Raltegravir Pharmacokinetics and Safety in Neonates
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

IMPAACT P1097 
 
RALTEGRAVIR PHARMACOKINETICS AND SAFETY IN NEONATES 
 
A Multi-center 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:  
Merck & Co., Inc. 
 
IND # 77,787 held by NIAID 
DAIDS ES ID# 11790 
 
 
 
IMPAACT HIV Treatment  
Scientific Committee Chair:  
Elaine Abrams, M.D., Chair  
 
 
Protocol Chair: 
 Diana F. Clarke, Pharm. D. 
 
 
 
 
Protocol Vice Chairs: 
 Yvonne Bryson, M.D. 
 
 Mark H. Mirochnick, M.D. 
 
NIAID Medical Officer: 
 Elizabeth Smith, M.D. 
 
NICHD Medical Officer: 
 Lynne Mofenson, M.D., F.A.A.P. 
 
Clinical Trials Specialist: 
 Kat Richards, M.P.H. 
 
 
Version 2.0 
22 January 2014

IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
IMPAACT P1097 PROTOCOL TEAM ROSTER 
 
All questions concerning this protocol should be sent via e-mail to 
impaact.teamp1097@fstrf.org.  Remember to include the subject’s PID when applicable. The 
appropriate team member will respond to questions via e-mail with a "cc" to 
impaact.teamp1097@fstrf.org.  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 
by fax at 1-800-418-3544 or 301-897-1701.  For EAE questions, e-mail 
DAIDSRSCsafetyoffice@tech-res.com or call 1-800-537-9979 or 301-897-1709 or fax 1-800-
275-7619 or 301-897-1710. For enrollment questions, contact the Data Management Center at 
716-834-0900 or by e-mail at sdac.random.desk@fstrf.org .  
 
Protocol Chair 
Diana F. Clarke, Pharm.D. 
Section of Pediatric Infectious Diseases 
Boston Medical Center 
670 Albany Street, 6th Floor 
Boston, MA 02118 
Phone: 617-414-7508 
E-mail: diana.clarke@bmc.org 
 
Protocol Vice Chairs 
Yvonne Bryson, M.D. 
UCLA-Los Angeles/Brazil AIDS 
Consortium 
10833 Le Conte Avenue, MDCC 22-442 
Los Angeles, CA 90095-1752 
Phone: 310-825-5235 
E-mail: ybryson@mednet.ucla.edu 
 
Mark H. Mirochnick, M.D. 
Chief, Division of Neonatology 
Boston Medical Center 
771 Albany Street, Room 4111 
Boston, MA 02118 
Phone: 617-414-3754 
E-mail: markm@bu.edu 
 
 
 
 
 
 
 
NIAID/DAIDS Medical Officer  
Mary Elizabeth Smith, M.D. 
IMAPB/DAIDS/NIAID/NIH/DHHS 
6700-B Rockledge Drive, Room 5157  
Bethesda, MD  20892-7624 
Phone: 301-402-3226 
E-mail: betsysmith@niaid.nih.gov 
 
NICHD Medical Officer 
Lynne Mofenson, M.D., F.A.A.P.  
Chief, Maternal and Pediatric Infectious 
Disease Branch 
Eunice Kennedy Shriver NICHD   
6100 Executive Blvd., Room 4B11 
Rockville, MD 20852 
Phone: 301-435-6870 
E-mail: lm65d@nih.gov 

IMPAACT P1097 
 
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Clinical Trials Specialist  
Kat Richards, M.P.H. 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 27701 
Phone:  919-544-7040 ext. 11306 
E-mail:  krichards@fhi360.org 
 
Protocol Statistician 
Mae P. Cababasay, M.S., M.A. 
Center for Biostatistics in AIDS Research 
Harvard School of Public Health 
651 Huntington Ave 
Boston, MA  02115-6017 
Phone: 617-432-4516 
E-mail: maec@sdac.harvard.edu 
 
Jiajia Wang, M.S. 
Center for Biostatistics in AIDS Research 
Harvard School of Public Health 
651 Huntington Avenue 
Boston, MA  02115 
Phone: 617-432-1464 
Email: jwang@sdac.harvard.edu 
 
Protocol Data Managers 
Bobbie Graham, B.S. 
Frontier Science & Technology Research 
Foundation  
4033 Maple Road  
Amherst, NY  14226-1056 
Phone: 716-834-0900, ext 7265 
E-mail: graham.bobbie@fstrf.org 
 
John Gaeddert, MPH 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900, ext 7477 
E-mail: gaeddert.john@fstrf.org 
 
 
 
 
Pharmaceutical Company Representatives 
Hedy Teppler, M.D. 
Executive Director, Clinical Research 
Merck Research Laboratories 
351 N. Sumneytown Pike 
P.O. Box 1000 
North Wales, PA 19454-2505 
Phone: 267-305-7403 
E-mail: hedy_teppler@merck.com 
 
Carolee Welebob, M.S. 
Associate Principal Scientist 
Merck Research Laboratories 
351 N. Sumneytown Pike, 
P.O. Box 1000 
North Wales, PA 19454-2505 
Phone: 267-305-7587 
E-mail: carolee_welebob@merck.com 
 
Elizabeth Rhee, M.D. 
Principal Scientist, Clinical Pharmacology 
Merck Research Laboratories  
2000 Galloping Hill Road, K-15-3-3005  
Kenilworth, NJ 07033 
Phone: 908-740-4849 
E-mail : elizabeth_rhee@merck.com 
 
Matthew Rizk, Ph.D. 
Associate Principal Scientist 
Merck Research Laboratories 
770 Sumneytown Pike, WP 75B-110 
West Point, PA 19486 
E-mail: matthew_rizk@merck.com 
 
Larissa Wenning, PhD 
Senior  Principal Scientist 
Merck  Research Laboratories 
351 N. Sumneytown Pike, P.O. Box 1000 
North Wales, PA 19454-2505 
Phone: 267-305-4345 
E-mail: Larissa_wenning@merck.com 

IMPAACT P1097 
 
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Laboratory Technologist 
Patricia Anthony, C.L.S., M.T. (ASCP) 
Laboratory Manager 
University of Southern California 
Maternal, Child, and Adolescent Virology 
Research Laboratory 
1801 E. Marengo Street 
Los Angeles, CA 90033 
Phone: 323-226-4162 
E-mail: patricia.anthony@usc.edu 
 
Protocol Immunologist 
Katherine Luzuriaga, M.D. 
Professor of Pediatrics  
University of Mass. Med. School  
Biotech II, Suite 318  
373 Plantation St.  
Worcester, MA  01605-2377 
Phone: 508-856-6282 
E-mail: katherine.luzuriaga@umassmed.edu 
 
Protocol Pharmacologist 
Edward P. Acosta, Pharm. D. 
Division of Clinical Pharmacology  
Department of Pharmacology and 
Toxicology  
1530 3rd Avenue South, VH 116  
Birmingham, AL  35294-0019 
Phone: 205- 934-2655 
E-mail: eacosta@uab.edu 
 
 
 
 
 
 
Protocol Virologists 
Deborah Persaud, M.D. 
Associate Professor 
Johns Hopkins University School of 
Medicine Pediatric Infectious Diseases 
200 N. Wolfe Street PMOB 3-3151  
Baltimore, MD 21287 
Phone: 443-287-3733 
E-mail: dpers@jhmi.edu 
 
Stephen A. Spector, M.D. 
University of California, San Diego  
Department of Pediatrics, Division of 
Infectious Diseases  
Stein Clinical Research Bldg, Room 430  
9500 Gilman Dr., Mail Code 0672  
La Jolla, CA  92093-0672 
Phone: 858-534-7055 
E-mail:saspector@ucsd.edu 
 
Laboratory Data Coordinator  
Derek Weibel  
Frontier Science and Technology Research 
Foundation  
4033 Maple Rd  
Amherst, NY  14226  
Phone: 716- 834-0900, ext 7463  
E-mail: weibel@fstrf.org 
 
Field Representative 
Catherine Kneut, C.P.N.P., M.S. 
CHAP, 301 Longwood Avenue 
Boston, MA 02111 
Phone: 617-355-7879 
E:mail: 
catherine.kneut@childrens.harvard.edu 
 

IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
SUMMARY OF CHANGES for P1097 
 
Raltegravir Pharmacokinetic and Safety in Neonates, Version 2.0, dated 22 January 2014 
 
All changes in this version appear in boldface type.  Editorial changes, including corrections of 
typographical errors and other changes required to update information that does not affect 
regulatory issues or subject consent may also be included.  
 
P1097, Version 1.0, dated 12/22/10 enrolled full term infants and closed to follow-up on 
2/21/13.  P1097 is being amended to enroll a new study population, low birth weight infants.  
All information pertaining to Version 1.0 is being retained in the amendment and the full term 
cohort that is closed to follow-up in Version 1.0 has been retroactively named Cohort 1. The 
new population being studied in the amendment, low birth weight infants, is named Cohort 2.  
Cohort 1 and Cohort 2 designations appear in all appropriate sections of the protocol. 
 
1) The cover page has been updated to include Merck & Co., Inc. as providing Pharmaceutical 
Support and the DAIDS Document ID Number.  
 
2) The Team Roster has been updated.   
 
3) The Glossary has been updated. 
 
4) The Schema has been revised to describe the fully accrued and closed to follow-up of full 
term infants in Cohort 1, and the new study population of low birth weight infants in Cohort 2. 
  
5) Section 1.1, last sentence added: In addition, the use of raltegravir immediately prior to 
delivery in the HIV-infected mother in preterm labor may provide sufficient raltegravir drug 
levels in preterm infants at the time of birth to provide protection against peripartum HIV 
transmission.   
 
6) Section 1.11, Recent raltegravir data from Version 1.0 and in vitro analysis, has been added 
to describe washout elimination of raltegravir in full term infants studied in P1097, Version 
1.0. 
 
7) Section 1.12, Background and rationale for opening Version 2.0, Cohort 2 (low  
birth weight infants), has been added to describe the rationale for studying raltegravir in low 
birth weight infants. 
 
8) Section 1.21, Raltegravir Pharmacokinetics in Adults, 3rd paragraph, 1st sentence has been 
added: Raltegravir is approved for use in both adults and children (age ≥2 years of age and 
weighing ≥10 kg).  Raltegravir is commercially available as the 400 mg film-coated 
(poloxamer) tablet and the 100 mg and 25 mg chewable tablets.   
 

IMPAACT P1097 
 
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9) Section 1.24, Raltegravir in Children, 1st paragraph, 3rd sentence has been added: These 
data have supported the approval of the raltegravir film-coated tablet in children and 
adolescents ≥12 years of age and the chewable tablet in children and adolescents 2 to <12 years 
of age.  
 
10) Section 1.24, Raltegravir in Children, 2nd paragraph has been added: Raltegravir in the 
investigational oral granules for suspension formulation in children ≥4 weeks to < 2 years of 
age is currently being studied in IMPAACT P1066. PK and safety data in this age group are 
now available, including  in children 6 months to < 2 years of age (31) and an abstract by 
Frenkel, et al, in infants 4 weeks to <6 months of age (32). For infants ≥6 months to <2 years of 
age, the GM t1/2 was 3.0 hours (range:  1.9-7.4 hours, n=8). For infants ≥4 weeks to <6 months 
of age, the GM t1/2 was 8.2 hours (range:  2.5-111 hours, n=11).  The younger children 
demonstrated a prolonged distribution phase that made direct estimation of raltegravir 
pharmacokinetic parameters difficult and a modeling approach was used to estimate these 
parameters, which may be responsible for some of the apparent increase in raltegravir 
elimination t1/2 in these subjects. 
 
11) Section 1.25, Special Concerns for the Use of Raltegravir in the Neonate, has been revised 
to describe the effect of raltegravir on bilirubin-albumin binding and to provide mean 
standard deviation unbound bilirubin concentrations in Table 2. 
 
12) Section 1.26, Results of Cohort 1 Full Term Neonates Enrolled in P1097, Version 1.0, has 
been added to describe study population accrual and demographics, and the safety and 
washout pharmacokinetics of raltegravir when given to the mother and passed 
transplacentally to full term infants enrolled in Cohort 1 in Version 1.0. 
 
13) Section 3.0, Study Design, Cohort 1 and Cohort 2 designations have been added and the 
following sections have been added: 
 
Version 1.0, Cohort 1 
 
Version 1.0, Cohort 1 enrolled full term infants and is fully accrued and closed to follow-up. 
Cohort 1 women were followed until discharge from the labor/delivery units while their infants 
were followed for 20 weeks after birth.  
 
Version 2.0, Cohort 2  
 
Version 2.0, Cohort 2 will enroll up to 20 mother-infant pairs to achieve 15 evaluable low birth 
weight infants (≤2500 grams at birth).  
 
Mother/infant pairs may be enrolled prior to delivery or within 48 hours after birth.  In 
addition, infants may be enrolled up to 48 hours after birth if birth weight  ≤ 2500 grams and 
born to an HIV-infected pregnant woman who received at least one dose of raltegravir 400 mg 
within 2 to 24 hours prior to delivery.  All infants will have a history, physical examination, 

IMPAACT P1097 
 
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22 January 2014 
 
and hematology and chemistry laboratory evaluations performed around the time of birth and 
at a week 1-2 follow-up visit.   
 
When possible, cord blood will be drawn immediately after cord is clamped and a single blood 
sample will be collected in women within one hour after delivery to determine maternal 
plasma raltegravir concentration.   
 
Women will be followed until discharge from the labor/delivery unit. Infants will be followed 
for 6 weeks after birth. Since no toxicities attributed to raltegravir exposure were observed in 
Cohort 1 at the 6 or 20 week visits, and since raltegravir is not administered to infants in this 
study, infants in Cohort 2 will have their last study visit at 6 weeks of age. 
 
Only infants who meet the following criteria are eligible for pharmacokinetic blood sampling 
in Cohort 2: 
• Infant born to woman who received at least one dose of raltegravir within  
2 to 24 
hours prior to delivery.  Dose administered to mother must have  been at least 2 hours 
prior to delivery to allow time for adequate  
absorption and distribution. 
• Infant birth weight ≤ 2500 grams. 
• Infant not receiving disallowed medications described in Section 4.8.  If  these 
medications are required for the infant’s care, the infant will be  ineligible for further 
PK (pharmacokinetic) sampling.  Data will be  
 
obtained up to the time of the 
introduction of the disallowed medication,  but such infant will not be considered one of 
the evaluable 15 infants. 
• Infant ≤ 48 hours of age. 
 
Blood samples for raltegravir assay will be collected at 1-6, 12-24, 36-48, 72-84, and 108-132 
hours after birth, and on day 7-14.  Infants may enroll up to 48 hours of age, and any 
pharmacokinetic samples scheduled for collection prior to the time of enrollment will be 
skipped and not replaced.  Safety/toxicity laboratory samples scheduled for collection prior to 
the time of enrollment must be collected after enrollment.  Infants enrolling close to the 48-
hour time point should have the first pharmacokinetic blood sample collected within 4 hours of 
enrollment (i.e., within 52 hours after birth) so that a minimum of three blood samples can be 
obtained for pharmacokinetic evaluation. 
 
With regard to infant blood samples for safety/toxicity laboratory testing:  In the event that 
the study-required study safety/lab samples have not been collected prior to enrollment, (e.g., 
due to infant enrolled after delivery), these must be collected as soon as possible after 
enrollment.   
 
