Conditions: HIV Infections
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the safety and pharmacokinetics (PK) of raltegravir (RAL) when given to HIV-1-exposed, normal birth weight newborn infants at risk of acquiring HIV-1 infection. (PK is the study of the time course of absorption, distribution, metabolism, and excretion of drugs in the body.) The primary goal of this study was to determine a dose of RAL that was safe and met the PK targets for infants when administered during the first 6 weeks of life in addition to standard of care antiretroviral (ARV) agents for prevention of perinatal transmission.

Detailed description:
This is a Phase I multi-center, open label, non-comparative study to evaluate the safety and PK of RAL administered to HIV-1-exposed full-term (≥37 weeks of gestation) infants when administered during the first 6 weeks of life in addition to the infants' standard HIV-1 ARV prophylaxis.

IMPAACT P1097 (NCT01828073) demonstrated that RAL crossed the placenta from mother to fetus after maternal dosing during pregnancy and RAL was slowly eliminated by the newborn after birth. Therefore, for P1110, within each cohort, infants were stratified into the "RAL-naive" or "RAL-exposed" groups depending on infants' in utero exposure to maternal RAL. The study stratification with respect to in utero RAL exposure allowed for adjustment of the initial RAL dosing (i.e. timing and/or dose size).

Study participants were enrolled in two sequential cohorts with the following actual dosing of RAL in addition to their local standard of care ARV agents for prevention of perinatal transmission. PK and safety data from Cohort 1 (two single doses) provided information for the starting dosing for Cohort 2 (daily dosing through 6 weeks of life).

Cohort 1: Two single RAL doses: first dose within 48 hours of birth and second dose at 7-10 days of life.

* Cohort 1, RAL-naive: 3 or 2 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life. (P1110 V1.0 Clarification Memorandum #3, dated January 15, 2015, adjusted the first dose from 3 mg/kg to 2 mg/kg based on available PK data.)
* Cohort 1, RAL-exposed: 1.5 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life.

Cohort 2: Daily RAL dosing through 6 weeks of life.

* Cohort 2, RAL-naive: Daily dosing through 6 weeks of life with initial RAL dosing within 48 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.
* Cohort 2, RAL-exposed: Daily dosing through 6 weeks of life with initial RAL dosing between 12-60 hours of birth: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

Target enrollment was approximately 50 infants and their mothers in order to have a minimum of 12 and 20 PK evaluable infants in Cohorts 1 and 2, respectively. Cohort 1 and Cohort 2 RAL-naive infants (and their mothers) were enrolled under protocol Version 1.0. Cohort 2 RAL-exposed infants (and their mothers) were enrolled under protocol Version 2.0.

Infants and their mothers were enrolled within 48 and within 60 hours of delivery under protocol Versions 1.0 and 2.0, respectively. Infants were followed through 24 weeks of life and their mothers were followed until discharge from the labor and delivery unit.

Infant PK samples were collected as follows:

Cohort 1:

* Dose #1 (within 48 hours of birth) intensive PK sampling: Within 30 min pre-dose, and 1-2 hours post-dose, 4-8 hours post-dose, 12 (±1) hours post-dose, and 24 (±1) hours post-dose.
* One random PK sample at 3-4 days of life.
* Dose #2 (7-10 days of life) limited PK sampling: Within 30 min pre-dose, and 1-2 hours post-dose and 24 (±1) hours post-dose.

Cohort 2:

* Initial dose (within 48 and 12-60 hours of birth for RAL-naive and RAL-exposed infants, respectively) intensive PK sampling: Within 1 hour pre-dose, and 1-2 hours, 6-10 hours, 20-24 hours post-dose.
* PK sampling for second dose: 3-6 hours post-dose.
* PK sampling at 6-9 days of life: Within 1 hour pre-dose of initiating 3mg/kg twice daily.
* Intensive PK sampling at 15-18 days of life: Within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-12 hours post-dose.
* PK sampling at 28-32 days of life: Within 1 hour pre-dose of initiating 6 mg/kg twice daily.
* PK sampling at 33-42 days of life done at Week 5-6 visit: Within 1 hour pre-dose, and 3-6 hours post-dose.

Protocol defined infant safety evaluations were done at:

Cohort 1: Entry, 3-4 days of life, 7-10 days of life, 2 weeks of life, 6 weeks of life and 24 weeks of life.

Cohort 2: Entry, 2-4 days of life, 6-9 days of life, 15-18 days of life, 28-32 days of life, 5-6 weeks of life, 8-10 weeks of life and 24 weeks of life.

Infant safety data included death, signs/symptoms, diagnoses and laboratory test results. Laboratory test results included results from evaluations specified in the protocol and evaluations done as part of the infant's clinical care which the sites considered relevant.

PK evaluable infants were those determined by the protocol pharmacologist to have PK results which provide analyzable data on the primary PK parameters of interest. Infants who were PK unevaluable were replaced for PK analysis but continued with the study safety follow-up visits.

Infants were evaluable for safety analysis if they received at least one dose of RAL. The safety analyses were based on data from all safety evaluable infants, regardless of whether they were evaluable for PK analysis.

The study initially opened accrual to Cohort 1 RAL-naive group. The PK and safety data from IMPAACT P1110 Cohort 1 RAL-naive group and from IMPAACT P1097 were used to determine the starting dose for the Cohort 1 RAL-exposed group. Opening accrual to the Cohort 2 RAL-naive group was contingent upon infants enrolled in Cohort 1 RAL-naive and RAL-exposed groups successfully meeting safety criteria and providing adequate PK data to determine a regimen to be tested for daily dosing through 6 weeks of life for the Cohort 2 RAL-naive group. The initial dosing regimen for the Cohort 2 RAL-naive group was determined using population PK modeling and simulations incorporating IMPAACT P1110 Cohort 1 data, along with data from the following IMPAACT studies: P1097, P1066 (NCT00485264) (Cohorts IV and V) and P1026s (NCT00042289). Since the PK results of Cohort 1 RAL-naive and exposed groups were similar except in the first 1-2 days of life and P1097 Cohort 1 results suggested that maternal RAL readily crosses the placenta and results to washout RAL exposure in neonates, Cohort 2 RAL-exposed group was determined to receive the same dose of RAL as Cohort 2 RAL-naive group, except the initial dose for RAL-exposed was delayed to within 12 to 60 hours of life.

Arms:
arm 1: HIV-1-exposed full-term infants. Infants received two single doses of RAL: first dose within 48 hours of birth and second dose at 7-10 days of life:

* RAL-naive: 3 or 2 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life.
* RAL-exposed: 1.5 mg/kg within 48 hours of birth and 3 mg/kg at 7-10 days of life. arm 2: HIV-1-exposed full-term infants. Daily RAL through 6 weeks of life with first dosing within 48 hours of birth and between 12-60 hours of birth for in utero RAL-naive and RAL-exposed infants, respectively.

Daily RAL through 6 weeks of life: 1.5 mg/kg once daily during Days 1-7 of life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-42 of life.

Interventions: intervention 1: Raltegravir
Intervention descriptions: intervention 1: RAL was given as oral granules for suspension.

Protocol document:
Prot_000.pdf: 
IMPAACT P1110 
(DAIDS Document ID 11891) 
 
A PHASE I TRIAL TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF 
RALTEGRAVIR IN HIV-1-EXPOSED NEONATES AT RISK OF ACQUIRING HIV-1 
INFECTION 
 
A Multicenter, US Domestic and International Trial of the 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network  
(IMPAACT) 
 
 
This file contains the current IMPAACT P1110 protocol, 
which is comprised of the following documents, 
presented in reverse chronological order: 
 
Letter of Amendment #1, dated 6 September 2018 
Clarification Memorandum #2, dated 15 June 2017 
Clarification Memorandum #1, dated 08 February 2017 
Protocol Version 2.0, dated 18 January 2017 


Letter of Amendment #1       
Page 1 of 5 
 
6 September 2018 
IMPAACT P1110 Version 2.0, dated 18 January 2017 
IMPAACT P1110 
 A PHASE I TRIAL TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF 
RALTEGRAVIR IN HIV-1-EXPOSED NEONATES AT RISK OF ACQUIRING HIV-1 
INFECTION 
 
LoA # 1 to Version 2.0, dated 18 January 2017  
 
 
 DAIDS ID # 11891 
IND # 77,787 Held By DAIDS 
 
Letter of Amendment Date: 6 September 2018 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) impacts the IMPAACT P1110 study 
Version 2.0 and must be submitted to site Institutional Review Boards and/or Ethics Committees 
(IRBs/ECs) as soon as possible for their review and approval.  The LoA serves to clarify the correct 
interpretation of eligibility criteria with respect to participants with known vs. newly discovered HIV 
status. While most working from 2.0 have interpreted Section 4.0 of the protocol as the team intended and 
as training slides further explained, this LOA serves to reinforce the correct understanding of Section 4.0 
of the protocol, independent of protocol training. Approval must also be obtained from site regulatory 
entities if applicable per the policies and procedures of the regulatory entities.  All IRB/EC and regulatory 
entity requirements must be followed. 
 
Upon obtaining IRB/EC approval and any other applicable regulatory entity approvals, each site should 
immediately begin implementing this LoA. Sites are required to submit a LoA registration packet to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC).  Sites will 
receive a registration notification for the LoA after the DAIDS PRO verifies that all required registration 
documents have been received and are complete.  Sites should not await this notification before 
implementing this LoA.  
 
Please file this LoA, all associated IRB/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential documents files for IMPAACT P1110.  If the IMPAACT P1110 
protocol is amended in the future, the contents of this LoA will be incorporated into the next version of 
the protocol. 
 
 
 
 


Letter of Amendment #1       
Page 2 of 5 
 
6 September 2018 
IMPAACT P1110 Version 2.0, dated 18 January 2017 
IMPAACT P1110 
A PHASE I TRIAL TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF 
RALTEGRAVIR IN HIV-1-EXPOSED NEONATES AT RISK OF ACQUIRING HIV-1 
INFECTION 
 
LoA # 1 to Version 2.0, dated 18 January 2017  
(DAIDS Document ID 11891) 
 
Dated 6 September 2018 
 
Letter of Amendment Signature Page 
 
I will conduct this study in accordance with the provisions of this protocol, including this Letter of 
Amendment, and all applicable protocol-related documents. I agree to conduct this study in compliance 
with United States (US) Health and Human Service regulations (45 CFR 46); applicable US Food and 
Drug Administration regulations; standards of the International Conference on Harmonization Guideline 
for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee determinations; all 
applicable in-country, state, and local laws and regulations; and other applicable requirements (e.g., US 
National Institutes of Health, Division of AIDS) and institutional policies. 
 
 
 
 
 
 
 
Signature of Investigator of Record 
 
Date 
 
 
 
 
 
Name of Investigator of Record 
 
 
(printed) 
 
 
 


Letter of Amendment #1       
Page 3 of 5 
 
6 September 2018 
IMPAACT P1110 Version 2.0, dated 18 January 2017 
Summary of Modifications and Rationale 
 
The purpose of this LoA is to: 
 
1. Provide background, clarify maternal inclusion criterion 4.11 and to define the terms used.  
 
Background:  In designing P1110, the team recognized that in some countries mothers with a history 
of HIV infection could present in labor at delivery sites separate from where they received their 
routine HIV care.  At some research sites, mothers travel to delivery sites with Prenatal Cards that 
serve as medical records for their prenatal history, laboratory tests results, documentation of 
antiretroviral treatment, and overall delivery of health care. Mothers with HIV infection may be 
referred to another location for delivery by referring health care providers.  
 
Clarification of Maternal Inclusion Criterion 4.11:  To be eligible to enroll in IMPAACT P1110, 
participating infants had to be enrolled within 48 hours of birth. The protocol team recognized that 
source documentation of past HIV test results might not be available at the delivery site and that there 
might be difficulty in obtaining this documentation within the infant enrollment window of 48 hours 
after delivery.  For this reason, the team included the stipulation in the protocol section 4.11 that HIV 
test results “documented in the clinical record from past testing may be used to satisfy the criteria for 
documentation of HIV-1 infection.”  Documentation in the medical record that the diagnosis of HIV 
infection had previously been done using in-country standard of care diagnostic tests could be used to 
document HIV infection, qualifying the mother as “known to be HIV infected,” and therefore 
additional HIV testing as part of study procedures would not be required.  An additional pragmatic 
factor, which further made the medical record documentation of past HIV positive test results an 
inclusion criterion was the situation that for women known to be HIV positive for some duration of 
time and on  cART,   they might have such low viral load that test results from re-confirming HIV 
infection could take longer than 48 hours, making it either impossible to enroll the infant or making 
maternal test results of no usefulness, being obtained after the baby is already on dosing. The 
algorithm for newly diagnosing HIV would be the less useful approach for a woman known to be 
HIV positive and medically managed for a period of time prior to study entry. 
 
Definitions 
“Known” to be HIV infected: can be documented in the medical clinic file at the research site and 
may include the following: 1) maternal subject is documented to be HIV positive in the medical 
record per the usual designation at the site, either on or starting prescribed treatment with cART 
(combination Anti-Retroviral Treatment) for the current pregnancy; 2)  based on available medical 
records, or per her history obtained at the research site , from a referring clinic documented by mail ( 
electronic or other), or phone contact with the referring prescribing healthcare provider.    
 
“Medical record” can include: Mobile paperwork carried throughout the pregnancy as a mother gets 
treatment in one or more clinics; patient file hard-copy or electronic copy in the research clinic or 
from another clinic which notes the HIV status of the mother; or other medical record that is normally 
accepted by the research site. 
 
“HIV test results” documented in the clinical record for “known” HIV positive women: the standard 
method of designation will be confirmed by the research site. This may include the designation of 
RVD positive=Retroviral Disease Positive. This designation is routinely used in some countries to 
document positive HIV test on the Prenatal Cards.  This is done to protect the confidentiality of the 
HIV status of women where stigma and discrimination are potential barriers to their health care. 
 


Letter of Amendment #1       
Page 4 of 5 
 
6 September 2018 
IMPAACT P1110 Version 2.0, dated 18 January 2017 
In summary, “HIV testing documentation required for mothers known to be HIV-infected”:  For 
mothers known to be HIV-infected (as defined above), testing obtained and documented per the local 
in-country health department standard of care applicable to the research site (e.g. SOC using 2 
separate tests and samples, without naming them) are sufficient for meeting the requirement of HIV-1 
testing documentation in the medical record as clarified under part (i) in Section 4.11.  After noting 
the HIV positive designation in the maternal medical record, per the health department guidelines for 
the site, if two samples and two timepoints are used, no further HIV testing is needed for enrollment.  
The HIV testing documentation algorithm only applies for mothers identified as HIV infected at the 
time of labor or in the immediate postpartum period, as clarified under part (ii) in Section 4.11.   
 
 
Implementation 
 
The modification included in this Letter of Amendment will be incorporated into the next protocol 
amendment as specified below.  Additions to the text are indicated in bold; deletions are indicated by strike-
through.   
 
1. Section 4.11, Maternal Inclusion Criteria, is clarified regarding the required source documentation 
for mothers known to be HIV infected versus mothers diagnosed at the time of labor or in the 
immediate postpartum period.  Additions to the text are indicated in bold.  Furthermore, formatting 
changes have been made separating the first paragraph after “Documentation of HIV infection” into 
three paragraphs with added text shown in bold.  The first paragraph applies to both groups of 
mothers, whereas the second paragraph is clarified as only applying to mothers who are known to be 
HIV infected (clarified under i). The third paragraph (newly added) and all remaining text under 
Section 4.11 is clarified as only applying to mothers who are diagnosed at the time of labor or in the 
immediate postpartum period (clarified under ii). 
 
4.11   Mother is either i) known to be HIV-1 infected prior to labor (testing obtained and designated 
per local SOC in the medical record and either on or recently started CART prior to delivery   
or ii) identified as HIV-1 infected at the time of labor or in the immediate postpartum period. 
 
Documentation of HIV infection for (i) and (ii): 
 
Documentation of HIV-1 infection is defined as positive results from two samples (whole blood, 
serum, or plasma) collected at different time points. This can occur at enrollment or can be 
historical and documented by a notation of HIV positivity in the maternal medical record for 
women known to be HIV positive before delivery.  
 
(i):  Results documented in the clinical record from past testing may be used to satisfy the criteria for 
documentation of HIV-1 infection.  No further testing for HIV is needed for this group of 
mothers. 
 
(ii): For mothers identified as HIV-1 infected at the time of labor or in the immediate 
postpartum period the following testing algorithm should be applied. 
 
If both samples are tested using antibody tests, at least one of the samples must be tested in a 
laboratory that operates according to Good Clinical Laboratory Practice (GCLP) guidelines and 
participates in an appropriate external quality assurance program.  If nucleic acid testing is used, at 
least one test must be performed in a CLIA-certified (US sites) or VQA-certified (non-US) 
laboratory.  For tests performed in other (non-GCLP-compliant or non-VQA-certified) settings, 


Letter of Amendment #1       
Page 5 of 5 
 
6 September 2018 
IMPAACT P1110 Version 2.0, dated 18 January 2017 
adequate source documentation including the date of specimen collection, date of testing, test 
performed, and test result must be available. 
 
Sample #1 must be tested using any of the following: 
• 
Up to two rapid antibody tests from different manufacturers or based on different principles and 
epitopes.  
• 
One EIA OR Western Blot OR immunofluorescence OR chemiluminescence  
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 
• 
One HIV DNA PCR 
• 
One qualitative HIV RNA PCR 
• 
One total HIV nucleic acid test 
 
Note: Confirmatory testing (Sample #2) may be pending at the time of enrollment of the mother-
infant pair.  If maternal confirmatory testing is negative, the infant will be removed from active 
dosing but will be followed for safety as part of the study. 
 
Sample #2 must 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 confirmed by Western Blot OR immunofluorescence OR chemiluminescence  
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 
• 
One HIV DNA PCR 
• 
One qualitative HIV RNA PCR 
• 
One total HIV nucleic acid test 
 


Clarification Memorandum #2       
Page 1 of 1 
15 June 2017 
IMPAACT P1110 Protocol Version 2.0, dated 18 January 2017 
Clarification Memorandum #2 for: 
 
IMPAACT P1110 
A Phase I Trial to Evaluate the Safety and Pharmacokinetics of Raltegravir in 
HIV-1-Exposed Neonates at Risk of Acquiring HIV-1 Infection  
 
Version 2.0, dated 18 January 2017 
IND # 77,787 
 DAIDS ES # 11891 
 
Clarification Memorandum Date: 15 June 2017   
 
 
Summary of Clarifications  
 
This Clarification Memorandum (CM) clarifies that infant exclusion criterion 4.43 applies to all infant 
participants, including Cohort 2 RAL-exposed participants as well as Cohort 1 RAL-naïve, Cohort 1 
RAL-exposed, and Cohort 2 RAL-naïve.  The specification of RAL-naïve was a typo in Version 2.0, and 
inconsistent with the intention of Section 4.5 Disallowed Medications. 
 
 
Implementation 
 
Institutional Review Board/Ethics Committee (IRB/EC) approval of this CM is not required by the study 
sponsor prior to implementation; however, sites may submit it to IRBs/ECs for their information or, if 
required by the IRBs/ECs, for their approval prior to implementation. The clarifications included in this 
memorandum will be incorporated into the next full protocol amendment.  Modifications are shown 
below, using strikethrough for deletions and bold type for additions. 
 
Section 4.4, Infant Exclusion Criteria, page 34, is clarified to emphasize that the infant exclusion criteria 
apply to all infants.  
4.43     For Cohort 2 RAL naïve and Cohort 1 (RAL-naive and RAL-exposed): Receipt of 
disallowed medications (phenytoin, phenobarbital, rifampin) 
 


Clarification Memorandum #1       
Page 1 of 1 
08 February 2017 
IMPAACT P1110 Protocol Version 2.0, dated 18 January 2017 
Clarification Memorandum #1 for: 
 
IMPAACT P1110 
A Phase I Trial to Evaluate the Safety and Pharmacokinetics of Raltegravir in 
HIV-1-Exposed Neonates at Risk of Acquiring HIV-1 Infection  
 
Version 2.0, dated 18 January 2017 
IND # 77,787 
 DAIDS ES # 11891 
 
Clarification Memorandum Date: 08 February 2017   
 
 
Summary of Clarifications  
 
This Clarification Memorandum (CM) removes the pre-dose monitoring call and the post-dose 
monitoring call from the Early Discontinuation visit for Cohort 2, as participants at this visit will be off 
study drug and no longer being dosed. 
 
This CM also clarifies that Appendix V-A, Sample Informed Consent for Cohort 1 (Closed), will not be 
used in P1110 Version 2.0, as Cohort 1 is closed to accrual, all Cohort 1 participants are no longer in 
follow-up and have exited the study. 
 
 
Implementation 
 
Institutional Review Board/Ethics Committee (IRB/EC) approval of this CM is not required by the study 
sponsor prior to implementation; however, sites may submit it to IRBs/ECs for their information or, if 
required by the IRBs/ECs, for their approval prior to implementation. The clarifications included in this 
memorandum will be incorporated into the next full protocol amendment. 
 
In Appendix II-B: Infant Schedule of Evaluations for Cohort 2, Column for Early Discontinuation 
Visit, Rows for Pre-dose monitoring and Post-dose monitoring:  
 
Pre-dose monitoring 
X 
Post-dose monitoring 
X  
 
 
 


 
 
 
 
 
IMPAACT P1110 
 
 
A Phase I Trial to Evaluate the Safety and Pharmacokinetics of Raltegravir 
in HIV-1-Exposed Neonates at Risk of Acquiring HIV-1 Infection  
 
A Study of the International Maternal Pediatric Adolescent  
AIDS Clinical Trials Network (IMPAACT) 
 
 
Sponsored by: 
The National Institute of Allergy and Infectious Diseases (NIAID) 
Eunice Kennedy Shriver  
National Institute of Child Health and Human Development (NICHD) 
National Institute of Mental Health (NIMH) 
 
Pharmaceutical Support Provided by: 
Merck & Co., Inc. 
 
DAIDS ES 11891 
IND # 77,787 held by NIAID 
 
 
The HIV Treatment Scientific  
Committee Chair:  
 
 
Elaine J. Abrams, M.D. 
 
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: 
 
Rohan Hazra, M.D. 
 
Clinical Trials Specialist: 
 
Kat Calabrese, M.P.H. 
 
