggregate and broken down by age. Listings 
of all Grade 3+ events will be provided, broken down by type of toxicity (hepatic, hematologic etc.). 
 
The proportions of subjects experiencing Grade 3+ adverse events will be presented in aggregate and 
broken down by age cohort, with these proportions bounded by exact 95% confidence intervals. Similar 
analyses will present the proportions of subjects exhibiting Grade 3+ events which have been judged to be 
at least possibly related to study medication, again bounded by exact 95% confidence intervals. 
 
8.632  Key Secondary Analyses 
 
8.6321 Viral Load 
Virologic outcomes, based on HIV-1 RNA (copies/ml), will be assessed at weeks 8, 12, 24 and 48.  The 
criteria for success are: at least a 0.5 log10reduction in HIV-1 RNA (copies/ml) at week 8, at least a 1 log10 
reduction in HIV-1 RNA (copies/ml) at week 12 and either HIV-1RNA ≤400 copies/ml or at least a 2 log 
reduction in HIV-1 RNA at weeks 24 and 48. 
 
For regulatory submissions, at each of these time points the primary definition of virologic outcome will be 
calculated according to a Missing, Switch or Discontinuation = Failure (MSDF) algorithm – as codified by 
the FDA’s snapshot algorithm. Subjects may be classified as virologic failures if they have missing HIV-1 
RNA data throughout the window surrounding the time point of interest. (This window and related details 
will be defined in the analysis plan.) In addition subjects will be classified as virologic failures at any of 
these time points if they meet any of the following conditions prior to that time point: 
 
a) Discontinuation of study treatment due to reasons other than AE or death and viral load was > 400 
copies/mL at last available visit. 
b) Change in background therapy not allowed in the protocol. 
c) Change in background ART substitutions permitted per protocol unless the decision to switch is 
documented as being before or at the first on-treatment visit where HIV-1 RNA is assessed (Week 
4). 
 
Subjects who only discontinued a background ARV or who had formula substitutions (substituting single 
agents for fixed dose combinations and vice versa of the same ARV) in their OBT are not considered as 
having OBT changes and will not be analyzed as virologic failures. Otherwise, virologic success will be 
defined as having HIV-1 RNA ≤400 copies/mL by the last available HIV-1 RNA assessment while the 
subject is on-treatment within the visit of interest window. The proportions of subjects meeting the criteria 
for virologic success at each of these time points will be bounded by exact 95%  confidence intervals, and 
will be presented both in the aggregate and broken down by age cohort. 
 


 
 
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Table 9 presents exact 95% confidence intervals around various potential rates of virologic success which 
might be observed in a total sample of 36 subjects or in subsamples of various sizes (N = 12, 24). 
 
Table 9. Percent of Subjects Meeting Criterion for Virologic Success with Exact 95% 
Confidence Intervals 
N 
No. of Subjects (%) with Undetectable RNA 
95% C.I. 
12 
1 (8%) 
0.2% -- 38% 
24 
2 (8%) 
1% -- 27% 
36 
4 (11%) 
3% -- 26% 
12 
3 (25%) 
5% -- 57% 
24 
6 (25%) 
10% -- 47% 
36 
9 (25%) 
12% -- 42% 
12 
6 (50%) 
21% -- 79% 
24 
12 (50%) 
29% -- 71% 
36 
18 (50%) 
33% -- 67% 
12 
9 (75%) 
43% -- 95% 
24 
18 (75%) 
53% -- 90% 
36 
27 (75%) 
58% -- 88% 
12 
11 (92%) 
62% -- 99.8% 
24 
22 (92%) 
73% -- 99% 
36 
33 (92%) 
78% -- 98% 
 
8.6322 CD4 Response 
Change from baseline to weeks 24 and 48 in CD4 count, CD4 percent and CD4/CD8 ratio and percent will 
be bounded by 95% confidence intervals and presented both in the aggregate and by age cohort. In 
addition, the proportions of subjects exhibiting an absolute drop of > 5% in CD4 percent from baseline to 
weeks 12, 24 and 48 will be presented, bounded by 95% confidence intervals. Subjects who meet any of 
the conditions (a) to (c) of Section 8.6321 or who have absolute drop of > 5% in their CD4% will be 
considered as treatment failures in these analyses. 
 
8.6323 HIV Drug Resistance 
Correlations between baseline HIV genotypic and phenotypic drug resistance and any subsequent virologic 
failure will be evaluated. Subjects will be assessed for HIV genotypic and phenotypic drug resistance to the 
OBT and ETR at screening, at the time of virologic failure (if this occurs) and at early discontinuation. 
 
8.6324 Additional Interim Analyses for Regulatory Purposes 
To comply with regulatory requirements, additional interim analyses of data from Cohort 1 will be 
performed when at least 12 evaluable subjects have reached Week 24 and Week 48.  Also to address 
regulatory expectations, an additional analysis across all age cohorts will be performed through Week 48 
on at least 18 subjects. These analyses will be performed by Janssen R&D and will focus primarily on 
safety data, presented as described in Section 8.631 and pharmacokinetic data, presented as described in 
Section 9.0. A secondary analysis of virologic success, as described in Section 8.6321 will also be 
presented.  These analyses will be shared with the P1090 Team.  
 


 
 
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8.633   Exploratory Analyses 
 
8.6331 CYP Gene Profiles 
Descriptive analyses will examine the association between pharmacokinetic parameters of ETR and 
subject-specific CYP gene profiles. 
 
9.0 
CLINICAL PHARMACOLOGY PLAN 
 
9.1 
Pharmacology Objectives 
 
The clinical pharmacology studies are designed to determine the steady-state pharmacokinetic (PK) profile 
and dosing schedule of orally administered etravirine (ETR) in HIV-1-infected children ≥ 2 months to < 6 
years of age. ETR PK and dose requirements will be determined when given with other ARV agents. All 
subjects (in the mini cohort and then the full cohort for that age) will need to undergo an initial 12 hour 
intensive PK study on day 14 (± 4 days) of study drug administration. 
 
 
9.2 
Primary and Secondary Data 
 
Primary: 
AUC12h 
Secondary: 
Cmax, C12hr, Tmax, CL/F,T1/2,Vd and PK parameters (Cmax and C12hr) by CYP2C9 and 
CYP2C19 genotype 
 
9.3 
Study Design, Modeling and Data Analysis 
 
 
9.31 
PK Criteria 
 
For this study, the area under the plasma concentration-time curve over 12 hours (AUC12h) of ETR, as 
determined following an observed dose under fed, steady-state conditions will be the PK parameter for 
determination of the acceptability of the ETR dose, and any individual subject dose adjustments. The 
target geometric mean ETR AUC12h for this study is between 60% and 150% of the geometric mean 
AUC12h observed in HIV-1-infected treatment-experienced adults from the DUET studies (i.e. between 
2713 and 6783 ng•h/mL). For the individual subject management in this study, subjects with an individual 
AUC12h below the 10th percentile of adult exposure (i.e. <2350 ng•h/mL) will be dose-adjusted in order to 
meet an AUC12h ≥  2350 ng•h/mL. 
 
No apparent pharmacodynamic relationship for ETR has been identified in adults, implying that the plasma 
concentrations achieved (in the DUET studies) were, largely, on the flat portion of the expected sigmoid 
exposure-response relationship. The threshold AUC12h value of < 2350 ng•h/mL representing the 10th 
percentile of AUC in adults was selected, with the objective of achieving a distribution for ETR AUC12h 
values in children that approximates that in HIV- infected adults who received ETR 200 mg twice daily (in 
combination with darunavir/ritonavir). While the ETR AUC12h will be the primary PK parameter for 
acceptability of dose determination, the P1090 core protocol team will also consider the C12h of ETR in 
their evaluation. 
 


 
 
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9.32 
Starting Dose 
 
The starting dose for ETR in cohort I (≥ 2 years to < 6 years of age) was 5.2 mg/kg twice daily. This dose 
was based on the results of the analysis of trial TMC125-C213 (see Section 1.32). Based on the safety 
profile of ETR, the concern for under-dosing in children (25) (26) (27) (28) and the usual need for slightly 
higher Cmax in children to achieve comparable trough concentrations (due to a faster apparent oral 
clearance) the initial starting dose of 5.2 mg/kg twice daily reflected an appropriate balance of these 
considerations based on available data at that time. 
 
An evaluation of the PK data from the first 6 children enrolled in Cohort I of P1090 indicated that the 
geometric mean etravirine exposure (at the 5.2mg/kg BID dose for the whole cohort) was lower than 
expected, and the chance of meeting the required geometric mean etravirine AUC12h (comparable to adults) 
for the full cohort was very low (see also section 1.32). 
 
All available etravirine PK data in pediatric subjects, including the P1090 subjects, were used in a 
modeling and simulation approach to better inform the choice of a revised starting dose for ETR for 
Cohort I and the starting dose for other cohorts in this study. It was also decided that, instead of a mg/kg 
dose across all ages, it would be more appropriate to develop dosing based on weight bands. The starting 
doses for Cohorts II and III are also informed and chosen by the results of Cohort I, as detailed in Section 
8.1. For example, after evaluation of the first 6 subjects of Cohort I and criteria were met, Cohort I re-
opened to accrual of additional subjects to complete the full cohort. Opening of Cohort II to accrue the 
first mini-cohorts of 6 subjects was done based on the assessment by the protocol team that sufficient data 
(PK and safety) were available to appropriately inform the choice of starting dose regimen for this cohort. 
The same applies for opening of Cohort III. Within Cohort III, subjects below 6 months of age will only 
be enrolled upon availability of initial safety and PK data from subjects between 6 months and 1 year of 
age. Appendix III gives the tables for the revised starting dose for Cohort I, starting doses for Cohort II 
and III and guidelines about re-evaluating the dose regimen if warranted based on the PK data. 
 
9.33 
Intensive PK Evaluations 
 
All subjects will undergo an intensive PK study. This PK evaluation will be conducted on day 
14 (± 4 days).  Subjects should have taken their ETR doses as directed by the study physician, for 7 days 
prior to the intensive PK visit, without any missed doses.  Sites are encouraged to call the subjects family, 
the day before the intensive PK visit, so that the site staff can confirm that the subject has not missed any 
doses in the previous 7 days. 
 
If the subject has missed a dose, the intensive PK visit should be rescheduled to occur 7- 14 days after the 
last missed dose. The site is again encouraged to call the subjects family the day before the rescheduled 
intensive PK Visit so the staff can confirm the subject has not missed any doses in the previous 7 days.  If 
the subject has missed a dose, the PK visit will be cancelled, and the subject will be withdrawn from the 
study. 
 
The intensive PK visit should be scheduled so that a witnessed dose of ETR is taken within a range of 11 to 
13 hours after their previous dose. Once the subject has arrived at the clinic, he/she should be offered a 
meal appropriate for age. The team suggests that a heparin lock be used for the intensive PK visit if at all 
possible. The PK dose of medication should be administered within 30 minutes following the start of the 
meal. If the subject vomits within 15 minutes of taking their medication, the dose should be re-


 
 
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administered. Re-dosing is not allowed if the subject vomits more than 15 minutes after study medication 
intake. In the event that the subject vomits more than 15 minutes after study medication intake on the day 
of pharmacokinetic evaluation, that assessment must be rescheduled. Subjects may resume food intake 2 
hours after their dose of ETR at the intensive PK visit. 
 
The intensive PK evaluation will consist of obtaining a pre-dose plasma concentration, and following an 
observed dose, post dose plasma concentrations at 1, 2, 4, 6, 9 and 12 hours.  To allow for some flexibility, 
the 9-hour sample can be collected within a window of 8 to 10 hours post-dose and the 12-hour sample 
within a window of 11 to 13 hours post-dose. If necessary, the sample 1 hour post-dose and/or 9 hours 
post-dose can be deleted to reduce the amount of total blood drawn from 7 samples over 12 hours to 5 or 6 
samples, over 12 hours.  ETR plasma concentrations will be determined in “real time” in a CLIA-certified 
IMPAACT pharmacology laboratory. The goal is for ETR plasma concentration information to be 
available for individual and cohort dose evaluation within 2 weeks, or at study week 4. 
 
If the protocol team believes the intensive PK was conducted incorrectly or the results inaccurate, subjects 
may be asked to repeat an intensive PK visit on the same dose. 
 
For the intensive PK evaluations of ETR, the primary PK parameter will be AUC12h. Other secondary 
parameters that will be calculated include CL/F, Vd,T1/2, Cmax, C12h and Tmax. Plasma concentration-time 
data will be graphically inspected, and standard non-compartmental techniques will be used to assess PK 
parameters. Cmax and C12h will be taken as the maximum and 12 hour observed concentration, respectively, 
and Tmax is the time at which Cmax occurs. The AUC12h will be determined using the linear-linear 
trapezoidal rule. CL/F will be calculated as dose/AUC12h.  The terminal elimination half-life is also a 
secondary parameter and will be determined using regression analysis on a minimum of 3 points (not 
including Cmax) in the terminal elimination phase when possible. 
 
9.34 
Individual Subject Dose Evaluation and Adjustments 
 
Doses of ETR will be adjusted in an individual subject to attain an AUC12h of < 2350 ng•h/mL. 
 
 If the subject's current dose is well tolerated (no toxicity ≥ Grade 3) but AUC12h is 
< 2350 ng•h/mL, then a new dose will be determined by prorating the current dose to attain an 
AUC12h of approximately 2864 ng•h/mL (the 20th percentile of exposure in adults). The maximum 
dose increase for the initial PK-guided dose adjustment would be capped at the adult dose of 200 
mg twice daily. If a second PK evaluation again reveals an AUC12h< 2350ng•.h/mL, then the dose 
may be increased above the 200 mg twice daily initial BID cap, again, targeting an AUC12h of 
approximately 2864 ng•h/mL. 
 If the subject's AUC12h is >4380 ng•h/mL(the median AUC12h value in adults receiving ETR 200 
mg twice daily) but current dose is not well tolerated (no toxicity ≥ Grade 3) then the dose will be 
prorated, if possible given available dosage forms to achieve an AUC12h of 4380 ng•h/mL. If no 
dose reduction is possible, then the subject will be discontinued from study treatment. 
 If a subject has not achieved an AUC12h of < 2350 ng•h/mL, but is experiencing a Grade 3 or 
greater toxicity that is deemed probably or definitely related to study drug, that subject will be 
discontinued from study treatment. 
 
Although ETR displays non-proportional PK, dose adjustments will be prorated on a linear scale using 
multiples of 12.5 mg (the smallest incremental dose change possible given the available formulations). 


 
 
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Initial PK-guided dose increases will be capped at the adult dose of 200 mg twice daily. However, if after a 
second PK evaluation the subject’s AUC12h has not achieved the minimum target (2350 ng•h/mL), doses 
may exceed 200 mg twice daily. The core protocol team will communicate all individual dose adjustments 
to the participating site. 
 
All subjects with an individual dose adjustment (not related to weight gain) will have repeat intensive 12 
hour PK evaluations performed between Day 7 to 14 after initiation of the new dose. 
 
Subjects who require a dose adjustment but refuse to undergo repeat intensive PK (see Section 
9.34 for management of individual dose adjustments) will have ETR therapy discontinued and will be 
replaced. 
 
9.35 
Cohort Dose Evaluation and Adjustment 
 
Enrollment will be temporarily halted after PK data are obtained for 6 subjects within a given mini cohort. 
PK parameters and 28-day safety data will be reviewed for these subjects. If safety data are acceptable, 
and the geometric mean AUC12h of the first six is judged acceptable, then an additional 6 subjects will be 
enrolled to equal N = 12 in each full cohort. Failure with respect to the safety and/or PK guidelines will 
result in a dose adjustment within this cohort, with the starting dose adjusted in the appropriate direction. 
 
NOTE: Please refer to Sections 6.6 and 6.8 if non-adherence is suspected. 
 
Subjects who require a dose adjustment but refuse to undergo repeat intensive PK (see Section 9.34 for 
management of individual dose adjustments) will have ETR therapy discontinued and will be replaced 
(will remain on study but off study drug). 
 
PK parameters for ETR will be summarized and descriptive statistics calculated. As stated, the 
AUC12h for ETR is the primary PK parameter. 
 