14) Section 3.0, Study Design, 9th paragraph, 2nd sentence changed to read: To meet the primary 
objectives of the study, only those infants who have at least 3 pharmacokinetic blood samples 
collected from the first 5 time points will be considered to be evaluable. 
 
15) Section 3.0, Study Design, 10th paragraph, 1st and 2nd sentences changed to read: 

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Optional genotyping for polymorphisms of UGT1A1 were performed on Cohort 1 infants and 
will be performed on Cohort 2 infants who undergo pharmacokinetic sampling.  The goal of the 
genotypic analysis is to determine if certain polymorphisms, particularly those with the 
UGT1A1*28/*28 genotype have slower RAL elimination than those with the UGT1A1*1/*1 
genotype. 
 
16) Section 3.0, Study Design, 12th paragraph, 4th sentence changed to read:  Refer to Appendix 
II-A, Cohort 2 Maternal Schedule of Evaluations and Appendix II-B, Cohort 2 Infant Schedule 
of Evaluations, for a complete description of the clinical and laboratory evaluations to be performed 
for Cohort 2. 
 
17) Section 4.0, Selection and Enrollment of Subjects, has been revised to state that eligibility 
criteria for Cohort 1 can be found in Version 1.0 of the protocol and to add eligibility criteria 
for Cohort 2 mothers and infants. 
 
18) Section 6.3, Premature Discontinuation/Early Withdrawal/ Safety Follow-up for PK 
Unevaluable Infants, 2nd paragraph has been added:  
Cohort 2: If fewer than 3 pharmacokinetic samples from the first 5 time points are collected, 
the infant is not considered evaluable for pharmacokinetics but will continue with scheduled 
safety evaluations.  If the parent withdraws consent at any time after enrollment, no further 
information will be collected and additional laboratory evaluations will not be performed.   
 
19) Section 8.0, Statistical Considerations, has been revised to update information for Cohorts 
1 and 2. 
 
20) Section 9.3, Study Design, Modeling and Data Analysis, 4th, 5th, and 6th paragraphs, have 
been added: 
 
Cohort 2 
There will be no infant dosing for this study. Women must have received at least one dose of 
raltegravir within 2 to 24 hours prior to delivery.  Dose must be administered at least 2 hours 
prior to delivery to allow adequate time for absorption and distribution. 
 
Maternal and cord blood raltegravir concentrations: When possible one maternal blood 
sample will be obtained within one hour after delivery and a single cord blood specimen will be 
obtained at the time of birth. For infants enrolled after delivery up to 48 hours after birth, it 
will not be possible to obtain maternal or cord blood samples. 
 
Neonatal raltegravir concentrations: Blood samples for raltegravir assay will be collected at 1-
6, 12-24, 36-48, 72-84, and 108-132 hours after birth, and on day 7-14.  Infants may enroll up 
to 48 hours of age, and any pharmacokinetic samples scheduled for collection prior to the time 
of enrollment will be skipped and not replaced.  Infants enrolling close to the 48-hour time 
point should have the first pharmacokinetic blood sample collected within 4 hours of 
enrollment (i.e., within 52 hours after birth) so that a minimum three blood samples can be 
obtained for pharmacokinetic evaluation. 

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21) Section 10.1, Institutional Review Board and Informed Consent, 1st sentence has been 
revised: This protocol, the informed consent documents (Appendix IV-A and IV-B), and any 
subsequent modifications must be reviewed and approved by the Institutional Review Board 
(IRB) or Ethics Committee (EC) responsible for oversight of the study. 
 
22) Appendix I-B, Cohort 2 Maternal Schedule of Evaluations, has been added. 
 
23) Appendix II-B, Cohort 2 Infant Schedule of Evaluations, has been added. 
 
24) Appendix III, P1097 Testing Laboratories, has been added. 
 
25) Appendix IV-B, Sample Informed Consent for Cohort 2, has been added. 

IMPAACT P1097 
 
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TABLE OF CONTENTS 
 
GLOSSARY……………………………………………………………………………………….1 
 
SCHEMA …………………………………………………………………………………………2 
 
1.0 
INTRODUCTION ………………………………………………………………………………… .4 
 
1.1 
Background and Rationale…………………………………………………………………... .4 
 
1.2 
Raltegravir…………………………………………………………………………………… .6 
 
2.0 
STUDY OBJECTIVES…………………………………………………………………………....14 
 
2.1 
Primary Objectives ……………………………………………………………………. 14 
 
2.2 
Secondary Objective…………………………………………………………………………. 15 
 
3.0 
STUDY DESIGN………………………………………………………………………………….. 15 
 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS…………………………………………….. 17 
 
4.1 
Maternal Inclusion Criteria, Cohort 2 - M-I pairs enrolled prior to delivery…………….17 
 
4.2 
Maternal Exclusion Criteria, Cohort 2 M-I pairs enrolled prior to delivery……………..19 
 
4.3 
Infant PK blood sampling eligibility Criteria, for Cohort 2 M-I pairs enrolled prior to   
Delivery……………………………………………………………………………… 19 
 
4.4 
Maternal Inclusion Criteria, Cohort 2 M-I pairs enrolled after delivery……………………. 20 
 
4.5 
Maternal Exclusion Criteria,  Cohort 2 M-I pairs enrolled after delivery ………………….20 
 
4.6 
Infant Inclusion Criteria, Cohort 2 M-I pairs enrolled after delivery……………………….. 20 
 
4.7 
Infant Exclusion Criteria, Cohort 2 M-I pairs enrolled after delivery………………………. 20 
 
4.8 
Disallowed Medications…………………………………………………………………….. 21 
 
4.9 
Enrollment Procedures……………………………………………………………………… 21 
 
4.10 Co-enrollment Procedures…………………………………………………………………… 22 
 
5.0 
STUDY TREATMENT……………………………………………………………………………22 
 
6.0 
SUBJECT MANAGEMENT………………………………………………………………………. 22 
 
6.1 
Toxicity Management………………………………………………………………………. 22 
 
6.2 
Permanent Study Discontinuation…………………………………………………………… 23 
 
6.3 
Premature Discontinuation/Early Withdrawal/Safety follow-up for PK unevaluable infants..23 
 
7.0 
EXPEDITED ADVERSE EVENT REPORTING………………………………………………… 23 
 
8.0  
STATISTICAL CONSIDERATIONS……………………………………………………………… 24 
 
8.1 
General Design Issues………………………………………………………………………. 24 
 
8.2 
Outcome Measures ……………………………………………………………………..25 
 
8.3 
Randomization and Stratification……………………………………………………………. 25 
 
8.4 
Sample Size and Accrual ………………………………………………………………26 
 
8.5 
Monitoring…………………………………………………………………………………… 27 
 
8.6 
Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
28 

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9.0 
CLINICAL PHARMACOLOGY PLAN…………………………………………………………………29 
 
9.1 
Pharmacology Objective…………………………………………………………………………..29 
 
9.2 
Primary and Secondary Data……………………………………………………………………...29 
 
9.3 
Study Design, Modeling and Data Analysis……………………………………………………...29 
 
9.4 
Anticipated Outcomes…………………………………………………………………………….31 
 
10.0 HUMAN SUBJECTS……………………………………………………………………………………..31 
 
10.1 Institutional Review Board and Informed Consent………………………………………………31 
 
10.2 Subject Confidentiality…………………………………………………………………………….31 
 
10.3 Study Discontinuation……………………………………………………………………………..32 
 
11.0 PUBLICATION OF RESEARCH FINDINGS…………………………………………………………..32 
 
12.0 BIOHAZARD CONTAINMENT………………………………………………………………………...32 
 
13.0 REFERENCES……………………………………………………………………………………………33 
 
APPENDICES: 
 
APPENDIX I-A: COHORT 1 MATERNAL SCHEDULE OF EVALUATIONS (CLOSED)……….38
 
 
 
APPENDIX I-B: COHORT 2 MATERNAL SCHEDULE OF EVAUATIONS……………………...39 
 
APPENDIX II-A: COHORT 1 INFANT SCHEDULE OF EVALUATIONS (CLOSED)……………...40 
 
APPENDIX II-B: COHORT 2 INFANT SCHEDULE OF EVALUATIONS……………………...41 
 
APPENDIX III: P1097 TESTING LABORATORIES 
……………………………………………...42 
 
APPENDIX IV-A: DAIDS SAMPLE INFORMED CONSENT FOR COHORT 1 (CLOSED)……….43 
 
APPENDIX IV-B: DAIDS SAMPLE INFORMED CONSENT FOR COHORT 2………………...49 

 
IMPAACT P1097 
 
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Page 1 of 54 
 
GLOSSARY 
 
3TC 
 
 
 
Lamivudine 
ALT 
 
 
 
Alanine aminotransferase 
ARV  
 
 
Antiretroviral  
AST 
 
 
 
Aspartate aminotransferase 
AUC  
 
 
Area under the curve 
BID 
 
 
 
Twice a day 
CBC  
 
 
Complete blood count 
CI  
 
 
 
Confidence interval 
d4T 
 
 
 
Stavudine 
DAIDS PRO   
Division of AIDS Protocol Registration Office 
DMC  
 
 
Data Management Center 
EAE 
 
 
 
Expedited adverse event 
EC  
 
 
 
Ethics Committee 
FTC 
 
Emtricitabine 
HAART 
 
Highly active antiretroviral therapy 
 
 
 
HIV  
 
 Human immunodeficiency virus 
IMPAACT      
 International Maternal Pediatric Adolescent AIDS Clinical Trials 
Group 
IRB 
 
Institutional Review Board 
LAR 
 
Legally authorized representative 
LBW 
 
Low birth weight 
LDMS 
 
Laboratory Data Management System   
MD  
 
Multiple dose 
M-I  
 
Mother-infant pairs 
NFV  
 
Nelfinavir 
NVP  
 
Nevirapine 
OHRP 
 
Office for Human Research Protections 
PID  
 
Patient Identification Number 
PK 
 
Pharmacokinetic 
PMTCT 
 
Prevention of Mother-to-Child Transmission   
QD  
 
Once a day 
RAL  
 
Raltegravir 
RE 
 
 
Regulatory entity 
RSC  
 
Regulatory Support Center 
SD 
 
 
Single dose 
SES  
 
Subject enrollment system 
SID  
 
Study Identification Number 
UDP  
 
Uridine diphosphate 
UGT  
 
Uridine diphosphate glucuronyl transferase 
ZDV  
 
Zidovudine 
 

 
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SCHEMA 
 
RALTEGRAVIR PHARMACOKINETICS AND SAFETY IN NEONATES  
 
DESIGN: 
Phase 0, multicenter, washout pharmacokinetic trial 
 
SAMPLE SIZE:  
Cohort 1 (Closed): 15 evaluable mother-infant 
pairs for the washout pharmacokinetic analysis 
(which is projected to require enrolling 25 mother-
infant pairs) 
 
Cohort 1 was fully accrued and closed to follow-
up under Version 1.0. The protocol is being 
amended to include low birth weight (LBW) 
infants in Version 2.0. 
 
Cohort 2: 15 evaluable low birth weight (LBW) 
infants (≤2500 grams at birth) for the washout 
pharmacokinetic analysis, and their mothers 
(projected to require enrolling 20 mother-infant 
pairs) 
 
POPULATION: 
Cohort 1 (Closed): HIV-infected pregnant women 
receiving raltegravir (RAL) 400mg twice daily for 
at least two weeks prior to delivery and continuing 
to receive ARVs during labor, and their infants. 
 
 
Cohort 2: HIV-infected pregnant women who 
received at least one dose of raltegravir (RAL) 
400mg within 2 to 24 hours prior to delivery and 
their LBW infants ≤ 2500 grams at birth. 
 
STRATIFICATION: 
None   
 
REGIMEN: 
No study-specific treatment will be given during 
this study.  
 
STUDY DURATION:  
Women will be followed until discharge from the 
labor/delivery unit. 
Cohort 1 infants (Closed): Infants will be  
 
followed for 20 weeks after birth. 
 
Cohort 2 infants will be followed for 6 weeks 
after birth based on lack of toxicity observed in 
Cohort 1 (See Section 1.26).  

 
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PRIMARY OBJECTIVES: 
 
1. To evaluate the washout pharmacokinetics of raltegravir in infants born to HIV-
infected pregnant women receiving raltegravir during pregnancy. 
 
2. To evaluate bilirubin levels and the safety of in utero/intrapartum exposure to 
raltegravir in infants born to HIV-infected pregnant women receiving raltegravir 
during pregnancy. 
 
3. To develop a neonatal raltegravir dosing regimen to be evaluated in a follow-up study 
of this protocol.  
 
SECONDARY OBJECTIVE: 
 
1. To investigate the relationship between neonatal raltegravir elimination and UGT1A1 
genotype. 
 

 
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1.0 
INTRODUCTION 
 
1.1 
Background and Rationale 
 
Alternative antiretroviral (ARV) agents for use in neonates are urgently 
needed for both HIV prophylaxis and treatment.  Postnatal prophylaxis 
with multiple antiretroviral agents is currently recommended for neonates 
at high risk for HIV infection. Turn-around time for diagnostic tests of 
HIV infection has improved in recent years, and HIV infected neonates are 
now routinely identified in the first weeks of life.  These infants require 
immediate initiation of ARV treatment with potent three-drug combination 
ARV regimens.  Strategies for early treatment of HIV-infected newborns 
with more intensive four drug regimens have been proposed, with a goal 
of either improving outcome or eradicating infection. 
There are limited safety and dosing information for ARVs in neonates.  
Only zidovudine (ZDV), lamivudine (3TC), emtricitabine (FTC), 
nevirapine (NVP), and stavudine (d4T) are approved for use in neonates < 
14 days of age.  Nelfinavir (NFV) pharmacokinetics and safety have been 
studied in neonates, but its use is not approved in children less than 2 
years old.  The three-drug ARV regimen with the greatest experience in 
neonates is ZDV/3TC/NVP.  Of the protease inhibitors, only NFV has 
pharmacokinetic data available for neonates, but these data demonstrate 
highly variable plasma concentrations and the optimal dosing regimen 
remains uncertain [1,2].  Lopinavir/ritonavir, another protease inhibitor, is 
available as a pediatric solution, but dosing is uncertain in the first weeks 
of life and its use has been discouraged in neonates after several cases of 
life-threatening bradyarrhythmias and cardiac dysfunction were reported 
in preterm infants [3,4].   
Raltegravir has the potential to play an important role in both prophylaxis 
and treatment of infants at high risk of HIV-1 infection.  Raltegravir, an 
integrase inhibitor, has a unique mechanism of action, is extremely potent 
against HIV, and is well tolerated in children and adults.  Overall, the 
currently available preclinical and clinical data support the evaluation of 
this highly promising antiretroviral agent in HIV-exposed neonates who 
are at high risk of becoming infected. The primary goal of this protocol is 
to describe raltegravir pharmacokinetics in infants < four weeks of age in 
order to develop an appropriate raltegravir dosing regimen for prophylaxis 
or treatment of HIV in neonates.  This current study will determine 
washout pharmacokinetics of raltegravir in HIV-exposed neonates born to 
mothers receiving raltegravir during pregnancy. These data plus 
pharmacokinetic data from raltegravir pharmacokinetic studies in HIV-
infected older infants will be used to develop a dosing regimen for 
raltegravir in infants at high risk of acquiring HIV-1 infection that will be 

 
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evaluated in a subsequent follow-up study. In addition, the use of 
raltegravir immediately prior to delivery in the HIV-infected mother 
in preterm labor may provide sufficient raltegravir drug levels in 
preterm infants at the time of birth to provide protection against 
peripartum HIV transmission.   
 