 
 
 
Version 2.0 
18 January 2017


 
 
 
IMPAACT P1110 Final Version 2.0 
Page 1 of 92  
18 January 2017 
IMPAACT P1110 PROTOCOL TEAM ROSTER 
 
All questions concerning this protocol should be sent via e-mail to 
impaact.teamp1110@fstrf.org.  Remember to include the participant’s PID when applicable. 
The appropriate team member will respond to questions via e-mail with a "cc" to 
impaact.teamp1110@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 
 
 
 
 
 
 
 
 
 
Division of AIDS Medical Officer  
Mary Elizabeth Smith, M.D.  
MAPRB/DAIDS/NIAID/NIH/DHHS 
5601 Fishers Lane  
Room 8B48 
Rockville, MD  20852  
Phone: 
240-292-4788 
E-mail: betsysmith@niaid.nih.gov  
 
NICHD Medical Officer 
Rohan Hazra, M.D. 
Eunice Kennedy Shriver National 
Institute of Child Health and Human 
Development (NICHD) 
6710B Rockledge Drive, Room 2113 
Bethesda, MD 20817 
Phone: (301) 435-6868 
E-mail:  hazrar@mail.nih.gov 
 
Clinical Trials Specialist 
Kat Calabrese, M.P.H. 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone:  919-544-7040, ext. 11306 
Email:  kcalabrese@fhi360.org 
 
 
 
 
 
 


 
 
 
IMPAACT P1110 Final Version 2.0 
Page 2 of 92  
18 January 2017 
Protocol Statisticians 
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. 
Harvard School of Public Health 
Center for Biostatistics in AIDS 
Research (CBAR) FXB Building, Room 
614A 
651 Huntington Avenue 
Boston, MA  02115 
Phone: 617-432-1464 
Fax: 617-432-3163 
Email: jwang@sdac.harvard.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 Pharmacist 
Nayri Khairalla, Pharm.D. 
Pharmaceuticals Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane,  9D35 
Rockville, MD 20852 
Phone: 301-761-6659 
E-mail: khairallann@niaid.nih.gov 
 
Protocol Virologist 
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 
 
Protocol Data Managers 
Bobbie L. Graham, B.S. 
Frontier Science & Technology 
Research Foundation  
4033 Maple Road  
Amherst, NY  14226-1056 
Phone:  716- 834-0900x7265 
E-mail:  graham.bobbie@fstrf.org 
 
Stephanie Popson, Ph.D. 
Frontier Science and Technology 
Research Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226 
Phone: (716) 834-0900 x 7356 
Fax: (716) 834-8432 
Email: popson@fstrf.org 
 
Laboratory Data Coordinator  
Oswald Dodson, M.S. 
Frontier Science & Technology 
Research Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7238 
E-mail: dadson@fstrf.org 
 


 
 
 
IMPAACT P1110 Final Version 2.0 
Page 3 of 92  
18 January 2017 
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 
 
Brenda Homony, M.S. 
Clinical Development Scientist, CSSM 
Merck Research Laboratories 
351 N. Sumneytown Pike 
P.O. Box 1000 
North Wales, PA 19454-2505 
Phone: 267-305-7255 
Email:  brenda_homony@merck.com 
 
Anne Chain, Ph.D. 
Assoc. Principal Scientist 
Quantitative Pharmacology and 
Pharmacometrics, PPDM 
Merck Research Laboratories 
RY34-A500 
126 East Lincoln Avenue 
Rahway, New Jersey 07065-0900 
Email: anne.chain@merck.com 
 
RoseAnn Murray, PhD 
Clinical Development Scientist 
Clinical Science and Study Management 
Merck Research Laboratories 
126 East Lincoln Avenue 
Rahway, New Jersey 07065-0900 
Phone: 732-594-5331 
Email: roseann_murray@merck.com 
 
IMPAACT Central Laboratory 
Specialists 
Carolyn Yanavich 
Children's Hospital of Los Angeles 
4546 Sunset Blvd 
Smith Research Tower room 902 
Los Angeles CA 90027 
Phone: 1-443-249-3851 
Email: cyanavich@chla.usc.edu 
 
Diane Costello. BS 
Children’s Hospital of Los Angeles 
4546 W. Sunset Blvd 
Los Angeles, CA 90027 
Phone: (703) 862-0820 
Email: dcostello@impaactlabcenter.org 
 


 
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TABLE OF CONTENTS 
GLOSSARY................................................................................................................................... 6 
SCHEMA ....................................................................................................................................... 7 
1.0 INTRODUCTION................................................................................................................... 9 
1.1 Background and Rationale ........................................................................................................ 9 
1.2 Raltegravir............................................................................................................................... 10 
2.0 STUDY OBJECTIVES ......................................................................................................... 27 
2.1 Primary Objectives.................................................................................................................. 27 
2.2 Secondary Objectives.............................................................................................................. 28 
3.0 STUDY DESIGN ................................................................................................................... 28 
3.1 Evidence of HIV infection and resistance testing (Cohorts 1 and 2):..................................... 31 
3.2 Optional genotyping (Cohorts 1 and 2): ................................................................................. 31 
3.3 Raltegravir Compassionate Use (Cohorts 1 and 2): ................................................................ 32 
4.0 SELECTION AND ENROLLMENT OF PARTICIPANTS ............................................ 32 
4.1  Maternal Inclusion Criteria .................................................................................................... 32 
4.2 Maternal Exclusion Criteria .................................................................................................... 33 
4.3 Infant Inclusion Criteria .......................................................................................................... 34 
4.4 Infant Exclusion Criteria ......................................................................................................... 34 
4.5 Disallowed Medications.......................................................................................................... 35 
4.6 Enrollment Procedures ............................................................................................................ 35 
4.7 Co-enrollment Procedures ...................................................................................................... 36 
5.0 STUDY TREATMENT ........................................................................................................ 36 
5.1 Drug Regimens, Administration, and Duration ...................................................................... 36 
5.2 Study Drug Formulation and Storage ..................................................................................... 39 
5.3 Drug Supply, Distribution, and Pharmacy .............................................................................. 39 
6.0 PARTICIPANT MANAGEMENT...................................................................................... 40 
6.1 Toxicity Management ............................................................................................................. 40 
6.2 Study Management Plan ......................................................................................................... 43 
6.3 Criteria for Treatment Discontinuation ................................................................................... 45 
6.4 Permanent Study Discontinuation........................................................................................... 45 
7.0 EXPEDITED ADVERSE EVENT REPORTING ............................................................. 45 
7.1 Adverse Event Reporting to DAIDS ....................................................................................... 45 
7.2 Reporting Requirements for this Study................................................................................... 46 
7.3 Grading Severity of Events ..................................................................................................... 46 
7.4 Expedited AE Reporting Period.............................................................................................. 47 
8.0 STATISTICAL CONSIDERATIONS ................................................................................ 47 
8.1 General Design Issues ............................................................................................................. 47 
8.2 Outcome Measures.................................................................................................................. 48 
8.3 Randomization and Stratification ........................................................................................... 49 
8.4 Sample Size and Accrual ........................................................................................................ 49 
8.5 Monitoring and Safety Guidelines .......................................................................................... 49 
8.6 Accrual Rate Evaluation ......................................................................................................... 56 


 
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8.7 Analyses .................................................................................................................................. 57 
9.0 CLINICAL PHARMACOLOGY PLAN ............................................................................ 58 
9.1 Pharmacology Objective ......................................................................................................... 59 
9.2 Primary and Secondary Data .................................................................................................. 59 
9.3 Study Design, Modeling and Data Analysis ........................................................................... 60 
9.4 Anticipated Outcomes ............................................................................................................. 61 
10.0  HUMAN SUBJECTS ...................................................................................................... 61 
10.1 Institutional Review Board and Informed Consent .............................................................. 61 
10.2 Participant Confidentiality .................................................................................................... 62 
10.3 Study Discontinuation………………………………………………………………………62 
11.0 
PUBLICATION OF RESEARCH FINDINGS ............................................................ 62 
12.0 
BIOHAZARD CONTAINMENT .................................................................................. 62 
13.0 
 REFERENCES ............................................................................................................... 63 
APPENDIX I MATERNAL SCHEDULE OF EVALUATIONS ........................................... 68 
APPENDIX II-A INFANT SCHEDULE OF EVALUATIONS FOR COHORT 1 .............. 69 
APPENDIX II-B INFANT SCHEDULE OF EVALUATIONS FOR COHORT 2 .............. 71 
APPENDIX II-C SCHEDULE OF EVALUATIONS FOR INFANTS WHO BECOME HIV 
INFECTED ............................................................................................................................ 73 
APPENDIX III RALTEGRAVIR WEIGHT BAND DOSING TABLES FOR ORAL 
GRANULES FOR SUSPENSION ....................................................................................... 74 
APPENDIX IV DIAGRAM AND CAREGIVER INSTRUCTIONS FOR PREPARING 
AND ADMINISTERING RALTEGRAVIR ORAL GRANULES FOR SUSPENSION 76 
APPENDIX V-A SAMPLE INFORMED CONSENT FORM FOR COHORT 1 ................ 78 
APPENDIX V-B SAMPLE INFORMED CONSENT FORM FOR COHORT 2 ................ 85 
 
 
 
 


 
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GLOSSARY 
 
 
3TC 
 
Lamivudine 
ALT 
 
Alanine aminotransferase 
ARV 
 
Antiretroviral  
AST 
 
Aspartate aminotransferase 
AUC 
 
Area under the curve 
BID 
 
Twice a day 
cART 
 
Combination antiretroviral therapy 
CI 
 
Confidence interval 
DAIDS PRO  
Division of AIDS Protocol Registration Office 
DMC 
 
Data Management Center 
DNA 
 
Deoxyribonucleic Acid 
EAE 
 
Expedited adverse event 
EC 
 
Ethics Committee 
FTC 
 
Emtricitabine 
GCLP 
 
Good Clinical Laboratory Practice 
GM 
 
Geometric mean 
HAART 
 
Highly active antiretroviral therapy 
HIV 
 
Human immunodeficiency virus 
IMPAACT       
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IRB 
 
Institutional Review Board 
LAR 
 
Legally authorized representative 
LDMS 
 
Laboratory Data Management System   
NAT 
 
Nucleic acid test 
NFV 
 
Nelfinavir 
NVP 
 
Nevirapine 
OHRP 
 
Office for Human Research Protections 
PID 
 
Patient Identification Number 
PK 
 
Pharmacokinetic 
PMTCT 
 
Prevention of Mother-to-Child Transmission   
RAL 
 
Raltegravir 
RE 
 
Regulatory entity 
RNA 
 
Ribonucleic Acid 
RSC 
 
Regulatory Support Center 
SES 
 
Subject enrollment system 
SID 
 
Study Identification Number 
UDP 
 
Uridine diphosphate 
UGT 
 
Uridine diphosphate glucuronyl transferase 
ZDV 
 
Zidovudine 
 


 
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SCHEMA 
A Phase I Trial to Evaluate the Safety and Pharmacokinetics of Raltegravir in 
HIV-1-Exposed Neonates at Risk of Acquiring HIV-1 Infection  
 
 
DESIGN: 
 
Phase I, open label, non-comparative dose-finding study 
 
SAMPLE SIZE: 
Approximately 50 infants in order to accrue a minimum of 32 
pharmacokinetic (PK) evaluable HIV-1-exposed infants, and their 
mothers. Cohort 1 will enroll a minimum of 12 PK evaluable infants and 
Cohort 2 will enroll a minimum of 20 PK evaluable infants.  
 
Note:  Cohort 1 RAL-naïve, Cohort 1 RAL-exposed, and Cohort 2 RAL-
naïve groups were fully accrued under protocol Version 1.0. Cohort 2 
RAL-exposed group will be opened to accrual under protocol Version 2.0 
and will enroll a minimum of 8 PK evaluable infants.  
 
POPULATION: 
HIV-1 exposed full-term infants (aged ≤48 hours in protocol Version 1.0 
and ≤ 60 hours in protocol Version 2.0) assessed as risk of acquiring HIV-
1 infection and their mothers. Two groups of infants will be enrolled in 
each Cohort according to infant in-utero exposure to maternal raltegravir 
(RAL):  
 RAL–naïve (infants born to mothers not receiving RAL prior to 
delivery) and  
 RAL–exposed (infants born to mothers who received at least one dose 
of RAL within 2 – 24 hours prior to delivery).  
 
REGIMEN: 
Cohort 1:  Raltegravir as oral granules for suspension administered at two 
time points:  as a single dose within 48 hours of birth in addition to 
standard of care ARV for PMTCT prophylaxis, with a second single dose 
administered at 7-10 days of life.   
  
 
Cohort 2:  Raltegravir as oral granules for suspension initiated in RAL–
naive infants within 48 hours of birth and in RAL–exposed infants 
between 12 and 60 hours of birth, as outlined below, in addition to 
standard of care ARV for PMTCT prophylaxis.  
 
 1.5 mg/kg once daily during Days 1–7 of life (week 1) 
 3.0 mg/kg twice daily during Days 8-28 of life (weeks 2-4) 
 6.0 mg/kg twice daily during Days 29-42 of life (weeks 5-6) 
 
Based on ongoing interim analysis of pharmacokinetic data and safety 
information, raltegravir dosing may be modified in the range of 1.5 mg/kg 
to 6 mg/kg per dose. Dosing frequency may also be modified from once to 
twice daily, reaching a maximum daily dose of 12 mg/kg/day.  
 


 
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STUDY DURATION: Infants will be followed for 24 weeks after birth.  Women will be 
followed until discharge from the labor and delivery unit. 
 
PRIMARY OBJECTIVES: 
 
1. To evaluate the safety and tolerability through 6 weeks of life of 
raltegravir oral granules for suspension when administered during the first 
6 weeks of life with standard PMTCT ARV prophylaxis to infants 
exposed to HIV-1 assessed at risk of infection. 
 
2. To evaluate the pharmacokinetics of raltegravir oral granules for 
suspension during the first 6 weeks of life along with standard PMTCT 
ARV prophylaxis. 
 
3. To determine an appropriate dose of raltegravir oral granules for 
suspension for use in neonates and infants during the first 6 weeks of life.  
 
SECONDARY OBJECTIVES: 
 
1. To assess safety and tolerability of raltegravir oral granules for suspension 
through 24 weeks of life when administered during the first 6 weeks of life 
with standard PMTCT ARV prophylaxis to infants exposed to HIV-1 
assessed at risk of infection. 
 
2. To investigate the relationship between neonatal raltegravir elimination 
and UGT1A1 genotype, and whether there is an association of UGT1A1 
(*28/*28) and SLCO1B3 (rs2117032-C/T) with hyperbilirubinemia. 
 
 


 
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1.0 
INTRODUCTION 
1.1 
Background and Rationale  
 
Although significant progress has been made in identifying strategies to prevent perinatal of 
HIV transmission by administering antiretroviral drugs to pregnant women with HIV 
infection and their infants, new pediatric HIV infections continue, with an estimated 370,000 
infant infections in 2009 [1-3]. It is estimated that only 35% of pregnant women with HIV 
infection in low-resource countries received antiretroviral prophylaxis for prevention of 
mother-to-child HIV transmission [1]. When the diagnosis of HIV infection in a pregnant 
woman goes unrecognized and antiretrovirals have not been used during pregnancy and 
labor, infant prophylaxis with zidovudine and either nelfinavir plus lamivudine or nevirapine 
can reduce the risk of HIV transmission by 44% compared with the use of zidovudine alone 
[4].  In HIV endemic settings up to 3-10% of pregnant women become infected during 
pregnancy placing their infants at even higher risk for acquiring HIV infection [5].    
 
It is critically important to develop new and potentially more effective regimens for postnatal 
prophylaxis for perinatal transmission in high-risk settings. Use of integrase inhibitors as part 
of neonatal prophylaxis may further reduce transmission risk as these agents block 
integration of viral DNA into the host cell, a critical step in the virus lifecycle required for 
productive infection to occur. Integrase inhibitors as part of postnatal infant prophylaxis also 
have a potential role in the setting of high-risk pregnancies or maternal infection with drug-
resistant HIV.  
 
In addition, integrase inhibitors have theoretical advantages as part of early highly active 
antiretroviral therapy for neonates with HIV infection.  Neonates with HIV infection can be 
identified in the first few weeks of life, allowing for immediate or early initiation of HAART.  
Early therapy is now standard of care for infants with HIV infection globally due to the 
survival benefit conferred, but limited antiretroviral agents are available for this purpose [6]. 
As such, there is a critical need for additional potent antiretroviral drugs for the treatment of 
pediatric HIV infection. Studies such as P1115 involving strategies for early treatment of 
newborns infected with HIV with more intensive antiretroviral drug regimens are being 
conducted, with the goal of either improving clearance of HIV-infected cells that contribute 
to prolonged second-phase decay in plasma viremia during HAART in infants, or even 
potentially to eradicate or lower HIV reservoirs throughout the body of the infant with HIV 
infection.  In a recent study, time to undetectable plasma viremia in infants treated with a 
lopinavir-based HAART regimen (PACTG P1030) was strongly correlated with resting 
CD4+ T cell latent reservoir size at two years of age [7].  This relationship suggests that more 
rapid clearance of plasma viremia during HAART may reduce viral reservoir seeding in 
infants with HIV infection and antiretroviral drugs that block viral integration may have a 
role to play in accelerating the rate of viral decay.  
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 and used as part of a prophylaxis regimen in the recently 
reported HPTN/NICHD 040 trial [8], but its use is not approved in children less than 2 years 


 
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old.  The three-drug ARV regimen with the greatest experience in neonates for prophylaxis 
and treatment 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 [9, 10].  Lopinavir/ritonavir, the protease 
inhibitor used most commonly to treat HIV infection in infants, is available as a pediatric 
solution, but dosing is uncertain in the first weeks of life.  The solution contains 15% 
propylene glycol and 42% ethanol, and its use in the first two weeks of life is not 
recommended after several cases of life-threatening brady-arrhythmias and cardiac 
dysfunction were identified in preterm infants [11, 12].  Evaluation of the pharmacokinetics 
and safety of additional antiretroviral drugs for use in neonates for prevention or treatment of 
HIV infection is vitally important.   
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 effective in rapidly clearing plasma virus, 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 neonates exposed to HIV who are 
at risk of becoming infected. The primary goal of this protocol is to define the 
pharmacokinetics of raltegravir in at risk infants less than 6 weeks of age in order to develop 
an appropriate raltegravir dosing regimen for prophylaxis and or treatment of HIV in exposed 
neonates.  This current study will evaluate the safety and pharmacokinetics of raltegravir in 
neonates at risk of acquiring HIV-1 infection and determine the appropriate dose that can be 
administered to infants. It is also hoped that a multi-dose regimen will be established for 
subsequent use for treatment in order to examine the effects of early neonatal therapy with 
integrase inhibitors towards eliminating widespread establishment of HIV reservoirs. 
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 and treatment experienced infants and children at least 4 weeks of age [13-20].   
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 [21].  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 [22].   
 


 
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Extrinsic and intrinsic factors have been evaluated in adults.  Gender, age, body mass 
index, race, and HIV status had no clinically meaningful effect on raltegravir 
pharmacokinetics.  Moderate hepatic insufficiency and severe renal insufficiency also 
had no clinically meaningful effect on raltegravir pharmacokinetics [23].  
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 adults.  A summary of drug interaction studies appears below.   
Table 1 
Comparison of Drug-Drug Interactions of Raltegravir Plasma  
Pharmacokinetic Parameter: Mean % Effect on Raltegravir 
 
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 [21]. Raltegravir is approximately 
83% bound to plasma proteins.  
1.23 
Raltegravir in Pregnancy for Prevention of Perinatal Transmission of HIV 
 
In the United States, while transmission has been significantly reduced, perinatal 
transmission of HIV continues to occur.  The Centers for Disease Control and Prevention 
conducts Enhanced Perinatal Surveillance in 15 U.S. jurisdictions.  In a study evaluating 
transmission risk in 2005-2008 in 8,054 births to mothers with HIV infection, 179 infants 
(2.2%) were diagnosed with HIV infection [24]. The odds of having an infant with HIV 
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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infection were higher among women with HIV infection who were tested late, had no 
antiretroviral (ARV) medications, abused illicit substances, breastfed, or had lower CD4 
cell counts.  In another report of nearly 8,600 births to women with HIV infection 
reported to the CDC, 8% of women did not receive prenatal care; of those with prenatal 
care, 3% did not receive HIV testing during pregnancy; of those with HIV testing, 6% did 
not receive ARV prophylaxis or treatment during pregnancy; of those who received 
antenatal therapy, 5% did not receive ARV drugs during labor and delivery [25].  In a 
study of 707 women receiving HAART during pregnancy, overall transmission was 
1.6%; MTCT was directly correlated with HIV viral load nearest delivery and duration of 
HAART during pregnancy and CD4 count near delivery were correlated with viral load 
[26]. A number of studies have demonstrated that duration of ARV prophylaxis during 
pregnancy is significantly associated with the risk of MTCT [27], [28]; in the European 
Collaborative Study, MTCT was significantly related to insufficient antenatal HAART, 
defined as no  or <13 days of HAART [27].  An additional important risk factor for 
transmission in the U.S. is acute HIV infection during pregnancy in women with initially 
negative HIV tests, who therefore initiate ARV late and have high levels of viremia 
[29].  Perinatal transmission with multi-class drug resistant virus despite antiretroviral 
prophylaxis, even with viral suppression, has been described [30]. Finally, the number of 
women with HIV infection giving birth in the U.S. has increased by approximately 30% 
since the year 2000 to approximately 9,000 annually, which can result in increased 
perinatal transmission secondary to these missed opportunities for prevention [25].  Thus, 
infants born to mothers with late diagnosis of HIV, receiving no antiretroviral drugs or 
short duration of HAART, have multi-class drug-resistant virus, or detectable viral load 
at delivery, are at particularly high risk of HIV transmission in the U.S. as well as in 
developing countries. 
 
Raltegravir is now included in the list of recommended regimens for use in pregnant 
women[31]. Raltegravir pharmacokinetics (PK) were evaluated in 42 women during 
pregnancy in the IMPAACT P1026s study. Raltegravir PKs in these women showed 
extensive variability as seen in non-pregnant individuals. Median raltegravir area under 
the curve was reduced by approximately 50% during pregnancy. No significant 
difference was seen between the third trimester and postpartum trough concentrations. 
Plasma HIV RNA levels were under 400 copies/mL in 92% of women at delivery. Given 
the high rates of virologic suppression and the lack of clear relationship between 
raltegravir concentration and virologic effect in non-pregnant adults, no change in dosing 
was recommended during pregnancy [32]. In a study of 22 women with paired third-
trimester and postpartum data from the PANNA Network, the geometric mean ratios of 
third trimester/postpartum values were AUC0-12hr 0.71 (0.53–0.96), Cmax 0.82 (0.55–
1.253), and C12hr 0.64 (0.34–1.22). One patient was below the target C12hr in the third 
trimester and none were below the threshold postpartum. No change in dosing during 
pregnancy was recommended based on these data [33]. 
 
In the P1026s Study and the PANNA study, raltegravir was well tolerated, with no 
treatment-related serious adverse events in pregnant women, and all infants were at least 
36 weeks’ gestation at delivery [32, 33]. 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 [34].  In multiple case reports and case series of 4, 5, and 14 


 
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pregnant women treated with raltegravir in combination with 2 or 3 other antiretroviral 
drugs because of persistent viremia or late presentation, the drug was well tolerated and 
led to rapid reduction in HIV RNA levels [35-40].  
 
1.24 
Raltegravir in Children  
 
IMPAACT P1066, conducted by the International Maternal, Pediatric, Adolescent AIDS 
Clinical Trials (IMPAACT) Group and entitled “A Phase I/II, Multicenter, Open-Label, 
Noncomparative Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Antiretroviral Activity of Raltegravir (Isentress™, MK-0518) in HIV-1 Infected Children 
and Adolescents,” evaluated the safety, tolerability, pharmacokinetic parameters, and 
efficacy of three raltegravir formulations across the pediatric age range of 4 weeks to 18 
years.  Patients were stratified by age, enrolling adolescents first (Cohort I) and then 
successively younger children. Patients received the film-coated tablet formulation 
(Cohorts I and IIA; 6 through 18 years of age); or the chewable tablet formulation 
(Cohorts IIB and III; 2 through 11 years of age); or the granules for oral suspension 
(Cohorts IV and V; 4 weeks through 2 years of age).  Raltegravir was administered with 
an optimized background regimen.   
 
The initial dose-finding stage included intensive pharmacokinetic evaluation. Dose 
selection for each cohort (see Table 2, Cohorts I, IIA, IIB and III and Table 4, Cohorts IV 
and V) was based upon achieving similar raltegravir plasma exposure and trough 
concentration as seen in adults, with a specific goal to maintain both a geometric mean 
(GM) AUC0-12hr between 14 and 25 uM*hr and a GM C12hr greater than 33 nM (the in 
vitro IC95 for antiviral activity), and acceptable short term safety.  After dose selection, 
additional patients were enrolled for evaluation of long term safety, tolerability, and 
efficacy.  
 
2 to 18 Years of Age 
As shown in Table 2, for Cohorts I-III, the targeted PK parameters (area under the curve 
[AUC]0-12hr and C12hr) were achieved for each cohort allowing for dose selection. 
 
 
 


 
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Table 2 
Raltegravir Pharmacokinetic Parameters Following 
Administration of Recommended Pediatric Doses in IMPAACT P1066 
Cohorts I - III 
 
Of the 126 children and adolescents enrolled (All Treated population), 96 patients 
received only the recommended dose of raltegravir (Final Dose population). In the 96 
patients who received the recommended dose of raltegravir, the frequency, type, and 
severity of drug related adverse reactions through Week 24 were comparable to those 
observed in adults [41-45].  One patient experienced drug related clinical adverse 
reactions of Grade 3 psychomotor hyperactivity, abnormal behavior and insomnia; one 
patient experienced a Grade 2 serious drug related allergic rash.  One patient  experienced 
drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were 
considered serious. These adverse events did not result in discontinuation.  
 
Ninety-one (94.8%) patients 2 through 18 years of age completed 48 weeks of treatment. 
At Week 48, 78.9% achieved ≥1 log10 HIV RNA drop from baseline or <400 copies/mL; 
56.7% achieved HIV RNA <50 copies/mL. The mean CD4 count (percent) increase from 
baseline to Week 48 was 155.7 cells/mm3 (4.6%). 
 
In December 2011, based on review of complete Week 24 and partial Week 48 data from 
this study, the United States Food and Drug Administration (US FDA) approved the use 
of raltegravir (as chewable or 400 mg film-coated tablet) in combination with other 
antiretroviral agents in pediatric patients 2 through 18 years of age.  
 12 years of age and older: One 400 mg film-coated tablet twice daily, orally  
 6 through 11 years of age (2 dosing options): 
o Film-coated tablet: One 400 mg tablet twice daily, orally (if at least 25 kg in 
weight) OR 
o Chewable tablets: weight based to maximum dose 300 mg, twice daily, as 
specified in Table 3. 
 2 through 5 years of age (and at least 10 kg in weight):  
o Chewable tablets: weight based to maximum dose 300 mg, twice daily, as 
specified in Table 3. 
Age 
Formulation 
Mean Dose 
mg/kg 
N† 
Geometric Mean 
(%CV) 
AUC 0-12hr 
(μM●hr) 
Geometric Mean 
(%CV) 
C12hr (nM) 
 
12 to < 19 years  
400 mg tablet ‡ 
9.3 
11 
15.7 (98) 
333 (78) 
 
6  to < 12 years  
400 mg tablet 
13.5 
11 
15.8 (120) 
246 (221) 
6  to < 12 years  
Chewable tablet 
6.5 
10 
22.6 (34) 
130 (88) 
 
2 to < 6 years  
Chewable tablet 
6.2 
12 
18.0 (59) 
71 (55) 
 † Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose. 
 ‡ Patients in this age group received approximately 8 mg/kg dose at time of intensive PK which met PK and safety targets. Based 
on review of the individual profiles and receipt of a mean dose of 390 mg, 400 mg b.i.d was selected as the recommended dose 
for this age group.  


 
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Table 3  
Recommended Dose for Raltegravir Chewable Tablets in 
Pediatric Patients 2 through 11 Years of Age 
Body Weight 
Dose 
Number of Chewable 
Tablets per dose 
(kg) 
(lbs) 
10 to < 14 
22 to < 31 
75 mg twice daily 
3 x 25 mg  
14 to < 20 
31 to < 44 
100 mg twice daily 
1 x 100 mg  
20 to < 28 
44 to < 62 
150 mg twice daily 
1.5 x 100 mg† 
28 to < 40 
62 to < 88 
200 mg twice daily 
2 x 100 mg   
at least 40 
at least 88 
300 mg twice daily 
3 x 100 mg  
† The 100 mg chewable tablet can be divided into equal halves. 
4 Weeks to < 2 Years of Age 
  
As shown in Table 4, the targeted PK parameters (area under the curve [AUC]0-12hr and 
C12hr) were achieved for Cohort IV and V, allowing for dose selection.   
 
 
Table 4 
Raltegravir Pharmacokinetic Parameters Following 
Administration of Recommended Pediatric Doses in IMPAACT P1066 
Cohorts IV and V 
Age 
Formulation 
Mean Dose mg/kg 
N† 
Geometric Mean 
(%CV) 
AUC 0-12hr (μM●hr) 
Geometric Mean 
(%CV) 
C12hr (nM) 
6 months to < 2 years  Granule Suspension 
5.9 
8 
19.8 (34) 
108.2 (52) 
4 weeks to < 6 months  Granule Suspension 
5.7 
11 
22.3 (40) 
116.6 (68) 
 † Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose. 
 
Twenty-six enrolled and were treated in Cohorts IV (6 months to < 2 years) and V (4 
weeks to < 6 months) [20]. All 26 patients were included in the safety analysis. Through 
Week 48, there were 10 patients with Grade 3+ AEs. Two were judged related to study 
drug. There was 1 discontinuation due to an AE of skin rash, 1 event of immune 
reconstitution syndrome, and no drug-related deaths.  
 