9.351   The dose of ETR will be judged acceptable if: 
 The ETR dose is tolerated 
AND 
 The geometric mean ETR AUC12h is between 60% and 150% of the geometric mean AUC12h in HIV-
1-infected treatment-experienced adults from the DUET studies (i.e. between 2713 and 6783 
ng•h/mL) 
 
If a revised starting dose of ETR is needed, modeling and simulation will be used (incorporating all 
available PK data at that time) to propose a revised weight-based dosing table for ETR for which the 
calculated chance of success for a given age cohort (i.e., geometric mean AUC12h between 60 and 150% of 
adults) will be at least 80% (see also Appendix III). 
 
In making any revision to the starting dose, the team will estimate the C12h expected with the revised dose.  
The goal of dose finding is to identify a dose that approximates ETR exposure in adults who receive an 
ETR dose of 200 mg twice daily (when given with darunavir/ritonavir). The median AUC12h in adults is 
4380 ng•h/mL and 75th percentile is 6339 ng•h/mL. The median C12h in adults is 298 ng/ml and the 75% 
percentile is 467 ng/ml. The team will compare the expected C12h with that achieved in adults, and may 
use this comparison to refine the revised starting dose to approximate both the AUC12h and C12h exposure. 


 
 
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Any change in the starting dose will be communicated by the protocol team to all participating sites via 
written notification. 
 
As detailed in Section 3.0 of the protocol, subjects may be dose-adjusted to the new dose and additional 
new subjects will be treated at the new dose, and safety and PK will be evaluated as described. 
 
If more than 2 of the 6 children in a cohort has an AUC12h greater than the 75th percentile of adult values 
(6339 ng•h/mL) and the cohort has passed the safety criteria, the team will review the starting dose and the 
expected distribution of ETR C12h and AUC12h. This review is to assess the goal of objective of achieving a 
distribution for ETR C12h and AUC12h values in children that approximates that in HIV-1-infected treatment 
experienced adults. The team may decide to revise the starting dose; however, there is no requirement for 
the team to adjust the starting ETR dose. 
 
If the starting dose for a cohort of older subjects is revised, the protocol team may preemptively change the 
starting dose for subsequent younger cohort that has not yet opened to enrollment. Any change in the 
starting dose will be communicated by the protocol team to all participating sites, with instructions to use 
the appropriate table of starting doses.  It is not unreasonable to suspect that the three cohorts planned for 
enrollment may each have different dosage requirements. This protocol will determine appropriate doses 
for each of these strata. 
 
 
 
9.36 
Population PK Evaluations 
 
Blood samples for estimation of population PK characteristics of ETR will be collected at study weeks 4, 
8, 12, 24 and 48, and at the determination of virologic failure, as outlined in the schedule of evaluations 
(Appendix I).  At Weeks 4 and 24, one sample should be timed to fall within a window of 1 to 4 hours 
following a dose of ETR; at week 8, one sample should be timed to fall within a window of 4 to 8 hours 
following a dose of ETR; and at weeks 12 and 48, one sample should be timed to fall within a window of 8 
to 12 hours following a dose of ETR. ETR plasma concentrations will be determined in a CLIA-certified 
IMPAACT Pharmacology Laboratory (refer to LPC). 
 
 
9.4 
Population Pharmacokinetic Study Design, Modeling and Data Analysis 
 
For this analysis, the primary interest will be the PK characteristics of ETR and these will be evaluated 
using NONMEM version VII (GloboMax, Hanover, MD). NONMEM uses mixed effects (random and 
fixed) regression to estimate population means and variances of PK parameters and to identify intrinsic and 
extrinsic factors, such as body weight, sex or concomitant drug that may influence these parameters. Base 
models will be developed using first-order conditional estimation with or without interaction. A stepwise 
procedure will be used to determine whether a one- or two-compartment model best fits the plasma data 
under the principle of parsimony. A log-normal error distribution will be assumed for the description of 
both interpatient and intrapatient (residual) PK parameter variability. If necessary, poorly identified 
structural parameters, such as the absorption rate constant, may be fixed. The following covariates will be 
collected at baseline or during follow-up visits: sex, age, weight, race, HIV regimen (e.g., boosted PI) and 
HIV response markers. The influence of each covariate on the PK characteristics of ETR will be tested 
sequentially. At each step, the goodness of fit plots will also be evaluated. At the end of the analysis, all 


 
 
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covariates that show an influence on the parameters will be evaluated again by comparison of the full 
model (with all factors included) with a model from which each of the factors is deleted sequentially. For 
forward addition and backward elimination a decrease in objective function value by 3.84 (p ≤ 0.05) and 
6.64 (p ≤ 0.01), respectively, would advocate sufficiently influential covariates. P1090 data may be 
supplemented with other pediatric PK data from previous etravirine studies (TMC125-C213, TMC125-
C126) to support structural model and/or parameter precision if needed. 
 
NONMEM uses extended least squares to calculate the objective function and the difference in the value of 
the objective function between models is approximately chi squared distributed. A difference in objective 
function of greater than 6.6 is considered significant (6.6 corresponds to a chi square for p = 0.01 with 1 
degree of freedom) when one parameter is added or the covariate (e.g., body weight) is replaced. This is 
analogous to the commonly used F test to select among regression models. The primary outcome of this 
analysis is to identify the model that best describes the plasma PK of ETR and to investigate whether any 
of the covariates influences the PK of ETR. The final model will include all significant covariates (if any) 
and the parameter estimates for all parameters together with the estimates of residual and inter-individual 
variability. A secondary objective of this combined analysis will be to develop a linked population PKPD 
model in NONMEM to evaluate potential relationships between these plasma concentrations/PK 
characteristics and therapeutic outcomes (i.e. response to HIV therapy after 
48 weeks of ETR and adverse events). 
 
 
 
9.5 
Anticipated Outcomes 
 
The anticipated outcomes of the pharmacology evaluations are: 
 
(1)   
A description of the pharmacokinetics of ETR, when given in combination with other antiretroviral 
agents including a ritonavir-boosted HIV PI, in children ≥ 2 months to < 6 years of age and; 
 
(2) 
 Identification of a dose of ETR, when given in combination with other antiretroviral agents 
including a ritonavir-boosted PI, which achieves etravirine exposures in a distribution comparable 
to a 200 mg twice daily dose in adults (when given with darunavir/ritonavir) and with a comparable 
geometric mean AUC12h. 
 
(3)  
An investigation of the pharmacodynamics of ETR, given in combination with an OBR, after 48 
weeks of therapy. 
 
10.0 
HUMAN SUBJECTS 
 
 
10.1 
Institutional Review Board and Informed Consent 
 
This protocol, the informed consent document (Appendix VIII), and any subsequent modifications must be 
reviewed and approved by the IRB or EC responsible for oversight of the study. Written informed consent 
must be obtained from the subject (or parents or legal guardians of subjects who cannot consent for 
themselves, such as those below the legal age). The subject's assent must also be obtained if he or she is 
able to understand the nature, significance, and risks of the study. The informed consent will describe the 


 
 
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purpose of the study, the procedures to be followed, and the risks and benefits of participation. A copy of 
the consent form will be given to the subject (or parent or legal guardian). 
 
Each site which receives US DHHS funding and follows the United States Code of Federal Regulations 
Title 45-Public Welfare, Part 46-Protection of Human Subjects (also known as the Common Rule) should 
have on record at the site a plan that detects and addresses any change in guardianship occurring in 
pediatric subjects and determines when a study subject must have a consent process which involves a 
legally authorized representative (LAR) other than a family member with guardianship. The plan will 
include how the site determines when a LAR is initially or no longer needed and how frequently the LAR 
re-signs the consent. The plan should follow all IRB/EC, local, state, national and/or host country 
guidelines. Confirmation of such a plan at a site should be submitted with protocol registration materials.  
 
The team has made a risk/benefit analysis for the P1090 protocol of “greater than minimal risk with 
prospect of direct benefit.” The team anticipates that the study will lead to confirmation that this drug is 
safe for use in infants and young children and to determination of the appropriate dose in infants and young 
children. The approach of sequential cohorts and mini-cohorts serves to reduce the risk to participants. 
 
10.2 
Subject Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records will be identified only by a coded 
number to maintain subject confidentiality. All records will be kept in a secured area. All computer entry 
and networking programs will be done with coded numbers only. Clinical information will not be released 
without written permission of the subject, except as necessary for monitoring by the FDA, the Office for 
Human Research Protections (OHRP), the NIH, the local IRB or Ethics Committee, Janssen R&D, host 
country regulatory agencies and by the study staff, and study monitors. 
 
10.3 
Study Discontinuation 
 
The study may be discontinued at any time by the NIH, the FDA, the IRB or EC, Janssen R&D, OHRP or 
other governmental agencies as part of their duties to ensure that research subjects are protected. 
 
11.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by IMPAACT policies. Any presentation, abstract, 
or manuscript will be made available for review by the pharmaceutical sponsors prior to submission. 
 
12.0 
BIOHAZARD CONTAINMENT 
 
Transmission of HIV and other blood borne pathogens can occur through contact with contaminated 
needles, blood, and blood products. Respiratory viruses are transmitted by droplet aerosolization and 
fomites. Appropriate blood and secretion precautions will be employed by all personnel in the collection of 
samples and the shipping and handling of all specimens for this study, as currently recommended by the 
CDC. 
 


 
 
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All infectious specimens will be transported in compliance with Federal Regulations and the International 
Air Transport Association Dangerous Goods Regulations-Packing Instruction 602. Refer to individual 
carrier guidelines (e.g., Federal Express or Airborne) for specific instructions and to the ACTN Guidelines 
for Shipment and Receipt of Category B Biological Substance Shipment and ACTN Instruction for 
Overnight Shipments documents at 
http://www.hanc.info/labs/labresources/procedures/Pages/actnShippingDemo.aspx 
 
 


 
 
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13.0 
REFERENCES 
 
1. 
Jittamala P, Puthanakit T, Chaiinseeard S, Sirisanthana V. Predictors of virologic failure and 
genotypic resistance mutation patterns in thai children receiving non-nucleoside reverse 
transcriptase inhibitor-based antiretroviral therapy. Pediatr Infect Dis J. 2009;28(9):826-30. 
2. 
Arrive E, Newell ML, Ekouevi DK, Chaix ML, Thiebaut R, Masquelier B, et al. Prevalence of 
resistance to nevirapine in mothers and children after single-dose exposure to prevent vertical 
transmission of HIV-1: a meta-analysis. Int J Epidemiol. 2007;36(5):1009-21. 
3. 
Eshleman SH, Becker-Pergola G, Deseyve M, Guay LA, Mracna M, Fleming T, et al. Impact of 
human immunodeficiency virus type 1 (hiv-1) subtype on women receiving single-dose nevirapine 
prophylaxis to prevent hiv-1 vertical transmission (hiv network for prevention trials 012 study). J 
Infect Dis. 2001;184(7):914-7. 
4. 
Eshleman SH, Hoover DR, Chen S, Hudelson SE, Guay LA, Mwatha A, et al. Resistance after 
single-dose nevirapine prophylaxis emerges in a high proportion of Malawian newborns. AIDS. 
2005;19(18):2167-9. 
5. 
Martinson NA, Morris L, Gray G, Moodley D, Pillay V, Cohen S, et al. Selection and persistence 
of viral resistance in HIV-infected children after exposure to single-dose nevirapine. J Acquir 
Immune Defic Syndr. 2007;44(2):148-53. 
6. 
Kurle SN, Gangakhedkar RR, Sen S, Hayatnagarkar SS, Tripathy SP, Paranjape RS. Emergence of 
NNRTI drug resistance mutations after single-dose nevirapine exposure in HIV type 1 subtype C-
infected infants in India. AIDS Res Hum Retroviruses. 2007;23(5):682-5. 
7. 
Palumbo P, Lindsey JC, Hughes MD, Cotton MF, Bobat R, Meyers T, et al. Antiretroviral 
treatment for children with peripartum nevirapine exposure. The New England journal of 
medicine. 2010;363(16):1510-20. 
8. 
World Health Orginization. Antiretroviral drugs for treating pregnant women and preventing HIV 
infection in infants. Switzerland: WHO Press; 2006. 88 p. 
9. 
Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M, Heeres J, et al. TMC125, a novel next-
generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse 
transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents 
Chemother. 2004;48(12):4680-6. 
10. 
De Corte BL. From 4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one 
(TIBO) to Etravirine (TMC125):  Fifteen Years of Research on Non-Nucleoside Inhibitors of HIV-
1 Reverse Transcriptase. Journal of Medicinal Chemistry. 2005;48(6):1689-96. 
11. 
Scholler-Gyure M, Boffito M, Pozniak AL, Leemans R, Kakuda TN, Woodfall B, et al. Effects of 
different meal compositions and fasted state on the oral bioavailability of etravirine. 
Pharmacotherapy. 2008;28(10):1215-22. 
12. 
Scholler-Gyure M, Kakuda TN, De Smedt G, Vanaken H, Bouche MP, Peeters M, et al. A 
pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in 
HIV-negative volunteers. Br J Clin Pharmacol. 2008;66(4):508-16. 
13. 
I TT. Intelence (etravirine) Package Insert. 2008. 
14. 
Scholler-Gyure M, Kakuda TN, Raoof A, De Smedt G, Hoetelmans RM. Clinical 
pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet. 2009;48(9):561-74. 
15. 
Kakuda TN, Scholler-Gyure M, Hoetelmans RM. Clinical perspective on antiretroviral drug-drug 
interactions with the non-nucleoside reverse transcriptase inhibitor etravirine. Antivir Ther. 
2010;15(6):817-29. 
16. 
Kakuda TN, Scholler-Gyure M, Hoetelmans RM. Pharmacokinetic interactions between etravirine 
and non-antiretroviral drugs. Clin Pharmacokinet. 2011;50(1):25-39. 


 
 
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17. 
Kakuda TN, Scholler-Gyure M, Workman C, Arasteh K, Pozniak AL, De Smedt G, et al. Single- 
and multiple-dose pharmacokinetics of etravirine administered as two different formulations in 
HIV-1-infected patients. Antivir Ther. 2008;13(5):655-61. 
18. 
Katlama C, Haubrich R, Lalezari J, Lazzarin A, Madruga JV, Molina JM, et al. Efficacy and safety 
of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two 
randomized, controlled trials. AIDS. 2009;23(17):2289-300. 
19. 
Katlama C, Clotet B, Mills A, Trottier B, Molina JM, Grinsztejn B, et al. Efficacy and safety of 
etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and 
DUET-2 trials. Antivir Ther. 2010;15(7):1045-52. 
20. 
Vingerhoets J, Tambuyzer L, Azijn H, Hoogstoel A, Nijs S, Peeters M, et al. Resistance profile of 
etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, 
controlled Phase III clinical studies. AIDS. 2010;24(4):503-14. 
21. 
Kakuda TN, Wade J, Snoeck E. Pharmacolinetics and Pharmacodynamics of the NNRTI TMC125 
in treatment experienced HIV-1 infected Patients: Pooled 24-week Results of DUET-1 and DUET-
2 15th Conference on Retroviruses and Opportunistic Infections, ; February 3-6, 2008; Boston, 
MA2008. 
22. 
Kakuda TN, Wade JR, Snoeck E, Vis P, Scholler-Gyure M, Peeters MP, et al. Pharmacokinetics 
and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in 
treatment-experienced HIV-1-infected patients. Clinical pharmacology and therapeutics. 
2010;88(5):695-703. 
23. 
Scholler-Gyure MKT, Van Solingen-Ristea R, Berchmans C, De Smedt G, . Bioavailability of the 
100 mg etravirine tablet dispersed in water and of the 25 mg pediatric tablet formulation.  17th 
International AIDS Conference; August 3-8, 2008. ; Mexico City2008. 
24. 
Konigs C F-SC, Esposito S, et al. Pharmacokinetics and Dose Selection of Etravirine in HIV-
infected Children between 6 and 17 years, inclusive. .  16th Conference on Retroviruses and 
Opportunistic Infections; February 8-11, 2009; Montreal2009. 
25. 
Menson EN, Walker AS, Sharland M, Wells C, Tudor-Williams G, Riordan FA, et al. Underdosing 
of antiretrovirals in UK and Irish children with HIV as an example of problems in prescribing 
medicines to children, 1997-2005: cohort study. BMJ. 2006;332(7551):1183-7. 
26. 
ter Heine R, Scherpbier HJ, Crommentuyn KM, Bekker V, Beijnen JH, Kuijpers TW, et al. A 
pharmacokinetic and pharmacogenetic study of efavirenz in children: dosing guidelines can result 
in subtherapeutic concentrations. Antivir Ther. 2008;13(6):779-87. 
27. 
Verweel G, Burger DM, Sheehan NL, Bergshoeff AS, Warris A, van der Knaap LC, et al. Plasma 
concentrations of the HIV-protease inhibitor lopinavir are suboptimal in children aged 2 years and 
below. Antivir Ther. 2007;12(4):453-8. 
28. 
Hirt D, Urien S, Jullien V, Firtion G, Rey E, Pons G, et al. Age-related effects on nelfinavir and 
M8 pharmacokinetics: a population study with 182 children. Antimicrob Agents Chemother. 
2006;50(3):910-6. 
29. 
Tudor-Williams G, Cahn P, Chokephaibulkit K, Fourie J, Karatzios C, Dincq S, et al. Etravirine in 
treatment-experienced, HIV-1-infected children and adolescents: 48-week safety, efficacy and 
resistance analysis of the phase II PIANO study. HIV Med. 2014;15(9):513-24. 
30. 
Koukouritaki SB, Manro JR, Marsh SA, Stevens JC, Rettie AE, McCarver DG, et al. 
Developmental expression of human hepatic CYP2C9 and CYP2C19. J Pharmacol Exp Ther. 
2004;308(3):965-74. 
31. 
Briz V, Palladino C, Navarro M, Jimenez de Ory S, Gonzalez-Tome M, Leon J, et al. Etravirine-
based highly active antiretroviral therapy in HIV-1-infected paediatric patients. HIV Med. 
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32. 
Nelson M, Stellbrink HJ, Podzamczer D, Banhegyi D, Gazzard B, Hill A, et al. A comparison of 
neuropsychiatric adverse events during 12 weeks of treatment with etravirine and efavirenz in a 
treatment-naive, HIV-1-infected population. AIDS. 2011;25(3):335-40. 
33. 
World Health Orginization. Antiretroviral therapy for HIV infection in infants and children 
Recommendations for a public health approach. Switzerland: WHO Press; 2010. 
 