1.11  Recent raltegravir data from Version 1.0 and in vitro analysis: 
Washout elimination of raltegravir in term infants studied in 
Version  1.0 of P1097 was prolonged but highly variable, with a 
median half-life of 26.6 hours and a range of 9.3 to 184 hours 
[5]. It is crucial to understand raltegravir pharmacokinetics in 
all newborn populations who may receive this drug in order to 
develop developmentally appropriate dosing regimens that will 
avoid accumulation of  raltegravir to potentially toxic 
concentrations.   
 
1.12   Background and rationale for opening Version 2.0, Cohort 2 
(low birth weight infants):  In mid and lower income settings, 
prematurity and/or low birth weight (LBW) occurs in 20% of 
pregnancies [6].  Maternal HIV infection is associated with an 
increased rate of preterm delivery and LBW, and HIV exposed 
infants who are premature or LBW are more likely to become 
HIV infected [7]. It is critically important to develop new and 
potentially more effective antiretroviral regimens for use in all 
neonates of all gestational ages, and especially for LBW infants 
for both postnatal prophylaxis to prevent mother-to-child 
transmission and for early treatment of HIV infection. 
 
There are few antiretroviral agents with sufficient safety and 
pharmacokinetic data to allow their safe use in the term 
neonate, and only zidovudine (ZDV) can be used safely in 
LBW infants [8]. The physiologic immaturity of premature 
and LBW infants has a major impact on pharmacokinetics and 
any drug proposed for use in this population must be studied 
directly in such infants to obtain the necessary 
pharmacokinetic and safety data.  The only ARV that has been 
well studied in LBW infants is ZDV [9]. These data 
demonstrated a reduction in ZDV elimination associated with 
prematurity/LBW and resulted in development of a 
gestational-age specific ZDV dosing regimen for 
premature/LBW  infants.  There is a critical need for 
analogous safety and pharmacokinetic data for additional 
antiretrovirals to be used in potent combination regimens in 
LBW infants, and raltegravir is high on the list of 
antiretrovirals that need to be studied.  Raltegravir has  the 

 
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potential to play an important role in both prophylaxis and 
treatment of infants at high risk of HIV-1 infection.  
 
1.2 
Raltegravir  
 
Raltegravir (Isentress™) is a potent and selective HIV-1 integrase 
inhibitor.  Integrase, one of three HIV-1 enzymes required for viral 
replication, catalyzes the stepwise process which results in the integration 
of the HIV-1 DNA into the genome of the host cell.  Raltegravir inhibits 
HIV-1 replication by interfering with this process of integration. The drug 
is well tolerated and has demonstrated potent HIV-1 suppression in 
treatment naïve and experienced adults [10-16].   
 
1.21  Raltegravir Pharmacokinetics in Adults 
 
There is considerable variability in the pharmacokinetics of 
raltegravir.  In adults raltegravir has an initial (α) t ½ of 
approximately 1 hour and a terminal elimination (β) t ½ of 
approximately 7 to 12 hours [17].  In normal adults, approximately 
7-14% of an administered raltegravir dose is excreted unchanged 
in urine.  The primary route of raltegravir elimination is hepatic 
metabolism by UDP (uridine diphosphate)-
glucuronosyltransferases (UGT), primarily UGT1A1 but with 
minor contributions from UGT1A3 and UGT1A9, followed by 
excretion of raltegravir-glucuronide via stool and urine [18].   
 
Moderate hepatic insufficiency and severe renal insufficiency also 
had no clinically meaningful effect on raltegravir pharmacokinetics 
[19].   
 
Raltegravir is approved for use in both adults and children 
(age ≥2 years of age and weighing ≥10 kg).  Raltegravir is 
commercially available as the 400 mg film-coated (poloxamer) 
tablet and the 100 mg and 25 mg chewable tablets.  Raltegravir 
poloxamer tablets are rapidly absorbed after oral administration, 
with Tmax averaging 3-4 hours in the fasted or fed states [20]. 
Current dosing guidelines are to administer raltegravir without 
regard to food [21].  Raltegravir is approximately 83% bound to 
plasma protein.   
 
1.22 
Summary of Raltegravir Drug-Drug Interactions 
 
The potential for raltegravir drug-drug interactions was 
investigated in a series of clinical studies in uninfected subjects.  
Comparison of raltegravir pharmacokinetics in the absence and 
presence of ritonavir, efavirenz, or etravirine indicated no 

 
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clinically significant effect on raltegravir C12 hr to warrant dose 
adjustment.  Co-dosing of raltegravir with atazanavir resulted in an 
increase in raltegravir pharmacokinetic parameters by ~50 to 100% 
(AUC, Cmax, and C12 hr); however, the degree of increase does not 
warrant raltegravir dose adjustment when these drugs are co-
administered.  Plasma levels of raltegravir were modestly 
increased by co-dosing with atazanavir and ritonavir, although the 
effect was somewhat less than that observed for atazanavir alone 
[22]. Co-dosing of raltegravir with tenofovir disoproxil fumarate 
indicates that raltegravir C12 hr was similar in the presence and 
absence of tenofovir while raltegravir AUC0-12 hr and Cmax values 
were modestly increased.  Additionally, co-administration of the 2 
drugs did not substantially affect the overall plasma 
pharmacokinetic profile of tenofovir.  Rifampin co-administered 
with raltegravir resulted in lower raltegravir plasma concentrations.  
The geometric mean raltegravir C12 hr is 60% lower in the presence 
versus absence of rifampin.  Approximately 40% lower AUC and 
Cmax values were also observed for raltegravir following rifampin 
treatment [23].  When administration of raltegravir 800 mg q12h 
coadministered with rifampin was compared with administration of 
standard raltegravir doses of 400 mg q12h without rifampin, 
administration of the larger dose with rifampin resulted in a 27% 
increase in AUC, a 62% increase in Cmax  but a 53% decrease in 
C12hr [24]. Doubling the dose of raltegravir in the presence of 
rifampin compensates for the effect of rifampin on raltegravir 
AUC and Cmax but does not overcome the effect of rifampin on 
raltegravir trough concentrations (C12) and raltegravir trough 
concentrations in the presence of rifampin are likely to be at the 
lower limit of clinical experience.  Midazolam is a known CYP 
3A4 substrate sensitive to drug interactions.  Co-administration of 
rifampin and midazolam is associated with a ~96% decrease in 
midazolam AUC.  In contrast, co-administration of raltegravir and 
midazolam has no effect on plasma levels of midazolam, implying 
that raltegravir is not an inducer or inhibitor of CYP3A4 [25]. 
 
 

 
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Table 1: Comparison of Drug-Drug Interactions of Raltegravir Plasma 
Pharmacokinetic Parameter: Mean % Effect on Raltegravir 
 
In summary, drug interaction studies to date have investigated the effects 
of strong inducers and inhibitors on raltegravir metabolism, and it is 
anticipated that these data would bracket the effects of other more modest 
inhibitors or inducers.  In particular, the impact on raltegravir of 
atazanavir (a UGT1A1 inhibitor) is modest and that of rifampin (a strong 
inducer) is clinically manageable.  Additionally, raltegravir was shown not 
to be an inducer or inhibitor of CYP3A4, as demonstrated in the 
midazolam interaction study, suggesting that raltegravir will not impact 
the pharmacokinetics of drugs metabolized by CYP3A4.   
 
1.23 
Raltegravir in Pregnancy for Prevention of Mother to Child     
Transmission of HIV 
 
There is limited data available describing raltegravir use during 
pregnancy.  The potential for integrase inhibitors to prevent 
establishment of infection in viral reservoirs of exposed individuals 
or attenuating infection have not been studied.  Raltegravir has 
been shown to induce a rapid decline in viral load and could be 
beneficial in women who present late in pregnancy with detectable 
virus [26].  
Antiretroviral 
C12h 
AUC † 
 
Cmax 
Atazanavir (ATV) ‡ 
 
↑ 100% 
↑ 73% 
↑ 53% 
ATV/RTV ‡ § 
 
↑ 77% 
↑ 41% 
↑ 24% 
Ritonavir (RTV) ‡ 
 
↓ 1% 
↓ 16% 
↓ 24% 
Efavirenz ‡ 
 
↓ 21% 
↓ 36% 
↓ 36% 
Tipranavir/RTV ‡ § 
 
↓ 55% 
↓ 24% 
↓ 18% 
Rifampin (400 mg RAL) ‡ 
 
↓ 61% 
↓ 40% 
↓ 38% 
Rifampin (800 mg RAL) §, || 
 
↓ 53% 
↑ 27% 
↓ 62% 
Tenofovir ‡ § 
 
↑ 3% 
↑ 49% 
↑ 64% 
Etravirine 
↓34% 
↓10% 
↓11% 
† AUC0-∞ for SD  raltegravir ; AUC0-12h for MD  raltegravir 
‡ Multiple doses of concomitant medication plus single dose (SD) of  raltegravir 
§ Multiple doses of concomitant medication plus multiple doses (MD) of  raltegravir 
|| 800 mg BID raltegravir + 600 mg QD rifampin compared to 400 mg BID raltegravir alone. 

 
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Raltegravir is currently being prescribed most commonly in 
pregnant women who are highly treatment experienced and have 
drug resistant virus or in women intolerant of other antiretroviral 
agents [27,28]. Rosenvinge et al. described 3 cases of raltegravir 
use during the 3rd trimester of pregnancy, reporting rapid reduction 
in maternal viral load.  Maternal raltegravir concentrations 3-9 
hours after delivery ranged from 22-493 ng/mL while infant 
concentrations 3-13 hours after delivery ranged from 209 – 3634 
ng/mL [29].  Pharmacokinetic data from 10 pregnant women 
during the 3rd trimester reported by Best et al., demonstrated 
raltegravir exposure equivalent to that seen in non-pregnant adults 
[30].  All subjects exceeded the target concentration of a 
raltegravir trough concentration of 33 ng/mL.  Cord blood and 
maternal delivery raltegravir concentrations were available from 7 
mother-infant pairs - median (range) cord blood raltegravir 
concentration was 125 (22-939) ng/mL, median (range) maternal 
plasma concentration was 145 (28-626) ng/mL and the ratio of 
cord blood/maternal plasma concentration was 1.20 (0.09-2.26). 
 
1.24 
Raltegravir in Children 
 
 
 
IMPAACT P1066, a study of the International Maternal, Pediatric, 
Adolescent AIDS Clinical Trials (IMPAACT) Group, entitled, “A 
Phase I/II, Multicenter, Open-Label, Non-comparative Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Antiretroviral Activity of Raltegravir (Isentress™, MK-0518) in 
HIV-1 Infected Children and Adolescents,” is a study of 3 
raltegravir formulations across the pediatric age range of 4 weeks 
to 18 years of age.  Raltegravir therapy was well tolerated and 
associated with significant improvements in virologic and 
immunologic outcomes.  These data have supported the 
approval of the raltegravir film-coated tablet in children and 
adolescents ≥12 years of age and the chewable tablet in 
children and adolescents 2 to <12 years of age.  
Raltegravir in the investigational oral granules for suspension 
formulation in children ≥4 weeks to <2 years of age is currently 
being studied in IMPAACT P1066, and PK and safety data in 
this age group are now available, including in children 6 
months to <2 years of age [31] and in an abstract by Frenkel, et 
al, in infants 4 weeks to <6 months of age [32]. For infants ≥6 
months to <2 years of age, the GM t1/2 was 3.0 hours (range: 
 1.9-7.4 hours, n=8). For infants ≥4 weeks to <6 months of age, 
the GM t1/2 was 8.2 hours (range:  2.5-111 hours, n=11).  The 

 
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younger children demonstrated a prolonged distribution phase 
that made direct estimation of raltegravir pharmacokinetic 
parameters difficult and a modeling approach was used to 
estimate these parameters, which may be responsible for some 
of the apparent increase in raltegravir elimination t1/2 in these 
subjects. 
1.25 
Special Concerns for the use of Raltegravir in the Neonate 
 
UGT1A1, the enzyme primarily responsible for raltegravir 
metabolism, is also the only enzyme that contributes to bilirubin 
glucuronidation in human hepatocytes, and as such is essential for 
the biliary elimination of bilirubin from the body [33]. 
Glucuronidation activity is low in fetuses and in the newborn 
immediately after birth but increases exponentially over the first 
weeks and months of life.  Hepatic UGT activity in liver samples is 
very low in samples from 2nd trimester fetuses, and increases 
roughly 10 fold during the 3rd trimester and then another 100-fold 
during the first 3 months following a full term delivery [34].  The 
low level of hepatic UGT activity at birth plays a major role in the 
elevations of bilirubin routinely seen in the newborn, referred to as 
physiologic jaundice.   
 
In adults, decreased UGT1A1 activity has been shown to result in 
increased plasma concentrations of both bilirubin and raltegravir.  
Atazanavir, an HIV protease inhibitor, is also an inhibitor of 
UGT1A1 and elevation of direct bilirubin is a very common side 
effect of atazanavir use in HIV infected adults.  When raltegravir 
and atazanavir are co-administered, raltegravir AUC increases on 
average by 41% and Cmax by 77% [22]. Similarly, the UGT1A1 
*28/*28 genotype, one of the common genotypes found in 
individuals with Gilbert’s Syndrome, is characterized by a roughly 
30% decrease in UGT1A1 activity and increased serum bilirubin 
concentrations [35,36]. Following standard dosing with raltegravir, 
individuals with the UGT1A1 *28/*28 genotype have on average 
an increase of 40% in raltegravir AUC and Cmax and of 90% in 
trough concentration compared to individuals with wild type 
UGT1A1.  Raltegravir elimination t ½ was not prolonged in the 
UGT1A1 *28/*28 individuals, suggesting that increased raltegravir 
bioavailability due to decreased hepatic first pass metabolism may 
play a major role in the increase in raltegravir plasma 
concentrations seen in these individuals [23].   
 
Administration of an exogenous drug that is eliminated by 
glucuronidation poses special risks in the newborn. Low UGT 

 
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activity that results in decreased elimination of endogenous 
bilirubin and physiologic jaundice will also result in decreased 
metabolism of an exogenous drug whose major elimination 
pathway is glucuronidation.  A neonatal dosing regimen for such a 
drug extrapolated from older infants or children may result in 
accumulation of unexpectedly high and potentially toxic plasma 
drug concentrations [37]. Chloramphenicol, a drug metabolized 
predominantly by glucuronidation that causes cardiovascular 
collapse at elevated plasma concentrations, provides the classic 
example of the harm that may result from using a drug in the 
newborn without an adequate understanding of its pharmacology in 
this population.  When chloramphenicol was first administered to 
neonates in the 1950s, the use of neonatal doses extrapolated from 
those used in older infants and children in ignorance of the low 
level of neonatal glucuronidation activity led to the accumulation 
of chloramphenicol to toxic concentrations and the clinical 
syndrome of fatal cardiovascular collapse known as gray baby 
syndrome [38]. More recently, elimination of zidovudine, which is 
also metabolized by hepatic glucuronidation, has been shown to be 
decreased in neonates, necessitating use of reduced doses during 
the first months of life in both term and preterm infants [39,40]. 
The reduction in neonatal zidovudine glucuronidation was 
associated not only with reduced clearance but also with higher 
bioavailability, consistent with decreased first pass metabolism 
[41].   
 