Of the 26 patients treated, 23 patients were included in the efficacy analysis.  At Week 
48, for Cohorts IV and V, 87.5% of patients achieved virologic success and 45.5% had 
HIV RNA <50 copies/mL. At Week 48, gains in CD4 cells of 527.6 cells/mm(3) and 
7.3% were observed. A total of 6 mg/kg per dose twice daily of RAL for oral suspension 
was well tolerated and showed favorable virologic and immunologic responses. 
 
Based upon these data, US FDA in December 2013 approved the use of raltegravir (as 
granules for oral suspension) in combination with other antiretroviral agents in pediatric 
patients 4 weeks to 2 years of age.  During review of this data, the raltegravir pediatric 
dosing and administration (D&A) was restructured to a weight-based rather than age 
based cut-off approach.  Table 5 displays PK data from IMPAACT P1066 based on the 
new weight-based dosing scheme without age categories.  


 
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The current pediatric doses recommended for each formulation, based on the United 
States Product Circular (USPC), are as follows: 
 If at least 25 kg: One 400 mg film-coated tablet orally, twice daily.  
 If unable to swallow a tablet, consider the chewable tablet, as specified in Table 5. 
 
Table 5 
Alternative Dose* with ISENTRESS Chewable Tablets for Pediatric Patients Weighing at 
Least 25 kg 
 
Body 
Weight
Dose 
Number of 
Chewable
25 to less than 28 
150 mg twice daily 
1.5 x 100 mg† twice daily 
28 to less than 40 
200 mg twice daily 
2 x 100 mg twice daily 
At least 40 
300 mg twice daily 
3 x 100 mg twice daily 
*The weight-based dosing recommendation for the chewable tablet is based on 
approximately 6 mg/kg/dose twice daily. 
†The 100 mg chewable tablet can be divided into equal halves. 
 
 If at least 4 weeks of age and weighing at least 3 kg to less than 25 kg: Weight 
based dosing, as specified in Table 6.  
 For patients weighing between 11 and 20 kg, either the chewable tablet or oral 
suspension can be used, as specified in Table 7. Patients can remain on the oral 
suspension as long as their weight is below 20 kg.  
 
 
Table 6 
Recommended Dose* for ISENTRESS For Oral Suspension and Chewable Tablets in 
Pediatric Patients Weighing Less than 25 kg 
 
Body Weight 
(kg) 
Volume (Dose) of Suspension 
to be Administered 
Number of Chewable Tablets 
3 to less than 4 
1 mL (20 mg) twice daily 
4 to less than 6 
1.5 mL (30 mg) twice daily 
6 to less than 8 
2 mL (40 mg) twice daily 
8 to less than 11 
3 mL (60 mg) twice daily 
11 to less than 14† 
4 mL (80 mg) twice daily 
3 x 25 mg twice daily 
14 to less than 20† 
5 mL (100 mg) twice daily 
1 x 100 mg twice daily 
20 to less than 25 
1.5 x 100 mg‡ twice daily 
*The weight-based dosing recommendation for the chewable tablet and oral suspension is based on 
approximately 6 mg/kg/dose twice daily [see Clinical Pharmacology (12.3)]. 
†For weight between 11 and 20 kg either formulation can be used. 
Note: The chewable tablets are available as 25 mg and 100 mg tablets. 
‡The 100 mg chewable tablet can be divided into equal halves.  
Note: Oral suspension reconstituted to 20 mg/mL 
 
 
 
 
 
 


 
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Table 7 
Raltegravir Steady State Pharmacokinetic Parameters in Pediatric 
Patients Following Administration of Recommended Doses 
 
Body Weight 
Formulation 
Dose 
N 
Geometric Mean 
(%CV)** 
Geometric Mean 
(%CV)** 
AUC0-12hr (uM*hr) 
C12hr (nM) 
≥25 kg 
Film-coated 
tablet 
400 mg twice daily 
18 
14.1 (121%) 
233 (157%) 
≥25 kg 
Chewable tablet 
Weight based dosing, 
see [Table 5] 
9 
22.1 (36%) 
113 (80%) 
11 to less than 
25 kg 
Chewable tablet 
Weight based dosing, 
see [Table 6] 
13 
18.6 (68%) 
82 (123%) 
3 to less than 
20 kg 
Oral Suspension 
Weight based dosing, 
see [Table 6] 
19 
24.5 (43%) 
113 (69%) 
*Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose. 
**Geometric coefficient of variation.  
1.25 
Relative Bioavailability of Raltegravir Formulations 
 
Protocol 068 provides relevant biocomparison data in adults for the current approved 
pediatric formulations oral granules for suspension) and/or approved and chewable 
tablets.  The data provided below indicate that both oral granules for suspension and the 
chewable tablet formulations have somewhat greater bioavailability than the adult, film-
coated tablet. Protocol 068 was an open label, 4-period, randomized, crossover study in 
healthy, adult, male and female subjects. Twelve (12) subjects each received 4 treatments 
(Treatments A, B, C, and D) randomized in a balanced, crossover design in Periods 1 
through 4. Treatment A consisted of a single oral dose of 400 mg raltegravir adult 
formulation tablet. Treatment B consisted of a single oral dose of 400 mg raltegravir 
ethylcellulose pediatric chewable tablet formulation (administered as 4 x 100 mg tablets). 
Treatment C consisted of a single oral dose of 400 mg raltegravir oral granules in a liquid 
suspension. Treatment D consisted of a single oral dose of 400 mg raltegravir 
ethylcellulose pediatric chewable tablet formulation (as 4 x 100 mg tablets) administered 
following a high fat meal. Treatments A-C were administered in the fasted state.  All 
doses of raltegravir, regardless of formulation, were administered under supervision and 
retention of drug in the mouth was not permitted.  There was a minimum of 4 days of 
washout between the single doses in each treatment period. 
 
The geometric mean pharmacokinetic parameter values for the raltegravir pediatric 
chewable tablet and oral granules for suspension formulations were estimated and 
compared to the corresponding values for the adult tablet, all following single dose 
administration of 400 mg in the fasted state, with results shown in Table 8. The geometric 
mean C12hr values were similar for all formulations, while AUC0-∞ and Cmax values were 
higher for both the pediatric chewable tablet and the oral granules formulation compared 
to the adult tablet. For the oral granules formulation, AUC0-∞ and Cmax were moderately 
higher (2.6- and 4.6-fold) than those obtained with the adult tablet and slightly higher 
(1.5- and 1.4-fold) than those obtained with the pediatric chewable tablet. Both the 
pediatric chewable tablet and oral granules formulations had earlier median Tmax values 


 
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compared with the adult tablet (0.5 and 1.0 hours for the chewable tablet and oral 
granules, respectively, compared to 4.0 hours for the adult tablet). Half-life values for 
both the initial (α) and terminal (β) phases were similar for all formulations.  The results 
were consistent with some difference in the absorption portion of the pharmacokinetic 
profile among the formulations, but little difference in the later part of the profile. Mean 
plasma concentration–time profiles for all formulations are shown in Figure 1. 
 
The higher AUC0-∞ and Cmax values for the oral granules formulation are not expected to 
have any meaningful clinical consequences. The pharmacokinetic properties of the two 
pediatric formulations are similar to the raltegravir Phase I lactose formulation which was 
well tolerated in adults.  To date in the development program for raltegravir, there have 
been no acute safety findings that were temporally associated with peak concentrations, 
and raltegravir has been found to be generally well tolerated in the clinical program with 
no dose-related toxicities. Based on the lack of a statistically significant difference in 
trough values, and the otherwise moderate dissimilarities in the other pharmacokinetic 
parameters, these results supported continued clinical development of both the chewable 
tablet and oral granules for suspension pediatric formulations in IMPAACT P1066.  
Acceptable pharmacokinetic, efficacy, and safety profiles for the chewable tablet and oral 
granules for suspension formulations have been observed in pediatric patients in 
IMPAACT P1066 to date [46, 47]. 
 
 
 


 
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Table 8 
Comparison of Raltegravir Plasma Pharmacokinetics Following Single-Dose Administration of 
the Raltegravir Adult Tablet, Pediatric Chewable Tablet (Fasted or Fed), and Raltegravir Oral 
Granules in a Liquid Suspension to Healthy, Adult, Male and Female Subjects (Protocol 068)  
 
Pharmacokinetic 
 
A† 
B† 
C† 
D† 
Comparison 
 
Parameter (Units) 
N 
GM 
GM 
GM 
GM 
Treatment X/ 
Treatment Y 
GMR (90% CI) 
 
 
 
 
 
 
 
 
C12hr (nM)§         
12 
149  
134  
162 
387  
C / A  
1.09 (0.84 , 1.41) 
 
 
 
 
 
 
C / B  
1.20 (0.92 , 1.56) 
 
 
 
 
 
 
D/ B  
2.88 (2.21 , 3.75) 
 
 
 
 
 
 
B/ A  
0.90 (0.70 , 1.18) 
 
 
 
 
 
 
 
 
AUC0- (µM•hr)§ 
12 
19.2  
34.2  
50.4 
32.3  
C / A  
2.62 (2.17 , 3.17) 
 
 
 
 
 
 
C / B  
1.47 (1.22 , 1.78) 
 
 
 
 
 
 
D/ B  
0.94 (0.78 , 1.14) 
 
 
 
 
 
 
B/ A  
1.78 (1.47 , 2.15) 
 
 
 
 
 
 
 
 
Cmax (µM)§         
12 
5.00  
16.1  
23.2 
6.14  
C / A  
4.64 (3.41 , 6.30) 
 
 
 
 
 
 
C / B  
1.44 (1.06 , 1.95) 
 
 
 
 
 
 
D/ B  
0.38 (0.28 , 0.52) 
 
 
 
 
 
 
B/ A  
3.22 (2.37 , 4.38) 
 
 
 
 
 
 
 
 
Tmax (hr)•          
12 
4.0  
0.5  
1.0 
1.0  
   
   
 
 
 
 
 
 
 
 
t1/2I (hr)¶           
   
1.5 
(0.3) 
1.7 
(0.2) 
1.6 
(0.3) 
2.0 
(0.6) 
   
   
 
 
 
 
 
 
 
 
t1/2T (hr)¶          
12 
9.0 
(5.9) 
9.3 
(5.1) 
10.0 
(3.2) 
9.2 
(3.8) 
   
   
 
† 
Treatment A = 400 mg raltegravir, adult tablet (administered fasted). 
 
Treatment B = 400 mg raltegravir, chewable tablet (administered fasted). 
 
Treatment C = 400 mg raltegravir, oral granules in a liquid suspension (administered fasted). 
 
Treatment D = 400 mg raltegravir, chewable tablet (administered with a high-fat meal). 
§ 
Back-transformed least squares mean and confidence interval from mixed effects model performed on the 
natural log-transformed values. 
• 
Median values presented for Tmax. 
¶ 
Harmonic mean (jack-knife standard deviation) values presented for t1/2I and t1/2T. For t1/2I, the N's for 
Treatments A, B, C, and D are 11, 12, 12, and 10, respectively. 
 


 
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Figure 1 
Arithmetic Mean Raltegravir Plasma Concentration-Time Profiles Following Single-Dose 
Administration of the Raltegravir Adult Tablet, Pediatric Chewable Tablet (Fasted or Fed), 
and Oral Granules in a Liquid Suspension to Healthy, Adult, Male and Female Participants 
(N=12; inset = semilog scale) 
 
 
1.26 
Raltegravir Resistance 
 
The mutations observed in the HIV-1 integrase coding sequence associated with 
phenotypic resistance to raltegravir include the following amino acid substitutions: at 
either Q148H/K/R, N155H, or Y143C/H/R) plus one or more additional substitutions.  In 
the raltegravir clinical development program, virologic failure was associated with 
emergent integrase signature mutations (at amino acids 143, 148, and 155) in 66% of 
treatment-experienced adults and 44% of treatment-naïve adults failing raltegravir 
therapy. 
 
In IMPAACT P1066, the emergence of raltegravir-resistant viruses was monitored by 
isolating viral RNA from all patients displaying virologic failure and determining the 
Time, hr
0
2
4
6
8
10
12
Raltegravir Plasma Concentration, nM
0
5000
10000
15000
20000
25000
Adult Tablet, fasted
Chewable Tablet, fasted
Oral Granules, fasted
Chewable Tablet, high-fat meal
0
12
24
36
48
10
100
1000
10000


 
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amino acid sequences of the HIV integrase gene, the reverse transcriptase (RT) gene, and 
the protease inhibitor (PI) gene if the HIV RNA plasma level was >1000 copies/mL, the 
approximate limit of the resistance assay, and adequate sample was available for testing.  
In Cohorts I, II, and III (N=126), a total of 27 (21.4%) patients were considered virologic 
failures by Week 24 and 36 (28.6%) patients were virologic failures by Week 48.  Of the 
33 Cohort I-III patients for whom genotypic data were available, viruses from 12 (36.4%) 
displayed signature resistance mutations as follows:  1 at AA 143, 7 at AA 148, and 8 at 
AA155, which is consistent with observations in adults.  In Cohort IV, no patients failed 
by Week 24 and 4 patients failed by Week 48. No patients in Cohort V met virologic 
failure criteria by Week 24 or 48.  Because of limited blood volume obtained, only 2 of 
the 4 patients with virologic failure had genotypic data available. One patient had a 
mutation at AA155 (without other raltegravir associated resistance mutations), and one 
patient had no known raltegravir mutations detected during study treatment. 
1.27 
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 [48]. 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 [49].  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% [50]. 
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 [51, 52]. 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 
[53].   
 
Administration of an exogenous drug that is eliminated by glucuronidation poses special 
risks in the newborn. Low UGT activity that results in decreased elimination of 
endogenous bilirubin and physiologic jaundice will also result in decreased metabolism 


 
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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 [54]. 
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 [55]. 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 [56, 57]. 
The reduction in neonatal zidovudine glucuronidation was associated not only with 
reduced clearance but also with higher bioavailability, consistent with decreased first pass 
metabolism [58].   
 
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 [22]. 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 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 [59]. 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 [60]. 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 [61]. 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.  By comparison, kernicterus developed 
in premature infants when sulfisoxazole concentrations exceeded 205 µmol/L [62].  


 
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In vitro evaluation of the effect of raltegravir on bilirubin-albumin binding was 
performed in pooled neonatal serum using the peroxidase method [59, 61, 62]. 
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 potentially harmful increases at 500 and 1000 µM.  The effect of raltegravir on 
neonatal bilirubin binding is unlikely to be clinically significant unless concentrations 
exceed typical peak concentrations of 10 µM (4440 ng/mL) by 50–100-fold [63]  
 
Recently a genetic variant in the SLCO13 gene (rs2117032-C/T) was found to have a 
strong association with bilirubin levels in neonates [64] 
In order to try to identify potential predisposing factors that might be associated with 
elevated bilirubin levels in the study population, the UGT1A1 and SLCO1B3 (rs2117032) 
genetic variant will be evaluated at the end of the study. 
 
Table 9: 
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)  
Total Bilirubin 
No Drug 
Raltegravir (µM) 
Sulfisoxazole (µM) 
 
5 
10 
100 
500 
1000 
500 
1000 
10.7 mg/dL 
3.46 
(0.25) 
3.39 
(0.22) 
3.37 
(0.18) 
3.95 
(0.30)* 
4.87 
(0.24)* 
6.11 
(0.26)* 
6.60 
(0.25)* 
8.64 
(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)* 
----- 
 
 
 


 
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Figure 2 
Mean (SD) unbound bilirubin concentrations (µg/dL) with no additional drug or in presence of 
varying concentrations of raltegravir or sulfisoxazole. 
  
 
 


 
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1.28 
P1097:  Raltegravir Washout PK Results  
 
IMPAACT P1097 is an ongoing multicenter trial to determine the washout PK and safety 
of in utero/intrapartum exposure to RAL in both low birth weight (≤ 2500 grams) and 
full-term infants born to pregnant women with HIV infection receiving RAL at the FDA 
approved adult dose of 400 mg twice daily as part of their cART regimen.  Cord blood 
and a single maternal blood sample are collected at delivery.  In Version 1, which 
enrolled full term infants has been completed [65]. In full term infants, blood samples 
were collected at 1-5, 8-14, 18-24, and 30-36 hours after birth.  In version 2, which is 
currently enrolling low birth weight infants, blood samples are collected at 1-6, 12-24, 
36-48, 72-84, and 108-132 hours after birth. RAL concentrations are measured using a 
validated HPLC-MS-MS method. Infant t ½ is estimated using terminal 2 or 3 
concentration-time points for each infant.  Safety of in utero/intrapartum exposure to 
RAL has been evaluated in the full-term infants for up to 6 months of age.  
 
In full-term infants, twenty-two mother-infant pairs were enrolled: 59% of the mothers 
were African American, 36% were Hispanic.  Evaluable PK data were obtained from 19 
mother-infant pairs (Figure 3).  Median (range) ng/mL RAL plasma concentration values 
were: maternal at delivery: 540 (12-5809); cord blood 957 (24-3974); ratio of 
cord/maternal blood: 1.48 (0.32-4.33); initial infant plasma: 671 (13-2672); and infant 
plasma at 30-36 hours: 291 (<10-1402). Median infant apparent t ½ of RAL was 26.6 
(9.3-184) hours.  Infant washout RAL concentrations initially increased before decreasing 
in 9 of 19 (47%) evaluable infants. All infants tolerated RAL exposure well with 20 week 
follow-up evaluations completed with no unexpected adverse events or transmission of 
HIV infection [66]. 
 
Raltegravir readily crosses the placenta. The plasma t ½ of RAL in  neonates is highly 
variable suggesting potential roles for developmental aspects of neonatal UGT1A1 
enzyme activity, redistribution and/or enterohepatic recirculation of RAL. Understanding 
the features of RAL PK in neonates will be critical for development of a neonatal dosing 
regimen. P1097 version 2 includes LBW infants and is currently enrolling at both sites in 
the United States and internationally.  It is anticipated that LBW infants will have 
delayed elimination of RAL as UGT1A1 activity is extremely low in this patient 
population. 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Figure 3 
P1097 Washout PK Full term infants 
RAL Infant Concentration Time Plot (n=19) 
 
 
 
 
1.29 
P1110 Cohort 1: Raltegravir Pharmacokinetic Results  
 
P1110 Cohort 1 infants received RAL administered as a single oral dose within 48 hours 
of birth in addition to standard of care antiretroviral agents (ARVs) for prevention of 
perinatal transmission, and a second dose administered at 7- 10 days of life. The initial 
dose was RAL 3 mg/kg and doses were adjusted on a rolling basis.  RAL-exposed infants 
(infants born to mothers receiving RAL prior to and during delivery) were excluded 
initially but later were allowed to enroll and received a lower initial dose of 1.5 mg/kg.   
 
Sixteen mother-infant pairs enrolled: 10 RAL- naïve infants (born to mothers who did not 
receive RAL during pregnancy and delivery) and 6 RAL-exposed infants.  There were 8 
females and 8 males; the median (range) gestational age was 38.7 (37-40) weeks; and the 
10
100
1000
10000
0
6
12
18
24
30
36
42
Time Post Delivery
Raltegravir Concentration (ng/mL)


 
IMPAACT P1110 Final Version 2.0 
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median birth weight (range) was 3.02 (2.32-4.20) kg.  Evaluable PK results were 
available for 15 of 16 infants.  The first 6 RAL naïve infants received 3 mg/kg initial 
doses.  While none of the 6 infants exceeded the Cmax upper limit, there were 3 out of 6 
infants who exceeded the AUC12 upper limit of 28 mg*h/L.  The initial dose was 
reduced after interim analysis and for subsequent enrollments RAL-naïve infants received 
a 2 mg/kg dose while RAL-exposed infants received a 1.5 mg/kg for the initial dose.  All 
infants, regardless of maternal RAL usage, received 3 mg/kg for the second dose at 7-10 
days of life.   
P1110 Cohort 1 (RAL-naïve): Raltegravir Pharmacokinetic Preliminary Results  
 
PK results from Cohort 1 [67-69] were combined with that from older infants and 
children receiving daily dosing in a population PK model and simulations performed to 
develop a daily RAL dosing regimen to be evaluated in 20 infants in Cohort 2 [70-72]. 
The RAL dosing regimen studied in Cohort 2 for infants unexposed to RAL in utero is: 
1.5 mg/kg daily starting within 48 hours of life through day 7; 3 mg/kg twice daily on 
days 8-28 of life; 6 mg/kg twice daily after 4 weeks of age [71, 72].  
 
PK results and 6 week safety data were presented for the first 10 RAL-naïve infants who 
received the dose under study: 1.5 mg/kg daily through day 7; 3 mg/kg twice daily on 
days 8-28 of life; 6 mg/kg twice daily after 4 weeks of age [69, 73, 74].  After the first 
dose of 1.5 mg/kg, geometric mean RAL AUC24 was 38.9 mgxh/L (range18.6-78.3 
mgxh/L).  On 3 mg/kg twice daily the geometric mean for RAL AUC12 was 12.1 mgxh/L 
(range 4.7-24.5 mgxh/L) and Cmin estimated to be 120.4 ng/mL. Sparse sampling 
confirmed that RAL plasma concentrations were within the expected range.   
 
There have been no safety concerns associated with daily RAL administration based on 
safety data through 6 weeks of life. Daily RAL has been well tolerated in the infants 
receiving this regimen during the first 6 weeks of life.  The PK targets and the safety 
guidelines have been met for the RAL-naive infants in cohort 2.   
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.11  To evaluate the safety and tolerability through 6 weeks of life of raltegravir oral 
granules for suspension when administered during the first 6 weeks of life with 
standard PMTCT ARV prophylaxis to infants exposed to HIV-1 assessed at risk 
of infection. 
2.12  To evaluate the pharmacokinetics of raltegravir oral granules for suspension 
during the first 6 weeks of life along with standard PMTCT ARV prophylaxis. 
2.13  To determine an appropriate dose of raltegravir oral granules for suspension for 
use in neonates and infants during the first 6 weeks of life. 
 


 
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2.2 
Secondary Objectives 
2.21 
To assess safety and tolerability of raltegravir oral granules for suspension 
through 24 weeks of life when administered during the first 6 weeks of life with 
standard PMTCT ARV prophylaxis to infants exposed to HIV-1 assessed at risk 
of infection. 
 
2.22 
To investigate the relationship between neonatal raltegravir elimination and 
UGT1A1 genotype and whether there is an association of UGT1A1 (*28/*28) and 
SLCO1B3 (rs2117032-C/T) with hyperbilirubinemia. 
 
3.0 
STUDY DESIGN 
 
This is a Phase I multi-center, open label, non-comparative study to evaluate the safety and 
pharmacokinetics (PK) of raltegravir (RAL) administered to HIV-1-exposed neonates at risk of 
acquiring HIV-1 infection.  The goal is to determine the appropriate dosing regimen of RAL oral 
granules for suspension that can be safely administered to neonates and infants in the first 6 
weeks of life.  
 
The study will enroll approximately 50 mother-infant pairs in order to accrue a minimum of 32 
PK evaluable HIV-1-exposed infants.   
 
Mother-infant pairs will enroll at the time of delivery/birth (up to 48 hours of life under protocol 
Version 1.0 and up to 60 hours of life under protocol Version 2.0).  Pregnant women who are 
expected to have a full term uncomplicated delivery will be identified prior to delivery. The 
informed consent process will typically be conducted during the 2nd or 3rd trimester; however, the 
consent process may be conducted in whole or in part after infant birth.  Women will be followed 
until discharge from the labor and delivery unit. Infants will be followed on study for 24 weeks 
after birth. 
 


 
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Cohort 1:   
 
A minimum of 12 neonates will be enrolled into Cohort 1 to provide data for 12 PK evaluable 
neonates. All neonates enrolled in Cohort 1 will receive RAL 2 mg/kg as oral granules for 
suspension administered as single dose within 48 hours of birth, in addition to standard of care 
ARV for PMTCT prophylaxis, and a second dose administered at 7 to 10 days of life.   
 
The primary purpose of Cohort 1 is generation of PK data that will help inform RAL dose 
selection for Cohort 2.  As this is the first time neonates will be actively dosed with RAL, the 
extent to which PK may differ from older infants with respect to absorption and metabolism is 
unknown. The first dose (<48 hours) will provide PK data when infant glucuronidation is known 
to be at its nadir, and the second dose (7-10 days) will provide information about changes in 
metabolism in Week 2. The 2 mg/kg single starting dose of RAL is 25% of the total daily dose (6 
mg/kg BID) that was studied in infants with HIV infection 4 weeks to < 6 months of age in 
IMPAACT P1066. Since RAL clearance is substantially lower in the first days of life, based on 
interim data from IMPAACT P1097, the 3 mg/kg single dose was selected as a conservative first 
dose to minimize potential safety concerns and still provide informative PK data. 
 
RAL dosing in Cohort 1 may be modified in the range of 1.5 mg/kg to 6 mg/kg per dose. The PK 
results and safety will be assessed through regular team monitoring (done at least every 4 weeks) 
and at full cohort accrual to ensure that the individual RAL concentrations are in the target range 
(not exceeding Cmax of 19.63 µM and not exceeding an AUC12 of 63.05 µM-hr) and that there 


 
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are no life-threatening toxicities probably or definitely related to RAL administration.  Based on 
team assessment of the PK data and review of safety information, the dose may be modified 
within the stated range for the subsequent participants entering into Cohort 1.   
 
All Cohort 1 infants will have a history, physical examination, and hematology and chemistry 
laboratory evaluations performed at the time of dosing for each of  the two doses, and follow-up 
visits at 2 weeks, 6 weeks and 24 weeks of life.  
 
Pharmacokinetic sampling for infants in Cohort 1 will include the following:  
 
Dose 1 (within 48 hours of birth) Intensive PK: Pre-dose, 1-2 hours post-dose, 4-8 hours post-
dose, 12 (±1) hours post-dose, and 24 (±1) hours post-dose.   
 
Day 3-4 Single Random PK: One random PK sample will be obtained with laboratory 
evaluations on Day 3-4 of life.  
 
Dose 2 (7-10 days of life) Limited PK: Pre-dose, 1-2 hours post-dose and 24 (±1)  hours post-
dose. 
 