 
 
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APPENDIX IA: SCHEDULE OF EVALUATIONS - Cohort I 
 
Study Visits 
Screen1 
 
Entry 
(Day 0) 
Day 14 
Intensive PK Visit 
Week 
4 
Week 
8 
Week 
12 
Week 16 
Week 
24 
Week 
32 
Week 
40 
Week 
48 
Early 
Study 
D/C 
Virologic 
failure21 
Visit Windows 
±4 days 
±1wk 
±1wk 
±1wk 
±2wk 
±2wk 
±2wk 
±2wk 
±2wk 
CLINICAL EVALUATIONS 
Informed Consent 
X 
History and Physical2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDC Classification 
X 
X 
X 
X 
X 
X 
X 
Adherence / Pill Count Form 
X15 
X15 
X 
X 
X 
X 
X 
X 
X 
X15 
X 
Adherence phone call 
X16 
Electrocardiogram (ECG)3 
X 
X12, 17 
STUDY DRUG 
Distribution of Study Drug4 
X 
X 
X 
X 
LABORATORY EVALUATIONS 
Hematology5 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
Chemistries6 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
Cholesterol/triglycerides7 
2mL 
2mL 
2mL 
2mL 
Coagulation assays8 
2mL 
2mL 
2mL 
Urinalysis9 
X 
X 
X 
X 
X 
X 
Virology Evaluations 
HIV-1 RNA PCR10 
3mL 
3mL14 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
CYP genotyping 
X14 
HIV genotype & phenotype 
4mL 
4mL 
4mL 
Immunology Evaluations 
Lymphocyte subset11 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
Pellets / plasma for storage 
2mL 
2mL 
Pharmacology Evaluations 
Intensive Pharmacokinetics12 
7mL 
Population PKs13 
1mL18 
1mL19 
1mL20 
1mL18 
1mL20 
1mL22 
TOTAL BLOOD VOLUME 
14mL 
10mL 
13mL 
9mL 
9mL 
13mL 
8mL 
15mL 
8mL 
8mL 
13mL 
12mL 
13mL 
 


 
 
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Footnotes 
 
1. Informed consent must be obtained prior to performing Screening evaluations.  The entry (Day 0) evaluations should be completed within 60 days 
following screening. 
2. A complete history and physical should be done at screening.  At subsequent visits, an interim history and physical should be performed.  This should 
include history (including occurrence of adverse events since last study visit and any HIV-1 associated conditions) and physical exam (including height 
[without shoes], weight [with minimal clothing], vital signs [temperature, pulse, respirations, blood pressure and head circumference for those <3 years 
old]). 
3. The electrocardiogram should be read locally by the investigator and also sent in duplicate to the ECG central reading service. Turnaround time for the 
central reading service is 72 hours. For normal values of PR see Appendix V; any value above the 98th percentile is considered abnormal.  If there is 
evidence of significant abnormality on the ECG (including ≥Grade 3 PR or QTc interval, the site investigator should request a 24 hour turnaround on 
central reading of the ECG. A local cardiologist can also be consulted if the investigator wishes.  For normal and abnormal values of PR and QTc 
intervals for this protocol, see Appendix V. Additional details regarding the ECG can be found in the MOPs. Note that a repeat EKG is required at the 
time of an intensive PK visit, including any PK-directed dose adjustments. 
4. Study drug may be dispensed at other clinic study visits. 
5.  Hematology tests should include complete blood count (CBC), differential and platelets. 
6. Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs.  LFTs should include total bilirubin, indirect bilirubin, 
direct bilirubin, alkaline phosphatase, AST, ALT, and albumin.  If indirect bilirubin is not reported by the site laboratory, it should be calculated at the 
site and documented. 
The following (listed in order of preference) should be used to determine the upper limit of normal (ULN) values for indirect bilirubin. 
a. 
"ULN" values reported by the laboratory report for the test, or 
b. "ULN" values routinely used/established by the site, or 
c. 
"ULN" values as per the Harriet Lane Handbook 
Sites must be consistent with the way toxicities are evaluated for all subjects in the study; sites should use the same source throughout the study. 
Remember to have documentation of calculated indirect bilirubin and source of "ULN", when not reported by your laboratory. 
7. If a subjects laboratory results show elevated cholesterol/triglycerides AND if the subject is ≥1 year old, the subject should be asked to return to clinic 
for fasting cholesterol/triglycerides.  Children ≥1 year to ≤2 years of age, should be fasting for 4 hours. Children >2 years of age, should be fasting 
overnight. 
8. Coagulation assays should include PT, PTT and INR. Required only from study sites with access to laboratories with existing coagulation testing 
capabilities for the tests as determined by IMPAACT. 
9. A urine dipstick should be performed at each of the visits indicated.  A complete microscopic urine assessment is required only if a urine dipstick is 
abnormal. 
10. Virology assays should be performed at an IMPAACT/VQA approved laboratory. The Abbott platform MUST be used for the HIV-1 RNA assay. 
11.  Lymphocyte subsets include CD4 and CD8 assays. 
12.  Subjects should have taken ETR for at least 7 consecutive days prior to the intensive PK, without missing a dose.  Intensive PK should be scheduled so 
that a witnessed dose of ETR is taken approximately 12 hours after the previous dose. PK dosing within a range of 11 to 13 hours after the previous dose 
is acceptable. The team suggests that an indwelling catheter such as a saline or heparin lock be used for the intensive PK. Once the subject has arrived at 
the clinic, he/she should be offered a breakfast appropriate for age. Within 30 minutes following breakfast, the PK medications should be administered 
followed by the PK sampling at the specified time points. If the subject vomits within 15 minutes of taking study drug, the dose should be repeated. 
Subjects may resume food intake 2 hours after their dose of ETR at the intensive PK visit. One (1) mL of blood will be collected at the following time 
points: pre-dose, 1, 2, 4, 6, 9 and 12 hours post dosing. To allow for some flexibility, the 9-hour sample can be collected with a window 


 
 
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of 8 to10 hours post-dose and the 12 hour sample with a window of 11 to 13 hours. If necessary, the 1-hour post-dose sample and/or the 9-hours post- 
dose sample can be deleted to reduce the amount of total blood drawn from 7 samples over 12 hours to 5 or 6 samples, over 12 hours. 
 
If a subject requires individual dose adjustment for low or high AUCs, they will be asked to return to clinic to have an intensive PK evaluation between 
Day 7-14 on the new dose. 
 
If a mini or full cohort fails, the failing subjects may have their ETR dose adjusted.  In those cases, subjects will be asked to return to clinic to have a 
truncated intensive PK between Day 7-14 on the new dose with samples collected at the following time points: pre-dose, 2, and between 3-5 hours post 
dosing. 
 
Note that a repeat EKG is required at the time of a PK visit required for any of the reasons described above. 
 
13.  1.0mL of blood will be collected for each of the population pharmacokinetic samples.  NOTE: An absolute minimum of 0.5 mL is necessary for 
population PK sample. 
14.  Wherever possible, the CYP genotyping and viral load PCR can be run from the same blood sample.  The blood draw should be collected and spun  
down to isolate pellets for PBMCs (for CYP genotyping) and the plasma can be used for the viral load. Otherwise, a separate blood tube should be 
drawn. 
15.  Sites should also perform the palatability assessment at these visits. 
16.  Subjects must have taken their ETR doses as directed by the study physician, for 7 days prior to the intensive PK visit, without any missed doses. Sites 
are strongly encouraged to call the subject, the day before the intensive PK visit, so that the site staff can confirm that the subject has not missed any 
doses in the previous 7 days.  If the subject has missed a dose, the PK visit must be re-scheduled within the Day 14 (± 4 days) window. 
17.  The ECG at the intensive PK visit should be collected following the 4 hour blood draw. This time point is generally when the drug level is at its highest. 
18.  At weeks 4 and 24, one sample should be timed to fall within a window of 1 to 4 hours following a dose of etravirine. 
19.  At week 8, one sample should be timed to fall within a window of 4 to 8 hours following a dose of etravirine. 
20.  At weeks 12 and 48, one sample should be timed to fall within a window of 8 to 12 hours following a dose of etravirine. (See Section 9.36 for 
additional information). 
21.  If a subject is experiencing virologic failure (as defined in section 6.3), a visit to confirm failure must be conducted between 1 to 4 weeks of the initial 
suspected failure or rebound. 
22.  At virologic failure, one sample may be collected at any time following a dose of etravirine. 
 
 
For insufficient blood draws, priorities are as follows: 
Hematology (1mL); Chemistry (2mL);  Pharmacology (intensive [7mL] or population [1mL]);Virology (HIV-1 RNA PCR – 3mL); Resistance testing (HIV 
genotype and phenotype – 4mL); Lymphocyte subsets (2mL); CYP genotyping (2mL); Cholesterol / triglycerides (2mL); Coagulation assays (2mL); Plasma/cell 
pellet for storage (2mL) 
 
 


 
 
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APPENDIX IB: SCHEDULE OF EVALUATIONS – Cohort II 
 
Study Visits 
Screen1 
Entry 
(Day 0) 
Day 14 
Intensive 
PK Visit 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
24 
Week 
32 
Week 
40 
Week 
48 
Early 
Study 
D/C 
Virologic 
failure21 
Visit Windows 
±4 days 
±1wk 
±1wk 
±1wk 
±2wk 
±2wk 
±2wk 
±2wk 
±2wk 
CLINICAL EVALUATIONS 
Informed Consent 
X 
History and Physical2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDC Classification 
X 
X 
X 
X 
X 
X 
X 
Adherence / Pill Count Form 
X15 
X15 
X 
X 
X 
X 
X 
X 
X 
X15 
X 
Adherence Phone Call 
X16 
Electrocardiogram3 
X 
X12, 17 
STUDY DRUG 
Distribution of Study Drug4 
X 
X 
X 
X 
LABORATORY EVALUATIONS 
Hematology5 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
Chemistries6 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
Cholesterol/triglycerides7 
2mL 
2mL 
2mL 
2mL 
Coagulation assays8 
2mL 
2mL 
2mL 
Urinalysis9 
X 
X 
X 
X 
X 
X 
Virology Evaluations 
HIV-1 RNA PCR10 
3mL 
3mL14 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
CYP genotyping 
X14 
HIV genotype & phenotype 
4mL 
4mL 
4mL 
Immunology Evaluations 
Lymphocyte subset11 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
2mL 
Pellets/plasma for storage 
2mL 
2mL 
Pharmacology Evaluations 
Intensive Pharmacokinetics12 
7mL 
Population PKs13 
1mL18 
1mL19 
1mL20 
1mL18 
1mL20 
1mL22 
TOTAL BLOOD VOLUME 
14mL 
10mL 
13mL 
9mL 
9mL 
13mL 
8mL 
15mL 
8mL 
8mL 
13mL 
12mL 
13mL 
 


 
 
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Footnotes 
 
1. Informed consent must be obtained prior to performing Screening evaluations.  The entry (Day 0) evaluations should be completed within 60 days 
following screening. 
2. A complete history and physical should be done at screening.  At subsequent visits, an interim history and physical should be performed.  This should 
include history (including occurrence of adverse events since last study visit and any HIV-1 associated conditions) and physical exam (including height 
[without shoes], weight [with minimal clothing], vital signs [temperature, pulse, respirations, blood pressure and head circumference]). 
3. The electrocardiogram should be read locally by the investigator and also sent in duplicate to the ECG central reading service. Turnaround time for the 
central reading service is 72 hours.  For normal values of PR see Appendix V; any value above the 98th percentile is considered abnormal.  If there is 
evidence of significant abnormality on the ECG (including ≥Grade 3 PR or QTc interval, the site investigator should request a 24 hour turnaround on 
central reading of the ECG. A local cardiologist can also be consulted if the investigator wishes.  For normal and abnormal values of PR and QTc 
intervals for this protocol, see Appendix V. Additional details regarding the ECG can be found in the MOPs. Note that a repeat EKG is required at the 
time of an intensive PK visit, including any PK-directed dose adjustments. 
4. Study drug may be dispensed at other clinic study visits. 
5.     Hematology tests should include complete blood count (CBC), differential and platelets. 
6. Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs.  LFTs should include total bilirubin, indirect bilirubin, 
direct bilirubin, alkaline phosphatase, AST, ALT, and albumin.  If indirect bilirubin is not reported by the site laboratory, it should be calculated at the 
site and documented. 
The following (listed in order of preference) should be used to determine the upper limit of normal (ULN) values for indirect bilirubin. 
a. 
"ULN" values reported by the laboratory report for the test, or 
b. "ULN" values routinely used/established by the site, or 
c. 
"ULN" values as per the Harriet Lane Handbook 
Sites must be consistent with the way toxicities are evaluated for all subjects in the study; sites should use the same source throughout the study. 
Remember to have documentation of calculated indirect bilirubin and source of "ULN", when not reported by your laboratory. 
7. If a subjects laboratory results show elevated cholesterol/triglycerides AND if the subject is ≥1 year old, the subject should be asked to return to clinic 
for fasting cholesterol/triglycerides.  Children ≥1 year to ≤2 years of age, should be fasting for 4 hours. Children >2 years of age, should be fasting 
overnight. 
8. Coagulation assays should include PT, PTT and INR. Required only from study sites with access to laboratories with existing coagulation testing 
capabilities for the tests as determined by IMPAACT. 
9. A urine dipstick should be performed at each of the visits indicated.  A complete microscopic urine assessment is required only if a urine dipstick is 
abnormal. 
10. Virology assays should be performed at an IMPAACT/VQA approved laboratory.  The Abbott platform MUST be used for the HIV-1 RNA. 
11.  Lymphocyte subsets should include CD4 and CD8. 
12.  Subjects should have taken ETR for at least 7 consecutive days prior to the intensive PK, without missing a dose.  Intensive PK should be scheduled so 
that a witnessed dose of ETR is taken approximately 12 hours after the previous dose. PK dosing within a range of 11 to 13 hours after the previous dose 
is acceptable. The team suggests that an indwelling catheter such as a saline or heparin lock be used for the intensive PK. Once the subject has arrived 
at the clinic, he/she should be offered a breakfast appropriate for their age. Within 30 minutes following breakfast, the PK medications should be 
administered followed by the PK sampling at the specified time points. If the subject vomits within 15 minutes of taking study drug, the dose should be 
repeated. Subjects may resume food intake 2 hours after their dose of ETR at the intensive PK visit. One (1) mL of blood will be collected at the 
following time points: pre-dose, 1, 2, 4, 6, 9 and 12 hours post dosing. To allow for some flexibility, the 9-hour sample can be collected with a window 


 
 
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of 8-10 hours post-dose and the 12 hour sample with a window of 11 to 13 hours. If necessary, the 1-hour post-dose sample and/or the 9-hours post- 
dose sample can be deleted to reduce the amount of total blood drawn from 7 samples over 12 hours to 5 or 6 samples, over 12 hours. 
 