Another potential risk posed by neonatal administration of a drug 
metabolized by UGT1A1 is an increase in neonatal bilirubin levels.  
Since both the drug and bilirubin share the same elimination 
pathway via UGT1A1 metabolism, the drug may compete with 
bilirubin for UGT binding sites, leading to a further reduction in 
bilirubin clearance and an increase in total serum bilirubin.  This is 
unlikely to be a problem for raltegravir, which has a Km for 
UGT1A1 of 99 µM  and binds much less avidly to UGT than does 
bilirubin, which has a Km of 5 µM for  UGT1A1 [18]. Km, the 
Michaelis constant, is the substrate concentration at which an 
enzymatic reaction rate is at half its maximum speed.  A low Km 
value indicates high affinity between substrate and enzyme, while 
a high Km value indicates low affinity. 
 
Competition for neonatal albumin binding sites between bilirubin 
and an exogenous drug may also present a significant risk to the 
infant.  Under normal circumstances, most circulating bilirubin in 
the newborn is in the unconjugated (indirect) form rather than the 
glucuronidated (conjugated or direct) form.  Unconjugated 

 
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bilirubin bound by albumin and other plasma proteins is unable to 
cross the blood-brain barrier.  If the concentration of circulating 
unconjugated bilirubin exceeds the capacity of albumin for 
bilirubin binding, then the excess bilirubin will be unbound or 
“free”, with the potential to cross the blood-brain barrier and cause 
kernicterus [42]. In the newborn when bilirubin concentrations are 
high, a drug that displaces bilirubin from albumin binding sites 
may place the infant at increased risk of kernicterus and death, as 
was the case when sulfisoxazole was first used in premature 
neonates [43]. However, raltegravir is unlikely to cause a 
significant problem by displacement of bilirubin from albumin.  
The typical concentration of albumin in the healthy newborn 
ranges from about 3.5 to 4.5 g/dL, or 529 to 680 µmol/L [44]. The 
95% CI for raltegravir Cmax following 400 mg doses in adults is 
15.5 µmol/L.  After factoring in raltegravir protein binding of 83%, 
raltegravir should occupy approximately 2% of albumin under 
normal physiologic conditions, which should not increase 
kernicterus risk significantly.  In addition, raltegravir has a 
modest plasma binding activity which may indicate less affinity 
relative to bilirubin for the bilirubin binding site on albumin. 
By comparison, kernicterus developed in premature infants when 
sulfisoxazole concentrations exceeded 205 µmol/L [45].  
 
  
Evaluation for the potential of raltegravir displacement of bilirubin 
from albumin was performed in the laboratory of Dr. David 
Stevenson at Stanford University [42,44,45].  
 
 
The in vitro effect of raltegravir on bilirubin-albumin binding 
was measured in pooled neonatal serum using the peroxidase 
method. Raltegravir had minimal effect on bilirubin-albumin 
binding at concentrations of 5 and 10 µM, caused a small but 
statistically significant increase in unbound bilirubin at 100 
µM, and caused potentially harmful increases at 500 and 1000 
µM [46]. These data suggest that the effect of raltegravir on 
neonatal bilirubin binding is unlikely to be clinically significant 
at typical peak concentrations reached with usual dosing. The 
median (range) adult peak concentration following twice daily 
dosing with 400 mg is 6.5 µM (0.8-10.2 µM) or 2889 ng/mL 
(356-4533 ng/mL) [14]. 
 

 
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Table 2: Mean (SD) unbound bilirubin concentrations (µg/dL) with no additional 
drug or in presence of varying concentrations of raltegravir or sulfisoxazole. 
*Significantly greater than no drug (p≤0.05), n=6 for each concentration 
 
Total Bilirubin 
No Drug 
Raltegravir (µM) 
Sulfisoxazole (µM) 
 
5 
10 
100 
500 
1000 
500 
1000 
10.7 mg/dL 
3.46  
3.39  
3.37  
3.95*  
4.87*  
6.11*  
6.60*  
8.64*  
(0.25) 
(0.22) 
(0.18) 
(0.30) 
(0.24) 
(0.26) 
(0.25) 
(0.17) 
18.8 mg/dL 
7.60 
(0.27) 
7.80 
(0.32) 
8.04* 
(0.18) 
8.39* 
(0.71) 
10.28* 
(0.46) 
11.22* 
(0.72) 
10.77* 
(0.36) 
----- 
 
 
1.26 
Results of Cohort 1 Full Term Neonates Enrolled in P1097, 
 
Version 1.0 
 
IMPAACT P1097, Version 1.0, Raltegravir Pharmacokinetics 
and Safety in Neonates, enrolled 22 mother-infant pairs:  
59% of infants were African-American, 32% were white.  
Evaluable PK data were obtained from 19 mother-infant 
pairs.  Median  (range) PK parameters are listed below:  
 
• Maternal delivery raltegravir concentration:  
540 ng/mL (12-5809 ng/mL) or 1.22 µM (12-13.07 µM)  
• Cord blood raltegravir concentration:  
957 ng/mL (24-3974 ng/mL) or 2.15 µM (0.05-8.94 µM) 
• Ratio of cord/maternal blood raltegravir concentration:  
1.48 (0.32-4.33) 
• Initial infant plasma raltegravir concentration:  
671 ng/mL (13-2672 ng/mL) or 1.51 µM (0.03-6.01 µM) 
• Infant plasma raltegravir concentration at 30-36 hours:  
291 ng/mL (BLQ-1402 ng/mL) or 0.65 µM (BLQ-3.15 µM) 
• Median infant apparent t ½ of  raltegravir concentration:   
26.6 (9.3-184) hours 
 
Infant washout raltegravir concentrations initially increased before decreasing in 9 
of 18 evaluable infants. All infants tolerated RAL exposure well with 20-week 
follow-up evaluations completed in all infants with no unexpected adverse events 
and no transmission of HIV infection.   
 

 
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From this study it was determined that raltegravir readily crosses the placenta. The 
plasma t ½ of raltegravir in neonates is highly variable suggesting potential roles for 
developmental aspects of neonatal UGT1A1 enzyme activity, redistribution and/or 
enterohepatic recirculation of raltegravir. Understanding the features of raltegravir 
PK in full-term and low birth weight neonates will be critical for development of a 
neonatal dosing regimen (see Figure 1). 
 
Figure 1: Infant RAL Concentration-Time (hours) Plot (P1097, Version 
1.0).
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
 
2.11 
To evaluate the washout pharmacokinetics of raltegravir in infants 
born to HIV-infected pregnant women receiving raltegravir during 
pregnancy. 
 
 
 
 
 
2.12 
To evaluate bilirubin levels and the safety of in utero/intrapartum 
exposure to raltegravir in infants born to HIV-infected pregnant 
women receiving raltegravir during pregnancy. 
 

 
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2.13 
To develop a neonatal raltegravir dosing regimen to be evaluated 
in a follow-up study of this protocol.  
 
 
 
2.2  
Secondary Objective 
 
 
 
2.21 
To investigate the relationship between neonatal raltegravir 
 
 
 
 
 
elimination and UGT1A1 genotype. 
 
3.0 
STUDY DESIGN 
 
This is a Phase 0 multi-center trial to determine the washout pharmacokinetics 
and safety of in utero/intrapartum exposure to raltegravir in infants born to HIV-
infected pregnant women receiving raltegravir 400 mg twice daily.  
 
Version 1.0, Cohort 1 (Closed) 
 
Version 1.0, Cohort 1 enrolled full term infants and is fully accrued and 
closed to follow-up. Cohort 1 women were followed until discharge from the 
labor/delivery unit while their infants were followed for 20 weeks after birth.  
 
Version 2.0, Cohort 2  
 
Version 2.0 Cohort 2 will enroll up to 20 mother-infant pairs to achieve 15 
evaluable low birth weight infants (≤2500 grams at birth).  
 
Mother-infant (M-I) pairs may be enrolled prior to delivery or within 48 
hours after birth.  In addition, infants may be enrolled up to 48 hours after 
birth if birth weight  ≤ 2500 grams and born to an HIV-infected pregnant 
woman who received at least one dose of raltegravir 400 mg within 2 to 24 
hours prior to delivery.  All infants will have a history, physical examination, 
and hematology and chemistry laboratory evaluations performed around the 
time of birth and at a week 1-2 follow-up visit.   
 
When possible, cord blood will be drawn immediately after cord is clamped 
and a single blood sample will be collected from women within one hour after 
delivery to determine maternal plasma raltegravir concentration.   
 
Women will be followed until discharge from the labor/delivery unit. Infants 
will be followed for 6 weeks after birth. Since no toxicities attributed to 
raltegravir exposure were observed in Cohort 1 at the 6 or 20 week visits, 
and since raltegravir is not administered to infants in this study, infants in 
Cohort 2 will have their last study visit at 6 weeks of age. 
 
Only infants who meet the following criteria are eligible for pharmacokinetic 
blood sampling in Cohort 2: 

 
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• Infant born to woman who received at least one dose of raltegravir within 
2 to 24 hours prior to delivery.  Dose administered to mother must have 
been at least 2 hours prior to delivery to allow time for adequate 
absorption and distribution. 
• Infant birth weight ≤ 2500 grams. 
• Infant not receiving disallowed medications described in Section 4.8.  If 
these medications are required for the infant’s care, the infant will be 
ineligible for further PK (pharmacokinetic) sampling.  Data will be 
obtained up to the time of the introduction of the disallowed medication, 
but such infant will not be considered one of the evaluable 15 infants. 
• Infant ≤ 48 hours of age. 
Blood samples for raltegravir assay will be collected at 1-6, 12-24, 36-48, 72-
84, and 108-132 hours after birth, and on day 7-14. Infants may enroll up to 
48 hours of age, and any pharmacokinetic samples scheduled for collection 
prior to the time of enrollment will be skipped and not replaced.  Infants 
enrolling close to the 48-hour time point should have the first 
pharmacokinetic blood sample collected within 4 hours of enrollment (i.e., 
within 52 hours after birth) so that a minimum of three blood samples can be 
obtained for pharmacokinetic evaluation.   
With regard to infant blood samples for safety/toxicity laboratory testing: In 
the event that the study-required study safety/lab samples have not been 
collected prior to enrollment, (e.g., due to infant enrolled after delivery), 
these must be collected as soon as possible after enrollment.  To meet the 
primary objectives of the study, only those infants who have at least 3 
pharmacokinetic blood samples collected from the first 5 time points will be 
considered to be evaluable. 
 
Optional genotyping for polymorphisms of UGT1A1 were performed on Cohort 
1 infants and will be performed on Cohort 2 infants who undergo 
pharmacokinetic sampling.  The goal of the genotypic analysis is to determine if 
certain polymorphisms, particularly those with the UGT1A1*28/*28 genotype 
have slower RAL elimination than those with the UGT1A1*1/*1 genotype. 
Because UGT1A1 activity is reduced in neonates, polymorphisms associated with 
reduced activity are likely to have a larger impact on the metabolism of 
raltegravir, especially those who are low birth weight. 
 
No study-specific drugs will be given to women or infants during this study.  
Women will be receiving raltegravir for clinical indications outside of the study.  
Infants will receive standard of care antiretroviral therapy for prevention of 
mother-to-child transmission (PMTCT) as prescribed by their primary care 
physicians.  
 

 
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Refer to Appendix II-A, Cohort 2 Maternal Schedule of Evaluations and 
Appendix II-B, Cohort 2 Infant Schedule of Evaluations, for a complete 
description of the clinical and laboratory evaluations to be performed for 
Cohort 2. 
 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS 
 
Mothers and infants will be enrolled as a pair but the accrual requirements 
will be based on the number of infants meeting the definition of evaluable for 
the washout PK analysis.   
 
Cohort 1 (closed) eligibility criteria can be found in Version 1.0 of the 
protocol.  
 
Cohort 2 will open to enrollment under Version 2.0 and will allow enrollment 
of mother-infant (M-I) pairs at two time points: prior to and within 48 hours 
after delivery.  
• For enrollment prior to delivery, the mother must meet all the 
eligibility criteria (i.e. there are no infant eligibility criteria for 
prenatal enrollment).   However, only infants who meet all the 
eligibility criteria will have PK blood sampling performed.  Infants 
must be PK eligible (see Section 4.3) and then meet the definition of 
evaluable to contribute to the sample size of 15 evaluable infants. PK 
ineligible infants will remain in the study and will be followed for 
safety (See Section 6.3). 
• For enrollment within 48 hours after delivery, both mother and 
infant(s) must meet all the eligibility criteria. For multiple births, only 
infants who meet all the eligibility criteria will be enrolled. 
 
4.1 
Maternal Inclusion Criteria, Cohort 2 - M-I pairs enrolled prior to 
delivery 
 
4.11 
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 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.  

 
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 Sample #2 must be performed in a CAP/CLIA-approved 
laboratory (for US 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 
 

 
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4.12 
Viable singleton or multiple birth pregnancy based on 
clinical or other obstetrical measurements with infant birth 
weight anticipated to be ≤ 2500 grams. 
 
4.13 
Raltegravir is currently used as part of maternal ARV 
regimen and planned to continue through labor and 
delivery. 
 
4.14 
Willing and intends to deliver at the study-affiliated clinic or 
hospital. 
 
4.15 
Willing and able to sign informed consent for participation of 
herself and her infant.  Subject must be of an age to provide 
legal informed consent as defined by the country in which she 
resides.  If not, informed consent must be signed by a legal 
guardian. 
 
4.2 
Maternal Exclusion Criteria, Cohort 2 M-I pairs enrolled prior to 
delivery 
 
4.21 
Receipt of disallowed medications within 4 weeks prior to 
enrollment (Section 4.8) or intent to be on any of the disallowed 
medications prior to delivery. 
Note:  Infant(s) of a woman who received any of the disallowed 
medications will be ineligible for PK sampling. 
 
4.3 
Infant PK blood sampling eligibility Criteria, for Cohort 2 M-I pairs 
enrolled prior to delivery 
 
Infants are enrolled prior to delivery so there are no infant inclusion 
criteria. Only infants who meet the following criteria will be eligible 
for pharmacokinetic blood sampling: 
 
• Infant born to woman who received at least one dose of RAL 
within 2 to 24 hours prior to delivery.  Dose administered to 
mother must have been at least 2 hours prior to delivery to allow 
time for adequate absorption and distribution. 
• Infant birth weight ≤ 2500 grams. 
• Infant not receiving disallowed medications described in Section 
4.8.  If these medications are required for the infant’s care, the 
infant will be ineligible for further PK sampling.  Data will be 
obtained up to the time of the introduction of the disallowed 
medication, but such infant will not be considered one of the 
evaluable 15 infants if fewer than 3 PK samples from the first 5 
time points are collected. 

 
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• Infant ≤ 48 hours of age. 
• Infant does not have any severe congenital malformation or other 
medical condition not compatible with life or that would interfere 
with study participation or interpretation, as judged by the 
examining clinician. 
 