*Note:  For the 12 and 24 hour PK sampling time points, it is necessary to collect blood samples 
within the window of ±1 hour for the accurate calculations of PK parameters of raltegravir.  
However, in the event that a sample collection in this window is not possible, the sample should 
be obtained within ±2 hours and this deviation from the sampling instructions should be 
recorded. 
 
Cohort 2:  
 
A minimum of 20 evaluable infants will be enrolled into Cohort 2 to receive raltegravir for 6 
weeks in addition to standard of care ARV for PMTCT prophylaxis. Cohort 2 dosing has been 
determined based upon modeling and simulation analyses, which included data generated from 
IMPAACT P1097, P1066 (Cohorts IV and V), P1026s, and P1110 Cohort 1 and incorporated 
information about UGT1A1 ontogeny to inform the development of neonate metabolic pathways.  
RAL-naïve infants in Cohort 2 will receive RAL at a dose of 1.5 mg/kg daily as oral granules for 
suspension starting within 48 hours of birth.  RAL-exposed infants in Cohort 2 will receive RAL 
at a dose of 1.5 mg/kg daily as oral granules for suspension starting within 12 to 60 hours of 
birth. Additionally, RAL dosing in Cohort 2 may be modified based on ongoing interim analysis 
of pharmacokinetic data and safety information.   
 
All Cohort 2 infants will have a history, physical examination, and hematology (except for the 
After Second Dose visit) and chemistry laboratory evaluations performed at all study visits. 
Additional repeat total and direct bilirubin will be done on day 2-4 of life (after the second dose).  
Follow-up visits will occur at Day 6-9, Day 15-18, Day 28-32, and 5-6 weeks, 8-10 weeks and 
24 weeks of life. 
 
 


 
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Note:  Cohort 1 (RAL-exposed and RAL-naïve groups) and Cohort 2 (RAL-naïve group) were 
fully enrolled under protocol Version 1.0 and the results of Cohort 1 were used to inform the 
dosing regimen for Cohort 2, see protocol Section 1.29 for a summary of these results. 
 
Pharmacokinetic sampling for infants in Cohort 2 will include the following:  
 
 
*Note:  PK sampling will ideally be scheduled after RAL has reached steady state 
(approximately 7-10 days after the dose increase).  For example, the Day 15-18 PK sampling 
collection visit should ideally be scheduled 7-10 days after the infant received his/her RAL dose 
regimen increased from 1.5 mg/kg once daily to 3 mg/kg twice daily.  
 
Entry with first dose: within 1 hour pre-dose, and 1-2 hours, 6-10 hours, 20-24 hours post-dose. 
 
After second dose: PK sample obtained 3-6 hours post-dose with laboratory evaluations.  
 
Day 6-9 of life: within 1 hour pre-dose of initiating 3mg/kg twice daily.  A physical exam will 
also be conducted at this visit. 
 
Day 15-18 of life: within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 8-
12 hours post-dose.   
 
Day 28-32 of life: within 1-hour pre-dose of initiating 6 mg/kg twice daily.   
 
Week 5-6 of life (33-42 Days of life): within 1 hour pre-dose, and 3-6 hours post-dose. 
 
See Section 6.21 for Cohort 1 and Cohort 2 PK target exposures.   
3.1 
Evidence of HIV infection and resistance testing (Cohorts 1 and 2): 
 
All infants will receive appropriate testing for evidence of HIV-1 infection within 60 hours of 
birth (if not done as per standard of care), and at 6 and 24 weeks of life.  If any study 
participant is found to be HIV-1 infected during the course of the study, blood samples for 
viral resistance testing to raltegravir and ARVs will be collected as soon as possible after 
confirmation of vertical transmission.  Infants who become HIV infected will have 
hematology, chemistry, lymphocyte subsets, and HIV viral load laboratory evaluations 
performed every 3 months up to 24 weeks of life. 
3.2 
Optional genotyping (Cohorts 1 and 2): 
 
Optional genotyping for UGT1A1 and SLCO1B1 polymorphisms will be performed in infants 
undergoing PK sampling to determine how polymorphisms, such as UGT1A1*28/*28 
genotype, associated with decreased UGT1A1 activity impact RAL elimination in the 
neonate. UGT1A1 activity is reduced in all neonates at birth but increases rapidly over the 
first weeks of life, and the effect of UGT1A1 polymorphisms on the metabolism of RAL 
during this period of time is unknown. 
 


 
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3.3 
Raltegravir Compassionate Use (Cohorts 1 and 2): 
 
Raltegravir will be provided to infants through the protocol for the duration of the study as 
part of combination antiretroviral therapy (cART), but the choice of the ARV regimen will 
be left to the discretion of the site investigator.  At the end of the study, infants with HIV 
infection who are receiving the RAL granules as part of their cART regimen at sites where 
the RAL granules are either 1) not commercially available in that country for the caregiver to 
purchase, or 2) the caregiver cannot gain access to the granules via a government program, 
then Merck will arrange for access to the granules through the local Merck subsidiary at no 
cost to the patient.   
 
See Appendix I, Maternal Schedule of Evaluations, Appendix II-A, Infant Schedule of 
valuations for Cohort 1, Appendix II-B, Infant Schedule of Evaluations for Cohort 2, and 
Appendix II-C, Schedule of Evaluations for Infants Who Become HIV Infected, for a 
complete description of the procedures to be performed.  
 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
4.1 
 
Maternal Inclusion Criteria  
4.11 
Mother is either known to be HIV-1 infected prior to labor or identified as HIV-1 
infected at the time of labor or in the immediate postpartum period. 
 
Documentation of HIV infection: 
 
Documentation of HIV-1 infection is defined as positive results from two samples (whole 
blood, serum, or plasma) collected at different time points.  Results documented in the 
clinical record from past testing may be used to satisfy the criteria for documentation of 
HIV-1 infection. 
 
If both samples are tested using antibody tests, at least one of the samples must be tested 
in a laboratory that operates according to Good Clinical Laboratory Practice (GCLP) 
guidelines and participates in an appropriate external quality assurance program.  If 
nucleic acid testing is used, at least one test must be performed in a CLIA-certified (US 
sites) or VQA-certified (non-US) laboratory.  For tests performed in other (non-GCLP-
compliant or non-VQA-certified) settings, adequate source documentation including the 
date of specimen collection, date of testing, test performed, and test result must be 
available. 
 
Sample #1 must be tested using any of the following: 
 
Up to two rapid antibody tests from different manufacturers or based on 
different principles and epitopes.  
 
One EIA OR Western Blot OR immunofluorescence OR chemiluminescence  
 
One quantitative HIV RNA PCR (above the limit of detection of the assay)  
 
One HIV DNA PCR 


 
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 
One qualitative HIV RNA PCR 
 
One total HIV nucleic acid test 
 
Note: Confirmatory testing (Sample #2) may be pending at the time of enrollment of the 
mother-infant pair.  If maternal confirmatory testing is negative, the infant will be 
removed from active dosing but will be followed for safety as part of the study. 
 
Sample #2 must 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 quantitative HIV RNA PCR (above the limit of detection of the assay)  
 
One HIV DNA PCR 
 
One qualitative HIV RNA PCR 
 
One total HIV nucleic acid test 
 
4.12 For Cohort 1 and Cohort 2 (RAL-naive): Mother is at high-risk of transmitting HIV to 
infant as evidenced by any of the following:  
 
1) Mother has not received any antiretroviral therapy during the current pregnancy 
prior to the onset of labor and delivery;  
 
 
 
2) HIV RNA > 1000 copies/mL within 4 weeks (28 days) prior to delivery 
 
3) Receipt of ARV for < 4 weeks (28 days) before delivery  
 
4) On ARVs for ≥ 4 weeks but has not taken any ARV for > 7 days prior to delivery  
 
5) Mother has documented drug resistant virus to at least one class of ARV drugs 
 
Note: Mothers may have received prenatal and/or intrapartum antiretrovirals.  
 
Note: For Cohort 2 RAL-exposed, there is no requirement that the mother be 
determined ‘high-risk’ of transmitting HIV to her infant.   
4.13 
Maternal written informed consent for study participation. 
4.2 
Maternal Exclusion Criteria 
4.21 
Known maternal-fetal blood group incompatibility as evidenced by the presence 
of an unexpected clinically significant maternal red cell antibody that is known to 
be capable of causing hemolytic disease of the fetus/newborn. 
4.22 
Mother receiving RAL as part of her cART regimen after delivery and intending 
to breastfeed her infant.  


 
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4.23  For Cohort 1 (up to 6 mothers only) and Cohort 2 RAL-naïve:  Mother who 
received RAL prior to and through delivery.  
4.3 
Infant Inclusion Criteria 
4.31 
For Cohort 1 and Cohort 2 (RAL-naive): Full-term infants exposed to HIV aged 
≤48 hours. Infant may have received up to 48 hours of standard of care ARV 
prophylaxis before enrollment. 
 
 
For Cohort 2 (RAL-exposed): Full-term infants exposed to HIV aged ≤ 60 hours. 
Infant may have received standard of care ARV prophylaxis/ treatment before 
enrollment. 
4.32 
Infant gestational age at birth at least 37 weeks. 
4.33 
No known 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. 
 
4.34 
Birth weight ≥2 kg. 
4.35 
Able to take oral medications. 
4.36 
Parent or legal guardian able and willing to provide signed informed consent. 
4.37 
For Cohort 2 RAL-exposed Group  
Infants born to a mother who received at least one dose of raltegravir (RAL) 
within 2 to 24 hours of delivery   
 
Note: Based on mother’s self-report and confirmed by medical records if 
available.  
 
Note: For Cohort 1 RAL-exposed Group infants were born to mothers receiving 
RAL as part of their ARV regimen. 
4.4 
Infant Exclusion Criteria  
4.41  Infant with bilirubin exceeding the American Academy of Pediatrics guidelines 
for phototherapy, using the infant’s gestational age and risk factors as described 
below [75].  


 
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4.42  Clinical evidence of renal disease such as edema, ascites, or  
 
   
 
encephalopathy. 
 
4.43     For Cohort 2 RAL naïve, and Cohort 1 (RAL-naive and RAL-exposed): Receipt 
of disallowed medications (phenytoin, phenobarbital, rifampin) 
 
4.5 
Disallowed Medications 
 
Phenytoin, phenobarbital, rifampin: RAL 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, RAL 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 RAL is neither an inducer nor inhibitor of 
cytochrome P-450 enzymes, RAL is not expected to result in metabolic drug interactions 
with substrates of cytochrome P-450.   
 
4.6 
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 


 
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required protocol registration documents to the DAIDS Protocol Registration Office (DAIDS 
PRO) at the Regulatory Support Center (RSC).  The DAIDS PRO will review the submitted 
protocol registration packet to ensure that all of the required documents have been received.   
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by the DAIDS 
PRO and sites will receive an Initial Registration Notification from the DAIDS PRO that 
indicates successful completion of the protocol registration process. A copy of the Initial 
Registration Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, 
sites should implement the amendment immediately.  Sites are required to submit an 
amendment registration packet to the DAIDS PRO at the RSC.  The DAIDS PRO will review 
the submitted protocol registration packet to ensure that all the required documents have been 
received. Site-specific ICF(s) WILL NOT be reviewed and approved by the DAIDS PRO and 
sites will receive an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification should be 
retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents 
required for initial and amendment registrations, refer to the current version of the DAIDS 
Protocol Registration Manual. 
 
Enrollment of participants onto the study will be done through the Subject Enrollment 
System (SES) on the DMC website (at https://www.frontierscience.org) under the Systems 
heading.  
 
4.7 
Co-enrollment Procedures 
 
Co- enrollment in P1081 is allowed as long as blood draw limitations are not exceeded. NIH 
and local restrictions apply. 
 
Co-enrollment in other research protocols will require the consent of the protocol chair(s) of 
P1110 and the other research protocol. 
 
5.0  
STUDY TREATMENT 
 
Study treatment is defined as Raltegravir (Isentress®, RAL) oral granules for suspension.  
 
5.1 
Drug Regimens, Administration, and Duration  
5.11 
Regimen  
 
 
 
Cohort 1: HIV-1 exposed full-term infants  


 
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For RAL-naïve (unexposed) infants:  RAL 2 mg/kg oral granules for suspension as a 
single dose within 48 hours of birth in addition to standard of care ARV for PMTCT 
prophylaxis (refer to Appendix III, Raltegravir Weight Band Dosing Table for Oral 
Granules for Suspension).  
 
For RAL-exposed infants:  RAL 1.5 mg/kg oral granules for suspension as a single dose 
within 48 hours of birth in addition to standard of care ARV for PMTCT prophylaxis 
(refer to Appendix III, Raltegravir Weight Band Dosing Table for Oral Granules for 
Suspension).  
 
For all Cohort 1 infants (RAL-naïve and RAL-exposed infants):  Administer a second 
single dose of RAL 3 mg/kg oral granules for suspension in addition to standard of care 
ARV for PMTCT prophylaxis (refer to tables in Appendix III) on day 7 to 10 of life.  
 
Cohort 2: HIV-1 exposed full-term infants   
 
For RAL-naïve (unexposed) infants:  RAL oral granules for suspension, provided as 
follows in addition to standard of care ARV for PMTCT prophylaxis (refer to tables in 
Appendix III): First Dose to be administered within 48 hours of life: 
 
 
1.5 mg/kg once daily during Days 1-7 of life (week 1) 
 
3.0 mg/kg twice daily during Days 8-28 of life (weeks 2-4) 
 
6.0 mg/kg twice daily during Days 29-42 of life (weeks 5-6) 
 
For RAL-exposed infants.  First dose to be administered between 12 and 60 hours of life 
(refer to tables in Appendix III): 
 
 
1.5 mg/kg once daily during Days 1-7 of life (week 1) 
 
3.0 mg/kg twice daily during Days 8-28 of life (weeks 2-4) 
 
6.0 mg/kg twice daily during Days 29-42 of life (weeks 5-6) 
 
The reference weight to be used for each dose, and throughout the duration of that dose, 
is shown in the Table 10 below.  The doses are calculated at 3 time points during the 6 
weeks: 
 
1. Initial dose based on birth weight; 
2. At day 6-9 of life study visit; and   
3. At day 28-32 of life study visit.   
 
Note:  Intent is to minimize the number of dose adjustments while receiving study 
treatment. 
 


 
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Table 10 
Weight for Weight Bands (Cohort 2 RAL-exposed) in Appendix III  
RAL dose regimen 
Weight to be used for Appendix III weight bands 
1.5 mg/kg once daily 
Birth Weight 
Note: First dose administered between 12 and 60 
hours of life 
3.0 mg/kg twice daily 
Weight on Day 6-9 of Life Study Visit 
(Note: if infant has lost weight during first week of 
life, use birth weight for dose calculation) 
6.0 mg/kg twice daily 
Weight on Day 28-32 of Life Study Visit 
 
NOTE: If dose adjustment is required for Cohort 1 and Cohort 2 based on pharmacokinetic 
data, this will be communicated by the protocol team to sites. A new prescription will be 
required for the site pharmacist. Refer to Appendix III for dosing tables of RAL oral granules 
for suspension based on 1.5, 2, 3, 4, 5, and 6mg/kg Daily or Twice Daily.  
 
5.12 
 Administration  
 
Cohort 1: The first single dose given within 48 hours of birth and the second single dose 
given on day 7 to 10 of life will be prepared by the study staff. Clinic Staff will provide 
phone call follow up prior to visit days for dosing and after dosing visits to review side 
effects to watch for, and to confirm no problems with tolerability. 
 
Cohort 2: The initial dose administered while the participant is in the hospital will be 
prepared and administered by the study staff. The initial dose will be administered in 
RAL–naive infants between 0 to 48 hours of birth and in RAL–exposed infants between 
12 and 60 hours of birth.  Prior to discharge from the hospital, the site staff will instruct 
the parent or caregiver how to properly prepare and administer the doses to the infant. 
Subsequent doses can be prepared and administered by caregivers as part of the teaching 
process.  Clinic staff will call the participant’s home prior to PK sampling days to 
confirm adherence, understanding of dosing, and no intercurrent illnesses that might 
preclude PK sampling. If correct dosing for 48 hours prior to PK sampling is not 
confirmed, PK sampling will be rescheduled. 
 
Competency of the parent or caregiver to both properly prepare and administer the doses 
to the participant must by documented in the participants chart by site staff prior to 
discharge from the hospital.  
 


 
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See Appendix IV, Diagram and Caregiver Instructions for Preparing and Administering 
Raltegravir Oral Granules for Suspension 10 mg/mL, for directions on the preparation 
and dosing of raltegravir oral granules for suspension.   
 
5.13 
Duration  
 
 
 
Cohort 1 will receive two single observed doses of RAL oral granules that are prepared 
by site staff in addition to standard of care ARV for PMTCT prophylaxis.  The first dose 
should be within 48 hours of birth and the second single dose at 7 to 10 days of life.  
 
Cohort 2 will receive 6 weeks of RAL oral granules in addition to standard of care ARV 
for PMTCT prophylaxis.  
 
Participants will be followed for 24 weeks after birth.  
 
 
 
5.2 
Study Drug Formulation and Storage  
5.21 
Description of Formulation of Raltegravir (Isentress®, RAL)  
 
Raltegravir oral granules for suspension will be provided in foil pouches with each pouch 
containing 100 mg of study drug. Raltegravir oral granules are for suspension in water 
only. After reconstitution the final concentration is 10 mg/mL.  
 
Note: Final concentration was changed from 20 mg/mL to 10 mg/mL in v.1 LOA#3.  
 
The oral granules for suspension formulation has a banana flavor, and contains the 
following: raltegravir, hydroxypropylcellulose, ethylcellulose, Opadry I film coat blend, 
sucralose, monoammonium glycyrrhizinate, natural banana flavor, crospovidone, 
mannitol, Avicel Cl-611, and magnesium stearate. 
 5.22 Storage Instructions 
 
Stability studies for the oral granules formulation are ongoing.  Raltegravir oral granules 
pouches should be securely stored in a dry place between 15 to 30°C (59 to 86°F).  Do 
not refrigerate, freeze, or put on ice. The foil pouches should remain sealed until used. 
Refer to Appendix IV for instructions for the caregiver.   
 
5.3 
Drug Supply, Distribution, and Pharmacy 
 
5.31 
Study Product Acquisition/Distribution 
 


 
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RAL oral granules will be supplied by Merck Research Laboratories. RAL 100 mg 
sachets of oral granules for suspension will be available through the Clinical Research 
Products Management Center (CRPMC). The site pharmacist can obtain the study 
product for this study by following the instructions in the manual Pharmacy Guidelines 
and Instructions for DAIDS Clinical Trials Networks in the section: Study Product 
Management Responsibilities. 
 
Ancillary supply kits that include mixing cups, spatulas, and syringes for preparation and 
administration of the oral granules for suspension as well as dosing and disposal 
instructions are also available through the CRPMC. 
 
The other components of the antiretroviral (ARV) regimen will not be supplied by the 
study and should be initiated per local standard of care. ARV regimen must be obtained 
outside of this study.  
 
5.32 
Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. All unused study product 
must be returned to the NIAID CRPMC (or as otherwise directed by the sponsor) after 
the study is completed or terminated. The procedures to be followed are provided in the 
manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks in the 
section Study Product Management Responsibilities. 
 
6.0 
PARTICIPANT MANAGEMENT 
6.1 
Toxicity Management 
 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS 
AE Grading Table), Version 1.0, December 2004, Clarification August 2009, which is 
available on the RSC website at http://rsc.tech-res.com/safetyandpharmacovigilance will be 
used for screening eligibility and for grading toxicities when specifically noted below.  
Alternate explanations for clinical or laboratory abnormalities that may at first appear to be 
related to the study agents(s) must be explored.  Expedited Adverse Event (EAE) reporting 
must be done according to Section 7.1 
 
*NOTE: SPECIAL MANAGEMENT PROCEDURES FOR BILIRUBIN WILL BE USED 
ACCORDING TO SECTION 6.13 
 
6.11 
Reporting of Suspected Adverse Drug Reactions (for bilirubin management, see 
Section 6.13) 
 


 
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A suspected adverse drug reaction (SADR) is an adverse event that could potentially 
have a causal relationship to the study agent (definitely, probably, or possibly related).  
General guidelines for study drug suspected adverse drug reactions SADRs are provided 
below. 
 
 
Grade 1 - All study drug SADRs should be recorded on Case Report Forms 
(CRFs) at each visit.    
 
 
Grade 2 - All study drug SADRs should be recorded on CRFs at each visit.   
Inform team monthly whether toxicity has resolved or not.   
 
 
Grade 3 or 4 -  
 
o The protocol team must be notified of study drug SADRs within 24 hours at 
impaact.teamp1110@fstrf.org. 
o The investigator should confirm all Grade 3 and 4 study drug SADR laboratory 
test results as soon as possible but always within 72 hours.    
o Expedited Adverse Event (EAE) reporting must be done according to Section 
7.1.  
 
6.12 
Management of RAL toxicity (for bilirubin management, see Section 6.13) 
 
Cohort 1:   
 
Grade 1 - The second RAL dose can be administered; routine monitoring.  
Grade 2 - The second RAL dose can be administered; monitor closely with more frequent 
visits; as per site PI, and work-up to exclude other causes. 
Grade 3 - The second RAL dose should be withheld while awaiting confirmatory results; 
other PMTCT antiretroviral prophylaxis may be continued.  If Grade 3 abnormalities are 
confirmed, contact the study team and the second RAL dose should be withheld until the 
abnormalities are Grade 2 or below unless the clinician, with the approval of the study 
team and medical officer, believes that the event is unlikely related to RAL 
administration and that antiretroviral therapy (including RAL) should be continued.  
Grade 4 - The second RAL dose should be withheld and concomitant antiretrovirals used 
for PMTCT should also be held and the study team contacted awaiting results of the 
confirmatory test unless the clinician, with the approval of the study team and medical 
officer, believes that withholding antiretroviral prophylaxis (including or excluding RAL) 
would be harmful to the participant and that continuing them would pose little additional 
risk. If the Grade 4 abnormality is confirmed but the adverse event is determined to be 
unrelated to RAL, the investigator should contact the team to determine if and when the 
second RAL dose should be administered; other antiretroviral drugs used for PMTCT 
prophylaxis can be restarted when abnormalities are Grade 2 or below unless the 
clinician, with the approval of the study team and medical officer, believes that the event 
is unlikely related to PMTCT prophylaxis.  If the Grade 4 abnormality is confirmed and 


 
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thought to be related to RAL the second RAL dose should not be given and the 
investigator should contact the study team for further instructions.   
 
Attempt to confirm any unexpected laboratory results as soon as possible, but always 
within 72 hours of the recognition of the event.  The protocol team should be notified of 
the results at impaact.teamp1110@fstrf.org 
 
 
*NOTE:  In the event of treatment discontinuation, participants will be asked to continue 
to be followed until the 24 week visit. 
 
Cohort 2: 
 
Grade 1 - Continue RAL; routine monitoring.  
Grade 2 - Continue RAL; monitor closely with more frequent visits; as per site PI, work-
up to exclude other causes. 
Grade 3 - Continue RAL while awaiting confirmatory results unless the clinician believes 
that remaining on RAL would be unsafe.  Other PMTCT antiretroviral prophylaxis may 
be continued pending confirmatory testing. 
 If Grade 3 abnormalities are confirmed, contact the study team, and the RAL should be 
withheld and other antiretroviral drugs used for PMTCT prophylaxis should be held until 
the abnormalities are Grade 2 or below unless the clinician, with the approval of the study 
team and medical officer, believes that the event is unlikely related to RAL 
administration and/or that PMTCT prophylaxis should be continued.  
Grade 4 – Contact the study team. Hold RAL and concomitant antiretrovirals used for 
PMTCT immediately unless the clinician, with the approval of the study team and 
medical officer, believes that withholding antiretroviral prophylaxis (including RAL) 
would be harmful to the patient and that continuing them would pose little additional risk.  
Attempt to confirm any unexpected laboratory results as soon as possible, within 72 
hours of awareness of the event. The protocol team should be notified of the results at 
impaact.teamp1110@fstrf.org. 
 
For confirmed drug related Grade 4 SADRs, RAL should be permanently discontinued.  
For Grade 4 adverse events that are determined to be unrelated to study drug, the 
investigator should contact the team to determine when RAL may be safely resumed. 
 
*NOTE:  In the event of treatment discontinuation, participants will be asked to continue 
to be followed until the 24 week visit. 
6.13 
Bilirubin Management 
 
Due to the potential for interactions between RAL and bilirubin affecting RAL 
pharmacokinetics and bilirubin elimination and toxicity (see Section 1.27) special 
management procedures for bilirubin will be used.  Bilirubin concentrations and 
interventions to lower bilirubin (such as phototherapy and exchange transfusion) will be 
recorded but bilirubin will be graded according to the DAIDS Toxicity Table and 


 
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managed according to the schema described below.  Hyperbilirubinemia will be managed 
by clinical caregivers according to local standards of care.  If total bilirubin is >16.0 
mg/dL or an exchange transfusion is performed, no further RAL doses will be 
administered but participants will continue to be followed for safety assessments.  
Participants who receive phototherapy may continue to receive study drug as long as total 
bilirubin concentration ≤16.0 mg/dL. 
 
The protocol team must be notified if study drug is held due to elevated bilirubin or of 
Grade 3 or 4 hyperbilirubinemia determined to be at least possibly related within 24 
hours of site awareness at impaact.teamp1110@fstrf.org. 
 
6.14 
Follow-up of Abnormal Events and Laboratory Values 
 
All abnormal clinical events and laboratory values, not related or probably not related 
(non-SADR events), occurring in enrolled participants will be followed closely until 
resolution. The urgency and frequency of repeat evaluations will depend on the clinical 
significance of the specific abnormality.  Study clinicians will provide appropriate 
clinical management of adverse events according to their best medical judgment and local 
practice.  For any persistent Grade 3 or 4 clinical or laboratory study drug SADRs, 
evaluations should be repeated approximately weekly (or more frequently if necessary) 
until toxicity falls to Grade 2 or below and as appropriate thereafter.  Alternate 
explanations will be sought for all clinical and laboratory abnormalities. 
 