If a subject requires individual dose adjustment for low or high AUCs, they will be asked to return to clinic to have an intensive PK evaluation between 
Day 7-14 on the new dose. 
 
If a mini or full cohort fails, the failing subjects may have their ETR dose adjusted.  In those cases, subjects will be asked to return to clinic to have a 
truncated intensive PK between Day 7-14 on the new dose with samples collected at the following time points: pre-dose, 2, and between 3-5 hours post 
dosing. 
 
Note that a repeat EKG is required at the time of a PK visit required for any of the reasons described above. 
 
13.  1.0mL of blood will be collected for each of the population pharmacokinetic samples.  NOTE: An absolute minimum of 0.5 mL is necessary for 
population PK sample. 
14.  Wherever possible, the CYP genotyping and viral load PCR can be run from the same blood sample.  The blood draw should be collected and spun 
down to isolate pellets for PBMCs (for CYP genotyping) and the plasma can be used for the viral load. Otherwise, a separate blood tube should be 
drawn. 
15.  Sites should also perform the palatability assessment at these visits. 
16.  Subjects must have taken their ETR doses as directed by the study physician, for 7 days prior to the intensive PK visit, without any missed doses. Sites 
are strongly encouraged to call the subject, the day before the intensive PK visit, so that the site staff can confirm that the subject has not missed any 
doses in the previous 7 days.  If the subject has missed a dose, the PK visit must be re-scheduled within the Day 14 (± 4 days) window. 
17.  The ECG at the intensive PK visit should be collected following the 4 hour blood draw. This time point is generally when the drug level is at its highest. 
18.  At weeks 4 and 24, one sample should be timed to fall within a window of 1 to 4 hours following a dose of etravirine. 
19.  At week 8, one sample should be timed to fall within a window of 4 to 8 hours following a dose of etravirine. 
20.  At weeks 12 and 48, one sample should be timed to fall within a window of 8 to 12 hours following a dose of etravirine. (See Section 9.36 for 
additional information). 
21.  If a subject is experiencing virologic failure (as defined in section 6.3), a visit to confirm failure must be conducted between 1 to 4 weeks of the initial 
suspected failure or rebound. 
22.  At virologic failure, one sample may be collected at any time following a dose of etravirine. 
 
 
 
For insufficient blood draws, priorities are as follows: 
Hematology (1mL); Chemistry (2mL);  Pharmacology (intensive [7mL] or population [1mL]);Virology (HIV-1 RNA PCR – 3mL); Resistance testing (HIV 
genotype and phenotype – 4mL); Lymphocyte subsets (2mL); CYP genotyping (2mL); Cholesterol / triglycerides (2mL); Coagulation assays (2mL); Plasma/cell 
pellet for storage (2mL) 
 
 


 
 
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APPENDIX IC: SCHEDULE OF EVALUATIONS – Cohort III 
 
Study Visits 
Screen1 
Entry 
(Day 0) 
Day 14 
Intensive 
PK Visit 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
24 
Week 
32 
Week 
40 
Week 
48 
Early 
Study 
D/C 
Virologic 
failure23 
Visit Windows 
±4 days 
±1wk 
±1wk 
±1wk 
±2wk 
±2wk 
±2wk 
±2wk 
±2wk 
CLINICAL EVALUATIONS 
Informed Consent 
X 
History and Physical2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDC Classification 
X 
X 
X 
X 
X 
X 
X 
Adherence / Pill Count Form 
X17 
X17 
X 
X 
X 
X 
X 
X 
X 
X17 
X 
Adherence Phone Call 
X18 
Electrocardiogram3 
X 
X13, 19 
STUDY DRUG 
Distribution of Study Drug4 
X 
X 
X 
X 
LABORATORY EVALUATIONS 
Hematology5 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 0.5mL 0.5mL 
0.5mL 
0.5mL 
Chemistries6 
1mL 
3mL 
1mL 
1mL 
1mL 
3mL 
1mL 
3mL 
1mL 
1mL 
3mL 
1mL 
1mL 
Cholesterol/triglycerides7 
X 
X 
X 
X 
Coagulation assays8 
2mL 
2mL 
2mL 
Urinalysis9 
X 
X 
X 
X 
X 
X 
Virology Evaluations 
HIV-1 RNA PCR10 
3mL 
3mL16 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
CYP genotyping11 
X16 
HIV genotype & phenotype 
4mL15 
4mL 
4mL 
Immunology Evaluations 
Lymphocyte subset12 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
Pellets/plasma for storage 
2mL11 
2mL11 
Pharmacology Evaluations 
Intensive Pharmacokinetics13 
3.5mL 
Population PKs14 
0.5mL20 0.5mL21 0.5mL22 
0.5mL20 
0.5mL22 
0.5mL24 
TOTAL BLOOD VOLUME 
11.5mL 
7.5mL 
8.0mL 
6.0mL 
6.0mL 
10.0mL 
5.5mL 
12.0mL 5.5mL 5.5mL 10.0mL 
9.5mL 
10.0mL 
 


 
 
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Footnotes 
1. Informed consent must be obtained prior to performing Screening evaluations.  The entry (Day 0) evaluations should be completed within 60 days 
following screening.  For children of low weight, the screening laboratory evaluations may be split over 2 visits. Safety labs and lymphocyte 
subsets should be obtained at the first timepoint and HIV RNA and HIV genotyping and phenotyping a week later. 
2. A complete history and physical should be done at screening.  At subsequent visits, an interim history and physical should be performed.  This should 
include history (including occurrence of adverse events since last study visit and any HIV-1 associated conditions) and physical exam (including height 
[without shoes], weight [with minimal clothing], vital signs [temperature, pulse, respirations, blood pressure and head circumference). 
3. The electrocardiogram should be read locally by the investigator and also sent in duplicate to the ECG central reading service. Turnaround time for the 
central reading service is 72 hours.  For normal values of PR see Appendix V; any value above the 98th percentile is considered abnormal.   If there is 
evidence of significant abnormality on the ECG (including ≥Grade 3 PR or QTc interval, the site investigator should request a 24 hour turnaround on 
central reading of the ECG. A local cardiologist can also be consulted if the investigator wishes.  For normal and abnormal values of PR and QTc 
intervals for this protocol, see Appendix V. Additional details regarding the ECG can be found in the MOPs. Note that a repeat EKG is required at the 
time of an intensive PK visit, including any PK-directed dose adjustments. 
4. Study drug may be dispensed at other clinic study visits. 
5. Hematology tests should include complete blood count (CBC), differential and platelets. 
6. Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs.  LFTs should include total bilirubin, indirect bilirubin, 
direct bilirubin, alkaline phosphatase, AST, ALT, and albumin.  If indirect bilirubin is not reported by the site laboratory, it should be calculated at the 
site and documented. 
The following (listed in order of preference) should be used to determine the upper limit of normal (ULN) values for indirect bilirubin. 
a. 
"ULN" values reported by the laboratory report for the test, or 
b. "ULN" values routinely used/established by the site, or 
c. 
"ULN" values as per the Harriet Lane Handbook 
Sites must be consistent with the way toxicities are evaluated for all subjects in the study; sites should use the same source throughout the study. 
Remember to have documentation of calculated indirect bilirubin and source of "ULN", when not reported by your laboratory. 
7. Cholesterol/triglycerides should be tested from the sample drawn for chemistries. If a subjects lab results show elevated cholesterol/triglycerides 
AND if the subject is ≥1 year old, the subject should be asked to return to clinic for fasting cholesterol/triglycerides.  Children ≥1 year to ≤2 years 
of age, should be fasting for 4 hours.  Children >2 years of age, should be fasting overnight. 
8. Coagulation assays should include PT, PTT and INR. Required only from study sites with access to laboratories with existing coagulation testing 
capabilities for the tests as determined by IMPAACT. 
9. A urine dipstick should be performed at each of the visits indicated.  A complete microscopic urine assessment is required only if a urine dipstick is 
abnormal. 
10. Virology assays should be performed at an IMPAACT/VQA approved laboratory. The Abbott platform MUST be used for the HIV-1 RNA. 
11. Collection of blood for genotyping and stored specimens may be omitted for the youngest infants if the necessary volume of blood is difficult to draw. Note 
that CYP genotyping and viral load PCR can be run from the same blood sample; see footnote 16. 
12. Lymphocyte subsets should include CD4 and CD8 assays. 
13. Subjects should have taken ETR for at least 7 consecutive days prior to the intensive PK, without missing a dose.  Intensive PK should be scheduled so 
that a witnessed dose of ETR is taken approximately 12 hours after the previous dose. PK dosing within a range of 11 to 13 hours after the previous dose 
is acceptable. The team suggests that an indwelling catheter such as a saline or heparin lock be used for the intensive PK. Once the subject has arrivedat 
the clinic, he/she should be offered a breakfast appropriate for their age. Within 30 minutes following breakfast, the PK medications should be 
administered followed by the PK sampling at the specified time points. If the subject vomits within 15 minutes of taking study drug, the dose should be 
repeated. Subjects may resume food intake 2 hours after their dose of ETR at the intensive PK visit. One (1) mL of blood will be collected at the 
following time points: pre-dose, 1, 2, 4, 6, 9 and 12 hours post dosing. To allow for some flexibility, the 9-hour sample can be collected with a window 


 
 
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Version 5.0 
of 8 to 10 hours post-dose and the 12 hour sample with a window of 11 to 13 hours. If necessary, the 1-hour post-dose sample and/or the 9-hours post- 
dose sample can be deleted to reduce the amount of total blood drawn from 7 samples over 12 hours to 5 or 6 samples, over 12 hours. 
 
If a subject requires individual dose adjustment for low or high AUCs, they will be asked to return to clinic to have an intensive PK evaluation between 
Day 7-14 on the new dose. 
 
If a mini or full cohort fails, the failing subjects may have their ETR dose adjusted.  In those cases, subjects will be asked to return to clinic to have a 
truncated intensive PK between Day 7-14 on the new dose with samples collected at the following time points: pre-dose, 2, and between 3-5 hours post 
dosing. 
 
Note that a repeat EKG is required at the time of a PK visit required for any of the reasons described above. 
 
14. 0.5mL of blood will be collected for each of the population pharmacokinetic samples.  NOTE: An absolute minimum of 0.5 mL is necessary for 
population PK sample. 
15. Cohort III subjects must wait until HIV-1 genotyping results are available BEFORE they can start ETR and OBR. 
16. Wherever possible, the CYP genotyping and viral load PCR can be run from the same blood sample.  The blood draw should be collected and spun 
down to isolate pellets for PBMCs (for CYP genotyping) and the plasma can be used for the viral load. Otherwise, a separate blood tube should be 
drawn. 
17. Sites should also perform the palatability assessment at these visits. 
18. Subjects must have taken their ETR doses as directed by the study physician, for 7 days prior to the intensive PK visit, without any missed doses. Sites 
are strongly encouraged to call the subject, the day before the intensive PK visit, so that the site staff can confirm that the subject has not missed any 
doses in the previous 7 days.  If the subject has missed a dose, the PK visit must be re-scheduled within the Day 14 (± 4 days) window. 
19. The ECG at the intensive PK visit should be collected following the 4 hour blood draw. This time point is generally when the drug level is at its highest. 
20. At weeks 4 and 24, one sample should be timed to fall within a window of 1 to 4 hours following a dose of etravirine. 
21. At week 8, one sample should be timed to fall within a window of 4 to 8 hours following a dose of etravirine. 
22. At weeks 12 and 48, one sample should be timed to fall within a window of 8 to 12 hours following a dose of etravirine. (See Section 9.36 for 
additional information). 
23. If a subject is experiencing virologic failure (as defined in section 6.3), a visit to confirm failure must be conducted between 1 to 4 weeks of the initial 
suspected failure or rebound. 
24. At virologic failure, one sample may be collected at any time following a dose of etravirine. 
 
 
For insufficient blood draws, priorities are as follows: 
Hematology (0.5mL); Chemistry (1mL);  Pharmacology (intensive [3.5mL] or population [0.5mL]);Virology (HIV-1 RNA PCR – 3mL); Resistance testing (HIV 
genotype and phenotype – 4mL); Lymphocyte subsets (1mL); CYP genotyping (2mL); Cholesterol / triglycerides (2mL); Coagulation assays (2mL); Plasma/cell 
pellet for storage (2mL) 


 
 
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APPENDIX ID: SCHEDULE OF EVALUATIONS FOR FOLLOW UP OF SUBJECTS WHO 
DISCONTINUE ETRAVIRINE (OFF STUDY DRUG – ON STUDY) 
 
Week 4 post ETR discontinuation 
(±2 weeks) 
CLINICAL EVALUATIONS 
History and Physical1 
X 
CDC Classification 
X 
LABORATORY EVALUATIONS 
Hematology2 
1mL 
Chemistries3 
3mL 
Cholesterol / triglycerides4 
1mL 
Virology 
HIV-1 RNA PCR5 
3mL 
Immunology 
Lymphocyte subsets6 
2mL 
TOTAL BLOOD VOLUME (mL) 
10mL 
 
 
NOTE:  Subjects who are withdrawn from study drug within the first 48 weeks of study will not enter long term 
follow-up, but will return to clinic 4 weeks after ETR discontinuation, as per Appendix ID. Subjects with AEs 
will be followed until satisfactory clinical resolution (i.e. value returns back to subjects baseline value) or 
stabilization (to be agreed upon with the sponsor). All grade 3 and grade 4 laboratory abnormalities as well as 
any 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.  If an AE resolves within 4 weeks of discontinuation of ETR, 
the subject should still return for the final 4 week study visit. 
 
Footnotes 
 
1. History (including occurrence of adverse events since last study visit and any HIV-1 associated 
conditions) and physical exam (including height [without shoes], weight [with minimal clothing], vital 
signs [temperature, pulse, respirations and blood pressure]). 
2. Hematology tests should include complete blood count (CBC), differential and platelets. 
3. Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs.  
LFTs should include total bilirubin, indirect bilirubin, direct bilirubin, alkaline phosphatase, AST, 
ALT, and albumin.  If indirect bilirubin is not reported by the site laboratory, it should be calculated 
at the site and documented. 
The following (listed in order of preference) should be used to determine the upper limit of normal (ULN) 
values for indirect bilirubin. 
a. 
"ULN" values reported by the laboratory report for the test, or 
b. "ULN" values routinely used/established by the site, or 
c. 
"ULN" values as per the Harriet Lane Handbook 
Sites must be consistent with the way toxicities are evaluated for all subjects in the study; sites should 
use the same source throughout the study.  Remember to have documentation of calculated indirect 
bilirubin and source of "ULN", when not reported by your laboratory. 
4. If a subjects laboratory results show elevated cholesterol/triglycerides AND if the subject is ≥1 year old, 
the subject should be asked to return to clinic for fasting cholesterol/triglycerides.  Children ≥1 year to ≤2 
years of age, should be fasting for 4 hours.  Children >2 years of age, should be fasting overnight. 
5. Virology assays should be performed at an IMPAACT/VQA approved laboratory. The Abbott platform 
MUST be used for the HIV-1 RNA. 
6. Lymphocyte subsets should include CD4 and CD8. 
 
 


 
 
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For insufficient blood draws, priorities are as follows: 
Hematology (1mL); Chemistry (2mL); Virology (HIV-1 RNA PCR – 3mL); Lymphocyte subsets (2mL); 
Cholesterol / triglycerides (2mL) 


 
 
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APPENDIX IE: SCHEDULE OF EVALUATIONS FOR LONG-TERM 
SAFETY FOLLOW-UP OF SUBJECTS RECEIVING STUDY-PROVIDED 
ETRAVIRINE 
 
Every 12 weeks 
(±2 weeks) 
Every 24 weeks 
(±2 weeks) 
Early 
Discontinuation 
14 Days Post Therapy 
(±1 week) 
CLINICAL EVALUATIONS 
History and Physical Exam1 
X 
X 
X 
Adherence follow-up 
X 
X 
CDC Classification 
X 
X 
X 
STUDY DRUG 
Distribution of Study Drug 
X 
LABORATORY EVALUATIONS 
Chemistries2 
X9 
2mL 
2mL 
3mL 
Hematology3 
X9 
2mL 
2mL 
2mL 
Cholesterol/triglycerides4 
X9 
2mL 
Urinalysis5 
X 
X 
X 
Urine pregnancy test (if applicable)6 
X 
X 
X 
X 
Virology 
HIV-1 RNA PCR7 
X9 
3mL 
3mL 
3mL 
HIV genotype & phenotype 
4mL 
Immunology 
Lymphocyte subset8 
X9 
2mL 
2mL 
TOTAL BLOOD VOLUME 
None 
11mL 
13mL 
8mL 
 
NOTE:  Visits during long term follow up are every 12 weeks with specific lab tests being collected every 24 weeks (for additional details, see footnote 9 below). 
 