4.4 
Maternal Inclusion Criteria, Cohort 2 M-I pairs enrolled after 
delivery 
 
4.41 
Documentation of HIV-1 infection (See Section 4.11) 
  Enrollment is allowed if an initial HIV test is positive and a 
 
confirmatory test has been drawn and is pending. 
 
4.42 
Received at least one dose of RAL within 2 to 24 hours prior to 
delivery. 
 
4.43 
Willing and able to sign informed consent for participation of 
herself and her infant.  Subject must be of an age to provide 
legal informed consent as defined by the country in which she 
resides.  If not, informed consent must be signed by a legal 
guardian. 
 
 
4.5 
Maternal Exclusion Criteria,  Cohort 2 M-I pairs enrolled after 
delivery 
 
4.51 
Receipt of disallowed medications within 4 weeks prior to 
delivery (See Section 4.8). 
 
4.6 
Infant Inclusion Criteria, Cohort 2 M-I pairs enrolled after delivery 
 
4.61. 
Infant birth weight ≤ 2500 grams. 
 
4.62. Infant ≤ 48 hours of age. 
 
4.7 
Infant Exclusion Criteria, Cohort 2 M-I pairs enrolled after delivery 
 
4.71. 
Received disallowed medications described in Section 4.8.   
 
Note:  If any of the disallowed medications are required for the 
infant’s care after enrollment, the infant will be ineligible for 
further PK sampling.  Data will be obtained up to the time of 
the introduction of the disallowed medication, but such infant 
will not be considered one of the evaluable 15 infants if fewer 
than 3 PK samples from the first 5 time points are collected.  

 
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4.72  Infant has a severe congenital malformation or other medical 
condition not compatible with life or that would interfere with 
study participation or interpretation, as judged by the 
examining clinician. 
 
4.8  Disallowed Medications 
 
Raltegravir is eliminated mainly via a UDP glucuronosyltransferase 
UGT1A1-mediated glucuronidation pathway and may be subject to drug-
drug interactions when co-administered with drugs that are known to be 
UGT1A1 inducers or inhibitors. However, raltegravir is not anticipated to 
affect the metabolic clearance of drugs metabolized by UGT1A1 given its 
low UGT1A1 inhibitory (IC50 for the inhibition of UGT1A1 >50 µM) and 
induction potential. Since raltegravir is neither an inducer nor inhibitor of 
cytochrome P-450 enzymes, raltegravir is not expected to result in 
metabolic drug interactions with substrates of cytochrome P-450.   
The following medications/therapies are not permitted within 4 weeks 
prior to enrollment in women because these medications are potent broad 
inducers of drug metabolism and have been demonstrated to cross the 
human placenta.  Their use with raltegravir may result in increased 
metabolism of raltegravir and lower raltegravir exposure in both mother 
and fetus: 1) phenobarbital; 2) phenytoin; 3) rifampin. 
 
4.9  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 

 
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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. 
 
Enrollment of participants onto the study will be done through the Subject 
Enrollment System (SES) on the DMC website (at https://www.fstrf.org) 
under the Systems heading.  
 
If a potential P1097 woman who signs informed consent for herself and 
her infant does not meet the eligibility criteria as outlined in Section 4.0, 
or the woman withdraws consent prior to enrollment, the site MUST 
notify the protocol team. This communication should include the reason 
the woman or infant was ineligible or if the woman withdrew consent. 
Data on reasons why the woman or infant is ineligible will be collected in 
the DMC database. This information may be used by Merck & Co., Inc. 
when reporting to Regulatory Agencies. 
 
4.10     Co-enrollment Procedures 
 
Co-enrollment in the raltegravir arms of P1026S and P1081 will be 
allowed.  Co-enrollment in other research protocols will require the 
consent of the protocol chair of P1097 and the other research protocol. 
 
5.0 
STUDY TREATMENT 
 
No treatment or intervention will be provided as part of this study.  Infants will 
receive standard of care antiretroviral therapy for PMTCT as prescribed by their 
primary care physicians.  HIV-infected pregnant women will be receiving 
raltegravir as prescribed by their care provider as part of a regimen for treatment 
of maternal HIV disease and/or prevention of mother to child transmission of 
HIV. 
 
6.0 
SUBJECT MANAGEMENT 
 
6.1 Toxicity Management 
 

 
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This study does not contain any study-specific treatment or intervention, 
thus there is no need for toxicity management through the DAERS system. 
However, safety data will be collected and reviewed by the study team on 
regular team conference calls.  
 
 
6.2 
Permanent Study Discontinuation 
 
The woman and/or infant will be discontinued from the study for the 
following reasons: 
• The woman and/or infant is lost to follow up. 
• The woman and/or infant is not able to attend study visits as 
required by the study. 
• The subject/parent/guardian withdraws consent. 
• The investigator determines that further participation would be 
detrimental to the woman’s or infant’s health or well-being. 
The study may be discontinued at any time by the IMPAACT network, the 
Office for Human Research Protections (OHRP), the National Institutes of 
Health (NIH), the local IRB or EC, U.S. Food and Drug Administration 
(FDA), the pharmaceutical sponsor, or other governmental agencies. 
 
6.3 
Premature Discontinuation/Early Withdrawal/Safety Follow-up for PK 
Unevaluable Infants 
 
Cohort 1 (Closed): If the infant is not eligible for pharmacokinetic 
sampling, study evaluations will be performed for safety monitoring 
between 8-14 hours after birth, 30-36 hours after birth, week 1-2 and week 
20.  If the parent withdraws consent at any time after enrollment, no 
further information will be collected and additional laboratory evaluations 
will not be performed.   
 
Cohort 2: If fewer than 3 pharmacokinetic samples from the first 5 
time points are collected, the infant is not considered evaluable for 
pharmacokinetics but will continue with scheduled safety evaluations.  
If the parent withdraws consent at any time after enrollment, no 
further information will be collected and additional laboratory 
evaluations will not be performed.   
 
7.0 
EXPEDITED ADVERSE EVENT REPORTING   
 
This study does not contain any study-specific treatment or intervention, thus no 
expedited adverse event (EAE) reporting is required.  Every effort will be made 
by study staff to provide appropriate care and counseling to the participant, and/or 
referral to appropriate resources for the safety of the participant as needed.  Any 
unanticipated problems will be reported to the DAIDS Medical Officer at the 

 
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same time as the problems are reported to the responsible site IRB/Ethics 
Committees (ECs) overseeing the research according to pre-established 
procedures as required by 45 CFR 46.   
8.0  STATISTICAL CONSIDERATIONS    
 
8.1 General Design Issues  
 
This is a multi-center pilot trial to estimate washout pharmacokinetics and 
safety of raltegravir in infants born to HIV-infected pregnant women 
receiving raltegravir prior to delivery and continuing during labor.  Results 
of the washout pharmacokinetics will be used to develop an initial 
neonatal dosing regimen of raltegravir to be evaluated in a follow-up 
study.   
 
There are two cohorts:  
• Cohort 1 (fully accrued and follow up complete): M-I pairs were 
enrolled prior to delivery (at ≥ 35 weeks gestation); and 
• Cohort 2:  This cohort will enroll low birth weight infants (weight ≤ 
2500 grams at birth) prior to delivery or within 48 hours after 
delivery.   
 
The protocol was amended to Version 2.0 to enroll low birth weight (≤ 
2500 grams) infants in Cohort 2.  Cohort 2 will accrue mother-infant 
(M-I) pairs until 15 evaluable infants have been enrolled for the 
washout pharmacokinetic analysis. 
 
No study-specific treatment will be given to mother or infant during this 
study.  Washout pharmacokinetic data and analyses are described in detail 
in Section 9.0. Safety data will include adverse birth outcomes and infant 
adverse events observed during follow-up. Cohort 1 safety data will be 
analyzed separately from Cohort 2 safety data. 
  
This is a pilot study and the sample size has been determined by the 
protocol pharmacologist to provide enough information needed to develop 
an initial LBW neonatal dosing regimen for a follow-up study 
(IMPAACT P1110). The safety analysis will include the data on all 
enrolled infants, including infants who were not evaluable for the washout 
pharmacokinetic analysis.  The study is not powered for the analysis of the 
safety data.  Descriptive statistics will be generated to summarize the 
safety data.   
 
Unless otherwise indicated, the rest of the subsections below refer to 
both Cohorts 1 and 2. 
 

 
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8.2 
Outcome Measures 
 
 
8.21 Primary Outcome Measures: 
 
Pharmacokinetic Outcome Measures: 
• Neonatal raltegravir elimination (t ½). See Section 9.0. 
• Raltegravir maternal-cord blood ratio.  ee Section 9.0 for Cohort 
1 only) 
Note:  Cord blood and maternal delivery plasma samples will 
not be collected from Cohort 2 M-I pairs who enroll after 
delivery. 
 
Safety Outcome Measures: 
• Infant adverse events of Grade 3 or 4 as defined  in DAIDS 
Table  
for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table), Version 1.0, dated December 2004, 
Clarification August 2009, which is available on the RSC website 
at  http://rsc.tech-res.com/safetyandpharmacovigilance  
• Adverse birth outcomes including stillbirth and low birth 
weight (for Cohort 1 only) 
• Infant death 
• Total bilirubin  
• Direct bilirubin 
 
For Cohort 1, occurrence of infant adverse events of Grades 3 or 4 
adverse birth outcomes, and infant death will constitute the infant 
meeting a toxicity endpoint. For Cohort 2, occurrence of infant 
adverse events of Grades 3 or 4 and infant death will constitute the 
infant meeting a toxicity endpoint. As part of the secondary safety 
analysis for Cohorts 1 and 2, (i) information on number and 
proportion of infants requiring therapy (e.g. phototherapy, 
exchange transfusion) to reduce bilirubin and (ii) summary 
statistics for total and direct bilirubin will be provided. 
 
 8.22  Secondary Outcome Measures:  
 
Pharmacokinetic Outcome Measures: 
• Optional genotyping for polymorphism of UGT1A1 from infants 
who are eligible for pharmacokinetic sampling as described in 
Section 9.0. 
 
8.3 
Randomization and Stratification 
 
There will be no randomization and no stratification.   

 
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For Cohort 1, because of the potential for a drug interaction between 
atazanavir and raltegravir, the number of women enrolled receiving an 
atazanavir-containing regimen was limited to three.  This restriction has 
been removed for Cohort 2. 
 
8.4 
Sample Size and Accrual 
 
The target accrual for Cohort 1 was 15 evaluable infants which was 
projected to require enrolling up to 25 M-I pairs and approximately 
12 months to fully accrue.  Cohort 1 is fully accrued with 19 evaluable 
infants (22 M-I pairs). 
 
Cohort 2 will enroll M-I pairs until a total of 15 evaluable infants are 
accrued which is projected to require enrolling up to 20 M-I pairs. 
The projected accrual period is 12 months.  Evaluable infants will be 
those who have at least 3 PK blood samples collected following the PK 
schedule in Section 9.3.     
  
This is a pilot study aimed at gathering information needed for the design 
of a follow-up study that will evaluate a neonatal raltegravir dosing 
regimen.  The sample size of 15 evaluable infants reflects the judgment of 
the team pharmacologists with respect to the amount of washout 
pharmacokinetic data needed to design the later follow-up dosing study.  It 
is based on practical considerations and experience with other 
antiretroviral drugs such as nevirapine and tenofovir in pregnant women 
and their neonates [47-50]. 
 
All infants enrolled to the study, including those not evaluable for the 
washout pharmacokinetic analysis, will be included in the safety analyses.  
The study is not powered for analysis of the safety data so that no 
hypothesis testing will be done but descriptive summary statistics will be 
calculated.  Given the relatively small study sample, the precision of the 
estimates will be relatively low and the confidence interval (CI) estimates 
will be relatively wide. Table 2 shows the precision with which rates of 
serious adverse events can be estimated, given the sample size of 15, 20 or 
25 infants. 
 

 
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Table 2.  Point and 90% confidence interval estimates of proportion of 
infants meeting the toxicity endpointa 
 
Number of infants 
Proportion of infants 
meeting  
toxicity endpoint 
90% CI of proportion 
of infants meeting the 
toxicity endpoint 
15 
0.00 
(0.00, 0.22) 
 
0.20 
(0.04, 0.48) 
 
0.40 
(0.16, 0.68) 
 
0.60 
(0.32, 0.84) 
 
0.80 
(0.52, 0.96) 
 
1.00 
(0.78, 1.00) 
20 
0.00 
(0.00, 0.17) 
 
0.20 
(0.06, 0.44) 
 
0.40 
(0.19, 0.64) 
 
0.60 
(0.36, 0.81) 
 
0.80 
(0.56, 0.94) 
 
1.00 
(0.83, 1.00) 
25 
0.00 
(0.00, 0.14) 
 
0.20 
(0.07, 0.41) 
 
0.40 
(0.21, 0.61) 
 
0.60 
(0.39, 0.79) 
 
0.80 
(0.59, 0.93) 
 
1.00 
(0.86, 1.00) 
a Clopper-Pearson exact confidence interval estimates using SAS Versiion 9.2. 
 
 
8.5 
Monitoring 
 
Reports on accrual and toxicity, compiled by the Data Management Center 
(DMC), will be reviewed and discussed by the Protocol Team on conference 
calls held monthly.  Conference calls will also be scheduled as needed in 
response to any adverse event that requires the immediate attention of the 
Protocol Team.   Notification of team members will be by e-mail, phone or 
fax, depending on time differences.   
 
The safety of maternal transfer of RAL to the neonate will be monitored by 
means of adverse events reports and toxicity reports presenting laboratory 
and clinical events.  It is the responsibility of the protocol team to interpret 
the toxicity data, and make any decisions needed to protect subjects from 
undue risk.   
 
 

 
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The team will monitor feasibility quarterly, first based on site registration 
and then on accrual.  Initially, the team will monitor site registration 
quarterly to ensure that an adequate number of sites have registered to 
complete the protocol.  If less than one-third of 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 will amend the protocol accordingly. 
 
See P1097, Version 1.0, for the monitoring of Cohort 1 accrual. 
 
Cohort 2 will be monitored for accrual by a Study Monitoring 
Committee (SMC) to be appointed per IMPAACT Standard Operating 
Procedures.  The SMC will assess accrual 6 months after Cohort 2 
opens to enrollment and protocol version 2.0 has been approved by 
IRB/ ECs at 50% of eligible sites, and perform an independent review 
of the data.  If Cohort 2 has not met the accrual target subjects (7 
eligible infants) by the 6-month timeframe, the protocol team will be 
required to provide a written plan to increase accrual prior to the SMC 
6-month review at which time the SMC will consider whether to 
recommend closing the study to enrollment. 
 
A full monitoring plan will be developed for each cohort before the cohort 
opens to accrual.  The monitoring plan would include the study monitoring 
described above as well as the details for monitoring the specimens needed 
for the pharmacokinetic analyses.   
 
8.6 
Analyses 
 
See Section 9.0 for a discussion of PK analyses. 
 