6.2 
Study Management Plan 
 
The Data Management Center (DMC) will maintain a web page informing sites as to the 
availability of enrollment slots per cohort.  The protocol team, including the co-chairs, 
medical officers, pharmacist, and pharmacologist, will respond to sites who contact the team 
with questions regarding toxicity management, dosing, or other issues within one business 
day.  Team responses will include the entire team. 
 
Sites will be given 7 days to respond to queries to allow the team to meet Merck data 
delivery requirements.  Sites will be contacted by the protocol data manager or co-chairs 
regarding any query responses or data issues that are outstanding after 7 days.   
 
All RAL dose modifications will be recommended by the protocol team.  See Section 6.21 
for information on dose modifications for Cohorts 1 and 2.  The protocol team will review 
the PK data for each participant as part of an on-going evaluation of the dosing regimen to 
determine whether a dose adjustment is required. The study team will conduct an extensive 
review of the data obtained from participants enrolled in Cohort 1 before opening enrollment 
for Cohort 2. Dose recommendations for Cohort 2, and supporting dose finding data from 
Cohort 1, must be approved by the Medical Officers, IMPAACT representatives and Merck 
representatives.  If all agree, Cohort 2 opens to enrollment.  If there is disagreement among 
IMPAACT, Merck and/or the study team, a Study Monitoring Committee (SMC) will be 


 
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appointed to review the data understanding that Cohort 2 will not open without Merck 
approval.  See Section 8.51 for more details on SMC monitoring of study data and progress. 
 
The P1110 team will notify sites of any change in dose and/or dosing frequency through an 
appropriate mechanism. Dosing tables found in Appendix III will be used for dosing changes 
and are based on weight bands.  
 
6.21 
Cohort Dosing Management 
 
Cohort 1 
A minimum of 12 neonates will be enrolled into Cohort 1 to provide data for 12 PK 
evaluable neonates.  All neonates enrolled in Cohort 1 will receive, per Section 5.11, oral 
granules for suspension as two separated single doses, the first given within 48 hours of 
birth and a second dose administered at 7 to 10 days of life, with PK assessed after each 
dose.  The PK results and safety will be assessed through the regular team monitoring 
(done at least every 4 weeks) and at full cohort accrual to ensure that the RAL 
concentrations in each individual do not exceed a Cmax of 19,630 nM (8,720 ng/mL) and 
do not exceed an AUC12 of 63,050 nM-hr (28,000 ngxh/mL), and that no life-threatening 
toxicities probably related to RAL administration have occurred.   
 
Based on the team assessment of the PK data and review of safety information, the dose 
may be modified for the subsequent participants receiving the 2 doses in Cohort 1, in 
which RAL dosing may be modified in the range of 1.5 mg/kg to 6 mg/kg per dose.  
 
 
 
 
 
 
 
Cohort 2 
After enrollment of participants into Cohort 1 RAL-exposed or RAL-naïve group is 
completed with acceptable safety and an appropriate multiple dose regimen from birth to 
6 weeks is determined, Cohort 2 will open for the respective group.  The initial multiple 
dose regimen for Cohort 2 may be determined based on results from P1097, P1110 
Cohort 1, P1066 (Cohorts IV and V), P1026s, and PK modeling and simulation.  The PK 
targets for Cohort 2 are geometric mean target exposures for:   
 
 
once-daily dosing of AUC24 of 28-90 µMxhr (12-40 mgxh/L) and an 
approximate GM trough (C24hr) > 75nM (33ng/mL) 
 
twice-daily dosing of AUC12 of 14-45 µMxhr (6-20 mgxh/L) and an approximate 
GM trough (C12hr) > 75nM (33ng/mL) 
 
A minimum of 20 neonates will be enrolled into Cohort 2 to provide data for 20 PK 
evaluable infants.  The dosing for RAL is further detailed in Section 5.11 of this protocol.   
 
Cohort 2 dosing may be modified based on observed pharmacokinetic data coupled with 
modeling and simulation to determine the optimal multiple dose regimen capable of 
meeting the selected PK targets: If the minimum targets above are not achieved, the dose 
will be increased in linear fashion.   


 
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6.3 
Criteria for Treatment Discontinuation 
 
The participant will have study drug discontinued for the following reasons: 
6.31 
The participant requires treatment with medications that are disallowed while on 
this study.  
6.32 
The participant experiences dose limiting or intolerable drug toxicity as defined in 
Section 6.1. 
6.33 
New data become available that indicate treatment should be discontinued. 
6.34 
It is determined by the study team or the treating healthcare providers that 
continued study treatment with RAL is not in the best interest of the participant 
and the participant will be followed off study treatment on study. 
6.4 
Permanent Study Discontinuation 
 
The participant will be discontinued from the study for the following reasons: 
6.41 
The parent or legal guardian refuses further treatment and/or follow-up 
evaluations. 
 
6.42 
The investigator determines that further participation would be detrimental to the 
participant's health or well-being. 
6.43 
The parent or legal guardian fails to comply with the study requirements so as to 
cause harm to the participant or seriously interfere with the validity of the study 
results. 
 
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 sponsors, or 
other governmental agencies. 
 
7.0 
EXPEDITED ADVERSE EVENT REPORTING  
7.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse Events (AEs) are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC website at  
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual.  
 
The DAIDS Adverse Experience Reporting system (DAERS), an internet-based reporting 
system, must be used for expedited AE reporting to DAIDS.  In the event of system outages 


 
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or technical difficulties, expedited AEs may be submitted via the DAIDS EAE Form.  For 
questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Site queries may also be sent from within the DAERS 
application itself. 
 
Where DAERS has not been implemented, sites will submit expedited AEs by documenting 
the information on the current DAIDS EAE Form.  This form is available on the RSC 
website: http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual. For questions 
about EAE reporting, please contact the RSC (DAIDSRSCSafetyOffice@tech-res.com). 
7.2 
Reporting Requirements for this Study 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be 
used for this study. 
 
The study agent for which relationship assessments are required is raltegravir. 
 
In addition to reporting all SAEs as defined above, other events that sites must report in an 
expedited fashion include bilirubin concentrations >16.0 mg/dL, exchange transfusions for 
hyperbilirubinemia, all malignancies, seizures, IRIS events, and hepatotoxicities whether or 
not symptomatic or related to study drug, and all other Grade 3 or 4 related toxicities for 
which a relationship to study drug cannot be ruled out. 
 
Over doses will be reported on a quarterly basis to the pharmaceutical sponsor. 
  
The death of any participant after enrollment or within 30 days of study completion, 
regardless of the cause, must be reported within three business days of first becoming aware 
of the death. If an autopsy is performed, the report must be provided. Reports of all deaths 
must be communicated as soon as possible to the appropriate IRB or EC and/or reported in 
accordance with local law and regulations.  
 
For all SAEs submitted to RSC, sites must file an updated SAE report to RSC with the final 
or stable outcome (Status Code p. 5 of the EAE form) unless the SAE reported in the initial 
EAE form already had a final or stable outcome. 
7.3 
Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table), Version 1.0, December 2004, Clarification August 2009, must 
be used and is available on the RSC website at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/daids-grading-tables 


 
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7.4 
Expedited AE Reporting Period 
 
The expedited AE reporting period for this study is the entire study duration for an individual 
participant (from initial administration of study drug until study completion or 
discontinuation of the participant from study participation for any reason). 
 
After the protocol-defined reporting period, unless otherwise noted, only  SUSARS as 
defined in Version 2.0 of the EAE Manual will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available information). 
 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
General Design Issues 
 
This is a Phase I multi-center, open label, non-comparative study to assess the safety and 
pharmacokinetics of raltegravir administered to full-term neonates, aged ≤ 48 hours (protocol 
Version 1.0) and ≤ 60 hours (protocol Version 2.), at risk of acquiring HIV-1 infection.  The 
goal is to determine a dose of raltegravir, that is safe, well-tolerated and meets PK targets, 
administered as an oral granules suspension to neonates and infants in the first 6 weeks of 
life.  Both the mother and the infant will be enrolled, with the mother having only a study 
entry visit and the infant followed through 24 weeks of life. 
 
Safety data will include signs/symptoms, diagnoses and laboratory test results, which will 
include results of evaluations specified in the protocol and results from the infant’s clinical 
care.  Infants will be evaluable for safety analysis if they received at least one dose of 
raltegravir. For CRF reporting and analysis of safety data, the sites’ assessments of AE 
relationship to raltegravir will be used.  However, with regards to participant safety and PK 
evaluations which will support the selection of a dose for a given cohort, the protocol team 
will also have input as to the causality and drug relation of specific adverse experiences.  
Regular monitoring of RAL safety, which could result in dose or study modification, 
described in detail in Section 8.5.  
 
Approximately 50 infants and their mothers will be enrolled in order to have a minimum of 
12 and 20 PK evaluable participants in Cohorts 1 and 2, respectively.  If a participant has 
unevaluable PK data, which reflects uncertainty about appropriate exposure to the study 
medication then the participant will be excluded from PK analyses and will be replaced.     
 
The study design consists of two cohorts with the following dosing regimens of raltegravir in 
addition to standard PMTCT: 
 
Cohort 1:    
Raltegravir as oral granules for suspension, per Section 5.11 administered as a single dose 
within 48 hours of birth, with a second dose administered at 7-10 days of life  
 


 
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Cohort 2:   
 
Raltegravir as oral granules for suspension, per Section 5.11 administered as daily dosing 
through 6 weeks of life with first dose given within 48 hours of birth for RAL-naïve infants 
and between 12 and 60 hours of birth for RAL-exposed infants.  
 
Study accrual will initially be for Cohort 1 only with accrual to Cohort 2 contingent upon 
neonates in Cohort 1 successfully meeting the safety criteria and providing adequate 
information for Cohort 2 initial dosing.  Initial dosing for Cohort 2 RAL-naïve and RAL-
exposed groups will be determined using modeling and simulation analyses based on P1110 
available data and data from IMPAACT P1097, P1066 (Cohorts IV and V) and P1026s. 
 
Criteria for defining PK evaluable neonates, along with descriptions of PK parameters and 
analyses can be found in Section 9.  
 
8.2 
Outcome Measures 
 
(Outcome Measures are for infants only; maternal data are to be used as covariates, not as 
outcomes) 
8.21 
Primary Endpoints for Cohorts 1 and 2 
 
Toxicity Endpoints: Toxicity from study entry through 6 weeks of life 
 
 Adverse events of Grade 3 or 4 severity or death (primary safety endpoint for 
final analysis) 
 
Suspected adverse drug reaction (SADR) of Grade 3 or 4 severity or death 
(primary safety endpoint for dose finding guidelines described in Section 
8.52) but secondary safety endpoint for the analyses described in Section 
8.71) 
 
 
Pharmacokinetic Endpoints: (See Section 9.0: Clinical Pharmacology Plan) 
 
8.22 
Primary Response Variables for Cohorts 1 and 2 Pharmacokinetic parameters 
(See Section 9.0)  
8.23 
Secondary toxicity endpoints for Cohorts 1 and 2: Toxicity from study entry 
weeks through 24 weeks of age 
 
 
 
 Adverse events of Grade 3 or 4 severity or death 
 Suspected adverse drug reaction (SADR) of Grade 3 or 4 severity or death 
 
8.24 
Secondary Response Variables for Cohorts 1 and 2 
 


 
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 UGT1A1 genotype(presence or absence of *28/*28  genetic variant) 
 SLCO1B3 (rs2117032-C/T) genotype 
 Hyperbilirubinemia defined as total bilirubin exceeding 16.0 mg/dL or infant 
receiving phototherapy, or transfusion therapy, or other therapies for 
hyperbilirubinemia 
8.3 
Randomization and Stratification  
 
There will be no randomization. The infant’s RAL exposure in utero will be an accrual and 
an analysis stratification factor.  
8.4 
Sample Size and Accrual  
 
Under Protocol Version 1.0, the study target enrollment was approximately 50 infants and 
their mothers in order to accrue minimum of 12 and 20 PK evaluable neonates in Cohorts 1 
and 2, respectively. These sample sizes have been determined on the basis of data needed for 
the PK analysis.  The team estimated it will take 4 years to accrue 32 evaluable participants. 
 
To date, Cohort 1 RAL-naïve, Cohort 1 RAL-exposed, and Cohort 2 RAL-naïve groups were 
fully accrued under protocol Version 1.0.  Cohort 2 RAL-exposed group will open to accrual 
under protocol Version 2.0 with a minimum accrual of 8 infants.  The team estimates it will 
take 1 year to accrue 8 evaluable participants. 
8.5 
Monitoring and Safety Guidelines 
 
The team will assess safety on routine monitoring conference calls which will occur at least 
every 4 weeks for Cohorts 1 and 2.  Safety analyses will be performed at full accrual to 
Cohort 1, at interim analysis when 8 participants have been accrued to Cohort 2 and at full 
accrual to Cohort 2, evaluating whether the safety guidelines specified in Section 8.52 have 
been met.  For dose finding purposes, infants who have been excluded from the PK analyses, 
due to evidence of problematic exposure to the study medication, will also be excluded from 
evaluation of the safety guidelines. 
 
The attribution of relationship of serious adverse events to study drug for the purposes of 
employing the start, stop and pause rules will be by consensus among the site investigator, 
study team (which includes representatives from Merck) and DAIDS medical officer; if 
unanimous agreement between them cannot be established, the attribution made by the 
majority of these 3 persons or entities will be used.  Gradation of relationship will use the 
following terminology: Not related, probably not related, possibly related, probably related or 
definitely related.  
8.51 
Monitoring of Safety Data by the Protocol Team and the Study Monitoring 
Committee (SMC) 
 


 
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Since Phase I studies are not routinely reviewed by a Data and Safety Monitoring Board 
(DSMB), it is the responsibility of the protocol team to interpret safety data, and make 
decisions regarding SADRs that are needed to protect participants from undue risk.  
 
The safety and tolerability of the study agent will be monitored by means of adverse 
events reports and toxicity reports presenting laboratory and clinical events.  It is required 
that the data required for the toxicity reports be entered into the database within 72 hours 
of the time at which the results of the laboratory tests or clinical examinations become 
available.   
 
Reports compiled by the Data Management Center (DMC) will be reviewed and 
discussed by the Protocol Team on conference calls held at least every 4 weeks. Data on 
accrual, pharmacokinetics and toxicity will be reviewed.   
 
In addition, an independent IMPAACT Study Monitoring Committee (SMC) will review 
this study regularly, following policies described in the IMPAACT Manual of 
Procedures.  The composition of the SMC will include the SMC Chair; IMPAACT Chair 
or Vice Chair; IMPAACT Treatment Scientific Committee Chair or Vice Chair; 
representatives of the IMPAACT Operations Center, Statistical and Data Management 
Center, and Laboratory Center; and representatives of NIAID and NICHD.  
 
SMC reviews will occur at least annually and on a more frequent or ad hoc basis if any 
safety issues or concerns arise.  Ad hoc reviews may also be triggered by temporary 
suspension of accrual or pausing administration of study product due to safety concerns, 
as outlined in Section 8.52 below.  Based on any of its reviews, the SMC may 
recommend that the study proceed as currently designed, proceed with design 
modifications, or be discontinued.  The SMC may also provide operational 
recommendations to help address any study implementation challenges that may be 
identified during their reviews.   
 
The SMC will monitor study progress (see Section 8.6), quality of study conduct, and 
participant safety.  The SMC will generally review the same types of data reports as the 
Protocol Team.  For ad hoc or triggered safety reviews, more limited data may be 
reviewed, focusing on the events that triggered the reviews.   
 
8.52 
Guidelines for the Evaluation of Safety Data (See Section 9.0 for Pharmacokinetic 
Guidelines) 
 
Accrual to Cohort 1 will be temporarily suspended if: 
 any participant has a new life threatening event or death judged to be a 
Suspected Adverse Drug Reaction (SADR) or if any of the participants has a 
new Grade 4 event that may not be judged to be life-threatening but is judged 
to be probably or definitely attributable to the study medication;  
OR 


 
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 at least 4 of the participants have had treatment discontinuation due to non-life 
threatening Grade 3 or 4 severity SADR, judged to be at least possibly 
treatment related. 
 
Accrual to Cohort 2 will be temporarily suspended if: 
 any participant has a new life threatening event or death judged to be an 
SADR or if any of the participants has a new Grade 4 event that may not be 
judged to be life-threatening but is judged to be probably or definitely 
attributable to the study medication;  
OR 
 at least 3 of the first 8 participants to be included in the Cohort 2 RAL-
unexposed group interim analysis have had treatment discontinuation due to 
non-life threatening Grade 3 or 4 severity SADR, judged to be at least 
possibly treatment related;  
OR  
 if after the Cohort 2 RAL-unexposed group interim analysis, 
o 
there was no dose adjustment and at least 6 of 20 participants to be 
included in Cohort 2 final analysis have had treatment discontinuation due 
to non-life threatening Grade 3 or 4 severity SADR, judged to be at least 
possibly treatment related; or 
o 
there was a dose adjustment and at least 4 of the 12 participants on the 
final dose for Cohort 2 have had treatment discontinuation due to non-life 
threatening Grade 3 or 4 severity SADR, judged to be at least possibly 
treatment related. 
 
Following any temporary suspension of accrual, the team will further review the safety 
data within 48 hours of notification of the event to determine if continuation of accrual is 
appropriate.  If the team, including the study chair, the DAIDS medical officer of record 
and Merck representatives, agrees that the study drug is likely to be safe for additional 
participants, they may decide to allow accrual to resume.  However, the P1110 SMC will 
be informed of this decision, and the study will not reopen without the approval of this 
committee. The SMC may ask for any data it may want to review before making its 
decision. Regulatory agencies will be notified of the event and the team’s and SMC’s 
decision.   
 
8.521  Final Evaluation of Cohort 1 Safety Data 
 
At final evaluation of the Cohort 1 RAL-exposed or RAL- naïve groups, safety 
guidelines will be assessed on infants on the final dose for each group in Cohort 1 
using safety data through week 6 of life.  If none of the participants has experienced a 
new life-threatening event or death judged to be an SADR or a new Grade 4 event 
that is probably or definitely attributable to the study medication; and no more than 
25% of the participants have had treatment discontinuation due to non-life threatening 
Grade 3 or 4 severity SADR at least possibly related to the study drug, then final dose 
in Cohort 1 has passed the safety guidelines. Otherwise the team will review the 


 
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safety data and will consult with the P1110 SMC to determine whether it is safe to 
proceed to Cohort 2 and under what conditions this will be allowed to occur. 
 
8.522 
Interim Evaluation of Cohort 2 RAL-naïve Group Safety Data 
 
The safety and PK of the starting dose for Cohort 2 will be assessed on the first 8 
participants based on safety data through 6 weeks of life, for the purpose of 
determining whether accrual to the full cohort can proceed and determining if any 
adjustment in dosing may be necessary (see Section 9.0 for PK evaluation.).   Accrual 
will be stopped while this interim analysis is being performed.  Dosing decisions will 
depend upon severity of adverse events, attribution of these events to the study drug 
and PK data.  
 
If none of the 8 participants has experienced a new life-threatening event or death 
judged to be an SADR or a new Grade 4 event that is probably or definitely 
attributable to the study medication; and no more than 2 of the participants have had 
treatment discontinuation due to non-life threatening Grade 3 or 4 severity SADR at 
least possibly treatment related to the study drug, then full accrual to Cohort 2 can 
proceed. Otherwise the team will review the safety data and will consult with the 
P1110 SMC to determine whether it is safe to complete full enrollment into Cohort 2 
and under what conditions this will be allowed to occur. 
    
8.523  
Final Evaluation of Cohort 2 Safety Data 
 
The safety guidelines will be assessed on the final dose for each group in Cohort 2 
based on safety data through week 6 of life.  If none of the participants has 
experienced a new life-threatening event or death judged to be an SADR or a new 
Grade 4 event that is probably or definitely attributable to the study medication and 
no more than 25% of the participants on the final dose for Cohort 2 have had 
treatment discontinuation due to non-life threatening Grade 3 or 4 severity SADR at 
least possibly treatment related to the study drug, then final dose in Cohort 2 has 
passed the safety guidelines. 
 
8.53 
Probabilities of Failing the Safety Guidelines  
 
The safety guidelines will be assessed at final analysis of Cohort 1, at interim analysis of 
Cohort 2 and at final analysis of Cohort 2, based on safety data through 6 weeks of life on 
samples of 12, 8, and maximum of 20 infants, respectively.  Given these small sample 
sizes, the information available for safety decisions will be imperfect.  Two types of 
sampling errors are possible:  
 
1) In a group where the true rate of toxicity is too high to warrant increased exposure to 
the current starting dose of the medication, the sample data may pass the safety 
guidelines;  


 
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2) In a group where the true rate of toxicity is low enough that further exposure to the 
current starting dose is warranted, the sample data may fail the guidelines.  
   
The extent to which the safety guidelines protect against the errors described above can 
be assessed by examining various hypothetical rates of "true toxicity" which could occur, 
if the study medication were used extensively among the participant population at the 
dose level under question.  The hypothetical situations presented in Tables 11,12, and 13 
are for the sample sizes of the 12 participants in Cohort 1, the first 8 participants for the 
interim analysis for Cohort 2, and 20 participants for final analysis of Cohort 2, 
respectively. Should there be a dose change following the interim analysis of Cohort 2, 
then only the 12 remaining participants will be exposed to the new dose; in that case the 
probabilities presented in Table 11 will apply.  Tables 11,12 and 13 show the 
probabilities of failing the safety guidelines for a range of conditions under which a given 
dose level would cause a high incidence of severe and life threatening SADRs to 
conditions under which severe SADRs would be relatively rare and would not be life 
threatening.  For each of these hypothetical situations, we assume that the sample is 
drawn from the participant population and that the safety guidelines for Cohort 1 (Section 
8.521), interim analysis for Cohort 2 (8.522) and final analysis for Cohort 2 (Section 
8.523) are followed.  
 
 


 
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Table 11. 
Probability of Failing Safety Guidelines for a Sample of 12 Participants for Final 
Analysis of Cohort 1 Under Potential Rates of True Toxicity 
 
True Toxicity Rates 
Probability of 
Failing 
Safety 
Guidelines 
Non-life threatening SADR that 
would result in treatment 
discontinuation, excluding Grade 
4 events probably or definitely 
attributable to study medication 
Death or life-
threatening SADR or 
Grade 4 events 
probably or definitely 
attributable to study 
medication 
0.50 
0.00 
0.93 
0.50 
0.05 
0.97 
0.50 
0.25 
1.00 
0.25 
0.00 
0.35 
0.25 
0.05 
0.67 
0.25 
0.25 
0.99 
0.05 
0.00 
0.00 
0.05 
0.05 
0.46 
0.05 
0.25 
0.97 
0.00 
0.05 
0.46 
0.00 
0.25 
0.97 
 
 
 


 
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Table 12. 
Probability of Failing Safety Guidelines for a Sample of 8 Participants for Interim 
Analysis of Cohort 2 under Potential Rates of True Toxicity 
True Toxicity Rates 
Probability of 
Failing Safety 
Guidelines 
Non-life threatening SADR 
that would result in treatment 
discontinuation, excluding 
Grade 4 events probably or 
definitely attributable to study 
medication 
Death or life-threating  
SADR or Grade 4 
events probably or 
definitely attributable 
to study medication 
0.50 
0.00 
0.86 
0.50 
0.05 
0.93 
0.50 
0.25 
1.00 
0.25 
0.00 
0.32 
0.25 
0.05 
0.57 
0.25 
0.25 
0.95 
0.05 
0.00 
0.01 
0.05 
0.05 
0.34 
0.05 
0.25 
0.90 
0.00 
0.05 
0.34 
0.00 
0.25 
0.90 
 


 
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Table 13. 
Probability of Failing Safety Guidelines for a Sample of 20 Participants for Final Analysis of  
Cohort 2 Under Potential Rates of True Toxicity 
True Toxicity Rates 
Probability of 
Failing Safety 
Guidelines 
Non-life threatening SADR 
that would result in treatment 
discontinuation, excluding 
Grade 4 events probably or 
definitely attributable to study 
medication 
Death or life-
threatening SADR or 
Grade 4 events 
probably or definitely 
attributable to study 
medication 
0.50 
0.00 
0.98 
0.50 
0.05 
1.00 
0.50 
0.25 
1.00 
0.25 
0.00 
0.38 
0.25 
0.05 
0.80 
0.25 
0.25 
1.00 
0.05 
0.00 
0.00 
0.05 
0.05 
0.64 
0.05 
0.25 
1.00 
0.00 
0.05 
0.64 
0.00 
0.25 
1.00 
 
For example, Table 11 shows that for a sample of size 12, there is a 97% chance of 
failing the safety guidelines under conditions in which the true rate of life-threatening 
toxicity is 5% and the rate of non-life threatening SADR is 50%. Assuming that it would 
be undesirable to accrue additional participants at a dose that had these true rates of 
adverse events, the 3% chance of NOT failing the safety guidelines would represent the 
probability of error.  
8.6 
Accrual Rate Evaluation 
 
Accrual to this study will be monitored by the IMPAACT leadership in accordance with 
standard operating procedures. The team monitored site registration and accrual to Cohort 1 
RAL-naïve, Cohort 1 RAL-exposed groups, and Cohort 2 RAL-naïve group as specified in 
protocol Version 1.0.  For Cohort 2 RAL-exposed group, if less than 4 infants have been 
accrued after 8 months of this study group opening, the team will re-assess the reasons for 
low accrual, and will possibly amend or close the protocol accordingly. 
 
 


 
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8.7 
Analyses 
8.71 
Primary and Secondary Safety Analyses of the Primary Safety Endpoints 
 
To evaluate the safety and tolerability of RAL through 6 weeks of  life, descriptive 
statistics will be calculated summarizing the safety data from study entry through 6 
weeks of life from all safety  evaluable infants in the four study groups: (i) Cohort 1 
RAL-naïve, (ii) Cohort 1 RAL-exposed, (iii) Cohort 2 RAL-naïve, and (iv) Cohort 2 
RAL-exposed infants.  Overall summary statistics for the cohort will be provided if the 
data suggests that there is no difference between RAL-naïve and RAL-exposed infants 
within that cohort.  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 primary toxicity endpoint of adverse event Grade 3 
or 4 severity or death. Secondary safety analyses will include point and 90% CI estimates 
of infants with a SADR of Grade 3 or 4 severity or death. Table 14 shows the precision 
with which confidence intervals around proportions of serious adverse events can be 
estimated, for  the 12 participants in Cohort 1 and for the 8 and 20 participants in the 
interim and final analyses for Cohort 2. 
 