Footnotes 
 
1. History (including occurrence of adverse events since last study visit and any HIV-1 associated conditions) and physical exam (including height [without 
shoes], weight [with minimal clothing], vital signs [temperature, pulse, respirations and blood pressure]). 
2. Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs.  LFTs should include total bilirubin, indirect bilirubin, 
direct bilirubin, alkaline phosphatase, AST, ALT, and albumin.  If indirect bilirubin is not reported by the site laboratory, it should be calculated at the site 
and documented. 


 
 
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The following (listed in order of preference) should be used to determine the upper limit of normal (ULN) values for indirect bilirubin. 
a. 
"ULN" values reported by the laboratory report for the test, or 
b. "ULN" values routinely used/established by the site, or 
c. 
"ULN" values as per the Harriet Lane Handbook 
Sites must be consistent with the way toxicities are evaluated for all subjects in the study; sites should use the same source throughout the study. Remember 
to have documentation of calculated indirect bilirubin and source of "ULN", when not reported by your laboratory. 
3. Hematology tests should include complete blood count (CBC), differential and platelets. 
4. If a subjects laboratory results show elevated cholesterol/triglycerides AND if the subject is ≥1 year old, the subject should be asked to return to clinic for 
fasting cholesterol/triglycerides.  Children ≥1 year to ≤2 years of age, should be fasting for 4 hours.  Children >2 years of age, should be fasting overnight. 
5. A urine dipstick should be performed at each of the visits indicated.  A complete microscopic urine assessment is required only if a urine dipstick is 
abnormal. 
6.    A urine pregnancy test should be performed at every visit on any female subject who is capable of becoming pregnant. 
7.    Virology assays should be performed at an IMPAACT/VQA approved laboratory. For protocol required plasma RNA testing, the Abbott platform MUST be 
used.  During the long term follow up, any standard of care HIV-1 RNA results (i.e. those obtained at non-protocol required time points) available within ±4 
weeks of the study visit should also be reported on the study CRF, even if done using non-Abbott assays. 
8. Lymphocyte subsets should include CD4 and CD8. 
9. If these tests are performed as part of standard of care for the subject within ±4 weeks of the visit, they should be recorded on the study CRFs. Otherwise; 
these tests should not be done for the study at this time point. 
 
 
 
For insufficient blood draws, priorities are as follows: 
Chemistry (2mL); Virology (HIV-1 RNA PCR – 3mL); Lymphocyte subsets (2mL); HIV genotype/phenotype (4mL); Cholesterol / triglycerides (2mL) 


 
 
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APPENDIX II: PLANNED LABORATORY TESTING ON COLLECTED SPECIMENS 
 
 
Specimen 
Assay 
Investigator / Laboratory 
Notes 
EDTA blood 
Hematology 
Local IMPAACT laboratory 
EDTA blood 
Lymphocyte subsets 
Local IMPAACT laboratory 
Serum or LiHeparin 
(site /method 
dependent) 
Chemistries/ 
cholesterol 
/triglycerides 
Local IMPAACT laboratory 
EDTA plasma 
HIV-1 RNA PCR 
(viral load) 
Local IMPAACT laboratory 
Laboratory must be using Abbott 
platform and be VQA certified 
EDTA plasma 
Resistance Testing 
(Genotyping) 
SCREENING Only 
U.S. Sites: 
University of Washington 
Seattle WA 
Specimens should be shipped in 
real time 
Africa Sites: 
Contract Laboratory Services, 
Johannesburg, SA 
Specimens should be shipped in 
real time 
South America Sites: 
FioCruz, Brazil 
Specimens should be shipped in 
real time 
Thailand Sites: 
PHPT Laboratory 
Chiang Mai, Thailand 
Specimens should be shipped in 
real time 
India Sites: 
Testing will be performed in 
country at a DAIDS network 
laboratory 
Specimens should be shipped in 
real time 
EDTA plasma 
Resistance Testing 
(Phenotyping) 
SCREENING Only 
U.S. / Brazil Sites: 
Monogram Sciences 
Specimens should be shipped in 
real time 
All Other Sites: 
BRI Repository 
Specimens should be shipped in 
real time and will ‘pass-through’ 
BRI to Monogram 
EDTA Plasma 
Resistance Testing 
(Genotyping) 
VIROLOGIC 
FAILURE 
/ EARLY STUDY 
D/C 
U.S. Sites: 
University of Washington 
Seattle WA 
Specimens should be batch 
shipped quarterly 
All Other Sites: 
BRI Repository 
Specimens should be batch 
shipped quarterlyand will ‘pass- 
through’ BRI to Monogram 
EDTA Plasma 
Resistance Testing 
(Phenotyping) 
VIROLOGIC 
FAILURE 
/ EARLY STUDY 
D/C 
U.S. / Brazil Sites: 
Monogram Sciences 
Specimens should be batch 
shipped quarterly 
All Other Sites: 
BRI Repository 
Specimens should be batch 
shipped quarterly 
 
 
 


 
 
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APPENDIX III: ETRAVIRINE DRUG DOSING TABLE FOR ORAL TABLET 
 
Note: If the protocol team determines that a revised starting dose of etravirine is needed, 
modeling and simulation will be used (incorporating all available PK data at that time) to 
propose a revised weight-based dosing table for ETR for which the calculated chance of success 
for a given age cohort (i.e., geometric mean AUC12h between 60 and 150% of adults) will be at 
least 80%. For this, available doses of ETR (based on available formulations of 100 mg tablet 
and 25 mg scored tablet) between 12.5 mg orally twice daily (BID) and 200 mg orally twice 
daily, in increments of 12.5 mg, will be considered. The new dosing table and clear instructions 
on how to handle subjects will be provided to all participating sites by the protocol team via a 
written notification. 
 
DOSING TABLE 1:  1 year – 6 years 
 
Etravirine (ETR) dose per weight band 
Weight Band 
(kg) 
Dose (mg/kg) 
Dose (mg) 
Number of Tablet(s) to 
Administer Orally per 
Dose 
Frequency 
<8 
8.8 
50 mg 
2 x 25 mg tablets 
Twice Daily 
8-<10 
8.8 
75 mg 
3 x 25 mg tablets 
Twice Daily 
10-<13 
8.8 
100 mg 
1 x 100 mg tablet 
Twice Daily 
13-<16 
6.8 
100 mg 
1 x 100 mg tablet 
Twice Daily 
16-<20 
5.2 
100 mg 
1 x 100 mg tablet 
Twice Daily 
20-<25 
5.2 
125 mg 
1 x 100 mg tablet PLUS 
1 x 25 mg tablet 
OR 
5 x 25 mg tablets 
Twice Daily 
25-<30 
5.2 
150 mg 
1 x 100 mg tablet PLUS 
2 x 25 mg tablets 
OR 
6 x 25 mg tablets 
Twice Daily 
>=30 
5.2 
200 mg 
2 x 100 mg tablets 
OR 
8 x 25 mg tablets 
Twice Daily 
 
 
 
 
 
 
 
 
 


 
 
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DOSING TABLE 2:  2 months to < 1 year 
 
Etravirine (ETR) dose per weight band 
Weight Band 
(kg) 
Dose (mg) 
Number of Tablet(s) to 
Administer Orally per Dose 
Frequency 
<6 
25 mg 
1 x 25 mg tablet 
Twice Daily 
6-<8 
37.5 mg 
1 and a half scored 25 mg tablets 
Twice Daily 
8-<10 
50 mg 
2 x 25 mg tablets 
Twice Daily 
≥10 
75 mg 
3 x 25 mg tablets 
Twice Daily 
Note: as of the age of 1 year, doses should be adjusted according to the specific ETR dosing 
table for 1 year to 6 years (Dosing Table 1). 
 
 


 
 
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APPENDIX IV: VISIT SCHEDULE FOR RASH MANAGEMENT IN PEDIATRIC SUBJECTS 
 
This visit schedule summarizes the visits and assessments to be performed in case of 
rash. NOTE: At the investigator’s discretion, whenever follow-up visits, laboratory 
tests or digital photos are NOT required by this schedule, these evaluations may be 
performed at the investigators discretion, if clinically indicated. All results should be 
documented in the study CRFs. 
 
Grade 1 Rash 
Grade 2 Rash 
Grade 3/4 Rash 
Day 01 
 
Study medication MAY be 
CONTINUED 
 
Unscheduled visit for initial 
rash evaluation REQUIRED. 
 
Referral to dermatologist 
ONLY IF rash diagnosis 
uncertain (within 24-48hr). 
 
Study medication MAY be 
CONTINUED. 
 
Unscheduled visit for initial 
rash evaluation REQUIRED. 
 
Referral to dermatologist 
REQUIRED (within 24-48hr). 
 
Blood sample for safety 
evaluations by local laboratory 
ONLY IF requested by investigator 
or dermatologist. 
 
Biopsy ONLY IF required by 
dermatologist. 
 
Study medication MUST be 
permanently DISCONTINUED. Re- 
challenge is NOT ALLOWED. 
 
Unscheduled visit for initial 
rash evaluation REQUIRED. 
 
Referral to dermatologist 
REQUIRED (within 24-48hr). 
 
Blood sample for safety 
evaluations by local laboratory. 
 
Biopsy REQUIRED within 24 
hours after onset of rash 
 
Digital pictures REQUIRED. 
Day 1 
 
Follow-up visit REQUIRED 
 
Follow-up visit REQUIRED 
 
Follow-up visit REQUIRED. 
 
Digital pictures REQUIRED. 
Day 2 
No follow-up visit required 
 
Follow-up visit REQUIRED 
 
Follow-up visit REQUIRED. 
Day 3 
No follow-up visit required 
No follow-up visit required 
 
Follow-up visit REQUIRED. 
Day 4 
No follow-up visit required 
No follow-up visit required 
 
Follow-up visit REQUIRED. 
Day 5 
No Rash follow-up visit required2 
No Rash follow-up visit required2 
 
Follow-up visit REQUIRED. 
Day 6 
No Rash follow-up visit required 
No Rash follow-up visit required 
No Rash follow-up visit required 
Day 7 
 
Follow-up visit REQUIRED. 
 
Follow-up visit REQUIRED. 
No Rash follow-up visit required 
Further 
Visits 
If rash is unresolved after second 
follow-up visit, subject should be 
referred to a dermatologist for 
further evaluation. 
If rash is unresolved after second 
follow-up visit, subject should be 
referred to a dermatologist for 
further evaluation. 
Weekly follow-up visits 
REQUIRED (with digital pictures) 
until resolution of Grade 3-4 rash to 
Grade ≤ 2 rash (further follow-up 
visits according to Grade 1 or Grade 
2 rash instructions). 
Upon Rash 
Resolution/ 
Stabilization3 
Complete final rash assessment 
pages in the CRFs 
Complete final rash assessment in 
the CRFs 
Complete final rash assessment 
pages in the CRFs 
Footnotes: 
1 
Note that Day 0 of the rash is the first day of investigator assessment and not the first day of rash 
as reported by the subject. 
2 
In case rash progresses from a Grade 1 or a Grade 2 to a higher Grade, start follow-up schedule 
for Grade 2, 3 or 4 rash as appropriate. 
 
 


 
 
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APPENDIX V: GRADING FOR PR AND QTc INTERVALS 
 
 
A.  TABLE TO DETERMINE 98TH PERCENTILE FOR PR RESULTS IN LEAD II 
 
This table should be used when evaluating ECGs for subjects <8 years of age. This table is 
to be followed in conjunction with exclusion criterion 4.211, toxicity management section 
6.15, and Appendix IA-ID.  If you have any questions regarding the implementation of this 
table, please contact the core protocol team at impaact.p1090cmc@fstrf.org. 
 
Subject’s Age 
Normal PR-
Interval 
(milliseconds) 
3 to <6 months 
≤ 150 
6 to <12 months 
≤ 160 
1 to <3 years 
≤ 150 
3 to <5 years 
≤ 160 
5 to <8 years 
≤ 160 
Source: The Electrocardiogram in Infants and Children: A Systematic Approach. Arthur Garson, Jr. Lea and 
Febiger Publishers. Philadelphia, 1983. (Original table, labeled A-3 in the book, was modified by the 
IMPAACT P1090 Protocol Team to suit the specific needs of the protocol) 
 
B.  DETERMININGADVERSE EVENTGRADING OFPROLONGED QTcINTERVALS 
Please refer to the DAIDS toxicity tables for adverse event grading of prolonged 
QTc intervals. The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events, (DAIDS AE Grading Table), Version 1.0, December 2004, Clarification August 
2009, must be used and is available on the RSC website at (http://rsc.tech- 
res.com/safetyandpharmacovigilance/). 
 
 
 
C.  DETERMINING ADVERSE EVENT GRADING OF PROLONGED PR RESULTS 
 
Please refer to the DAIDS toxicity tables for adverse event grading of prolonged PR intervals. 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, (DAIDS 
AE Grading Table), Version 1.0, December 2004, Clarification August 2009, must be used 
and is available on the RSC website at (http://rsc.tech-res.com/safetyandpharmacovigilance/). 


 
 
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APPENDIX VI: SUPPLEMENTAL TOXICITY TABLE FOR GRADING SEVERITY OF 
NEUROLOGIC ADVERSE EVENTS 
 
 
 
 
For the purposes of P1090, the following parameter and grading criteria are to be used in 
conjunction with the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events, dated December 2004, Clarification August 2009, in grading neurologic adverse events. 
This parameter supersedes Row 1 (alteration in personality-behavior or in mood) and Row 2 
(altered mental status) of the neurologic section of the DAIDS Toxicity Table. 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sleepiness, 
lethargy, irritability 
Transiently 
lethargic, irritable 
or fussy (above 
usual norm), but 
otherwise normal 
routine. 
More sleeping or 
crying than usual, 
not on normal 
routine without 
alternate 
explanation. 
≥7 days of a change 
in personality 
without alternate 
explanation and 
confirmed by 
objective 
observation by 
study staff 
OR 
Somnolent, needs 
to be stimulated to 
take feedings. 
Somnolent, unable to 
be stimulated to take 
feedings. 
OR 
Inconsolable 
irritability or crying 
with unusually high 
pitch or screaming 
for > 3 hours 


 
 
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APPENDIX VII-A: SUPPLEMENTAL TOXICITY TABLE FOR GRADING SEVERITY AND MANAGEMENT OF ADULT AND 
PEDIATRIC CUTANEOUS ADVERSE EXPERIENCES 
 
 
Since cutaneous adverse events are of particular interest for this drug, the following guidelines on monitoring and management should be followed.  Please 
refer to Appendix IV which describes the visit schedule for management of cutaneous adverse events. 
 
NOTE: These management guidelines are NOT applicable to rashes with clear alternative etiology, such as chicken pox, impetigo and cutaneous HSV. 
Cetirizine, levocetirizine, topical corticosteroids and anti-pruritic agents will be allowed at the investigator’s discretion for all grades of rashes. 
 