The safety analysis will consist of descriptive statistics summarizing the 
safety data through week 20 for Cohort 1 and through week 6 for 
Cohort 2. The primary safety analysis will be  the calculation of the point 
and 2-sided 90% confidence interval (CI) using the Clopper-Pearson exact 
method estimates of the proportion of infants meeting the composite 
toxicity endpoint. Secondary safety analyses will include (1) point and 
90% CI estimates of infants meeting each toxicity endpoint; (2) frequency 
tabulations of worst grade adverse events for each subject; (3) summary 
statistics of total and direct bilirubin at each required sampling time 
and (4) point and 90% CI estimates of infants requiring therapy (e.g. 
phototherapy, exchange transfusion) to reduce bilirubin.    
 
A statistical analysis plan specifying details of administrative analyses and 
full details of primary and secondary analyses of the safety data will be 

 
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developed for each cohort. It is expected that analysis of Cohort 2 will 
combine data from M-I pairs enrolled pre- and post-delivery.  
 
9.0 
CLINICAL PHARMACOLOGY PLAN 
 
9.1 
Pharmacology Objective 
 
The clinical pharmacology objective of this study is to estimate raltegravir 
elimination (t ½) in neonates born to women receiving raltegravir as part 
of HAART during pregnancy. When P1066 pharmacokinetic data are 
available for the 4 weeks to <2 year old cohort, there will be a much better 
understanding of infant dosing, and bioavailability of the new oral 
granules for suspension formulation will be known. Those data, coupled 
with data collected from this study examining the raltegravir washout 
pharmacokinetics in neonates born to women receiving raltegravir , will 
provide a more solid foundation upon which to base the design of the later 
follow-up study (active single dose and multiple dose raltegravir 
pharmacokinetic studies in infants).   
 
 
9.2 
Primary and Secondary Data 
 
Demographic data and recent dosing history including food intake, 
delivery information and sample collection times will be collected. The 
goal is to estimate clearance in the infants and provide guidance on when 
to initiate dosing, dose and dosing regimen in the infants for the later 
(active single dose and multiple dose) follow-up study. 
 
Information obtained about the effect of UGT1A1 polymorphisms on the 
pharmacokinetics of raltegravir will provide a better understanding of the 
effect of genetics on the metabolism of raltegravir in neonates.   
 
Laboratory Analysis and Reporting 
 
Blood samples will be collected in standard EDTA tubes. Frozen plasma 
will be batched and shipped to the University of Alabama Pharmacology 
Specialty Laboratory (UAB PSL). All PK samples and results will be 
registered in the Laboratory Data Management System (LDMS) database.  
 
Raltegravir concentrations will be measured using a validated HPLC-MS-
MS method [51].   
 
9.3 
Study Design, Modeling and Data Analysis 
 

 
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Cohort 1 (Closed) 
There will be no infant dosing for this study. Women must have received 
at least two weeks of raltegravir prior to delivery and continue to receive 
raltegravir during labor prior to delivery as well as their other ARVs.   
 
Maternal raltegravir concentration: One maternal blood sample will be 
obtained within one hour after delivery.  In addition, a single cord blood 
specimen will be collected at the time of birth.  
 
Neonatal: Blood samples for raltegravir concentration determinations will 
be collected between 1-5, 8-14, 18-24, and 30-36 hours post-delivery. 
Sample times chosen will allow for flexibility at the sites for the collection 
of raltegravir concentrations.  The first pharmacokinetic sample will be 
close to the time of the peak raltegravir concentration while the next three 
samples will be collected during the elimination phase.  
 
Cohort 2 
There will be no infant dosing for this study. Women must have 
received at least one dose of raltegravir within 2 to 24 hours prior to 
delivery.  Dose must be administered at least 2 hours prior to delivery 
to allow adequate time for absorption and distribution. 
 
Maternal and cord blood raltegravir concentrations: When possible, 
for example, pre-delivery enrollment, one maternal blood sample will 
be obtained within one hour after delivery and a single cord blood 
specimen at the time of birth. For infants enrolled after delivery up to 
48 hours after birth, it will not be possible to obtain maternal or cord 
blood samples. 
 
Neonatal raltegravir concentrations: Blood samples for raltegravir 
assay will be collected at 1-6, 12-24, 36-48, 72-84, and 108-132 hours 
after birth, and on day 7-14. Infants may enroll up to 48 hours of age, 
and any pharmacokinetic samples scheduled for collection prior to the 
time of enrollment will be skipped and not replaced.  Infants enrolling 
close to the 48-hour time point should have the first pharmacokinetic 
blood sample collected within 4 hours of enrollment (i.e., within 52 
hours after birth) so that a minimum three blood samples can be 
obtained for pharmacokinetic evaluation. 
 
Analysis for Cohort 1 and Cohort 2 
Regression analysis will then be used to estimate the terminal phase of 
raltegravir elimination in the neonates. Since this study will not include a 
full intensive PK evaluation we will not have an estimate of distribution 
volume and thus clearance cannot be calculated directly. To resolve this, 
we will assume the same average distribution volume from subjects ≥4 

 
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weeks to <6 months of age in Cohort V in P1066 to calculate raltegravir 
clearance in the neonates.  This will provide an initial estimate of the dose 
required in neonates to produce a similar AUC compared to the youngest 
P1066 cohort.  
 
9.4 
Anticipated Outcomes 
 
The goal is to estimate raltegravir clearance in both term and low birth 
weight neonates following maternal dosing of raltegravir as part of 
HAART. These data, along with those collected from P1066 will assist in 
understanding how to dose this drug in the neonatal population.  
 
 
 
10.0 
HUMAN SUBJECTS 
 
 
10.1 Institutional Review Board and Informed Consent 
 
This protocol, the informed consent documents (Appendix IV-A and 
IV-B), and any subsequent modifications must be reviewed and 
approved by the Institutional Review Board (IRB) or Ethics 
Committee (EC) responsible for oversight of the study. Written 
informed consent must be obtained from the parents or legal guardians of 
subjects who cannot consent for themselves, such as those below the legal 
age.  The informed consent will describe the 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 parent or legal guardian. 
Each site which receives US HHS 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. 
 
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 

 
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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 study staff, study monitors, drug 
company supporting the study, and designees, the OHRP, NIH, FDA, or 
the local IRB/EC. 
10.3 Study Discontinuation 
 
 
The study may be discontinued at any time by the IMPAACT network, the 
OHRP, NIH, FDA, or local IRB/EC, the pharmaceutical sponsor, 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 
 
As the transmission of HIV and other blood borne pathogens can occur through 
contact with contaminated needles, blood, and blood products, appropriate blood 
and secretion precautions will be employed by all personnel in the drawing of 
blood and shipping and handling of all specimens for this study, as currently 
recommended by the Centers for Disease Control and Prevention. 
All infectious specimens will be sent using the ISS-1 SAF-T-PAK mandated by 
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. 

 
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13.0 REFERENCES 
 
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 2.  Mirochnick M, Nielsen-Sines K, Pilotto JH, Pinto J, Veloso V, Holland D et al.. 
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MA, February, 2008.  2008.  
 
 Ref Type: Abstract 
 3.  Lopriore E, Rozendaal L, Gelinck LB, Bokenkamp R, Boelen CC, Walther FJ: 
Twins with cardiomyopathy and complete heart block born to an HIV-infected 
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 4.  McArthur MA, Kalu SU, Foulks AR, Aly AM, Jain SK, Patel JA: Twin preterm 
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 5.  Clarke DF, Acosta E, Rizk M, Bryson Y, Spector SA, Mofenson L et al.. 
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Conference on Retroviruses and Opportunistic Infections . 2013.  
 
 Ref Type: Abstract 
 6.  Lawn JE, Gravett MG, Nunes TM, Rubens CE, Stanton C: Global report on preterm 
birth and stillbirth (1 of 7): definitions, description of the burden and opportunities 
to improve data. BMC Pregnancy Childbirth 2010, 10 Suppl 1: S1. 
 7.  Spira R, Lepage P, Msellati P, Van De Perre P, Leroy V, Simonon A et al.: Natural 
history of human immunodeficiency virus type 1 infection in children: a five-year 
prospective study in Rwanda. Mother-to-Child HIV-1 Transmission Study Group. 
Pediatrics 1999, 104: e56. 
 8.  Mirochnick M, Best BM, Clarke DF: Antiretroviral pharmacology: special issues 
regarding pregnant women and neonates. Clin Perinatol 2010, 37: 907-27, xi. 
 9.  Capparelli EV, Mirochnick M, Dankner WM, Blanchard S, Mofenson L, McSherry 
GD et al.: Pharmacokinetics and tolerance of zidovudine in preterm infants. J 
Pediatr 2003, 142: 47-52. 
 10.  Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M et al.: 
Raltegravir with optimized background therapy for resistant HIV-1 infection. N 
Engl J Med 2008, 359: 339-354. 
 11.  Steigbigel RT, Cooper DA, Teppler H, Eron JJ, Gatell JM, Kumar PN et al.: Long-
term efficacy and safety of Raltegravir combined with optimized background 

 
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therapy in treatment-experienced patients with drug-resistant HIV infection: week 
96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect Dis 2010, 50: 
605-612. 
 12.  Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS et al.: 
Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy 
in treatment-naive patients with HIV-1 infection: a multicentre, double-blind 
randomised controlled trial. Lancet 2009, 374: 796-806. 
 13.  Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P et al.: 
Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N 
Engl J Med 2008, 359: 355-365. 
 14.  Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, 
Cooper DA et al.: Antiretroviral activity, pharmacokinetics, and tolerability of MK-
0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in 
treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr 2006, 
43: 509-515. 
 15.  Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C et al.: 
Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir 
as part of combination therapy in treatment-naive patients with HIV-1 infection: 
results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007, 46: 125-
133. 
 16.  Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D et al.: 
Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in 
treatment-experienced patients with multidrug-resistant virus: a phase II 
randomised controlled trial. Lancet 2007, 369: 1261-1269. 
 17.  Iwamoto M, Wenning LA, Petry AS, Laethem M, De SM, Kost JT et al.: Safety, 
tolerability, and pharmacokinetics of raltegravir after single and multiple doses in 
healthy subjects. Clin Pharmacol Ther 2008, 83: 293-299. 
 18.  Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K et al.: 
Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS 
drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab 
Dispos 2007, 35: 1657-1663. 
 19.  Iwamoto M, Hanley WD, Petry AS, Friedman EJ, Kost JT, Breidinger SA et al.: 
Lack of a clinically important effect of moderate hepatic insufficiency and severe 
renal insufficiency on raltegravir pharmacokinetics. Antimicrob Agents Chemother 
2009, 53: 1747-1752. 

 
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 20.  Brainard DM, Friedman EJ, Jin B, Breidinger SA, Tillan MD, Wenning LA et al.: 
Effect of Low-, Moderate-, and High-Fat Meals on Raltegravir Pharmacokinetics. J 
Clin Pharmacol 2010. 
 21.  Merck & Company Inc.. Isentress package insert.  2009.  
 
 Ref Type: Catalog 
 22.  Iwamoto M, Wenning LA, Mistry GC, Petry AS, Liou SY, Ghosh K et al.: 
Atazanavir modestly increases plasma levels of raltegravir in healthy subjects. Clin 
Infect Dis 2008, 47: 137-140. 
 23.  Wenning LA, Petry AS, Kost JT, Jin B, Breidinger SA, DeLepeleire I et al.: 
Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms. Clin 
Pharmacol Ther 2009, 85: 623-627. 
 24.  Wenning LA, Hanley WD, Brainard DM, Petry AS, Ghosh K, Jin B et al.: Effect of 
rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics 
of raltegravir. Antimicrob Agents Chemother 2009, 53: 2852-2856. 
 25.  Iwamoto M, Kassahun K, Troyer MD, Hanley WD, Lu P, Rhoton A et al.: Lack of 
a pharmacokinetic effect of raltegravir on midazolam: in vitro/in vivo correlation. J 
Clin Pharmacol 2008, 48: 209-214. 
 26.  Murray JM, Emery S, Kelleher AD, Law M, Chen J, Hazuda DJ et al.: 
Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of 
HIV, significantly reducing the second phase. AIDS 2007, 21: 2315-2321. 
 27.  Pinnetti C, Baroncelli S, Villani P, Fantoni M, Tozzi V, De LA et al.: Rapid HIV-
RNA decline following addition of raltegravir and tenofovir to ongoing highly 
active antiretroviral therapy in a woman presenting with high-level HIV viraemia at 
week 38 of pregnancy. J Antimicrob Chemother 2010, 65: 2050-2052. 
 28.  Jaworsky D, Thompson C, Yudin MH, Bitnun A, Brophy J, Samson L et al.: Use of 
newer antiretroviral agents, darunavir and etravirine with or without raltegravir, in 
pregnancy: a report of two cases. Antivir Ther 2010, 15: 677-680. 
 29.  Rosenvinge M, et al.. Raltegravir in the prevention of mother to child transmission 
of HIV: high concentrations demonstrated in newborns. XVIII International AIDS 
Conference, Vienna, Austria, July 2010.  2010.  
 
 Ref Type: Abstract 
 30.  Best BM, Capparelli EV, Stek A, Burchett SK, Huo Y, Aweeka F et al.. Raltegravir 
Pharmacokinetics during Pregnancy. Interscience Conference on Antimicrobial 
Agents and Chemotherapy, Boston, MA, Sept 2010.  2010.  
 
 Ref Type: Abstract 

 
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 31.  Spector SA, Acosta E, Zheng N, Teppler H, Homony B, Handelsman E et al.. 
Interim results from IMPAACT P1066: raltegravir oral granule formulation in 
children 6 months to < 2 years. ARV Pharmacokinetics and Pharmacogenetics in 
Children . 2012.  
 
 Ref Type: Abstract 
 32.  Frenkel L, Nachman S, Zheng N, Acosta E, Teppler H, Worrell C et al.: Dose-
finding Pharmacokinetics (PK) and 24- and 48-Week Safety and Efficacy of 
Raltegravir (RAL) Granules for Suspension (GFS) Formulation in Human 
Immunodeficiency Virus type-1 (HIV)-Infected Infants Starting Treatment at 4 Wk 
– 6 Mo of Age. Infectious Disease Society of America, San Francisco, CA, October 
2013.  
 
 Ref Type: Abstract 
 33.  Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR et 
al.: Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin 
glucuronidating isoform in man. J Biol Chem 1994, 269: 17960-17964. 
 34.  Kawade N, Onishi S: The prenatal and postnatal development of UDP-
glucuronyltransferase activity towards bilirubin and the effect of premature birth on 
this activity in the human liver. Biochem J 1981, 196: 257-260. 
 35.  Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de BA, Oostra BA et al.: The 
genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 
in Gilbert's syndrome. N Engl J Med 1995, 333: 1171-1175. 
 36.  Black M, Billing BH: Hepatic bilirubin udp-glucuronyl transferase activity in liver 
disease and gilbert's syndrome. N Engl J Med 1969, 280: 1266-1271. 
 37.  Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman 
RE: Developmental pharmacology--drug disposition, action, and therapy in infants 
and children. N Engl J Med 2003, 349: 1157-1167. 
 38.  WEISS CF, GLAZKO AJ, WESTON JK: Chloramphenicol in the newborn infant. 
A physiologic explanation of its toxicity when given in excessive doses. N Engl J 
Med 1960, 262: 787-794. 
 39.  Boucher FD, Modlin JF, Weller S, Ruff A, Mirochnick M, Pelton S et al.: Phase I 
evaluation of zidovudine administered to infants exposed at birth to the human 
immunodeficiency virus. J Pediatr 1993, 122: 137-144. 
 40.  Capparelli EV, Mirochnick M, Dankner WM, Blanchard S, Mofenson L, McSherry 
GD et al.: Pharmacokinetics and tolerance of zidovudine in preterm infants. J 
Pediatr 2003, 142: 47-52. 
 41.  Mirochnick M, Capparelli E, Connor J: Pharmacokinetics of zidovudine in infants: 
a population analysis across studies. Clin Pharmacol Ther 1999, 66: 16-24. 