Table 14 
90% Confidence Intervals Around Potential Proportions 
 of Infants Meeting a toxicity Endpointa 
Number of 
participants 
Proportion of 
participants 
meeting toxicity 
endpoint 
Clopper-
Pearson 90% 
CI 
 
8 
0.00 
(0.00, 0.37) 
 
0.25 
(0.03, 0.65) 
 
0.50 
(0.16, 0.84) 
 
 
 
12 
0.00 
(0.00, 0.26) 
 
0.25 
(0.05, 0.57) 
 
0.50 
(0.21, 0.79) 
 
 
 
20 
0.00 
(0.00, 0.17) 
 
0.10 
(0.01, 0.32) 
 
0.20 
(0.06, 0.44) 
 
0.50 
(0.27, 0.73) 
 
 
 
a Clopper-Pearson exact confidence interval estimates using SAS Version 9.2. 
 
The primary safety analyses population will include all infants who have had at least one 
dose of raltegravir. For Cohort 2 RAL-naïve group, if there was dose adjustment after the 
interim analysis, a sensitivity analysis will be performed on infants who were enrolled 
after dose adjustment and only took the adjusted dose. Patients who had an idiosyncratic 
dose adjustment, based on extreme PK data, will be included in the primary analysis. 


 
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However, this adjustment will be acknowledged in the narrative part of the report where 
these results are described. 
 
8.711 Secondary Analyses 
 
To assess the safety and tolerability of RAL through 24 weeks of life, descriptive 
statistics will be calculated summarizing the proportion of infants who had an adverse 
event of Grade 3 or 4 severity or death based on safety data from study entry through 
24 weeks of age on all safety evaluable infants in each of the four study groups.  A 
similar analysis will be done to summarize proportion of infants who had an SADR of 
Grade 3 or 4 severity or death. 
 
To investigate the relationship between neonatal raltegravir elimination and UGT1A-
1 genotype, participants will be divided into subgroups, based on whether or not they 
exhibit polymorphisms on UGT1A-1.  Descriptive analyses will be performed to 
compare these subgroups with respect to measures of central tendency and dispersion 
for raltegravir AUC. 
 
Similar descriptive analyses will also be performed to investigate the association of 
UGT1A1 (*28/*28) and SLCO1B3 (rs2117032-C/T) with hyperbilirubinemia.  If the 
sample size and the data distributions make this possible, a logistic regression model 
predicting for probability of neonatal hyperbilirubinemia with UGT1A1 (*28/*28) 
genotype, SLCO1B3 (rs2117032-C/T) genotype, gestational age and gender as 
predictors will be fitted on the pooled data across the two cohorts.  Note that the 
sample size may be too small and/or there may be insufficient cases of 
hyperbilirubinemia to make this possible.  If this analysis can be done, it will have 
minimal power, but the size and directionality of effects will be compared with those 
predicted on the basis of previous findings. 
 
9.0 
CLINICAL PHARMACOLOGY PLAN   
 
Protocol exposure limits from non-compartmental analysis for each participant were Cmax ≤ 
8723.6 ng/mL and AUC12 ≤ 28 mg*h/L. A population PK model was developed incorporating 
cohort 1 PK data with RAL concentration data from 24 infants and children ages 4 weeks to < 2 
years enrolled in IMPAACT P1066, a phase I/II, multicenter, open-label non-comparative 
intensive PK treatment study of RAL in infants and children [20]. Population modeling using 
PsN/3.7.6, NONMEM/7.3.0 and R/3.1.0 was performed to estimate RAL PK parameters, which 
were then used in simulations of potential dosing regimens.  The regimen that best met PK 
exposure targets (Ctrough, Cmax, AUC) defined for safety and efficacy from studies in older 
infants, children, and adults was selected for evaluation Cohort 2 infants (RAL-exposed and 
RAL- naïve).  
 
 


 
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9.1 
Pharmacology Objective 
 
This study is designed to assess the pharmacokinetics of raltegravir in newborn infants. 
Based on pharmacokinetic data from IMPAACT P1097 and P1066, a starting dose of 3 
mg/kg has been chosen, which is 25% of the total daily dose (6 mg/kg BID) currently under 
study in infants 4 weeks to <6 months of age in IMPAACT P1066.  In Cohort 1 of the study, 
raltegravir will be administered as a single dose using 3 mg/kg of the oral granules for 
suspension within 48 hours of birth, and a second dose will be administered at 7 to 10 days of 
life.  
 
PK evaluable infants are those whose PK results provide data on the primary 
pharmacokinetic parameters of interest. 
 
The PK targets for Cohort 1 are:   
 
 
RAL concentrations in each individual that do not exceed a Cmax of 19.63 µM and 
do not exceed an AUC12 of 63.05 µM-hr 
 
Prior to the start of Cohort 2, the initially proposed dosing regimen was modified based on 
observed pharmacokinetic data, including data from the Cohort 1 RAL-naïve and RAL-
exposed groups, coupled with modeling and simulation to determine the optimal multiple 
dosing regimen capable of meeting the selected PK targets, as well as the optimal PK 
sampling scheme for that dosing regimen.   
 
Based on these data, in addition to standard of care ARV for PMTCT prophylaxis, Cohort 2 
will receive the following dosing regimen (refer to tables in Appendix III): 
 
1.5 mg/kg once daily during Days 1-7 of life (week 1) 
 
3.0 mg/kg twice daily during Days 8-28 of life (weeks 2-4) 
 
6.0 mg/kg twice daily during Days 29-42 of life (weeks 5-6)  
 
The PK target AUC will depend on whether the drug is dosed once or twice daily.  The PK 
target GM trough is the same for both once daily and twice daily dosing. 
 
The PK targets for Cohort 2 are target exposures for:   
 
 
once-daily dosing of AUC24 of 28-90 µMxhr (12-40 mgxh/L) and an 
approximate GM trough (C24hr) > 75nM (33ng/mL) 
 
twice-daily dosing of AUC12 of 14-45 µMxhr (6-20 mgxh/L) and an approximate 
GM trough (C12hr) > 75nM (33ng/mL) 
9.2 
Primary and Secondary Data 
 
The primary data to be collected are plasma raltegravir concentrations for pharmacokinetic 
parameter estimation.  All PK samples will be registered in the Lab Data Management 
System (LDMS) database, and will be sent to the University of Alabama (UAB) Laboratory.  
The study database will be kept up to date by close tracking of samples.  Intensive PK sample 


 
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assays and pharmacokinetic calculations will be performed on a regular basis in the UAB 
Laboratory so that ongoing interim analysis can be done by the protocol team.  
 
9.3 
Study Design, Modeling and Data Analysis 
 
First dose and multiple dose raltegravir concentration-time data will be analyzed using 
standard non-compartmental methods. Whole blood for determination of raltegravir in 
plasma will be collected according to cohort.  These sample collection times may change 
depending upon the ongoing analyses of the pharmacokinetic results.  
 
Cohort 1  
Pharmacokinetic sampling for infants in Cohort 1 included the following:  
 
Dose 1 (within 48 hours of birth): Pre-dose, and 1-2 hours post-dose, 4-8 hours post-dose, 12 
(±1) hours post-dose, and 24 (±1) hours post-dose. 
 
Day 3-4 of life: One random PK sample will be obtained with laboratory evaluations. 
 
Dose 2 (7-10 days of life): Pre-dose, and 1-2 hours post-dose and 24 (±1) hours post-dose.  
 
*Note:  For the 12 and 24 hour PK sampling time points, it is necessary to collect blood 
samples within the window of ±1 hour for the accurate calculations of PK parameters of 
raltegravir.  However, in the event that a sample collection in this window is not possible, the 
sample should be obtained within ±2 hours and this deviation from the sampling instructions 
should be recorded. 
 
Modeling and simulation will be utilized after the completion of each RAL-exposed or RAL- 
naïve group in Cohort 1 to generate a multiple dosing scheme for the respective group in 
Cohort 2.  Specifically, data may be integrated from P1110 Cohort 1, P1097, P1066 (Cohorts 
IV and V), P1026s, and adult oral granule data to construct a population PK model capable of 
describing the raltegravir pharmacokinetics of oral granules for suspension.  A two-
compartment model will be fit using NONMEM version VII software, where various 
population attributes including, but not limited to, age, weight, sex and creatinine clearance 
will be examined to determine their influence on the pharmacokinetics of raltegravir, 
including the absorption, bioavailability and clearance.  Both intensive and sparse PK data 
from the above mentioned studies in both adults and children will be utilized to maximize the 
available information on the oral granules formulation and provide a rich and diverse dataset 
with regards to patient population, which should enable characterization of the population PK 
and associated variability for the oral granules for suspension formulation.  By incorporating 
all available information regarding the evolution of raltegravir clearance and UGT1A1 
ontogeny with age, the model can be used to simulate an optimal dosing scheme (with dose 
and/or frequency adjustments at appropriate times, such as at Day 14 and Day 28) to meet the 
PK targets throughout the course of dosing [76]. 
 
 


 
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Cohort 2 
Pharmacokinetic sampling for infants in Cohort 2 will occur at the Entry with first dose, after 
second dose, Day 6-9, Day 15-18, Day 28-32 visits, and Week 5-6 (33-42 Days of life) visit 
and include the following:  
 
Note:   PK sampling will ideally be scheduled after RAL has reached steady state 
(approximately 7-10 days after the dose increase).  For example, the Day 15-18 PK sampling 
collection visit should ideally be scheduled 7-10 days after the infant received his/her RAL 
dose regimen increased from 1.5 mg/kg once daily to 3 mg/kg twice daily. 
 
Entry with first dose: within 1 hour pre-dose, and 1-2 hours, 6-10 hours, 20-24 hours post-
dose. 
 
After second dose: PK sample obtained 3-6 hours post-dose with laboratory evaluations.  
 
Day 6-9 of life: within 1 hour pre-dose of initiating 3mg/kg twice daily.  A physical exam 
will also be conducted at this visit. 
 
Day 15-18 of life: within 1 hour pre-dose, and 1-2 hours post-dose, 4-6 hours post-dose, and 
8-12 hours post-dose.   
 
Day 28-32 of life: within 1 hour pre-dose of initiating 6 mg/kg twice daily.   
 
Week 5-6 of life (33-42 Days of life): within 1 hour pre-dose, and 3-6 hours post-dose. 
 
For sparse PK samples, the time of the previously administered dose (unobserved dose) 
should be recorded. 
9.4 
Anticipated Outcomes 
 
At the end of this trial we hope to have a much better understanding of raltegravir 
pharmacokinetics in neonates, the ontogeny of raltegravir metabolism, and to have defined 
the dose(s) and dosing interval that achieves the desired systemic exposure in this population. 
 
 
10.0  HUMAN SUBJECTS 
10.1 
Institutional Review Board and Informed Consent 
 
This protocol, the informed consent document (Appendix V-A and V-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 participants 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. 


 
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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 participants and determines when a study 
participant 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 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records will be identified only 
by a coded number to maintain participant confidentiality.  All records will be kept in a 
secured area.  All computer entry and networking programs will be done with coded numbers 
only.  Clinical information will not be released without written permission of the participant, 
except as necessary for monitoring by the study staff, study monitors, drug companies 
supporting the study, and their 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 sponsors, or other governmental agencies as part 
of their duties to ensure that research participants 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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Youth Aged 6-11 Years from IMPAACT P1066: A Phase I/II Study to Evaluate 
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Opportunistic Infections, San Francisco, CA, Feb 16-19, 2010., 2010. 
46. 
Nachman, S., et al., Interim Results from IMPAACT P1066: Raltegravir (RAL) Oral 
Chewable Tablet (OCT) Formulation in Children 6-11 Years. 17th Conference on 
Retroviruses and Opportunistic Infections, San Francisco, CA, Feb 16-19, 2010., 2010. 
47. 
Nachman, S., et al., Interim results from IMPAACT P1066: raltegravir (RAL) oral 
chewable tablet (CT) formulation in children 2-5 years. 18th Conference on Retroviruses 
and Opportunistic Infections, 2011 Feb 27.Boston, MA 2011., 2011. 
48. 
Bosma, P.J., et al., Bilirubin UDP-glucuronosyltransferase 1 is the only relevant 
bilirubin glucuronidating isoform in man. J Biol.Chem., 1994. 269(27): p. 17960-17964. 
49. 
Kawade, N. and S. Onishi, 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(1): p. 257-260. 
50. 
Iwamoto, M., et al., Atazanavir modestly increases plasma levels of raltegravir in healthy 
subjects. Clin.Infect.Dis., 2008. 47(1): p. 137-140. 
51. 
Bosma, P.J., et al., The genetic basis of the reduced expression of bilirubin UDP-
glucuronosyltransferase 1 in Gilbert's syndrome. N.Engl.J Med., 1995. 333(18): p. 1171-
1175. 
52. 
Black, M. and B.H. Billing, Hepatic bilirubin udp-glucuronyl transferase activity in liver 
disease and gilbert's syndrome. N.Engl.J Med., 1969. 280(23): p. 1266-1271. 


 
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53. 
Wenning, L.A., et al., Pharmacokinetics of raltegravir in individuals with UGT1A1 
polymorphisms. Clin.Pharmacol.Ther., 2009. 85(6): p. 623-627. 
54. 
Kearns, G.L., et al., Developmental pharmacology--drug disposition, action, and therapy 
in infants and children. N Engl J Med, 2003. 349(12): p. 1157-67. 
55. 
Weiss, C.F., A.J. Glazko, and J.K. Weston, Chloramphenicol in the newborn infant. A 
physiologic explanation of its toxicity when given in excessive doses. N.Engl.J Med., 
1960. 262: p. 787-794. 
56. 
Boucher, F.D., et al., Phase I evaluation of zidovudine administered to infants exposed at 
birth to the human immunodeficiency virus. J Pediatr, 1993. 122(1): p. 137-144. 
57. 
Capparelli, E.V., et al., Pharmacokinetics and tolerance of zidovudine in preterm infants. 
J.Pediatr., 2003. 142(1): p. 47-52. 
58. 
Mirochnick, M., E. Capparelli, and J. Connor, Pharmacokinetics of zidovudine in infants: 
a population analysis across studies. Clin.Pharmacol.Ther., 1999. 66(1): p. 16-24. 
59. 
Ahlfors, C.E., Bilirubin-albumin binding and free bilirubin. J Perinatol., 2001. 21 Suppl 
1: p. S40-S42. 
60. 
Sinclair, C.J., 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(1 Pt 2): p. 225-227. 
61. 
Ahlfors, C.E., Criteria for exchange transfusion in jaundiced newborns. Pediatrics, 1994. 
93(3): p. 488-494. 
62. 
Ahlfors, C.E., Unbound bilirubin associated with kernicterus: a historical approach. J 
Pediatr., 2000. 137(4): p. 540-544. 
63. 
Clarke, D.F., et al., Raltegravir In Vitro Effect on Bilirubin Binding. Pediatr.Infect Dis.J, 
2013. 
64. 
de Azevedo, L.A., et al., UGT1A1, SLCO1B1, and SLCO1B3 polymorphisms versus 
neonatal hyperbilirubinemia: is there an association? Pediatr.Res., 2012. 
65. 
Clarke, D.F., et al., Raltegravir Pharmacokinetics and Safety in Neonates (IMPAACT 
P1097), in 20TH Conference on Retroviruses and Opportunistic Infections (CROI). 2013: 
Atlanta, GA. 
66. 
Clarke D, Acosta E, Rizk ML, et al. Raltegravir pharmacokinetics in neonates following 
maternal dosing. J Acquir Immun Defic Syndr, 2014; 67:310-315. 
67. 
Clarke, D.F., et al., Raltegravir (RAL) Pharmacokinetics (PK) and Safety in HIV-1 
Exposed 
Neonates at High Risk of Infection (IMPAACT P1110), in 7th International HIV Pediatrics 
Workshop. 2015: Vancouver, Canada. 
68. 
Clarke, D.F., et al., Raltegravir (RAL) pharmacokinetics (PK) and safety in HIV-1 
exposed neonates at high risk of infection (IMPAACT P1110). , in Internationl AIDS 
Conference. 2015: Vancouver, Canada. 
69. 
Clarke, D.F., et al., Modeling and simulation to facilitate development of neonatal 
raltegravir ARV dosing regimen: IMPAACT P1110. , in 7th International HIV Pediatrics 
Workshop. 2015: Vancouver, Canada. 
70. 
Lommerse, J., et al., Raltegravir dosing in neonates (IMPAACT P1110) – Use of 
allometry and maturation in PK modeling to develop a daily dosing regimen for 
investigation during the first weeks of life., in Population Appraoch Group in Europe 
(PAGE). 2015: Hersonissos, Crete, Greece. 


 
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71. 
Lommerse, J., et al., An adaptive trial design to define an appropriate regimen for 
neonates from birth to 6 weeks of age. , in American Conference on Pharmacometrics 
(ACoP) 2016: Bellevue, Washington. 
72. 
Lommerse, J., et al., Modeling rising and declining PK profiles of newborns exposed to 
raltegravir in-utero., in American Conference on Pharmacometrics (ACoP) 2016: 
Bellevue, Washington. 
73. 
Clarke, D.F., et al., Raltegravir (RAL) Pharmacokinetics (PK) and Safety in HIV-1 
Exposed Neonates at High Risk of Infection (IMPAACT P1110) - Cohort 2 Preliminary 
Results.  , in 17th International Workshop on Clinical Pharmacology of HIV and 
Hepatitis Therapy. 2016: Washington D.C., USA. 
74. 
Clarke, D.F., et al., Raltegravir (RAL) Pharmacokinetics (PK) and Safety in HIV-1 
Exposed Neonates at High Risk of Infection (IMPAACT P1110) -Cohort 2 Preliminary 
Results.  , in 8th International Workshop on HIV Pediatrics 2016: Durban, South Africa. 
75. 
Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. 
Pediatrics, 2004. 114(1): p. 297-316. 
76. 
Long, M.C., C. Bennetto-Hood, and E.P. Acosta, A sensitive HPLC-MS-MS method for 
the determination of raltegravir in human plasma. J Chromatogr.B 
Analyt.Technol.Biomed.Life Sci., 2008. 867(2): p. 165-171. 
 
 
 
 


 
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APPENDIX I 
MATERNAL SCHEDULE OF EVALUATIONS 
 
 
Screening1  
Entry (V1.0 within 
48 hours of 
delivery and  
V 2.0 within 60 
hours of delivery) 1 
Labor and 
delivery4 
Informed Consent 
          X               (or)                 X   
 
CLINICAL EVALUATIONS 
 
History2                                                      X               (or)                  X 
 
HIV Test3 
 
    6mL 
 
TOTAL BLOOD 
 
    6mL 
 
 
1. May be done at screening or at entry. 
2. Obtain complete history including documentation of HIV-1 infection, demographic data, maternal antiretroviral dosing history, 
mode of delivery and obstetrical gestational age. 
3. If maternal HIV status is unknown at the time of delivery, HIV testing is required as described in Section 4.11 
4. The mother’s participation in the study ends when she is discharged from the labor and delivery unit. 
 
 
 


 
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APPENDIX II-A 
INFANT SCHEDULE OF EVALUATIONS FOR COHORT 1*  
* Pharmacokinetic sampling collection times may be changed based on initial results from Cohort 1.   
 
Entry (within 
48 hours of 
birth)  
Dose 1 
(within 48 
hours of 
birth) 
Pre-dose 
Dose 1  
1-2 
hours 
post-
dose 
Dose 1 
4-8 hours 
post- dose 
Dose 1 
12 hours 
(±1hours)  
post- dose   
Dose 1 
24 hours 
(±1hours)  
post- dose 
Day 3-4  
of life 
Dose 2  
7- 10 
days  
of life  
pre-dose 
Dose 2 
7-10 days 
of life  
1-2 hours 
post-dose 
Dose 2 
7-10 days 
of life  
24 hours 
(±1hours)  
post-dose 
2 weeks  
of life (± 2 
days) 
 
6 weeks  
of life (±1 
week) 
24 weeks  
of life (±4 
weeks) 
Event  
Driven 
Early  
Discontinuation 
CLINICAL EVALUATIONS 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History1 
X 
 
 
 
 
 
X 
X 
 
 
X 
X 
X 
 
X 
Physical exam 
X2 
 
 
 
 
 
X3 
X3 
 
 
X3 
X3 
X3 
 
X3 
Pre-dose 
Monitoring4  
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Post-dose 
Monitoring4 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
LABORATORY EVALUATIONS12 
Hematology5  
0.5mL 
 
 
 
 
 
 
0.5mL 
 
 
0.5mL 
0.5mL 
0.5mL 
 
 
Chemistries6 
1mL 
 
 
 
 
 
1mL7 
1mL 
 
 
1mL 
1mL 
1mL 
 
 
VIROLOGY 
HIV nucleic acid 
test (HIV NAT)8  
3mL9 
 
 
 
 
 
 
 
 
 
 
3mL 
3mL 
 
 
Resistance 
testing10 
 
 
 
 
 
 
 
 
 
 
 
 
 
2mL 
 
PHARMACOGENETICS16 
Genotyping11 
250-400 µl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETICS12,13,16   
PK sampling 
 
0.25mL 
0.25mL 
0.25mL 
0.25mL14 
0.25mL14 
0.25mL15 
0.25mL 
0.25mL 
0.25mL14 
 
 
 
 
 
TOTAL 
BLOOD  
1.5-4.9mL 
0.25mL 
0.25mL 
0.25mL 
0.25mL 
0.25mL 
1.25mL 
1.75mL 
0.25mL 
0.25mL 
1.5mL 
4.5mL 
4.5mL 
2mL 
 
 
 


 
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APPENDIX II-A - FOOTNOTES FOR INFANT SCHEDULE OF EVALUATIONS FOR COHORT 1 
 
 
1. History includes all non-protocol laboratory tests, HIV test results, antiretroviral agents (for PMTCT), concomitant medications, and any 
intercurrent illnesses since last visit. 
2. Physical examination includes infant Apgar score, birth weight and length, gestational age, gender, and ethnicity. 
3. Complete physical examination includes temperature, blood pressure, heart rate, respiratory rate, weight, length, and head circumference. 
4. Pre and post-dose monitoring includes a telephone call by study staff to review medication instructions and check any side effects before and after 
PK sampling visits. 
5. Hematology includes CBC with differential and platelet count which may be obtained any time on the first day of life. 
6. Chemistries include AST, ALT, creatinine, and total and direct bilirubin which may be obtained any time on first day of life but must be obtained 
prior to  enrollment of the infant. 
7. Only total and direct bilirubin required.  
8. HIV NAT may be either HIV RNA or HIV DNA. Collect 1-3mL depending on the type of platform performed at the site. 
9. Obtain HIV NAT at entry if NOT done as part of standard of care. 
10. Participants with confirmed vertical transmission should have 2mL of blood drawn for viral resistance testing to raltegravir and other ARVs as soon 
as possible after confirmation of HIV infection and should have safety assessments as described in Appendix II-C.  
11. Genotyping (optional) for UGT1A1 and SLCO1B1 polymorphisms will be done using dried blood spot on filter paper.  May be obtained with any 
blood sample.   
12. Acceptable methods of blood collection for PK samples and laboratory evaluations are by venipuncture, heel stick or indwelling line. 
13.  When possible, an assessment of infant feeding (type and time of last infant feeding prior to RAL dose) should be recorded. 
14. For 12 hour and 24 hour PK samples, window of ±1 hour is necessary for the accurate calculations of the PK parameters of raltegravir.  In the event 
that it is not possible to obtain sample within the ±1 hour window, obtain within ±2 hours. 
15. Random PK sample. 
16. See the Laboratory Processing Chart (LPC) on the P1110 Protocol Specific Webpage on the IMPAACT Website 
(http://www.impaactgroup.org) for collection, processing and shipping instructions. 
 