 
CUTANEOUS ADVERSE EVENTS 
Grade 
Description 
Subject Management 
 
Cutaneous 
rash / 
reaction 
GRADE 1 
Localized macular rash 
 Subjects with Grade 1 or Grade 2 rash may continue etravirine 
or temporarily interrupt therapy at the investigator’s discretion. 
 Close clinical follow up is recommended to monitor 
progression of rash. 
GRADE 2 
Diffuse macular, maculopapular or morbilliform rash or 
target lesions 
 Subjects with Grade 1 or Grade 2 rash may continue etravirine 
or temporarily interrupt therapy at the investigator’s discretion. 
 Close clinical follow up is recommended to monitor 
progression of rash. 
 All subjects with Grade 2 rash must be seen by a dermatologist 
within 24 to 48 hours. 
GRADE 3 
  Diffuse macular, maculopapular or morbilliform rash 
with vesicles or limited number of bullae 
  Cutaneous reaction /rash with superficial ulceration of 
mucous membrane limited to 1 mucosal site 
  Cutaneous reaction/rash with at least 1 of the following: 
o Elevations of ALT/AST > 2x baseline but at least 
5x upper limit of laboratory normal range (ULN) 
o Fever ≥38oC or 100.4oF 
o Serum sickness-like reaction 
o Eosinophil count >1000/mm3 
 Subjects experiencing a Grade 3 rash or cutaneous event must 
have etravirine discontinued permanently; but should remain 
on study for safety follow-up 
 OBR should be held at the discretion of the site investigator 
 Subjects must also be evaluated by a dermatologist within 24 to 
48 hours 
 The protocol team should be notified of a Grade 3 event at 
impaact.p1090cmc@fstrf.org 


 
 
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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) 
 Subjects experiencing a Grade 4 rash or cutaneous event must 
have etravirine discontinued permanently; but should remain 
on study for safety follow-up 
 OBR should be held at the discretion of the site investigator 
 Subjects must also be evaluated by a dermatologist within 24 to 
48 hours 
 The protocol team should be notified of a Grade 4 event at 
impaact.p1090cmc@fstrf.org 
 
 
 


 
 
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APPENDIX VII-B: SUPPLEMENTAL TOXICITY TABLE FOR GRADING SEVERITY AND MANAGEMENT OF ADULT AND 
PEDIATRIC ACUTE SYSTEMIC ALLERGIC ADVERSE EXPERIENCES 
 
 
 
ACUTE SYSTEMIC ALLERGIC ADVERSE EXPERIENCES 
Grade 
Description 
Subject Management 
Urticaria 
GRADE 1 
Localized urticaria with no medical intervention indicated 
Subject may continue intake of etravirine 
GRADE 2 
 Localized urticaria with medical intervention indicated 
 Mild angiodema with no medical intervention indicated 
Subject may continue intake of etravirine 
GRADE 3 
 Generalized urticaria or angioedema with  medical 
intervention indicated 
 Symptomatic mild bronchospasm 
 Subjects with Grade 3 acute systemic allergic reactions will be 
permanently discontinued from the investigational medication 
(ETR) and background regimen but will be followed on study on a 
modified schedule (Appendix IE) for safety outcomes 
 Subjects will be treated as clinically appropriate per the local 
physician 
GRADE 4 
 Acute anaphylaxis 
 Life-threatening bronchospasm 
 Laryngeal edema 
 Subjects with grade 4 acute systemic allergic reactions will be 
permanently discontinued form the investigational medication 
(ETR) AND background regimen (OBR) but will be followed on 
study on a modified schedule (Appendix IE) for safety outcomes 
 Subjects will be treated as clinically appropriate per the local 
physician 
 The protocol team should be notified of a Grade 4 event at 
impaact.p1090cmc@fstrf.org 
 
 
 


 
 
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APPENDIX VIII: SAMPLE INFORMED CONSENT 
 
DIVISION OF AIDS 
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS 
GROUP (IMPAACT) 
 
A Phase I/II, Open-Label Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Antiviral Activity of Etravirine (ETR) in Antiretroviral (ARV) Treatment-Experienced HIV-1 
Infected Infants and Children, Aged ≥ 2 Months to < 6 Years 
 
P1090, Version 5.0, dated March 10, 2016 
 
SHORT TITLE FOR THE STUDY: Safety and Pharmacokinetics of Etravirine in HIV-1 
Infected Infants and Children 
 
INTRODUCTION 
Your child is being asked to take part in this research study because he/she is infected with HIV. 
This study is sponsored by the National Institutes of Health (NIH).  The doctor in charge of this 
study at this site is: (insert name of Principal Investigator). Before you decide if you want your 
child to be a part of this study, we want you to know about the study. 
 
This is a consent form. It gives you information about this study. The study staff will talk with 
you about this information. You are free to ask questions about this study at any time. If you 
agree to allow your child to take part in this study, you will be asked to sign this consent form. 
You will get a copy to keep. 
 
WHY IS THIS STUDY BEING DONE? 
This study is being done to look at a new antiretroviral HIV medication called etravirine. This 
drug is a type of medicine called a non-nucleoside reverse transcriptase inhibitor (NNRTI). This 
drug has not been tested in younger children before but has been tested in animals, older children 
(6 to <18 years of age)and adults and is currently approved by the FDA for use in treatment- 
experienced HIV-1 infected adults and children>6 years of age. The study will help find the best 
amount or dose of etravirine for infants and younger children, when it is taken with other  
antiretroviral medications. This study will also find out the safety of using this medication in 
infants and children and if there are any side effects from the medication. This medication is 
produced by Janssen Research & Development, a pharmaceutical company. 
 
WHAT DOES MY CHILD HAVE TO DO IF HE/SHE IS IN THIS STUDY? 
If you decide to allow your child to enroll in this study, you will be asked to bring your child to 
the clinic approximately 11 times over 48 weeks. Your child will be asked to take the study drug 
(etravirine) 2 times a day, following a meal, in addition to his/her regular anti-HIV medicines. 
Your child’s regular anti-HIV medications will NOT be provided by the study, however, 
Darunavir will be provided by the study if not reasonably available locally. Etravirine will be 
provided for your child by the study, at no cost to you or your insurance. It is available in tablet 
form that can be swallowed whole or can be dispersed in a liquid. The formulation your child 
receives will depend on your child’s age and whether your child can swallow pills. 
 


 
 
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(Sites should delete the following sentence if appropriate): 
The clinic will provide you with sterile water so that your child can take the medication safely. 
 
This study will help doctors to find the right dose of study drug for your child; the study will 
then keep them on that dose to look for any side effects your child might experience. 
 
If your child misses a dose of etravirine, a dose of etravirine should be taken if it is within 6 
hours of the missed dose time. If your child vomits within 15 minutes of taking a dose of 
etravirine, a second dose of etravirine should be taken. 
 
As part of this study your child will be assigned to a group (cohort), based on his/her age. There 
are 3 cohorts in this study, each with a minimum of 12 participants. 
 
Screening: 
If you are interested in allowing your child to enroll in this study, we will see if your child is 
eligible for the study: 
 
 We will ask about your child’s medical history including questions about your child’s 
health and what symptoms, medications, and illnesses your child has had. 
 
 We will do a special test called an electrocardiogram (ECG).  Your child will have 
special electrical wires placed on their chest and a machine will read your child’s heart 
rhythm. This is a painless test. 
 
 We will do a physical exam including height, weight and vital signs (temperature, blood 
pressure, pulse and respiratory rate). 
 
 We will also ask your child to provide a urine sample for a urine test. 
 
 We will take a little less than 3 teaspoons (14mL) of blood if your child is older than 1 year of 
age and a little more than 2 teaspoons (10mL) of blood if your child is less than a year of age 
to check the following: 
o The amount of HIV in your child’s blood; 
o How well your child’s immune system and kidneys are working 
o Whether your child is resistant to certain HIV medications (if your child is 
resistant to the study drug, it will not work properly) 
You will be given the results of these tests as they become available. 
 
On Study: 
Your study doctor will tell you whether your child is eligible for this study. The study team will 
determine this based on the number of children in each age group that have already entered the 
study and your child’s results from the laboratory tests, history and physical at screening. 
 
If your child is eligible for this study, your child will come to the clinic approximately10 more 
times in about 48 weeks. Most of the visits will last about 1 to 2 hours.  More visits will be 
needed if the amount of study drug (etravirine) in your child’s blood is too low or too high and 
your child’s dose needs to be adjusted. Your child will come to the clinic for the first study visit 


 
 
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within 60 days of the screening visit. 
 
 At each visit, a medical history will be taken (including questions about your child’s 
health and what symptoms, medications, and any illnesses your child has had) and your 
child will have a physical exam. You will also be asked some questions to see if your 
child has been taking his/her medicine as directed. 
 We will draw between 5 to 15mL (1- 3 teaspoons) of blood at each visit, depending on 
the child’s age and the specific study visit. You will be informed of results of routine 
blood tests when available. Some of the blood collected will be stored for later tests. 
 We will also ask your child to provide a urine sample for a urine test. 
 A staff member from the clinic will call you the day before the intensive PK visit to make 
sure your child did not miss any study medications. 
 After your child has been taking the study medication for 14 days (± 4 days), your child 
will be asked to come to the clinic to have blood drawn 7 times over 12 hours during one 
visit (Intensive PK visit). 
 
o  Before the intensive PK visit: Your child will be asked not to take their morning 
dose of etravirine but to bring it with them to the clinic. It is very important that 
your child take all their etravirine medications as directed by the clinic, for 7 days 
prior to the PK visit. 
 
o  What will happen at the intensive PK visit: 
o This blood test is done to measure the amount of study drug in your child’s 
blood. 
o Your child will be offered breakfast appropriate for his/her age prior to taking 
their morning dose of etravirine. 
o A small plastic catheter will be placed in your child’s arm to draw blood 
samples up to seven times during the visit. A catheter is a needle that is 
placed in a vein for an extended period of time, so that blood can be collected 
several times, without having to stick your child with a needle each time. The 
needle will stay in place until all of the blood samples are drawn. 
o We will do a special test called an electrocardiogram (ECG).  Your child will 
have special electrical wires placed on their chest and a machine will read 
your child’s heart rhythm. This is a painless test. 
 
o  After the intensive PK visit:  Based on the results, a change in dose (either higher or 
lower) maybe required. If this test shows that the amount of study drug in your 
child’s blood is not high enough or is too high, your child will be asked to take a 
higher or lower dose of etravirine and return to the clinic for an additional visit for 
a repeat intensive PK visit, so that blood can be collected again, up to 7 times over 
12 hours.  If you decide not to have this test repeated, your child will come off the 
study drug.  An additional PK visit may also be required, if the results of the test 
are incomplete or hard to evaluate. 
 
 Approximately four weeks after your child started the study medications, your child will 
be asked to come back to clinic for a population PK visit. Your child will have a little 
between 1 and 2 teaspoons of blood drawn (6 to 9mL) for tests depending on your 


 
 
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child’s age, as well as a history and physical exam. Your child will also be asked to 
provide a urine sample. 
 
 Your child will be asked to come back to clinic for a repeat population PK visit at week 
8, week 12, week 24 and week 48 after starting study medications. Your child will have 
approximately 6-15mL (1 - 3 teaspoons) drawn at each visit for laboratory tests, as well as 
a history and physical exam. Your child will also be asked to provide a urine sample. 
 
 The study team will be reviewing the PK results of all of the children who have been 
enrolled and may determine that your child should have a higher or lower dose of 
etravirine. If so, your child will be asked to return to the clinic for an additional PK visit, 
so that blood can be collected again, but only 3 times over no more than 5 hours. 
 
 If during this research study, your child gets a rash, please contact the research doctor 
immediately (please insert a daytime and after hours contact number here) and make an 
appointment for your child to be seen the same day. The research doctor will help you 
decide if your child needs to stop taking etravirine. Your study doctor may want you to 
be seen by a dermatologist (a doctor that specializes in skin problems). This visit will be 
paid for by the study. 
 
 In the case that your child has a severe rash, a skin doctor (dermatologist) may request that 
a small piece of skin is taken to see what type of rash it is. This is called a skin biopsy. 
There is a slight risk of infection or bleeding or scar formation with this procedure. The 
skin doctor may wish to take pictures of the rash so it can be documented. You may be 
asked to sign a separate consent form to allow the doctor to do the skin biopsy and/or take 
a photograph of the rash.  This visit will be paid for by the study. 
 
Long Term Follow-Up 
After your child has been on study drug for approximately 48 weeks, he/she will enter the long 
term follow-up phase of the study which for up to 5 years. Your child will be asked to come 
back into the clinic every 12 weeks until the drug is available in your country by prescription. 
Most visits will last about 30 minutes. 
 At each visit, a medical history will be taken and you/your child will have a physical 
exam. You will also be asked if you have missed taking any of your medications. 
 2 teaspoons of blood (10 mL) will be drawn every 24 weeks (at every other visit). You 
will be informed of results of routine blood tests as they become available. 
Your child must continue to take his/her anti-HIV medications during the study as prescribed by 
your child’s HIV care provider. If your child’s HIV care provider changes your child’s anti-HIV 
medications during the study, your child can still take the study drug.  Your child will be asked 
questions about taking his/her anti-HIV medications and the schedule he/she takes them on and if 
you he/she has missed any medications. 
 
Blood Samples 
Some of your child’s blood samples will be shipped to a central repository in the USA so that 
they can be sent to specialized laboratories for testing later in the study. You will not receive the 
results of these tests. 
 


 
 
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FOR NICHD Sites: 
Some of your child’s blood specimens collected as part of this study will be stored for testing at a 
later date as part of this study. There is a separate consent form to explain this and get your 
consent. 
 
For NIAID Sites: 
Storage of Blood Samples 
 
Some of your child’s blood will be stored (with usual protectors of identity) and used for future 
IMPAACT-approved, HIV-related research. About 1teaspoon (4 mL) of blood will be taken for 
this purpose. 
 
Your child’s samples will be stored at a special laboratory facility. Only approved researchers 
will have access to them. People who work at the facility will also have access to your child’s 
samples to keep track of them. These people won’t have information that directly identifies your 
child. Your child’s samples will not be sold or directly used to produce commercial products. 
All proposed research studies using your child’s samples will be reviewed by the National 
Institutes of Health (NIH).  There is no time limit on how long your child’s samples will be 
stored. 
 
The researchers do not plan to contact you or your child’s regular doctor with the results of 
studies done using your child’s stored samples. This is because research studies are often done 
with experimental procedures. The results of such studies should not be used to make decisions 
about your child’s medical care. If the researchers decide that the result of a certain study 
provides important information for your child’s medical care, your child’s study doctor will be 
notified. If you would like to be contacted with this sort of information, you must notify the 
study staff of any changes in your address or phone number. 
 
You may decide that you do not want your child’s samples stored for future research studies. 
Your child can still participate in this study even if you make this decision. 
 
You may withdraw your consent for the storage and use of your child’s samples at any time. If 
you withdraw your consent, these stored samples will be destroyed. 
 
Please read the following statement carefully and then mark your initials in the appropriate space 
provided. 
 
 
I agree to allow my child’s blood samples to be stored for use in future IMPAACT-approved, 
HIV-related research studies. 
 
  
 Yes 
  
 No 
  
 Date 
 
 


 
 
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OTHER INFORMATION 
The information collected in this study may be used for other IMPAACT-approved HIV-related 
research. 
 
HOW MANY CHILDREN WILL TAKE PART IN THIS STUDY? 
Up to 50 babies and children will take part in this study. 
 
HOW LONG WILL MY CHILD BE IN THIS STUDY? 
Your child will be in this study for at least 48 weeks, depending on when your child joins, and 
how long it takes to find the right dose of study drug for children in your child’s age group.  As 
long as your child is doing well on the medicine, your child will then enter the long term safety 
follow-up phase of the study and will continue to come into clinic every 12 weeks, until the drug 
is available in your country by prescription. 
 
WHY WOULD THE DOCTOR TAKE MY CHILD OFF THIS STUDY EARLY? 
The study doctor may need to take your child off the study early without your permission if: 
 The study is cancelled by the U.S. Food and Drug Administration (FDA), National 
Institutes of Health (NIH), the drug companies supporting this study, the Office for 
Human Research Protections (OHRP) or other governmental agencies, or the site’s 
Institutional Review Board (IRB).  An IRB is a committee that watches over the 
safety and rights of research subjects. 
 A Study Monitoring Committee (SMC) recommends that the study be stopped early. 
An SMC is an outside group of experts that monitors the study. 
 Your child is not able to attend the study visits as required by the study. 
 Your child refuses to undergo repeat intensive PK for management of individual dose 
adjustments. Your child will have etravirine therapy discontinued and will be followed 
on study but off study drug. 
 
The study doctor may also need to take your child off the study drug(s) without your permission 
if: 
 Continuing the study drug(s) may be harmful to your child 
 Your child needs a treatment that your child may not take while on the study 
 Your child is not able to take the study drug(s) as required by the study 
 
If your child needs to stop taking etravirine during the first 48 weeks of the study, he/she will be 
asked to come back to clinic four weeks after they stop taking etravirine for a final study visit. 
This visit will include a medical history, physical exam and 2 teaspoons (10mL) of blood will be 
drawn for blood tests to check the amount of HIV in your child’s blood, to see how well your 
child’s immune system is working, and for other routine tests. Your child will not enter the long 
term follow-up phase of the study. 
 