 
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 42.  Ahlfors CE: Bilirubin-albumin binding and free bilirubin. J Perinatol 2001, 21 
Suppl 1: S40-S42. 
 43.  Sinclair CJ: A difference in mortality rate and incidence of kernicterus among 
premature infants allotted to two prophylactic antibacterial regimens, by William A. 
Silverman, et al, Pediatrics, 1956;18:614-624. Pediatrics 1998, 102: 225-227. 
 44.  Ahlfors CE: Criteria for exchange transfusion in jaundiced newborns. Pediatrics 
1994, 93: 488-494. 
 45.  Ahlfors CE: Unbound bilirubin associated with kernicterus: a historical approach. J 
Pediatr 2000, 137: 540-544. 
 46.  Clarke DF, Wong RJ, Wenning L, Stephenson DK, Mirochnick M: Raltegravir In 
Vitro Effect on Bilirubin Binding. Pediatr Infect Dis J 2013. 
 47.  Mirochnick M, Fenton T, Gagnier P, Pav J, Gwynne M, Siminski S et al.: 
Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected 
pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 
250 Team. J Infect Dis 1998, 178: 368-374. 
 48.  Musoke P, Guay LA, Bagenda D, Mirochnick M, Nakabiito C, Fleming T et al.: A 
phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected 
pregnant Ugandan women and their neonates (HIVNET 006). AIDS 1999, 13: 479-
486. 
 49.  Mirochnick M, Kafulafula G, Kreitchmann R, Pinto J, Parsons T, Nielsen-Saines K 
et al.: The pharmacokinetics (PK) of tenofovir disoproxil fumarate (TDF) after 
administration to HIV-1 infected pregnant women and their newborns. The 16th 
Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, 
February, 2009 2009. 
 50.  Mirochnick M, Kunwenda N, Joao E, Kreitchmann R, Pinto J, Santos B et al.: 
Tenofovir Disoproxil Fumarate (TDF) Pharmacokinetics (PK) with Increased Doses 
in HIV-1 Infected Pregnant Women and their Newborns (HPTN 057). 11th 
International Workshop on Clinical Pharmacology of HIV Therapy, Sorrento, Italy, 
April 7-9, 2010 2010. 
 51.  Long MC, Bennetto-Hood C, Acosta EP: A sensitive HPLC-MS-MS method for the 
determination of raltegravir in human plasma. J Chromatogr B Analyt Technol 
Biomed Life Sci 2008, 867: 165-171. 
 

 
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APPENDIX I-A 
 
COHORT 1 MATERNAL SCHEDULE OF EVALUATIONS 
(CLOSED) 
 
 
Screening 
Labor/delivery 
Informed Consent 
X 
 
CLINICAL EVALUATIONS 
 
 
History 
X1 
X2 
PHARMACOKINETICS  
 
 
Maternal RAL concentration3 
 
1mL 
OTHER 
 
 
Cord Blood4  
 
1mL 
TOTAL BLOOD  
 
2mL 
 
 
1. Obtain complete history including documentation of HIV-1 infection, 
demographic data and antiretroviral medications. 
2. Obtain complete history including maternal antiretroviral dosing history, 
labor and delivery record, and obstetrical gestational age.  
3. Collect 1mL of blood within one hour after delivery. 
4. Draw 1mL of cord blood immediately after cord is clamped. 
 
 

 
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APPENDIX I-B 
 
COHORT 2 MATERNAL SCHEDULE OF EVALUATIONS 
 
 
Screening/entry 
Labor/delivery6 
Post-Delivery 
(1-5 days after 
delivery) 
Informed Consent 
X 
 
 
CLINICAL EVALUATIONS 
 
 
 
History 
 X1 
X2 
  X2 
PHARMACOKINETICS7 
 
 
 
Maternal RAL concentration3 
1mL4 
1mL4   
 
If enrolled after delivery 
If enrolled before delivery   
OTHER7 
 
 
 
Cord Blood3,5 
 
X 
 
TOTAL BLOOD  
1mL 
1mL 
0mL 
 
1. 
History data at Screening/entry includes documentation of HIV-1 infection, 
demographic data and antiretroviral dosing history 3 months prior to entry. 
2. 
History data after Screening/entry includes antiretroviral dosing while on 
study, labor and delivery record, and obstetrical gestational age.  It is 
strongly recommended that the site report, prospectively if possible, the 
mother to the Antiretroviral Pregnancy Registry 
(http://www.apregistry.com/reg.htm): 
 
US/Canada telephone: 800-258-4263, fax 800-800-1052 
 
Brazil:  fax 888-259-5618 
 
International:  phone: 910-679-1598, fax: 910-256-0637 
 
Email:  pregnancyregistries@incresearch.com 
3. 
Mother/infant pairs may be enrolled up to 48 hours after delivery.  In these 
 
situations it may not be possible to collect the maternal and cord blood 
 
samples at labor and delivery.   
4. 
For women enrolled prior to delivery, collect 1mL of maternal blood within 
one hour after delivery.  For women enrolled after delivery, collect 1mL of 
maternal blood at the time of enrollment.  
5. 
Draw cord blood immediately after cord is clamped. 
6. 
Not applicable to women enrolled after delivery.   
7. 
See the Laboratory Processing Chart (LPC) on the P1097 Protocol Specific       
 
Webpage on the IMPAACT website (http://www.impaactgroup.org) for 
 
collection, processing and shipping instructions. 

 
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APPENDIX II-A  
 
COHORT 1 INFANT SCHEDULE OF EVALUATIONS  
(CLOSED) 
 
 
Birth 
1-5 hours after 
birth 
8-14 hours after 
birth 
18-24 
hours  after 
birth 
30-36 hours after 
birth 
Week 
1-2 
Week 
20 
CLINICAL EVALUATIONS 
History 
 
 
 
 
 
X2 
X2 
Physical exam 
X1 
 
 
 
 
X3 
X3 
LABORATORY EVALUATIONS 
Hematology4,6 
 
 
0.5 mL 
 
 
0.5mL 
 
Chemistries5,6 
 
 
1mL 
 
1mL 
1mL 
 
VIROLOGY 
Genotyping7 
 
 
 
 
Dried Blood Spot 
 
 
PHARMACOKINETICS*  
Washout8 
 
1mL 
1mL 
1mL 
1mL 
 
 
TOTAL BLOOD 
0mL 
1mL 
2.5mL 
1mL 
 2 mL 
1.5mL 
0mL 
*See section 3.0 and 4.3 for criteria for infants eligible for pharmacokinetic blood sampling. 
 
 
1. 
Physical examination includes infant Apgar score, birth weight and length, 
gestational age, gender, sex, and ethnicity.  
2. 
History includes all non-protocol laboratory tests, HIV test results, antiretroviral 
agents (for PMTCT), concomitant medications, and any intercurrent illnesses 
since the last visit. 
3. 
Complete physical exam includes temperature, heart rate, respiratory rate, weight, 
length, and head circumference.  
4. 
Hematology includes CBC (complete blood count) with differential and platelet 
count. 
5. 
Chemistries include AST, ALT, creatinine and total and direct bilirubin. 
6. 
Infants not eligible for pharmacokinetic sampling will have hematology and 
chemistries obtained at 8-14 hours after birth and at 1-2 weeks of age, with 
additional chemistries at 30-36 hours after birth. 
7.  
Genotyping (optional) for UGT1A1 polymorphisms will be done using dried 
blood spot on filter paper.  Only infants who have pharmacokinetic sampling will 
have genotyping done. (Option: Can collect at week 1-2 if unable to obtain 
immediately after birth).  
8. 
Only infants eligible for pharmacokinetic blood sampling (See Section 3.0 and 
4.3). Collect 1mL of blood for each sample  
 
Priority of blood draw should be as follows: 1) Chemistries; 2) Hematology;  
3) Pharmacokinetics; 4) Genotyping 

 
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APPENDIX II-B  
COHORT 2 INFANT SCHEDULE OF EVALUATIONS 
 
 
Birth/Entry 
1-6  
hours  
after  
birth11 
12-24 
hours  
after  
birth11 
36-48  
hours 
after 
birth 
72-84  
hours  
after  
birth 
108-132  
hours   
after 
birth 
Week 1-2 
(7-14 days 
after birth) 
Week 6 
(35-49 
days after 
birth) 
CLINICAL EVALUATIONS 
History 
 
 
 
X2 
 
 
X2 
X2 
Physical exam 
X1 
 
 
 
 
 
X3 
X3 
LABORATORY EVALUATIONS (if not obtained for standard of care) 
Hematology4,6 
 
 
 
  0.5mL4 
 
 
0.5mL 
 
Chemistries5,6 
 
 
 
 
1mL5 
 
1mL 
 
Bilirubin6,7 
 
 
 
1mL7 
 
 
 
 
PHARMACOGENETICS10 
Genotyping8 
 
 
 
 
    
0.125mL 
 
 
 
PHARMACOKINETICS*10  
Washout9 
 
 0.25 mL 
 0.25 mL 
0.25 mL 
0.25mL 
0.25mL 
0.25mL 
 
TOTAL 
BLOOD 
0mL 
  0.25mL 
0.25mL 
  1.75mL 
1.375mL 
 0.25mL 
   1.75mL 
0mL 
*See section 3.0 and 4.6 for criteria for infants eligible for pharmacokinetic  (PK) blood sampling. 
1. Physical examination includes infant Apgar score, birth weight and length, head circumference, 
 
gestational age, gender, sex, and ethnicity.  
2. History includes all non-protocol laboratory tests, HIV test results, antiretroviral agents for PMTCT, 
 
concomitant medications, signs and symptoms, diagnoses, and any intercurrent illnesses since the last 
 
visit, including any treatment to reduce bilirubin. 
3. Complete physical exam includes temperature, heart rate, respiratory rate, weight, length, and head 
 
circumference.   
4. Hematology to include CBC with differential and platelet count: If hematology testing was done as part 
 
of clinical care within 48 hours, report values obtained for clinical care and do not obtain additional study 
 
sample.  
5. Chemistries include AST, ALT, creatinine and total and direct bilirubin: If chemistry testing was done as 
 
part of clinical care within 24 hours, report values obtained for clinical care and do not obtain additional 
 
study sample.   
6. Both PK eligible and ineligible infants will have laboratory evaluations collected unless obtained as part 
 
of clinical care (see Footnotes 4, 5, and 7). If infant enrolls after birth, hematology, chemistries, and 
 
bilirubin should be obtained with first PK blood draw for those infants eligible for PK. 
7. Bilirubin includes total and direct: If bilirubin testing was done as part of clinical care within 24 hours, 
 
report values obtained for clinical care and do not obtain additional study sample.   
8.  Genotyping (optional) for UGT1A1 polymorphisms will be done using dried blood spot on filter paper.  
 
Only infants who have PK sampling will have genotyping.  
9. Only infants eligible for PK blood sampling (See Section 3.0 and 4.3). Collect 0.25mL of blood for each 
 
sample. Infants enrolled after delivery up to 48 hours may not have the initial PK samples obtained but 
 
will start as soon as possible. (Note: Infants enrolled close to the 48-hour time point should have the first 
 
PK blood sample collected within 4 hours of enrollment (i.e.,  within 52 hours after birth). 
10.  See the Laboratory Processing Chart (LPC) on the P1097 Protocol Specific Webpage on the 
 
IMPAACT Website (http://www.impaactgroup.org) for collection, processing and shipping  
instructions. 
11. Skip visit if enrolled after scheduled time of visit. 
 
Priority of blood draws should be: chemistries, hematology, pharmacokinetics, genotyping.

 
IMPAACT P1097 
 
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APPENDIX III 
 
P1097 TESTING LABORATORIES  
 
 
PHARMACOKINETICS 
 
University of Alabama at Birmingham  
Attn: Kedria Walker 
Division of Pharmacology 
1670 University Blvd. 
Volker Hall Room 270 
Birmingham, AL 35294-0019 
Phone: 205-975-2461 
Fax: 205-934-6201 
E-mail: kedria@uab.edu  
LDMS Lab# 191 
 
DBS FOR GENOTYPING 
 
Stephen A Spector, M.D. 
University of California, San Diego 
Department of Pediatrics 
Division of Infectious Diseases 
Stein Clinical Research Bldg. Room 430 
Attn: Rodney Trout 
9500 Gilman Drive, Mail Code 0672 
La Jolla, CA 92093-0672 
Office Phone: 858-534-7055 
Fax: 858-534-7411 
E-mail: saspector@ucsd.edu 
LDMS Lab# 173 
 

 
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APPENDIX IV-A  
 
DIVISION OF AIDS  
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS  
CLINICAL TRIALS GROUP (IMPAACT) 
 
SAMPLE INFORMED CONSENT FOR COHORT 1  
(CLOSED) 
 
IMPAACT P1097: Raltegravir Pharmacokinetics and Safety in Neonates, Version 2.0, 
dated 22 January 2014 
 
INTRODUCTION                                
 
You and your baby are being asked to take part in this research study because you are 
infected with the Human Immunodeficiency Virus (HIV), the virus that causes AIDS.  
This study is sponsored by the National Institutes of Health.  The doctor in charge of this 
study at this site is: (insert name of Principal Investigator).  Before you decide if you 
want to be/want your baby 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 baby 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? 
 
The purpose of this study is to find out if raltegravir, one of the drugs you are taking 
while pregnant for treatment of your HIV infection and to prevent passing HIV to your 
unborn baby, is getting into your unborn baby.  Another purpose of this study is to look 
for possible side effects of raltegravir in your baby, such as more jaundice (yellow color 
to skin).  Another purpose of this study is to look at your baby’s DNA and its effect on 
how raltegravir is broken down by the body.  We know that some people break down 
medications differently based on their DNA and could have much higher blood levels 
than other people and have more side effects.  Information from this study may be used to 
design a future study to find the right dose of raltegravir to give to infants who need 
additional anti-HIV medications to prevent them from getting HIV. 
 
WHAT DO I/DOES MY BABY HAVE TO DO AS PART OF THIS STUDY? 
 
You will continue to take the anti-HIV medications prescribed by your doctor while you 
are in this study. After you deliver your baby, your baby’s doctor may recommend that 
your baby take anti-HIV medication but neither you nor your baby will receive any 
medication as part of this study. 

 
IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
Page 44 of 54 
 
 
Screening visit to see if you can be in this study 
 
If you agree to/ allow your baby to take part in this study, you will be asked to sign this 
consent form. If you decide you want you and your baby to be in this study, we will get 
your medical history and we will ask you questions about how you are feeling and what 
medications you are taking.  This is the only test that will be done at screening. 
 