Priority of blood draw should be as follows:  
1) Chemistries  
2) Hematology  
3) Pharmacokinetics  
 


 
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APPENDIX II-B 
INFANT SCHEDULE OF EVALUATIONS FOR COHORT 2* 
 
Entry (within 48 hours 
of birth v1.0 and within 
60 hours of birth v2.0) 
After 
second 
dose  
Day 6-9 
of life 
Day 15-18 
of life 
Day 28-32 
of life  
5-6 weeks 
of life 
8-10 weeks of 
life (±1 week) 
24 weeks of life 
(±4 weeks) 
Event 
Driven 
Early  
Discontinuation 
CLINICAL EVALUATIONS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
History 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical exam 
X2 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
 
X3 
Pre-dose monitoring4 
 
X 
X 
X 
X 
X 
 
 
 
X 
Post-dose monitoring4 
 
X 
X 
X 
X 
X 
 
 
 
X 
LABORATORY EVALUATIONS13 
Hematology5 
0.5mL 
 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
 
 
Chemistries6 
1mL 
1mL7 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
 
 
VIROLOGY 
HIV nucleic acid test 
(HIV NAT)8 
1mL - 3mL9 
 
 
 
 
1mL - 3mL 
 
1mL - 3mL 
 
 
Resistance testing10 
 
 
 
 
 
 
 
 
2mL 
 
PHARMACOGENETICS15 
Genotyping11 
250-400 uL 
 
 
 
 
 
 
 
 
 
PHARMACOKINETICS 13,14,15 
PK sampling12 
0.8mL 
0.2mL 
0.2mL 
0.8mL 
0.2mL 
0.4mL 
 
 
 
 
TOTAL BLOOD  
2.3-5.7mL 
1.2mL 
1.7mL 
2.3mL 
1.7mL 
2.9-4.9mL 
1.5mL 
2.5-4.5mL 
2mL 
 


 
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APPENDIX II-B - FOOTNOTES FOR INFANT SCHEDULE OF EVALUATIONS  
FOR COHORT 2 
 
1.  History includes all non-protocol laboratory tests, HIV test results, antiretroviral agents (for PMTCT), concomitant medications, and any 
intercurrent illnesses since last visit. 
2.  Physical examination includes infant Apgar score, birth weight and length, gestational age, gender, and ethnicity. 
3.  Complete physical examination includes temperature, blood pressure, heart rate, respiratory rate, weight, length, and head circumference. 
4.  Pre and post-dose monitoring includes a telephone call by study staff to review medication instructions and check any side effects. Clinic staff will 
call the participant’s home prior to PK sampling days to confirm adherence, understanding of dosing, and no intercurrent illnesses that might 
preclude PK sampling. If correct doing for 48 hours prior to PK sampling is not confirmed, PK sampling will be rescheduled. Post PK sampling 
visit days, study staff will review for adverse events and answer any questions for participants’ parents by phone. If adverse events are noted, early 
return visits to clinic may be arranged. 
5.  Hematology includes CBC (complete blood count) with differential and platelet count which may be obtained any time on the first day of life. 
6. Chemistries include AST, ALT, creatinine, and total and direct bilirubin which must be obtained prior to enrollment of the infant.  
7.  Only total and direct bilirubin required. 
8.   HIV NAT may be either HIV RNA or HIV DNA. Collect 1-3mL depending on the type of platform performed at the site. 
9. Obtain HIV NAT at entry if NOT done as part of standard of care. 
10.  Participants with confirmed vertical transmission should have 2mL of blood drawn for viral  resistance testing to raltegravir and other ARVs as 
soon as possible after confirmation of HIV infection and should have safety assessments as described in Appendix II-C. 
11.  Genotyping (optional) for UGT1A1 and SLCO1B1polymorphisms will be done using dried blood spot on filter paper which may be obtained with 
any blood sample. 
12. Collect PK samples at time points as specified in Section 3.0.  
13. Acceptable methods of blood collection for PK samples and laboratory evaluations are by venipuncture, heel stick or indwelling line. 
14. When possible, an assessment of infant feeding (type and time of last infant feeding prior to RAL dose) should be recorded. 
15. See the Laboratory Processing Chart (LPC) on the P1110 Protocol Specific Webpage on the IMPAACT Website (http://www.impaactnetwork.org) 
for collection, processing and shipping instructions. 
Priority of blood draw should be as follows:  
1) Chemistries  
2) Hematology  
3) Pharmacokinetics  


 
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APPENDIX II-C 
SCHEDULE OF EVALUATIONS 
FOR INFANTS WHO BECOME HIV-INFECTED 
 
EVALUATION 
LABORATORY  
Hematology1 
0.5
mL 
Every 3 months up to 24 weeks of life 
Chemistries2 
1mL 
Every 3 months up to 24 weeks of life 
Lymphocyte subsets 
1mL 
Every 3 months up to 24 weeks of life 
VIROLOGY 
HIV viral load 
2mL 
Every 3 months up to 24 weeks of life 
TOTAL BLOOD  
4.5
mL 
 
 
1. Hematology includes CBC with differential and platelet count. 
2. Chemistries include AST, ALT, creatinine and total and direct bilirubin. 


 
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APPENDIX III 
 
RALTEGRAVIR WEIGHT BAND DOSING TABLES FOR ORAL GRANULES FOR 
SUSPENSION 
 
Note:  Dosing Tables A through F will not be used in protocol Version 2.0 and 
therefore have been removed.   
 
Dosing Tables G-I reflect reconstitution for suspension 10 mg/mL. Refer to section 
5.11 for the dosing regimen (i.e. once or twice daily).  
 
Table G. Dose of 1.5 mg/kg using RAL Oral Granules for Suspension 10 mg/mL 
 
Weight Band 
(kg) 
1.5 mg/kg 
Volume (mL) 
 
Dose in (mg) 
Volume to Administer 
2 to <3 
4 mg 
0.4 mL 
3 to <4 
5 mg 
0.5 mL 
4 to <5 
7mg 
0.7 mL 
 
 
Table H. Dose of 3 mg/kg using RAL Oral Granules for Suspension 10 mg/mL 
 
Weight Band 
(kg) 
3 mg/kg 
Volume (mL) 
 
Dose in (mg) 
Volume to Administer 
2 to <3 
8 mg 
0.8 mL 
3 to <4 
10 mg 
1mL 
4 to <5 
15 mg 
1.5 mL 
 
 
Table I. Dose of 6 mg/kg using RAL Oral Granules for Suspension 10 mg/mL 
 
Weight Band 
(kg) 
6 mg/kg 
Volume (mL) 
 
Dose in (mg) 
Volume to Administer 
2 to <3 
20 mg 
2 mL 
3 to <4 
25 mg 
2.5 mL 
4 to <5 
30 mg 
3 mL 
 


 
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Note:  The Tables J-M are included for potential future dose adjustments. Refer to 
section 5.11 on dosing schedule (i.e., once or twice daily). 
 
Table J. Dose of 2 mg/kg using RAL Oral Granules for Suspension 10 mg/mL 
 
Weight Band 
(kg) 
2 mg/kg 
Volume (mL) 
 
Dose in (mg) 
Volume to Administer 
2 to <3 
5 mg 
0.5 mL 
3 to <4 
7 mg 
0.7 mL 
4 to <5 
9 mg 
0.9 mL 
 
Table K. Dose of 4 mg/kg using RAL Oral Granules for Suspension 10 mg/mL 
 
Weight Band 
(kg) 
4 mg/kg 
Volume (mL) 
 
Dose in (mg) 
Volume to Administer 
2 to <3 
10 mg 
1 mL 
3 to <4 
15 mg 
1.5 mL 
4 to <5 
20 mg 
2 mL 
 
Table L. Dose of 5 mg/kg using RAL Oral Granules for Suspension 10 mg/mL 
 
Weight Band 
(kg) 
5 mg/kg 
Volume (mL) 
 
Dose in (mg) 
Volume to Administer 
2 to <3 
15 mg 
1.5 mL 
3 to <4 
20 mg 
2 mL 
4 to <5 
25 mg 
2.5 mL 
 
Table M. Dose of 1 mg/kg using RAL Oral Granules for Suspension 10 mg/mL 
 
Weight Band 
(kg) 
1 mg/kg 
Volume (mL) 
 
Dose in (mg) 
Volume to Administer 
2 to <3 
3 mg 
0.3 mL 
3 to <4 
4 mg 
0.4 mL 
4 to <5 
5 mg 
0.5 mL 


 
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APPENDIX IV 
 
 
DIAGRAM AND CAREGIVER INSTRUCTIONS FOR PREPARING AND 
ADMINISTERING RALTEGRAVIR ORAL GRANULES FOR SUSPENSION  
10 mg/mL 
 
 


 
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Caregiver Instructions for Preparing and Administering RAL oral granules for 
suspension 10 mg/mL 
 
Prepare raltegravir oral granules as follows: 
 
1. Get one foil pouch containing the study medicine. 
 
2. Using the mixing cup, fill approximately two-thirds full with room temperature 
(maximum 30° C), clean water (as defined by local standards). 
 
3. Using the 10 mL large  syringe and the markings on the side of the syringe as a 
guide, withdraw 10 mL of water from cup into syringe.  Discard any remaining water 
from cup. 
 
4. Shake down powder. Open the foil pouch of study medicine and pour the entire 
contents of pouch into mixing cup. 
 
5. Add 10 mL of water from the large  syringe back into the cup.  
 
6. Stir with spatula until the study medicine and water are evenly mixed.  
 
7. Using the dosing syringe withdraw the study medicine from the mixing cup; use 
the size syringe and amount of study medicine that the doctor has prescribed. 
Administer the study medicine into the baby’s mouth.  Use the markings on the side 
of syringe as a guide.  
 
*Note: Once the study medicine is mixed with water, it should be given to the baby as 
soon as possible (ideally within 10 to 15 minutes) and no later than 1 hour after 
mixing with water. If the baby spits up most or all the dose in the first 30 minutes 
after administration, the dose should be repeated.  
 
8. Throw away any remaining study medicine from the mixing cup in one of the 
following ways: 
a.   Pour excess medicine in the household trash bag containing an absorbent material 
such as paper tissue, coffee grounds, compost items, or dirt.  Then, the trash bag 
may be thrown away in the communal trash area.  
b.   If wastewater runs to a wastewater collection system, rinse the cup with water into 
the wastewater drain.  
 
Cleaning Supplies: After each use do the following: Hand wash syringe, mixing cup, 
and spatula in warm water with a mild soap. Rinse with water and air dry. 
 
 


 
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APPENDIX V-A 
DIVISION OF AIDS 
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS  
CLINICAL TRIALS NETWORK (IMPAACT) 
 
Sample Informed Consent Form for Cohort 1 [CLOSED] 
 
IMPAACT P1110 
A Phase I Trial to Evaluate the Safety and Pharmacokinetics of 
Raltegravir in HIV-1-Exposed Neonates at Risk of Acquiring HIV-1 
Infection 
VERSION 2.0, DATED 18 January 2017 
 
INTRODUCTION                                
 
You and your baby are being asked to take part in this research study because you are 
or may be infected with the Human Immunodeficiency Virus (HIV), the virus that 
causes AIDS and your baby is or may be at increased risk of getting the infection. 
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 be/allow your baby to be 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, an anti-HIV medicine, when 
given with other anti-HIV medicines, can help prevent infants from getting HIV.  
Raltegravir is a drug that has been used to treat infants and children with HIV.  
Raltegravir is not yet approved by the Food and Drug Administration (FDA) in 
children less than two year of age and its use in this study is experimental. We are 
trying to find out the best dose (amount) of Raltegravir to use to prevent babies from 
getting HIV infection.  Another purpose of this study is to look for possible bad 
effects of Raltegravir in babies such as more jaundice (yellow color to skin).  Another 
purpose of this study is to look at your baby’s DNA (genes) and to see how it breaks 
down the raltegravir.  Some people break down medicines differently based on their 
DNA and this can change the levels of the medicines in their bodies.  Information 
from this study will help us to find the right dose (amount) of Raltegravir to give to 
infants to prevent them from getting HIV infection. 
 
 
WHAT DO I/DOES MY BABY HAVE TO DO AS PART OF THIS STUDY? 


 
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Your participation in this study is minimal.  Only your medical record will be 
reviewed unless you need to have blood drawn to check for HIV.  Your baby will be 
given two doses of Raltegravir in water by mouth within 48 hours of birth and 
another when he/she is 7 to 10 days old.  The study staff will call you several times 
during the study to see how your baby is doing and to check for any bad effects. After 
your baby takes the Raltegravir, blood samples will be taken at different times to 
measure the amount of medicine in your baby’s body at these different times. These 
blood samples will be sent to the U.S. University of Alabama for testing. Your baby 
will also be taking other anti-HIV medicine(s) that are prescribed by your baby’s 
doctor that will start shortly after your baby is born.  The study will supply the 
Raltegravir for your baby as long as your baby is in this study, but not any of the 
other anti-HIV medicines.   
 
Screening visit to see if you can be in this study 
 
 If you agree to be in this study, we need to make sure you are eligible to enroll in 
this study.  We will collect information like your age and race. We will look at 
your medical record and ask you questions about your pregnancy, the birth of 
your baby and what medications you are taking.  This review of your medical 
record may be done while you are pregnant or within 48 hours after you deliver 
your baby. If your HIV status is unknown at the time you deliver your baby, 
blood will be drawn to test you for HIV.  The amount of blood needed for the 
HIV test is 6mL (slightly more than 1 teaspoon).  You will be in this study until 
you are discharged from the labor and delivery unit, but no other tests will be 
done. 
 
Study visits for your baby 
 
 If you agree to allow your baby to be in this study, we will do some tests to make 
sure your baby should be in this study. Some of the study visits will occur while 
your baby is still in the hospital.  Within 48 hours of birth, we will ask how your 
baby has been doing, if he/she has been sick, and any medicines he/she has been 
taking.  We will check your baby’s blood pressure, vital signs, length, weight, 
gender and race. Routine blood tests will be done to tell us about your baby’s 
blood cells and how well your baby’s liver and kidneys are working.  We will 
draw blood to test your baby for HIV if this has not already been done as part of 
your baby’s routine care.  The total amount of blood drawn at this visit will be 
between 1.5-4.9mL (less than ½ to 1 teaspoon) depending on the tests taken.    
 
 If your baby is found to have HIV, every three months until your baby is 24 
weeks old, your baby will have 3.5mL (a little more than ½ teaspoon) of blood 
drawn for routine tests, and to check how well your baby’s immune system is 
working and the amount of HIV in your baby’s blood.   Blood will also be drawn 
once during the study to see if the medicines your baby is taking are working 
against your baby’s type of HIV.  The total amount of blood for this test will be 
2mL (½ teaspoon). 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 


 
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About 50 HIV-infected women and their babies 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 are discharged from labor and delivery unit. 
Your baby will be in this study until he/she is 6 months old (24 weeks). 
 
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 participants. 
 You are/your baby is not able to attend the study visits as required by the study. 
 The investigator determines that further participation would be harmful to your/your 
baby’s health or well-being. 
 Your baby requires treatment with medications that are disallowed while on this 
study. 
 
IF MY BABY HAS TO PERMANENTLY STOP TAKING STUDY-PROVIDED 
MEDICINE, OR ONCE MY BABY LEAVES THE STUDY, HOW WOULD THE 
STUDY MEDICINE BE PROVIDED? 
 
During the study: 
If your baby has to stop taking his/her study medicine before the study ends, you will 
be asked to allow your baby to continue in the study and have regular study visits 
until your baby is 24 weeks of age, to make sure your baby is continuing to do well.  
If you decide you do not want your baby to continue to have the regular study visits, 
you will be asked to allow your baby to have a final visit. At this final visit,  
a review of your baby’s medical records and a physical examination will be done, but 
no blood will be drawn. 
 
After the study: 
Once your baby finishes the study, if your baby’s doctor decides your baby should 
continue taking the study medicine, it will be provided to your baby.  The study staff 
will talk to you about how to continue to get the study medicine for your baby. 
 


 
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WHAT ARE THE RISKS OF THE STUDY? 
 
General Disclaimer 
The drugs used in this study may have side effects, some of which are listed below. 
Please note that these lists do not include all the side effects seen with these drugs. 
These lists include the more serious or common side effects with a known or possible 
relationship.  If you have questions concerning additional study drug side effects 
please ask the medical staff at your site.  If your baby becomes infected with HIV, 
there is a risk that your baby may develop resistance to the study drug.  This means 
that the virus may grow and multiply even if your baby is taking the study drug. 
 
Use of Combination Antiretroviral Drugs 
Immune Reconstitution Syndrome: In some people with advanced HIV infection, 
symptoms from other infections or certain diseases may occur soon after starting 
combination anti-HIV treatment but can also occur later. Some of these symptoms 
may be life threatening. If your baby starts having new symptoms, or you notice that 
existing symptoms are getting worse after starting antiretroviral therapy, tell your 
healthcare provider right away. 
 
The use of potent antiretroviral drug combinations may be associated with an 
abnormal placement of body fat and wasting. Some of the body changes include: 
 Increase in fat around the waist and stomach area 
 Increase in fat on the back of the neck 
 Thinning of the face, legs, and arms 
 Breast enlargement 
 
Integrase Inhibitor  
 
Raltegravir, (RAL, Isentress™) 
Merck & Co., Inc. 
 
The following side effects have been associated with the use of raltegravir. There may 
be unforeseen risks as this is the first time Raltegravir will be given to babies. 
 Rash which can become severe or life-threatening.  Contact your Healthcare Provider 
right away if your baby develops a rash.  
 Nausea  
 Headache  
 Tiredness  
 Weakness  
 Trouble sleeping  
 Stomach pain  
 Dizziness  
 Depression  
 Suicidal thoughts and actions, change in behavior 
 Feeling anxious, paranoia 
 Decreased blood clotting cell (Low platelet count) 
 Diarrhea 


 
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18 January 2017 
 
 Liver failure  
 Clumsiness and lack of coordination 
 Muscle tenderness, weakness or injury which can be serious and lead to kidney 
damage 
Because raltegravir has been studied mostly in adults, we do not know as much about 
how it will affect babies. Newborn jaundice (yellow skin and eyes) has not been seen 
so far but it may be possible and is being carefully looked for in this study 
 
Blood drawing risks 
 
Blood drawing may cause some discomfort, bleeding or bruising where the needle 
enters the body.  A small blood clot may form at the site 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. The heel stick 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? 
 
You may benefit from this study by knowing the HIV status of your baby through 
study-provided HIV testing. Your baby may receive benefit from taking the 
Raltegravir along with other anti-HIV medicines but no guarantee can be made.  Your 
baby may receive no benefit from being in this study.  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/allow your baby to be in this study.  You may 
withdraw/take your baby out of this study at any time.  Please talk to your doctor 
about other choices available to you/your baby.   
 
WHAT HAPPENS IF MY BABY IS INJURED? 
 
If your baby is injured as a result of being in this study, 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/your baby, even by a court 
subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 


 
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other proceedings.  The researchers will use the Certificate to resist any demands for 
information that would identify you/your baby, 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/your baby’s 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, 
the IMPAACT network representatives, drug companies supporting the study, and 
their designees. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a 
member of your family from voluntarily releasing information about you/your baby 
or your/your baby’s 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 companies supporting this study and their designees. 
 
WHAT ARE THE COSTS TO ME? 
 
There is no cost to you for your study visits or your baby’s study visits, examinations, 
blood tests, or the study medication, Raltegravir. However, the study will not pay for 
the cost to deliver your baby. 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: Modify or delete language regarding insurance as 
appropriate for your site and insert appropriate language for added local costs if 
relevant]. 
 
WHAT ARE MY/MY BABY’S RIGHTS AS A RESEARCH SUBJECT? 
 
Taking part in this study is completely voluntary.  You may choose not to be/allow 
your baby to be in this study or withdraw yourself or your baby from the study at any 
time.  Your decision will not have any impact on your/your baby’s participation in 


 
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18 January 2017 
 
other studies conducted by the National Institutes of Health and will not result in any 
penalty or loss of benefits to which you are/your baby is 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   
                              
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 be/allow your baby to be in this study, please 
sign your name below. 
___________________________                ____________________________________ 
Participant’s Legal Guardian (print) 
 
Legal Guardian’s Signature and Date 
 
 
(As appropriate) 
 
____________________________  
____________________________________ 
Father (print) 
 
 
 
 
Father’s Signature and Date   
As appropriate) 
 
 
 
                   (As appropriate) 
________________________                        ____________________________________ 
Study Staff Conducting Study 
 
Study Staff Signature and Date 
 
 


 
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APPENDIX V-B 
 
DIVISION OF AIDS 
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS  
CLINICAL TRIALS NETWORK (IMPAACT) 
 
Sample Informed Consent Form for Cohort 2 
 
IMPAACT P1110 
A Phase I Trial to Evaluate the Safety and Pharmacokinetics of 
Raltegravir in HIV-1-Exposed Neonates at Risk of Acquiring HIV-1 
Infection 
 
VERSION 2.0, DATED 18 January 2017 
 
 
INTRODUCTION 
 
You and your baby are being asked to take part in this research study because you are 
or may be infected with the Human Immunodeficiency Virus (HIV), the virus that 
causes AIDS and your baby is or may be at risk of getting the infection.  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 be/allow your baby to be 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, an anti-HIV medicine, when 
given with other anti-HIV medicines, can help prevent infants from getting HIV.  
Raltegravir is a drug that has been used to treat infants and children with HIV.  
Raltegravir is not yet approved by the Food and Drug Administration (FDA) in 
children less than 4 weeks of age and its use in this study is experimental. We are 
trying to find out the best dose (amount) of Raltegravir to use to prevent babies from 
getting HIV infection.  Another purpose of this study is to look for possible bad 
effects of Raltegravir in babies such as more jaundice (yellow color to skin).  Another 
purpose of this study is to look at your baby’s DNA (genes) and to see how it breaks 
down the raltegravir.  Some people break down medicines differently based on their 
DNA and this can change the levels of the medicines in their bodies.  Information 
from this study will help us to find the right dose (amount) of Raltegravir to give to 
infants to prevent them from getting HIV infection. 
 


 
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WHAT DO I/DOES MY BABY HAVE TO DO AS PART OF THIS STUDY? 
 
Your participation in this study is minimal.  Only your medical record will be 
reviewed unless you need to have blood drawn to check for HIV. Your baby will be 
started on Raltegravir in water by mouth beginning within 12 to 60 hours of birth and 
your baby will continue to take this medicine every day for 6 weeks. The study staff 
will give you instructions on how to give the medicine to your baby. The study staff 
will call you before your baby takes his/her dose of raltegravir to make sure you 
understand how to give the medicine and several times during the study to check for 
any bad effects. After your baby takes the Raltegravir, blood samples will be taken at 
different times to measure the amount of medicine in your baby’s body at these 
different times. These blood samples will be sent to the U.S. University of Alabama 
for testing.  Your baby will also be taking other anti-HIV medicine(s) that are 
prescribed by your baby’s doctor that will start shortly after your baby is born.  The 
study will supply the Raltegravir for your baby but not any of the other anti-HIV 
medicines.   
 
Screening visit to see if you can be in this study 
 
 If you agree to be in this study, we need to make sure you are eligible to enroll in 
this study.  We will collect information like your age and race. We will look at 
your medical record and ask you questions about your pregnancy, the birth of 
your baby and what medications you are taking.  This review of your medical 
record may be done while you are pregnant or within 60 hours after you deliver 
your baby. If your HIV status is unknown at the time you deliver your baby, 
blood will be drawn to test you for HIV.  The amount of blood needed for the 
HIV test is 6mL (slightly more than 1 teaspoon).  You will be in this study until 
you are discharged from the labor and delivery unit, but no other tests will be 
done. 
 
Study visits for your baby 
 
 During the first 6 weeks of your baby’s life, 6 study visits will be scheduled for 
observed raltegravir dosing and blood will be drawn to measure the amount of 
raltegravir in your baby’s body.   
 At the first study visit we will also draw blood to test your baby for HIV if this 
has not already been done as part of your baby’s routine care.  If your baby is 
found to have HIV, every three months until your baby is 24 weeks old, your 
baby will have blood drawn for routine tests, and to check how well your baby’s 
immune system is working and the amount of HIV in your baby’s blood. Blood 
will also be drawn once during the study to see if the medicines your baby is 
taking are working against your baby’s type of HIV.   
 The first study visits and blood draws may be done while you and your baby are 
still in the hospital, and later study visits will require a return to the clinic.   
 It is important that you can tell study staff the exact time of the last dose given to 
your baby at home before returning to the clinic.  For some visits, study staff will 


 
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18 January 2017 
 
ask that the dose not be given at home so that Raltegravir can be given to your 
baby during the study visit in the clinic.   
 At each study visit, we will ask how your baby has been doing, if he/she has been 
sick, and any medicines he/she has been taking, and a physical examination of 
your baby will be done.  At each study visit, routine blood tests will be done to 
tell us about your baby’s blood cells, and/ or how well your baby’s liver and 
kidneys are working.   
 The blood draws will be obtained from your baby’s vein or heel.  The total 
amount of blood drawn from your baby at any single visit will range from 1.2–5.7 
mL (less than 1/3 of a teaspoon to less than 1 ¼ teaspoons).   
 The study staff will review the visit schedule with you. 
 Your baby will have one drop of blood taken once during the study to check your 
baby’s DNA (genes) to see how it breaks down the Raltegravir. Some people 
break down medicines differently based on their DNA and this can change the 
levels of the medicines in their bodies. 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 ________ 
 
Study Visit 
Entry 
(within 60 
hours of 
birth) 
After 
second 
dose of 
RAL 
Day 6-
9 of life 
Day 15-18 of 
life 
Day 28-
32 of life  
5-6 weeks of 
life 
8-10 
weeks of 
life 
24 
weeks 
of life 
Physical 
exam 
X 
X 
X 
X 
X 
X 
X 
X 
Routine blood 
test 
X 
X 
X 
X 
X 
X 
X 
X 
HIV test 
X 
 
 
 
 
X 
 
X 
DNA test 
X 
 
 
 
 
 
 
 
RAL blood 
test 
X 
X 
X 
X 
X 
X 
 
 
 
 Your baby will stop taking Raltegravir when he/she is 6 weeks old, and your 
baby’s participation in this study will end when he/she is 6 months old (24 
weeks). 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 50 HIV- infected women and their babies will be enrolled in this study. 
 


 
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HOW LONG WILL I/MY BABY BE IN THIS STUDY? 
 
You will only be in this study until you are discharged from the labor and delivery 
unit. Your baby will be in this study until he/she is 6 months old (24 weeks). 
 
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 are/your baby is not able to attend the study visits as required by the study. 
 The investigator determines that further participation would be harmful to your/your 
baby’s health or well-being. 
 Your baby requires treatment with medications that are disallowed while on this 
study. 
 
IF MY BABY HAS TO PERMANENTLY STOP TAKING STUDY-PROVIDED 
MEDICINE, OR ONCE MY BABY LEAVES THE STUDY, HOW WOULD THE 
STUDY MEDICINE BE PROVIDED? 
 
During the study: 
If your baby has to stop taking his/her study medicine before the study ends, you will 
be asked to allow your baby to continue in the study and have regular study visits 
until your baby is 24 weeks of age, to make sure your baby is continuing to do well.  
If you decide you do not want your baby to continue to have the regular study visits, 
you will be asked to allow your baby to have a final visit. At this final visit, a review 
of your baby’s medical records and a physical examination will be done, but no blood 
will be drawn. 
 
After the study: 
Once your baby finishes the study, if your baby’s doctor decides your baby should 
continue taking the study medicine, it will be provided to your baby.  The study staff 
will talk to you about how to continue to get the study medicine for your baby. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
General Disclaimer 
The drugs used in this study may have side effects, some of which are listed below. 
Please note that these lists do not include all the side effects seen with these drugs. 


 
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18 January 2017 
 
These lists include the more serious or common side effects with a known or possible 
relationship.  If you have questions concerning additional study drug side effects 
please ask the medical staff at your site.  There is a risk that your baby may develop 
resistance to the study drug.  This means that the virus may grow and multiply even if 
your baby is taking the study drug. 
 