IF MY CHILD HAS TO PERMANENTLY STOP TAKING STUDY-PROVIDED MEDICINE, 
OR ONCE HE/SHE LEAVES THE STUDY, HOW WOULD THE STUDY MEDICINE BE 
PROVIDED? 
 
During the Study: 
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participation is over, the study staff will discuss other options that may be of benefit to your 
child. 
 
After the Study: 
After your child leaves the study, if he/she is gaining benefit from the study-provided drug 
(etravirine), this drug will continue to be provided until it is available to your child in your 
country. 
 
EARLY STUDY DISCONTINUATION 
In the event that you or your child decides to withdraw from the study prior to Week 48, we will 
ask that your child returns for a final visit. At this visit: 
 
 A medical history will be taken (including questions about your child’s health and what 
symptoms, medications, and any illnesses your child has had) and your child will have a 
physical exam. You will also be asked some questions to see if your child has been 
taking his/her medicine as directed. 
 We will draw between 8 to 12mL (1½- 2½- teaspoons) of blood depending on the child’s 
age. 
 We will also ask your child to provide a urine sample for a urine test.  
WHAT ARE THE RISKS OF THE STUDY? 
 
The drug used in this study (etravirine) may have side effects, some of which are listed below. 
Please note that these lists do not include all the side effects seen with this type of drug. These 
lists include the more serious or common side effects with a known or possible relationship. If 
you have questions concerning additional study drug side effects please ask the medical staff at 
your site. It is important to report all side effects to your study doctor, even if not listed below. If 
any of the side effects gets serious, contact your study doctor immediately. 
 
Use of Combination Antiretroviral Drugs 
 
Immune Reconstitution Syndrome: In some people with advanced HIV infection, signs and 
symptoms of inflammation from other infections may occur soon after anti-HIV treatment is 
started. 
 
The use of potent antiretroviral drug combinations may be associated with an abnormal 
placement of body fat and wasting. Some of the body changes include: 
 Increase in fat around the waist and stomach area 
 Increase in fat on the back of the neck 
 Thinning of the face, legs, and arms 
 Breast enlargement 
 
Risks of Etravirine 
 
The following side effects have been associated with the use of etravirine: 
 
 Serious and life-threatening rash and allergic reactions (hypersensitivity). If you get a 
rash with any of the following symptoms contact your child’s HIV care provider and the 


 
 
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study doctor or nurse right away: 
 
 Fever 
 Muscle or joint aches 
 Hives or sores in your mouth, or your skin blisters and peels 
 Trouble swallowing or breathing 
 Swelling of the face, eyes, lips, tongue or throat 
 Red or inflamed eyes, like “pink eye” (conjunctivitis) 
 Yellowing of the skin or whites of the eyes, dark urine, or pain on the right side of 
the stomach. 
 Your doctor might also find some abnormalities in a certain type of your white 
blood cells. 
 
 Other serious side effects: 
 
 Muscle break down causing muscle aches, pain or weakness which can be serious 
 
 Additional side effects include: 
 
 Skin rash, mostly mild to moderate was sometimes seen, usually during the first 2 
weeks of taking etravirine and lasting for about a week. In clinical studies, rash 
occurred more frequently in females than in males. 
 Mild to moderate diarrhea (liquid stools), nausea (upset stomach or feeling the 
need to throw up), vomiting 
 Numbness, pain or tingling in the hands or feet 
 Headache, stuffy nose, tiredness 
 Some other less common, but serious reported side effects include a decrease in 
red blood cells or a decrease in the part of the blood that stops bleeding, decrease 
in kidney function, high blood pressure, increase in blood sugar, increase in 
cholesterol or fats in your blood and decreased appetite 
 Other less commonly occurring side effects of at least moderate intensity include 
gastro-esophageal reflux disease (GERD), flatulence, inflammation of the 
stomach, abdominal pain, anxiety, inability to sleep, and night sweats. 
 
Immune Reconstitution Syndrome:  In some people with advanced HIV infection, 
symptoms from other infections or certain diseases may occur soon after starting 
combination anti-HIV treatment. Other non-infectious diseases characterized by abnormal 
functioning of the immune system (so-called autoimmune disorders, like Graves’ disease) 
have also been reported after the start of anti-HIV treatment, but sometimes with a delay of 
many months. Some of these symptoms may be life threatening. If you start having new 
symptoms, or notice that existing symptoms are getting worse after starting your 
antiretroviral therapy, tell your healthcare provider right away. 
 
 
Other Risks 
There is the risk of serious and/or life threatening side effects when non-study medications are 
taken with etravirine. For your child’s safety, you must tell your child’s HIV care provider and 
the study doctor or nurse about all medications your child takes before the start of this study and 
also before starting any new medications while your child is on the study. In addition, you must 


 
 
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tell the study doctor or nurse before enrolling your child in any other clinical trials while on this 
study. 
 
The use of potent antiretroviral drug combinations may also be associated with abnormal 
processing of body and dietary fat including elevated triglycerides (fatty acid in the blood) and/or 
elevated cholesterol. 
 
Other side effects besides those listed and side effects from taking these drugs together may 
occur. If any unusual symptoms or changes happen, you should call your child’s doctor 
immediately. It is also important that while participating in the study, your child does not take 
any other prescription drugs or over-the-counter medications without first talking to your child’s 
doctor or study nurse. 
 
Blood Drawing and Heparin/Saline Lock Risks 
Blood drawing may cause some discomfort, bleeding or bruising where the needle enters the 
body.  A small blood clot may form at the site of venipuncture/heparin lock or there may be 
swelling in the area. There is a small risk of a minor infection at the blood draw/heparin lock 
site. Lightheadedness and fainting can also occur. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
If your child takes part in this study, the amount of HIV in your child’s body may go down and 
your child’s immune system may become stronger, but no guarantee can be made. Your child 
may receive no benefit from being in this study. Information learned from this study may help 
others who have HIV. 
 
WHAT OTHER CHOICES DOES MY CHILD HAVE BESIDES THIS STUDY? 
Instead of being in this study you have the choice of: 
 Treatment with prescription drugs available to your child 
 Treatment with other experimental drugs, if your child qualifies 
 
Please talk to your doctor about these and other choices available to your child. Your doctor will 
explain the risks and benefits of these choices. 
 
WHAT ABOUT CONFIDENTIALITY? 
(US sites only) 
To help us protect your child’s privacy, we have obtained a Certificate of Confidentiality from 
the National Institutes of Health. With this Certificate, the researchers cannot be forced to 
disclose information that may identify you, even by a court subpoena, in any federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings. The researchers will use 
the Certificate to resist any demands for information that would identify you, except as 
explained below. The Certificate cannot be used to resist a demand for information from 
personnel of the United States Government that is used for auditing or evaluation of federally 
funded projects or for information that must be disclosed in order to meet the requirements of 
the federal Food and Drug Administration (FDA). 
 
People who may review your child’s records include the U.S. Food and Drug Administration, the 
site IRB (insert name of site IRB), the National Institutes of Health, the Office of Human 
Subjects Protection (OHRP), host country regulatory agencies, study staff, study monitors, 


 
 
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Janssen R&D and their designees. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about you or your participation in this 
research. If an insurer, employer, or other person obtains your written consent to receive 
research information, then the researchers may not use the Certificate of Confidentiality to 
withhold that information. 
 
(For sites outside the U.S.) 
Efforts will be made to keep your child’s personal information confidential. We cannot guarantee 
absolute confidentiality. Your child’s personal information may be disclosed if required by law.  
Any publication of this study will not use your child’s name or identify your child personally.  
Your child’s records may be reviewed by the Ministry of Public Health in your country, the FDA, 
the Office of Human Research Protections (OHRP), the NIH, (insert name of site) IRB, study 
staff, study monitors and the drug companies supporting this study. 
 
WHAT ARE THE COSTS TO MY CHILD? 
There are no costs to you/your child for study drug (etravirine), study visits or study procedures. 
However, taking part in this study may lead to added costs to you and your insurance company if 
medical complications arise or if your doctor decides extra tests are needed. You will be 
responsible for the cost of your child’s anti-HIV medications that are not provided by the study. 
In some cases it is possible that your insurance company will not pay for these costs because 
you/your child are taking part in a research study. 
 
WILL MY CHILD RECEIVE ANY PAYMENT? 
You will receive [$XX] for each study visit you attend. If you attend all study visits, you may 
receive up to [$XX]. 
 
WHAT HAPPENS IF MY CHILD IS INJURED? 
If you are/your child is injured as a result of being in this study, you/your child will be given 
immediate treatment for your/his/her injuries. The cost for this treatment will be charged to you 
or your insurance company. There is no program for compensation either through this institution 
or the National Institutes of Health (NIH). You will not be giving up any of your/your child’s 
legal rights by signing this consent form. 
 
WHAT ARE MY CHILD’S RIGHTS AS A RESEARCH SUBJECT? 
Taking part in this study is completely voluntary. You may choose not to take part/not to allow 
your child to take part in this study or leave this study/take your child out of the study at 
anytime. Your decision will not have any impact on your participation in other studies 
conducted by the NIH and will not result in any penalty or loss of benefits to which you are 
otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 


 
 
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WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about this study or a research-related injury, contact: 
 Name of the investigator or other study staff 
 Telephone number of above 
 
For questions about your child’s rights as a research subject, contact: 
 Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
 Telephone number of above 
 
 
 
 
 


 
 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to allow your child to take part in this study, please sign your name 
below. 
 
 
 
 
Participant’s Name (print) 
 
 
 
 
 
Participant’s Mother (print) 
Mother’s Signature and Date 
 
 
 
 
 
Father’s Name 
Father’s Signature and Date 
(If father’s consent is required) 
(If father’s consent is required) 
 
 
 
 
 
Participant’s Legal Guardian (print) 
Legal Guardian’s Signature and Date 
(As appropriate) 
 
 
 
 
Study Staff Conducting 
Study Staff Signature and Date 
Consent Discussion (print) 
 
 
 
 
Witness’ Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 


 
 
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APPENDIX IX: FACT SHEET and TEMPLATE CONSENT FORM for SPECIMEN STORAGE 
AT REPOSITORIES FUNDED BY THE NATIONAL INSTITUE OF CHILD HEALTH AND 
HUMAN DEVELOPMENT (NICHD)  
 
When your child joins this NICHD sponsored study, you will be asked to give permission for 
having some specimens that the doctor or nurse will take from your child’s body saved in a 
repository. (A repository is a special laboratory with freezers where specimens like blood or 
tissue cells and body fluids that are taken from you during a study are kept. Your child’s name 
will not be on these specimens, only a special study number. The people who run the repository 
laboratory will not know your child’s name.) 
 
Why have a repository? 
 
Researchers can learn a lot from a study but as time goes by the tests that they used get better or 
brand new tests are developed, and more can be learned with these better or new tests. When 
study volunteers consent to put specimens in the repository and consent to the researchers doing 
new tests on the specimens at some time in the future after their time in the study is ended, 
researchers can learn new information by being able to use the specimens. Your child’s rights 
and privacy will be protected in any of these new studies. 
 
How will my child’s privacy be protected? 
 
The only record that your child participated in this NICHD sponsored study is at the clinic where 
it is kept separate from your child’s health records and locked away. 
 
Your child’s specimens in the repository will not have your child’s name on them. The 
specimens will have a special study code. It will be the same code that is on your child’s 
information in the NICHD sponsored Study from your child’s interviews and examinations. 
Again, none of this information will have your child’s name on it. 
 
How would a researcher get to use the specimens in the repository? 
 
If a researcher wants to do a test on specimens from the NICHD sponsored repository in the 
future, he or she will write up the idea and it will have to be approved by a committee to make 
sure the research is worthwhile. If the idea is approved, then coded specimens and coded 
information will be given to the researcher. The researcher will not know the names, addresses, 
or phone numbers of the people who gave the specimens to the repository. 
 
Why wouldn’t I find out the results of the research using my child’s specimens? 
 
You will not receive the results of research done with your child’s specimens. This is because 
research can take a long time and must use specimens from many people before results are 
known. Results from research using your child’s specimens may not be ready for many years. 
Often when studies are first done, it is not always clear how to use the information from the 
study to change the health care that people receive. So none of these study results is likely to 
affect your child’s care right now, but they may be helpful to people like your child in the future. 
Your child’s specimens can last in the freezer for many years and there is no time limit to when 


 
 
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studies could be done in the future. 
 
Would I ever be contacted in the future about research using my child’s specimens? 
 
All of the studies to be done in the future on your child’s specimens in the repository will be for 
the particular reasons that you agreed to. Every study that is planned to use specimens from your 
child and others from this NICHD Study has to be reviewed to make sure that what is planned is 
the same kind of study that you agreed to. If it is, then the research will go ahead since you 
would have agreed that these particular tests could be done without anyone contacting you to get 
your permission in the future. 
 
If the study to be done is not like the kind of tests you agreed could be done, then the committee 
will decide if you need to be contacted to give permission for the new study. 
 
I gave my permission to testing my child’s specimens in the repository, but what if I change my 
mind? 
 
People always have the right to stop participating in research. So if you decide that you do not 
want researchers to be able to use the specimens from your child in the repository, you can 
contact the clinic staff. They will tell the repository that the specimens with the study code 
number linked to your child’s name in the clinic should not be studied. These specimens can be 
removed from the repository and destroyed if you tell us to do that. 
 
What type of research will be done with my child’s specimens? 
 
Many different kinds of studies use specimens. Some researchers may develop new tests to find 
diseases. Others may develop new ways to treat or even cure diseases. In the future, some of the 
research may help to develop new products, such as tests and drugs. If this would happen and 
these tests or drugs make money, there are no plans to share that money with the people who 
gave the specimens. 
 
As part of this study (insert title), your child is being asked to have some (insert specimen 
source- blood, urine, tissue, genital fluid, saliva, etc.) taken. These specimens will go into the 
NICHD repository for research to be done at some time in the future so that more information 
can come from your child’s time in this NICHD sponsored Study. 
 
You do not have to agree to store your child’s specimens for future tests for your child to take 
part in this study. Your child will not lose any benefits to which your child is entitled if you 
decide against storing your child’s specimens. 
You will also be asked to agree that these particular tests can be done without anyone contacting 
you to get your permission sometime in the future. No one doing these tests would know that 
these specimens came from your child and no one would contact you or your doctor or nurse 
with the results from these tests that might happen in the future. 


 
 
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 TEMPLATE CONSENT FORM 
 
What are the general HIV-related studies that can be done with the repository specimens?  
 
Researchers would like to store your child’s specimens to understand how HIV causes disease 
and complications, and how best to treat or prevent HIV infection and its complications. They 
need specimens from people who have HIV and from those who do not. Sometimes, too, the 
specimens can be used to learn something about new problems that people with HIV have like 
liver disease, diabetes, and heart disease. These general studies would not include any genetic 
testing (looking at your child’s DNA). 
 
Benefits: There are no direct benefits to your child. Your child will be helping researchers learn 
more about how to help people with HIV or at risk of HIV infection. 
 
Risks: The specimens would be collected as part of your child’s study visits. (Insert text about 
collection procedures.) Once in the repository, there are few risks. Your child’s name will not be 
available to the repository or to the scientists who may be doing any future test. 
 
 
 
I give permission for the use of my child’s stored specimens for the purposes stated in the 
preceding section (general HIV-related tests). 
 
 
 
Parent or Legal Guardian Signature 
Witness Signature 
Date 
 
I give my assent to the use of my stored specimens for the purposes stated in the preceding 
section (general HIV-related tests). 
 
 
 
Participant Signature 
Witness Signature 
Date 
 
 
 
What are the special HIV-related studies that can be done with the repository specimens? 
 
Researchers in this study would also like to store your child’s specimens to understand how HIV 
causes disease and complications, and how best to treat or prevent HIV infection and its 
complications through looking at how each person’s genetic makeup (your child’s DNA) either 
protects them or puts them at greater risk. It may be that researchers use some of your child’s 
blood to make a “cell line”. That means the blood cells can keep dividing and give an endless 
supply of your child’s DNA for tests to be done in the future. This kind of information will be 
particularly important as scientists work toward a vaccine that could protect people from AIDS.  
They need specimens from people who have HIV and from those who do not. 
 
Benefits: There are no direct benefits to your child. Your child will be helping researchers learn 
more about how to help people with HIV or at risk of HIV infection. 
 