Study visit at labor/delivery 
 
You will have a medical history to find out how you are feeling and what medications 
you are taking. A blood sample will be collected from the placenta (afterbirth) after 
delivery. You will have one blood sample taken to measure the amount of medication in 
your blood.  About 2mL (less than one-half of a teaspoon of blood) will be drawn at this 
visit. After these tests are taken, your participation in the study will end. 
 
Study visits for your baby 
 
• At birth and two other times while your baby is in this study, your baby will have 
a medical check-up and a physical examination that includes length, weight, head 
measurement and temperature, heart rate, and respiratory rate.   
• All babies in this study will have blood taken 2 times within 36 hours after birth 
and once at 1-2 weeks of age for routine tests.   
• If your baby is able to have repeat blood samples taken to find out how much 
raltegravir you took during pregnancy is getting into your baby, your baby will 
also have one blood sample taken at four time points immediately after birth to 
measure the amount of medication in the blood.  About 1mL, or less than one-
quarter of a teaspoon (sites – add locally relevant description of blood volume) of 
blood will be taken for each sample.  These blood samples will be collected at the 
same time as the routine tests for this visit.   
• If you agree and your baby had repeat blood samples taken to check the amount 
of raltegravir in your baby, your baby will have one drop of blood taken once 
during the study to check your baby’s DNA (genes). You may decide that you do 
not want your baby’s DNA to be tested. Your baby can still participate in this 
study even if you make this decision.  Please read the following statement 
carefully and then mark your initials in the appropriate space provided:   
• I agree to allow my baby’s DNA to be tested. 
Yes_______      No_________ Initials ________ Date ________ 
• Each of your baby’s study visits will last about (sites – add local information 
about time for study visits) and the total amount of blood to be drawn for these 
visits will be between 1-2.5 mL (less than one quarter to one-half of a teaspoon) 
[sites - add locally relevant description of blood volume] depending on the tests to 
be done. 
• Your baby will be in this study until your baby is 5 months of age.  
 

 
IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
Page 45 of 54 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 25 HIV-infected pregnant women and their infants will take part in this study. 
 
HOW LONG WILL I/MY BABY BE IN THIS STUDY? 
 
You will only be in this study until you deliver your baby.  Your baby will be in this 
study until your baby is 5 months of age. 
 
WHY WOULD THE DOCTOR TAKE ME/MY BABY OFF THIS STUDY EARLY? 
 
The study doctor may need to take you/your baby off the study early without your 
permission for the following reasons.  If this happens, no further information will be 
collected and no further study visits or laboratory tests will be done. 
 
• The study is cancelled by the IMPAACT network, the National Institutes of Health, 
the Office for Human Research Protections, the U.S. Food and Drug Administration, 
the site’s Institutional Review Board (IRB) or Ethics Committee (EC), the 
pharmaceutical sponsors and other governmental agencies. An IRB/EC is a 
committee that watches over the safety and rights of research subjects. 
• You/your baby are/is not able to attend the study visits as required by the study. 
• The investigator determines that further participation would be detrimental to 
your/your baby’s health or well-being. 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Blood drawing may cause some discomfort, bleeding or bruising where the needle enters 
the body.  A small blood clot may form at the site where the blood was drawn or there 
may be swelling in the area.  There is a small risk of a minor infection at the blood draw 
site.  Lightheadedness and fainting can also occur. The DNA blood test can also be done 
by heel stick.  Heel stick test may cause some discomfort, bleeding, or bruising at the site 
of the heel stick.  There is a small risk of an infection at the site of the heel stick. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
This study will be of no direct benefit to you or your baby.  Information learned from this 
study may help others who have HIV.   
 
WHAT OTHER CHOICES DO I/DOES MY BABY HAVE BESIDES THIS STUDY? 
 
You may choose not to be in this study or allow your baby to take part in this study.  You 
may leave the study at any time or take your baby out of this study at any time.  Please 
talk to your doctor about other choices available to you.   
 
 
WHAT HAPPENS IF I AM/MY BABY IS INJURED? 

 
IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
Page 46 of 54 
 
 
If you are/your baby is injured as a result of being in this study, you/your baby will be 
given immediate treatment for your 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.  You will not be giving up any of your 
legal rights by signing this consent form. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
U.S. sites: 
To help us protect your 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 U.S. Food and Drug Administration. 
 
People who may review your records include the U.S. Food and Drug Administration, the 
Office for Human Research Protections, the site IRB/EC (insert name of site IRB/EC), 
the National Institutes of Health, study staff, study monitors, drug company supporting 
the study, and 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. 
 
Sites outside the U.S.: 
Efforts will be made to keep your/your baby’s personal information confidential.  We 
cannot guarantee absolute confidentiality.  Your/your baby’s personal information may 
be disclosed if required by law.  Any publication of this study will not use your/your 
baby’s name or identify you/your baby personally. 
 
Your/your baby’s records may be reviewed by the U.S. Food and Drug Administration, 
the Office for Human Research Protections, the site IRB/EC (insert name of site 
IRB/EC), National Institutes of Health, study staff, study monitors, and drug company 
supporting this study and designees. 

 
IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
Page 47 of 54 
 
WHAT ARE THE COSTS TO ME? 
 
There is no cost to you for your/your baby’s study visits, examinations, or blood tests. 
[Note to sites: This statement can be modified as needed for your site.] 
 
Taking part in this study may lead to added costs to you and your insurance company. In 
some cases it is possible that your insurance company will not pay for these costs because 
you are/your baby is taking part in a research study. [Note to sites: Language related to 
insurance can be deleted if it is not relevant to your site.] 
 
WHAT ARE MY/MY BABY’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 baby to take part in this study or leave this study/take your baby out of the 
study at any time.  Your decision will not have any impact on your or your baby’s 
participation in other studies conducted by the National Institutes of Health and will not 
result in any penalty or loss of benefits to which you or your baby are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect 
your/your baby’s health, welfare or willingness to stay in this study.  If you want the 
results of the study, let the study staff know. 
 
WHAT SHOULD 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/your baby’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   

 
IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
Page 48 of 54 
 
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 take part in this study or to allow your baby to take part 
in this study, please sign your name below. 
 
_____________________                              ____________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
 
____________________________                ____________________________________ 
Participant’s Legal Guardian (print) 
Legal Guardian’s Signature and Date 
 
 
(As appropriate) 
 
________________________                        ____________________________________ 
Study Staff Conducting  
            Study Staff Signature and Date 
 
 

 
IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
Page 49 of 54 
 
 
APPENDIX IV-B  
 
DIVISION OF AIDS  
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS  
CLINICAL TRIALS GROUP (IMPAACT) 
 
SAMPLE INFORMED CONSENT COHORT 2 
 
IMPAACT P1097: Raltegravir Pharmacokinetics and Safety in Neonates, Version 
2.0, dated 22 January 2014 
 
INTRODUCTION  
 
You and your baby are being asked to take part in this research study because you 
are infected with the Human Immunodeficiency Virus (HIV), the virus that causes 
AIDS.  This study is sponsored by the National Institutes of Health.  The doctor in 
charge of this study at this site is: (insert name of Principal Investigator).  Before 
you decide if you want to be/want your baby 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 baby 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? 
 
The purpose of this study is to find out if raltegravir, one of the drugs you are 
taking while pregnant for treatment of your HIV infection and to prevent passing 
HIV to your unborn baby, is getting into your unborn baby.  Another purpose of 
this study is to look for possible side effects of raltegravir in your baby, such as 
more jaundice (yellow color to skin).  Another purpose of this study is to look at 
your baby’s DNA and its effect on how raltegravir is broken down by the body.  We 
know that some people break down medications differently based on their DNA and 
could have much higher blood levels than other people and have more side effects.  
Information from this study may be used to design a future study to find the right 
dose of raltegravir to give to infants who need additional anti-HIV medications to 
prevent them from getting HIV. 
 
WHAT DO I/DOES MY BABY HAVE TO DO AS PART OF THIS STUDY? 
 
You will continue to take the anti-HIV medications prescribed by your doctor while 
you are in this study. After you deliver your baby, your baby’s doctor may 
recommend that your baby take anti-HIV medication but neitheryou nor your baby 
will receive any medication as part of this study. 

 
IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
Page 50 of 54 
 
 
Screening visit to see if you can be in this study 
 
If you agree to/ allow your baby to take part in this study, you will be asked to sign 
this consent form. If you decide you want you and your baby to be in this study, we 
will get your medical history and we will ask you questions about how you are 
feeling and what medications you are taking.  Your doctor may ask your permission 
to report the medicine you take to a national registry, which collects information 
anonymously on the use of HIV medicine during pregnancy, and any effects these 
medicines may have on infants. This information is completely confidential and 
your name will not be used.  
 
Study visit at labor/delivery 
 
You will have a medical history to find out how you are feeling and what 
medications you are taking. A blood sample will be collected from the placenta 
(afterbirth) after delivery. You will have one blood sample taken to measure the 
amount of medication in your blood.  About 1 mL (less than one-quarter of a 
teaspoon of blood) will be drawn at this visit. After these tests are taken, your 
participation in the study will end.   
 
Study visits for your baby 
 
• Your baby will have a medical check-up and a physical examination 3 times 
during the study.  The physical examination will include length, weight, head 
measurement and temperature, heart rate, and respiratory rate.   
• Your baby will have blood taken 3 times during this study for routine tests if 
these tests were not done by your baby’s doctor as part of your baby’s 
routine care.  Between 0.5 and 1.5mL (less than ¼ teaspoon of blood) will be 
taken for these tests if they are required. 
• 
Your baby will have repeat blood samples taken to find out how much 
 raltegravir you took during pregnancy is getting into your baby.  About 
 0.25mL (about 1/20th of a teaspoon (sites – add locally relevant description of 
 blood volume) of blood will be taken for each sample. These blood samples 
 will be collected at 1-6 hours, 12-24 hours, 36-48 hours, 72-84 hours, 108-132 
 hours and day 7-14 after birth 
 
If you agree and your baby had repeat blood samples taken to check the amount 
of raltegravir in your baby, your baby will have about 0.125mL (about 1/20th of 
a teaspoon) of blood taken once during the study to check your baby’s DNA 
(genes). You may decide that you do not want your baby’s DNA to be tested. 
Your baby can still participate in this study even if you make this decision.  
Please read the following statement carefully and then mark your initials in the 
appropriate space provided:  
 

 
IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
Page 51 of 54 
 
• I agree to allow my baby’s DNA to be tested. 
Yes_______      No_________ Initials ________ Date ________ 
• Each of your baby’s study visits will last about (sites – add local information 
about time for study visits) and the total amount of blood to be drawn at each 
visit will be between 0.25 to 1.75mL (about 1/20th to 1/3rd of a teaspoon [sites 
– add locally relevant description of blood volume] depending on the tests to be 
done. Your baby will be in this study until your baby is 6 weeks of age. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
A total of 22 HIV-infected pregnant women and their infants have completed the 
first part of the study. An additional 20 HIV-infected pregnant women and their 
infants will be enrolled. 
 
HOW LONG WILL I/MY BABY BE IN THIS STUDY? 
 
You will only be in this study until you are discharged from the labor/delivery unit.  
Your baby will be in this study until your baby is 6 weeks of age. 
 
WHY WOULD THE DOCTOR TAKE ME/MY BABY OFF THIS STUDY 
EARLY? 
 
The study doctor may need to take you/your baby off the study early without your 
permission for the following reasons.  If this happens, no further information will be 
collected and no further study visits or laboratory tests will be done. 
 
• The study is cancelled by the IMPAACT network, the National Institutes of 
Health, the Office for Human Research Protections, the U.S. Food and Drug 
Administration, the site’s Institutional Review Board (IRB) or Ethics Committee 
(EC), the pharmaceutical sponsor and other governmental agencies. An IRB/EC 
is a committee that watches over the safety and rights of research subjects. 
• You/your baby are/is not able to attend the study visits as required by the study. 
• The investigator determines that further participation would be detrimental to 
your/your baby’s health or well-being. 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Blood drawing may cause some discomfort, bleeding or bruising where the needle 
enters the body.  A small blood clot may form at the site where the blood was drawn 
or there may be swelling in the area.  There is a small risk of a minor infection at the 
blood draw site.  Lightheadedness and fainting can also occur. The DNA blood test 
can also be done by heel stick.  The heel stick test may cause some discomfort, 
bleeding, or bruising at the site of the heel stick.  There is a small risk of an infection 
at the site of the heel stick. 
 

 
IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
Page 52 of 54 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
This study will be of no direct benefit to you or your baby.  Information learned 
from this study may help others who have HIV.   
 
WHAT OTHER CHOICES DO I/DOES MY BABY HAVE BESIDES THIS 
STUDY? 
 
You may choose not to be in this study or allow your baby to take part in this study.  
You may leave the study at any time or take your baby out of this study at any time.  
Please talk to your doctor about other choices available to you.   
 
WHAT HAPPENS IF I AM/MY BABY IS INJURED? 
 
If you are/your baby is injured as a result of being in this study, you/your baby will 
be given immediate treatment for your 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.  You will not be 
giving up any of your legal rights by signing this consent form. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
U.S. sites: 
To help us protect your 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 U.S. Food and Drug Administration. 
 
People who may review your records include the U.S. Food and Drug 
Administration, the Office for Human Research Protections, the site IRB/EC (insert 
name of site IRB/EC), the National Institutes of Health, study staff, study monitors, 
drug company supporting the study, and 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. 
 
Sites outside the U.S.: 

 
IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
Page 53 of 54 
 
Efforts will be made to keep your/your baby’s personal information confidential.  
We cannot guarantee absolute confidentiality.  Your/your baby’s personal 
information may be disclosed if required by law.  Any publication of this study will 
not use your/your baby’s name or identify you/your baby personally. 
 
Your/your baby’s records may be reviewed by the U.S. Food and Drug 
Administration, the Office for Human Research Protections, the site IRB/EC (insert 
name of site IRB/EC), National Institutes of Health, study staff, study monitors, and 
drug company supporting this study and designees. 
 
WHAT ARE THE COSTS TO ME? 
 
There is no cost to you for your/your baby’s study visits, examinations, or blood 
tests. [Note to sites: This statement can be modified as needed for your site.] 
 
Taking part in this study may lead to added costs to you and your insurance 
company. In some cases it is possible that your insurance company will not pay for 
these costs because you are/your baby is taking part in a research study. [Note to 
sites: Language related to insurance can be deleted if it is not relevant to your site.] 
 
WHAT ARE MY/MY BABY’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 baby to take part in this study or leave this study/take your 
baby out of the study at any time.  Your decision will not have any impact on your 
or your baby’s participation in other studies conducted by the National Institutes of 
Health and will not result in any penalty or loss of benefits to which you or your 
baby are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect 
your/your baby’s health, welfare or willingness to stay in this study.  If you want the 
results of the study, let the study staff know. 
 
WHAT SHOULD 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/your baby’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   
 
 

 
IMPAACT P1097 
 
Version 2.0 
22 January 2014 
 
Page 54 of 54 
 
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 take part in this study or to allow your baby 
to take part in this study, please sign your name below. 
 
_____________________                              ____________________________________ 
Participant’s Name (print)  
 
Participant’s Signature and Date  
 
 
____________________________                ____________________________________ 
Participant’s Legal Guardian (print) 
Legal Guardian’s Signature and Date 
 
 
(As appropriate) 
 
________________________                        ____________________________________ 
Study Staff Conducting 
 
            Study Staff Signature and Date