Risks: The specimens would be collected as part of your child’s study visits. (Insert text about 


 
 
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collection procedures.) Once in the repository, there are few risks. Your child’s name will not be 
available to the repository or to the scientists who may be doing any future test. Since there are 
no plans to give participants the results of the tests performed on their stored specimens, you will 
not receive any information on your child’s genetic makeup. 
 
I give permission for the use of my child’s stored specimens for the purposes stated in the 
preceding section (special HIV-related tests). 
 
 
 
Parent or Legal Guardian Signature 
Witness Signature 
Date 
 
I give my assent to the use of my stored specimens for the purposes stated in the preceding 
section (special HIV-related tests). 
 
 
 
Participant Signature 
Witness Signature 
Date 
 
 
 
What if I have more questions? 
 
If you have any questions about the repository, about storage, or the use of your child’s samples, 
contact (Study personnel) at (phone). 
 
If you have questions about giving consent or your child’s rights as a research volunteer, contact 
the (Name of Institution) Institutional Review Board at (phone). 
 
 
 
I refuse to have any specimen collected from my child stored in the repository. 
 
 
 
Parent or Legal Guardian Signature 
Witness Signature 
Date 
 

SAP_000.pdf: 
 
 
 
 
This is the IMPAACT P1090 SAP Version 3.0 with names of authors, names 
of publication writing team members and analysis timeline redacted 
 
 
 
IMPAACT P1090 
A Phase I/II, Open-Label Trial to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Antiviral Activity of Etravirine (ETR) in 
Antiretroviral (ARV) Treatment-Experienced HIV-1 Infected Infants and 
Children, Aged ≥ 2 Months to <6 Years 
 
 
 
Statistical Analysis Plan 
(For Protocol Version 5.0 with Letter of Amendment #1 Dated March 30, 2018) 
                  Version 3.0 
 
 
 
Weeks 24 and 48 Primary Analyses 
(Week 240 Secondary Analysis) 
 
 
 
 
 
 
 
 
Date  
February 27, 2019 
 


Page 2 of 8 
 
1 
INTRODUCTION 
 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary outcome measures 
of P1090 that will be included in the primary manuscript, and which address the primary and 
secondary objectives of the study.  The Primary SAP outlines the general statistical approaches that 
will be used in the analysis.  It has been developed to facilitate discussion of the statistical analysis 
components among the study team, and to provide agreement between the study team and 
statisticians regarding the statistical analyses to be performed and presented in the Primary Statistical 
Analysis Report.  It also describes the results for the primary and secondary outcome measures that 
will be posted on ClinicalTrials.gov.  It is recognized that this statistical analysis plan (SAP) may be 
modified by the Study Team as new information becomes available. 
 
The P1090 SAPs, Version 1 (dated 11/30/2011), Version 2 (dated12/7/2018), and the current 
version, do not address the interim data analyses for Janssen’s submissions to regulatory agencies. 
As mentioned in P1090 protocol section 8.6324, Janssen performs these interim data analyses for 
their regulatory submissions, using P1090 study datasets provided to Janssen by the IMPAACT Data 
Management Center. 
 
Data for the Primary Statistical Analysis Report will be downloaded once the last participant of the 
last cohort has completed the Week 48 study visit, all queries have been resolved, and the database 
frozen for analysis.  The Primary Statistical Analysis Reports will be used for submission of results to 
ClinicalTrials.gov.  Results for primary outcomes are required to be submitted within one year of the 
primary completion date (PCD), which is the date the last participant is examined for the purposes of 
data collection for the primary outcome measure.  For this study, the PCD is based on 48 weeks of 
treatment.  A second submission to ClinicalTrials.gov will be done within one year after the last 
enrolled participant reaches Week 288 the last visit of the long-term safety follow-up) at which time 
point the adverse event tables will be updated. 
 
 
2 
STUDY DESIGN 
 
This is a Phase I/II, multicenter, open label 48 week pharmacokinetic, safety, tolerability and 
antiviral study of etravirine in combination with at least 2 active ARVs, including a boosted PI 
and NRTIs for treatment experienced HIV-1-infected infants and children ≥ 2 months to < 6 years 
cohorts.   
 
The study will, in a sequential manner, accrue subjects for an initial dose finding intensive PK 
component for age related cohorts. It is expected that approximately 50 subjects will be accrued, 
to yield a minimum of 36 evaluable subjects (a minimum of 12 subjects in each cohort).  Up to 18 
subjects may be enrolled into Cohort I. The total sample size will depend upon the number 
needed to complete the dose finding stage of the study and the number of subjects required for 
regulatory approval of etravirine in these populations.  
 
Evaluable will be defined as having been treated exclusively on the dose determined to be 
optimal for a given age cohort and having either completed 24 (or 48) weeks of exposure to the 
study drug or having been classified as a safety failure, due to a study drug related adverse event 
occurring during the first 24 (or 48) weeks of treatment.   
 
The P1090 core protocol team will be responsible for reviewing the PK and safety data and 
approving the dose selection for each full and mini-cohort.  The P1090 core protocol team will 
consist of the protocol chair and co-chairs, clinical trials specialist, NIAID and NICHD Medical 
Officers, data manager, pharmacologists, pharmacist, statisticians and Janssen representatives. 


Page 3 of 8 
 
This study is designed to determine the appropriate etravirine dose for HIV-1-infected infants and 
children and to evaluate the PK, safety and tolerability of etravirine in this population. Etravirine 
(ETR) will be administered as 25 mg scored tablets and/or 100 mg tablets swallowed as a whole 
or dispersed in an appropriate liquid vehicle (see Section 5.2). ETR will be started concurrently 
with an optimized background regimen (OBR), while OBR will be based on clinical status, 
treatment history, resistance data and availability of appropriate pediatric dosing and 
formulations. 
 
Children will be stratified by age, as follows: 
• Cohort I: ≥ 2 year to < 6 years who are treatment experienced* 
• Cohort II: ≥ 1 year to < 2 years who are treatment experienced* 
• Cohort III: ≥ 2 months to < 1 year who are treatment experienced*, † 
*Treatment experienced children on a failing combination antiretroviral regimen (containing at least 3 ARVs) for at least 8 weeks OR 
Treatment experienced children on a treatment interruption of at least 4 weeks with a history of virologic failure while on a combination 
antiretroviral regimen (containing at least 3 ARVs) 
† Subjects below 6 months of age will only be enrolled upon availability of initial safety and PK data from subjects between 6 months and 1 
year of age. 
 
3  STUDY ALGORITHM 
 
General Guidelines: 
 
Younger mini-cohorts will open when the mini-cohort (6) from the previous older cohort 
passes the safety (≤ 28 day data) & Day 7-12 PK evaluation (see Section 3.3) 
      
 


Page 4 of 8 
 
 
4 
STUDY OBJECTIVES 
 
Primary Objectives: 
 
1. To evaluate the pharmacokinetics of etravirine in combination with an OBR in HIV-
infected children aged ≥ 2 months to < 6 years  
2. To determine the safety and tolerability of etravirine in combination with an OBR through 
48 weeks of therapy.   
3. To determine the appropriate dose of etravirine in combination with an OBR for children 
aged ≥ 2 months to < 6 years. 
 
Secondary Objectives: 
1. To assess the antiretroviral activity of ETR containing regimens through 48 weeks of 
therapy. 
2. To determine the immunological changes (change in CD4 percent and absolute count; 
CD4/CD8 ratio and percent) through 48 weeks of ETR therapy in combination with an 
OBR. 
3. To determine changes in viral drug resistance during 48 weeks of ETR therapy in 
combination with an OBR. 
4. To assess the relationship between ETR pharmacokinetics and the antiviral activity and 
safety of ETR containing regimens.\ 
5. To explore the relationship between subject-specific gene CYP profile, sex, age, weight, 
race, HIV regimen (e.g., boosted PI) and HIV response markers and pharmacokinetics of 
ETR. 
 
 
5  ENDPOINTS AND OUTCOME MEASURES 
 
Primary Endpoints: 
Toxicity Endpoints: 
• Termination from treatment due to a suspected adverse drug reaction (SADR) 
• Adverse events of Grade 3 or higher severity 
• Death 
 
Pharmacokinetic Endpoint: 
• Failure to meet PK targets (specified in Section 9.0) 
 
Secondary Endpoints: 
• Adverse events of Grade 3 or higher severity judged to be at least possibly attributable to the 
study medications 
• Confirmed failure to suppress plasma HIV-1 RNA to ≤ 400 copies 
• AND 
• Failure to achieve at least a 2 log reduction (from baseline) in HIV-1 RNA at weeks 24 and/or 48 
(confirmed in 1 to 4 weeks) 
• Treatment discontinued due to toxicity or virologic failure 
• Change in optimized background regimen due to virologic failure 
• New onset OI or AIDS diagnosis 
• Decline in absolute CD4 percent of > 5% any time after 12 weeks of therapy 


Page 5 of 8 
 
 
Primary Response Variables: 
• Pharmacokinetic parameters - AUC12h 
 
Secondary Response Variables: 
• Plasma HIV-1 RNA (copies/mL) 
• CD4 counts and percent 
• CD4/CD8 ratio and percent 
• Genotypic and phenotypic measures of resistance at virologic failure and at early discontinuation 
• Pharmacokinetic parameters - C12h and Cmax 
 
Exploratory Response Variables: 
• Patient-specific CYP gene profiles. 
 
 
 
6 
STATISTICAL METHODS AND RESULTS 
 
6.1 Administrative Data:  Accrual and Baseline Demographics 
 
 
Frequency tables on accrual in aggregate and broken down by cohort  
 
 
Reasons/frequencies for treatment discontinuation in aggregate and broken down by cohort 
 
 
Deaths (if any): Frequency, list of patients and complete etiologies 
 
 
Baseline Demographics: provides descriptive statistics for some of the variables of interest such as: 
gender, race and/or ethnicity, weight, age, RNA and CD4 (count and percentage) in aggregate and 
broken down by cohort 
 
6.2  Safety 
 
 
Summary of Dose Finding Data (Through Week 4 – the point up to which the safety criteria 
are applied)   
 
Descriptive statistics summarizing the safety data during the dose finding phase of the study. 
The safety data will be broken down by cohort and will present the results of the safety 
evaluations applied to each starting dose tested within each cohort, including information 
indicating which starting doses have passed or failed the safety guidelines. For each starting 
dose within each cohort, every adverse event of grade 3 or higher will be listed, along with 
patient demographics, the dose prescribed to the patient at the time of the event and the 
protocol team’s assessment of the probability that this event was due to the study treatment.  
 
 
Analysis of Data Representing Exposure to the Doses Judged to be Optimal for Each Cohort 
 
Primary Analysis of Safety: consists of data from “evaluable” patients only, performed on data through 
the weeks 24 and 48 visit at the final dose.   
 
Each patient’s safety data will be summarized as: the worst grade of adverse event experienced 
while on the first 24 and 48 weeks on the optimal dose of the study treatment and the worst 
grade of adverse event judged to be at least possibly due to study treatment during this time 


Page 6 of 8 
 
period. Frequency distributions of these safety outcomes will be presented in the aggregate and 
broken down by cohort. Listings of all Grade 3+ events will be provided, broken down by type 
of toxicity (hepatic, hematologic, etc.). 
 
The proportions of subjects experiencing grade 3+ adverse events will be presented in 
aggregate and broken down by Cohort, with these proportions bounded by exact 95% 
confidence intervals. Similar analyses will present the proportions of subjects exhibiting grade 
3+ events which have been judged to be at least possibly related to study medication, again 
bounded by exact 95% confidence intervals.  
 
NOTE: Given that the small sample sizes within cohorts will provide limited power for 
statistical tests of differences across age cohorts, interpretation of the results will depend upon 
whether differences across cohorts are great enough to be considered to be clinically 
significant. If no such differences are observed, then the clearest interpretation of the findings 
will come from the aggregated data, where analyses will have the greatest statistical 
precision. However, if results vary across cohorts to a clinically important extent, 
interpretation of results should take into account the issues represented by the stratification 
factor. 
 
Key Secondary Safety Analysis  
 
Safety assessments will be performed on long term data collected until the final patient reaches 
5 years of follow-up.  The key analyses will be similar to the Weeks 24 and 48 analyses 
described above, which will be performed on the data for all subjects through 5 years of 
follow-up.   
 
 
6.3  Pharmacokinetics (this will come from the protocol pharmacologist) 
 
6.4  Viral Load at Weeks 24 and 48: 
 
Virologic outcomes, based on HIV-1 RNA (copies/ml), will be assessed at weeks 8, 12, 24 and 48.  
The criteria for success are: at  least a 0.5 log10 reduction in HIV-1 RNA (copies/ml) at week 8, at 
least a 1 log10 reduction in HIV-1 RNA (copies/ml) at week 12 and either HIV-1RNA <400 
copies/ml or at least a 2 log reduction in HIV-1 RNA at weeks 24 and 48. 
 
At each of these time points the primary definition of virologic outcome will be calculated 
according to a Missing, Switch or Discontinuation = Failure (MSDF) algorithm – as codified by 
the FDA’s snapshot algorithm. Subjects will be classified as virologic failures if they have missing 
HIV-1 RNA data throughout the window surrounding the time point of interest. 
 
In addition subjects will be classified as virologic failures at any of these time points if they meet 
any of the following conditions prior to that time point:  
a) Discontinuation of study treatment (except as allowed in protocol for Cohort IIIB subjects 
whose screening resistance data is not available at time of treatment initiation, but indicates 
lack of  sensitivity to ETR when it becomes available);  
b) Change in background therapy not allowed in the protocol;  
c) Change in background ART substitutions permitted per protocol but prescribed while HIV-1 
RNA ≥400 copies/mL, unless the decision to switch is documented as being before or at the 
first on-treatment visit where HIV-1 RNA is assessed (Week 4). 
 
 


Page 7 of 8 
 
6.5  Immunologic Response: CD4 Count and Percentages at Weeks 24 and 48: 
 
Change from baseline to weeks 24 and 48 in CD4 count, CD4 percent and CD4/CD8 ratio will be 
bounded by 95% confidence intervals and presented both in the aggregate and by age cohort.  In 
addition, the proportions of subjects exhibiting an absolute drop of >5% in CD4 percent from 
baseline to weeks 12, 24 and 48 will be presented, bounded by 95% confidence intervals.  Subjects 
who meet any of the conditions (a) to (c) of Section 8.6321 or who have absolute drop of >5% in 
their CD4% will be considered as treatment failures in these analyses. 
 
6.6  HIV Drug Resistance 
 
Correlations between baseline HIV genotypic and phenotypic drug resistance and any subsequent 
virologic failure will be evaluated. Subjects will be assessed for HIV genotypic and phenotypic 
drug resistance to the OBT and etravirine at screening, at the time of virologic failure (if this 
occurs) and at early discontinuation. 
 
 
 
7  Week Windows for Analyses: 
 
 
The week windows for all analyses will be as follows: 
 
Study Day of Assessment 
Assessment 
Window 
Target Study Day of 
Window 
-3 to 1 
Week 0 
1 
2 to 42 
Week 4 
29 
43 to 70 
Week 8 
57 
71 to 98 
Week 12 
85 
99 to 140 
Week 16 
113 
141 to 196 
Week 24 
169 
197 to 252 
Week 32 
225 
253 to 308 
Week 40 
281 
309 to 378 
Week 48 
337 
379 to 462 
Week 60 
421 
463 to 546 
Week 72 
505 
547 to 630 
Week 84 
589 
631 to 714 
Week 96 
673 
715 to 798 
Week 108 
757 
799 to 882 
Week 120 
841 
883 to 966 
Week 132 
925 
967 to 1050 
Week 144 
1009 
1051 to 1134 
Week 156 
1093 
1135 to 1218 
Week 168 
1177 
1219 to 1302 
Week 180 
1261 
1303 to 1386 
Week 192 
1345 


Page 8 of 8 
 
1387 to 1470 
Week 204 
1429 
1471 to 1554 
Week 216 
1513 
Study Day of Assessment 
Assessment 
Window 
Target Study Day of 
Window 
1555 to 1638 
Week 228 
1597 
1639 to 1722 
Week 240 
1681 
1723 to 1806 
Week 252 
1765 
1807 to 1890 
Week 264 
1849 
1891 to 1974 
Week 276 
1933 
1975 to 2030 
Week 288 
2017 
> (Study Day of last dose + 
1) 
Follow-up 
Study Day of last dose + 
14