Use of Combination Antiretroviral Drugs 
Immune Reconstitution Syndrome: In some people with advanced HIV infection, 
symptoms from other infections or certain diseases may occur soon after starting 
combination anti-HIV treatment but can also occur later. Some of these symptoms 
may be life threatening. If your baby starts having new symptoms, or you notice that 
existing symptoms are getting worse after starting antiretroviral therapy, tell your 
healthcare provider right away. 
 
The use of potent antiretroviral drug combinations may be associated with an 
abnormal placement of body fat and wasting. Some of the body changes include: 
 Increase in fat around the waist and stomach area 
 Increase in fat on the back of the neck 
 Thinning of the face, legs, and arms 
 Breast enlargement 
 
Integrase Inhibitor  
 
Raltegravir, (RAL, Isentress™) 
Merck & Co., Inc. 
 
The following side effects have been associated with the use of raltegravir. There may 
be unforeseen risks as this is the first time Raltegravir will be given to babies. 
 
 Rash which can become severe or life-threatening.  Contact your 
Healthcare Provider right away if your baby develops a rash.  
 Nausea  
 Headache  
 Tiredness  
 Weakness  
 Trouble sleeping  
 Stomach pain  
 Dizziness  
 Depression  
 Suicidal thoughts and actions, changes in behavior  
 Feeling anxious, paranoia 
 Decreased blood clotting cell (Low platelet count) 
 Diarrhea 
 Liver failure  
 Clumsiness and lack of coordination 
 Muscle tenderness, weakness or injury which can be serious and lead 
to kidney damage 


 
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18 January 2017 
 
Because raltegravir has been studied mostly in adults, we do not know as much about 
how it will affect babies. Newborn jaundice (yellow skin and eyes) has not been seen 
so far but it may be possible and is being carefully looked for in this study. 
 
Blood drawing risks 
 
Blood drawing may cause some discomfort, bleeding or bruising where the needle 
enters the body.  A small blood clot may form at the site 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. The heel stick 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? 
 
You may benefit from this study by knowing the HIV status of your baby through 
study-provided HIV testing. Your baby might receive benefit from taking Raltegravir 
along with other anti-HIV medicine but no guarantee can be made. Your baby may 
receive no benefit from being in this study. 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/allow your baby to be in this study.  You may 
withdraw/take your baby out of this study at any time.  Please talk to your doctor 
about other choices available to you/your baby.   
 
WHAT HAPPENS IF MY BABY IS INJURED? 
 
If your baby is injured as a result of being in this study, 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/your baby, 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/your baby, 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 


 
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18 January 2017 
 
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/your baby’s 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 companies supporting the study, and their designees. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a 
member of your family from voluntarily releasing information about you/your baby 
or your/your baby’s 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, 
IMPAACT network representatives, and drug companies supporting this study and 
their designees. 
 
WHAT ARE THE COSTS TO ME? 
 
There is no cost to you for your study visits or your baby’s study visits, examinations, 
blood tests, or the study medication, Raltegravir.  However, the study will not pay for 
the cost to deliver your baby. 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: Modify or delete language regarding insurance as 
appropriate for your site and insert appropriate language for added local costs if 
relevant]. 
 
WHAT ARE MY/MY BABY’S RIGHTS AS A RESEARCH SUBJECT? 
 
Taking part in this study is completely voluntary.  You may choose not to be/allow 
your baby to be in this study or withdraw yourself or your baby from the study at any 
time.  Your decision will not have any impact on your/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 are/your baby is otherwise entitled. 
 


 
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18 January 2017 
 
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   
 
 
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 be/allow your baby to be in this study, please 
sign your name below. 
 
__________________________               ____________________________________ 
Participant’s Legal Guardian (print)  
Legal Guardian’s Signature and Date  
 
(As appropriate) 
 
____________________________  
____________________________________ 
Father (print) 
 
 
 
 
Father’s Signature and Date   
As appropriate) 
 
 
 
 
(As appropriate) 
 
________________________                        ____________________________________ 
Study Staff Conducting Study 
            Study Staff Signature and Date 
 
 
 
 
 

SAP_001.pdf: 
 
 
Filename: Q:\CTgov\documents\P1110_SAP_v3.0.docx 
Directory mapping: Q maps to home/impact/P1110 
Printed on: April 23, 2020 
 
 
 
 
 
 
 
 
IMPAACT P1110 
A PHASE I TRIAL TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF 
RALTEGRAVIR IN HIV-1-EXPOSED NEONATES AT HIGH RISK OF ACQUIRING 
HIV-1 INFECTION 
 
 
DAIDS Study ID # 11891 
IND # 77,787 Held by NIAID 
ClinicalTrials.gov ID: NCT01780831 
 
 
 
 
STATISTICAL ANALYSIS PLAN  
Version 3.0 
 
 
 
 
 
 
 
This is IMPAACT P1110 SAP Version 3.0 with names of authors, names of publication writing 
team members and analysis timeline redacted 
 
Due to the fact that there was no hyperbilirubinemia in the study population, the objectives 
related to hyperbilirubinemia included in section 4.9 of the SAP was not pursued. 
 
 
 
 
 
 
January 3, 2017 


 
 
P1110 SAP Version 3.0                                                                                                             2  
 
 
 
DOCUMENT ADMINISTRATION 
 
General Information  
Protocol Document Definition  
 
IMPAACT P1110 Statistical Analysis Plan 
Version 3.0, January 3, 2017 
Related Documents 
IMPAACT P1110 (DAIDS Document ID 11891) A Phase I Trial to 
Evaluate the Safety and Pharmacokinetics of Raltegravir in HIV-1-
Exposed Neonates at High Risk of Acquiring HIV-1 Infection, 
International Trial of the International Maternal Pediatric Adolescent 
AIDS Clinical Trials (IMPAACT) Group,  
Final Version 1.0, Date: 10 December 2012 
 
Letter of Amendment #1 dated 22 April 2014 for: P1110 Version 1.0 
 
Letter of Amendment #2 dated 30 June 2015 for: P1110 Version 1.0 
 
Letter of Amendment #3 dated 18 May 2016 for: P1110 Version 1.0 
 
Clarification Memo #1 dated 1 April 2014 for: P1110 Version 1.0 
 
Clarification Memo #2 dated 16 September 2014 for: P1110 Version 
1.0 
 
Clarification Memo #3 dated 15 January 2015 for: P1110 Version 1.0 
 
Clarification Memo #4 dated 8 May 2015 for: P1110 Version 1.0 
 
IMPAACT P1110 Monitoring Plan dated 14 April 2014 for: P1110 
Version 1.0 
Document Owner  
SDAC/HSPH 
Version History  
Date  
Version  
Note of updates 
12 February 2015 
V1.0 
Analysis for Cohort 1 (with no RAL-exposed infants)                               
01 July 2015 
V2.0 
Additional summary statistics added to account for subgroups of infants 
within Cohorts 1 and 2 and in utero RAL exposure. 
 
 


 
 
P1110 SAP Version 3.0                                                                                                             3  
 
January 3, 2017 
V3.0 
• 
Specified that two final analysis reports will be generated: 
o 
For protocol Version 1.0:  A report focusing on Cohort 1 
(both RAL naïve and exposed groups) and Cohort 2 RAL 
naïve group 
o 
In the event that protocol Version 2.0 is approved:  A 
report focusing on Cohort 2 (both RAL naïve and 
exposed groups) 
• 
Added the definition of wide analysis visit windows 
• 
Added summary tables: 
o 
Study treatment status 
o 
Age at 1st RAL dose for Cohort 2 infants 
o 
Summary of worst grade baseline events 
• 
Added a section on Cohort 2 adherence to RAL 
• 
Modified the summary tables for summarizing infant infection 
status 
• 
Clarified that Adverse Events (AEs) and Suspected Adverse Drug 
Reactions (SADRs) exclude events assessed by the team as 
“baseline” or “ongoing baseline” 
• 
Clarified the definition of primary and secondary safety endpoints   
• 
Added infant listings which will be used internally at SDAC in 
writing the SDAC final analysis report and will be provided to the 
manuscript writing team 
• 
Removed analysis for CL/F among SLCO1B3 genotypes. 
• 
Added the definition of wild-type vs. mutation for UGT1A1 and 
SLCO1B3 genotypes 
• 
Added mock-up tables for CL/F analysis between different 
genotypes of UGT1A1 
• 
Added mock-up tables for Hyperbilirubinemia analysis among 
different genotypes of UGT1A1 and SLCO1B3 
• 
Updated team roster 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
P1110 SAP Version 3.0                                                                                                             4  
 
Table of Contents 
1 
Purpose of the Analysis Plan ............................................................................................5 
2 
Protocol Overview ............................................................................................................5 
3 
Protocol Team Roster .......................................................................................................7 
4 
Outline of Planned Analysis .............................................................................................8 
4.1 
Screening and Entry ..............................................................................................8 
4.1.1 
Accrual ......................................................................................................9 
4.1.2 
Eligibility Violations and Analysis Exclusions ........................................9 
4.2 
Baseline Characteristics ....................................................................................................9 
4.3 
Participant and Study Status ...........................................................................................11 
4.4 
Data Completeness for Safety Data ................................................................................12 
4.5 
RAL Adherence for Cohort 2 Infants .............................................................................13 
4.6 
Safety Analysis for SDAC Final Reports .......................................................................14 
4.7 
Safety Analysis for Dose Finding and Possible Early Study Discontinuation ...............15 
4.8 
Infant Infection Testing...................................................................................................17 
4.9 
Genotype Analysis ..........................................................................................................17 
 
 
 
 
Table of Tables 
 
Table 1: Eligibility Violation and Analysis Exclusion Example .................................................... 9 
Table 2: Cohort 1 Infant Baseline Characteristics (mock-up table) ............................................. 10 
Table 3: Number of Cohort 1 Infants Accrued and Evaluable for PK/Safety Analysis (mock-up 
table) ............................................................................................................................................. 11 
Table 4: Infant Safety Data Collection Schedule for Cohort 1 ..................................................... 12 
Table 5: Infant Safety Data Collection Schedule for Cohort 2 ..................................................... 13 
Table 6:  Proportion of Infants Meeting the Primary Safety Endpoint (mock-up table) .............. 15 
Table 7: Summary of Infants Meeting the Safety Endpoints for Dose Finding and Possible Early 
Study Discontinuation ................................................................................................................... 16 
Table 8:  Summary of Infant RAL CL/F between UGT1A1 Genotype Groups for Cohort 1 ...... 18 
Table 9:  Summary of Infant RAL CL/F between UGT1A1 Genotype Groups for Cohort 2 ...... 19 
Table 10: Summary of Cohort 1 Infant Hyperbilirubinemia between UGT1A1 Genotype Groups 
(mock-up table) ............................................................................................................................. 20 
Table 11: Summary of Cohort 1 Infant Hyperbilirubinemia among SLCO1B3 Genotype Groups 
(mock-up table) ............................................................................................................................. 20 


 
 
P1110 SAP Version 3.0                                                                                                             5  
 
1 
Purpose of the Analysis Plan 
This Analysis Plan outlines the components of the primary data analysis for IMPAACT P1110.  
The focus is on analyses of administrative, baseline and safety data, analyses needed to address 
the study’s primary and secondary objectives, and the analyses to assess whether safety 
guidelines have been met at interim and final accrual to Cohorts 1 and 2.  This document focuses 
on analyses necessary for scientific purposes; any additional analyses needed for the regulatory 
purposes of the pharmaceutical sponsor will be specified in a separate document.  The 
procedures and reports involved with protocol team monitoring of safety data during regular 
team calls are not fully described in this document (see the Study Monitoring Plan for details 
concerning monitoring). The pharmacology data will be analyzed separately by the protocol 
pharmacologist. The purpose of this analysis plan is: 
• to ensure that the protocol team is aware of all the major issues that will be in the 
proposed analyses, and agrees on the contents of these analyses; and 
• to specify how we intend to investigate the study questions listed in the protocol 
objectives and the way that data are to be analyzed and presented. 
 
This analysis plan, therefore, includes the key analyses which might lead to modification or 
termination of the study and which also form the core of any presentation or publication used to 
disseminate the primary conclusions of the study. It is, however, recognized that this analysis 
plan may be modified by the core study team as new information becomes available outside of 
the study, or to reflect recommendations made by the Study Monitoring Committee (SMC).   
 
2 
Protocol Overview 
This is a Phase I multi-center, open label, non-comparative study to evaluate the safety and 
pharmacokinetics (PK) of raltegravir (RAL) administered to HIV-1-exposed full-term (≥37 
weeks of gestation) neonates at high risk of acquiring HIV-1 infection.  The goal is to determine 
the appropriate dosing regimen of RAL oral granules for suspension that can be safely 
administered to neonates and infants in the first 6 weeks of life.  
 
This study will enroll approximately 50 neonates in order to accrue a minimum of 32 PK 
evaluable high risk HIV-1-exposed neonates and their mothers across Cohort 1 and Cohort 2. 
Mother-infant (M-I) pairs will enroll at the time of delivery up to 48 hours of life, which is the 
latest  time for administration of first neonatal RAL dose. Cohort 1 opened first and accrual to 
Cohort 2 was contingent upon neonates enrolled in Cohort 1 successfully meeting safety criteria 
and providing adequate PK data so that the dosing regimen was developed for daily dosing 
through 6 weeks of age for Cohort 2. Through Protocol Version 1.0 LoA #2 Cohort 2 RAL-naïve 
group was opened to accrual with the following dosage: 1.5 mg/kg once daily during Days 1-7 of 
life, 3.0 mg/kg twice daily during Days 8-28 of life, and 6.0 mg/kg twice daily during Days 29-
42 of life. 
 
At the time of this SAP update, Cohort 1 (both RAL-naïve and RAL-exposed groups) is closed 
to accrual and follow-up and Cohort 2 RAL-naïve group is closed to accrual but follow-up is 
ongoing.   The final accrual numbers are 10 M-I pairs for Cohort 1 RAL-naïve, 6 M-I pairs for 
Cohort 1 RAL-exposed, and 26 M-I pairs for Cohort 2 RAL-naïve groups under protocol 
Version 1.0. The team estimated that the study will take 3 years to fully accrue under protocol 


 
 
P1110 SAP Version 3.0                                                                                                             6  
 
Version 1.0. Protocol Version 2.0 is currently being drafted and if approved, will open accrual to 
Cohort 2 RAL exposed group. 
 
PK evaluable infants are those whose PK results provide data on the primary PK parameters of 
interest. If a participant has unevaluable PK data, which reflects uncertainty about appropriate 
exposure to the study medication, the participant will be excluded from PK analyses and will be 
replaced. PK analyses will be done by the protocol pharmacologist.   
 
Safety data will include death, signs/symptoms, diagnoses and laboratory test results, which will 
include results of evaluations specified in the protocol and results from the infant’s clinical care.  
Infants will be evaluable for safety analysis if they received at least one dose of RAL. The safety 
analyses for the final SDAC reports will be based on data on all safety evaluable infants, 
regardless of whether they are evaluable for PK analysis. 
 
Under protocol Version 1.0, the following describes the safety monitoring for dose finding 
purposes:  
• the team will monitor RAL safety during the regular team monitoring as specified in 
Protocol Section 8.52; and 
• the assessment of the safety guidelines will be performed at full accrual to Cohort 1 
(Protocol Section  8.521), at interim analysis when 8 participants have been accrued to 
Cohort 2 RAL-naïve group (Protocol Section 8.522) and at full accrual to Cohort 2 RAL-
naïve group (Protocol Section 8.523). 
For dose finding purposes, infants who have been excluded from the PK analyses due to 
evidence of problematic exposure to the study medication, will also be excluded from evaluation 
of the safety guidelines. 
 
Infants will be followed for 24 weeks after birth. Women will be followed until discharge from 
the labor and delivery unit. 
 
 
PRIMARY OBJECTIVES: 
 
1. To evaluate the safety and tolerability through 6 weeks of life of RAL oral granules for 
suspension when administered during the first 6 weeks of life with standard PMTCT ARV 
prophylaxis to HIV-1 exposed infants assessed at high risk of HIV infection. 
 
2. To evaluate the PK of RAL oral granules for suspension during the first 6 weeks of life along 
with standard PMTCT ARV prophylaxis. 
 
3. To determine an appropriate dose of RAL oral granules for suspension for use in neonates 
and infants during the first 6 weeks of life.  
 
 
SECONDARY OBJECTIVES: 
1.  To assess safety and tolerability of RAL oral granules for suspension through 24 weeks of life 
when administered during the first 6 weeks of life with standard PMTCT ARV prophylaxis to 
HIV-1 exposed infants assessed at high risk of HIV infection. 


 
 
P1110 SAP Version 3.0                                                                                                             7  
 
 
2. To investigate the relationship between neonatal RAL elimination and UGT1A1 genotype, and 
to determine whether there is an association of UGT1A1 (*28/*28) and SLCO1B3 (rs2117032-
C/T) with hyperbilirubinemia. 
3 
Protocol Team Roster 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
P1110 SAP Version 3.0                                                                                                             8  
 
4 
Outline of Planned Analysis  
This section contains the details of the analyses for: 
• interim and full cohort accrual safety reports: at full accrual to Cohort 1, at interim 
analysis when 8 participants have been accrued to Cohort 2 (safety analysis only) and at 
full accrual to Cohort 2 RAL-naïve group; and 
• SDAC final reports: the first report will focus on Cohort 1 (both RAL naïve and exposed 
groups) and Cohort 2 RAL naïve group.  Should protocol Version 2.0 be approved and 
Cohort 2 RAL-exposed group be opened to accrual, a second report will be generated at 
study closure to follow-up for Cohort 2 (both RAL naïve and exposed groups). 
 
When applicable, separate summary tables will be generated for the women and their infants.  
Separate summary tables will be generated for each cohort since Cohort 1 neonates will receive 
two single RAL dosing while Cohort 2 neonates will receive daily RAL dosing through 6 weeks 
of life.  Summary statistics for subgroups of infants will be provided alongside the overall cohort 
summary statistics.  Infant subgroups will be defined in terms of infant in utero RAL exposure 
and RAL dosing. For Cohort 1, there are 3 infant subgroups: (i) RAL-naïve (3mg/kg-3mg/kg), 
(ii) RAL-naïve (2mg/kg-3mg/kg), and (iii) RAL-exposed (1.5mg/kg-3mg/kg). Cohort 2 RAL-
naïve group only has one dosing which was specified in Section 2. 
 
The interim and full cohort accrual safety reports will be prepared for the core team and, if 
necessary, for the SMC.  These reports will include information concerning Screening and Entry, 
Participant and Study Status, Baseline, and Safety summary tables.  Unless otherwise noted the 
SDAC final reports will contain all summary tables. 
 
Additional participant listings necessary in writing up the SDAC final report will be generated 
and will be used internally at SDAC.  Highlights of these listings will be included in the SDAC 
final report.  These participant listings will be provided to the manuscript writing team.  The 
manuscript writing team, which is a subset of the protocol team, will be identified by the 
protocol team. 
 
The analysis of the PK data will be performed by the protocol pharmacologists and thus, not 
included in this document. 
 
Validation requirements as per SDAC SOPs will be as follows: 
a. All dataset creation programs will be validated with double coding for the primary and 
secondary safety endpoints. 
b. All study-specific formats will be validated. 
c. Validation of analysis programs is specified in the following subsections. 
4.1 
Screening and Entry 
Purpose:  
To give a summary of the accrual progress of the study during interim analyses and final 
analysis. 
 
Analysis Program Validation: 
Not required. 
 


 
 
P1110 SAP Version 3.0                                                                                                             9  
 
Data: 
Date and institution of enrollment and eligibility status will be from the STATUS table; 
comments related to eligibility deviations will be from COMENT table. Safety analysis 
exclusions will be from STUDMONR table and ADM0021 (first dose date); PK analysis 
exclusion will be from STUDMONR table; comments related to PK exclusion will be from 
STUMONR and COMENT tables. Reasons for screening failures and non-enrollment will be 
from the SCR0029 CRF. 
 
Analysis: 
4.1.1 
Accrual 
a) Mother-infant pair accrual: 
i. 
Accrual by month and by site 
ii. 
Total accrual  
 
b) Infants 
i. 
Birth by month 
ii. 
Total infants accrued (Overall and by infant subgroup) 
 
c) Screening failures and non-enrollment 
Table: Total number of M-I pairs who did not enroll 
Table: Reasons mother did not enroll 
Table: Reasons infant did not enroll 
4.1.2 
Eligibility Violations and Analysis Exclusions 
 
Table: Listing of M-I pairs eligibility criteria violations and analysis exclusions which 
will include (i) enrolling site; (ii) reason for eligibility violation or analysis 
exclusions; and (iii) team decision on whether to include the M-I pair in the 
safety/PK analyses; (iiii) infant subgroup information 
  
Table 1: Eligibility Violation and Analysis Exclusion Example 
 
Count 
Enrolling 
site 
Participant 
In Utero RAL 
Exposure 
RAL 
dosing 
Reason 
Eligibility 
Violation 
Safety 
Analysis 
Status 
PK Analysis 
Status 
1 
XXX 
MOTHER 
N/A 
N/A 
XXX 
Yes 
N/A 
N/A 
 
 
CHILD 1 
Yes 
XXX 
XXX 
Yes 
Include 
Include 
2 
YYY 
MOTHER 
N/A 
N/A 
YYY 
No 
N/A 
N/A 
 
 
CHILD 1 
No 
XXX 
YYY 
No 
Include 
Exclude 
 
4.2 
Baseline Characteristics 
Purpose:  
To describe maternal and infant baseline characteristics (demographic, health status and other 
key parameters). 
 
Analysis Program Validation: 


 
 
P1110 SAP Version 3.0                                                                                                             10  
 
Not required, but code review is recommended. 
 
Data: 
The following are the CRFs/tables for this section: 
• Infant and maternal demographic data:  
 
 
STATUS table 
• Timing of enrollment:  
 
 
 
 
STATUS table, EVW0252 
• Mode of delivery:                                                                   EVW0252 
• Infant birth outcome:                                                              EVW0252 
• Gestational age at birth:                                                          EVW0252, PE5896 
• Infant birth weight and length:                                               PE5896   
• APGAR score at 1 minute:                                                     PE5896 
 
Analysis: 
a) For mothers: 
• Age (years): N, N missing, median, 25th and 75th percentiles, min, max, mean, 
standard deviation 
• Race/ethnicity (used in the eligibility screening): N (%) by category  
• Timing of enrollment (before or after delivery) 
b) For infants: 
• Gender: N (%) by category 
• Race/ethnicity: N (%) by category 
• Birth outcome: N (%) by category 
• Mode of delivery: N (%) by category 
• Gestational age at birth: N, N missing, median, 25th and 75th percentiles, min, 
max, mean, standard deviation  
• Birth weight (gram): N, N missing, median, 25th and 75th percentiles, min, max, 
mean, standard deviation 
• Birth length (cm): N, N missing, median, 25th and 75th percentiles, min, max, 
mean, standard deviation  
• APGAR score at 1 minute: N, N missing, median, 25th and 75th percentiles, min, 
max, (if data have a reasonably normal distribution, mean and standard deviation 
will also be presented). 
• Age (hours) at 1st RAL dose for Cohort 2 infants: N, N missing, median, 25th and 
75th percentiles, min, max, mean, standard deviation 
c) Baseline Summaries: 
• When appropriate, three sets of baseline characteristics summary tables will be 
generated for: (i) overall enrollments, (ii) safety evaluable participants and (iii) 
PK evaluable participants. Infant summary tables will include summary statistics 
for each subgroups and overall. 
 
Table 2: Cohort 1 Infant Baseline Characteristics (mock-up table) 
Characteristics 
RAL-naïve  
RAL-exposed 
Cohort 
Overall 
3mg/kg-3mg/kg 
2mg/kg- 3mg/kg 
Overall 
1.5mg/kg-3mg/kg 
Gender 
F 
N (%) 
N (%) 
 N (%) 
N (%) 
N (%) 
M 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 


 
 
P1110 SAP Version 3.0                                                                                                             11  
 
Note: Additional variables will be added. Similar table will be generated for Cohort 2 with       
appropriate column labels appropriate for Cohort 2 subgroups of infants. 
4.3 
Participant and Study Status  
Purpose:  
To describe maternal and infant study status, including whether they are on study, and whether 
they are evaluable for analysis for both Cohort 1 and Cohort 2 infants, to summarize RAL 
adherence, and to summarize tolerability for Cohort 2 infants. 
 
Analysis Program Validation: 
Not required. 
 
Data: 
Mother and infant study status will be from PSTAT in CASE table. Reasons for off-study for 
mothers and infants will be from OFFST in F1601 CRF. Accrued and safety/PK evaluable 
infants information will be from STATUS, STUDMONR, COMENT tables and ADM0021 CRF. 
Duration of RAL while on study is from derived ARV dataset ARV2. Off-RAL reason will be 
from STATUS table (RSOFFRX from PE4005). 
 
Analysis: 
a) Study Status of the Mothers and the Infants.  
Table:  Reasons for off-study for mothers  
Table:  Reasons for off-study for infants  
 
b) Treatment Status of the Infants. 
Table: Reasons for off-treatment for infants 
 
c) Timing of 1st RAL Dosing for the Infants in Cohort 2 
Table: Summary statistics for age (hours) for 1st RAL dosing for Cohort 2 infants 
 
d) Number of Infants Accrued and Evaluable for PK/Safety Analysis. 
 
Table 3: Number of Cohort 1 Infants Accrued and Evaluable for PK/Safety Analysis 
(mock-up table) 
 
RAL-naive 
RAL-exposed  
Cohort  Overall 
 3mg/kg-3mg/kg 
 2mg/kg-3mg/kg 
Overall 
 1.5mg/kg-
3mg/kg 
Infants accrued  
N 
N 
N 
N 
N 
Infants evaluable for safety analysisa  
N 
N 
N(column %) 
N(column%) 
N(column %) 
Infants evaluable for PK analysisb  
N 
N 
N(column %) 
N(column%) 
N(column %) 
a   Based on if the patient received at least one dose of RAL 
b   Based on team determination 
Note: Similar table will be generated for Cohort 2 with appropriate column labels 
appropriate for Cohort 2 subgroups of infants. 
 
e) Reasons for analysis exclusions. 


 
 
P1110 SAP Version 3.0                                                                                                             12  
 
Table:  Reasons for PK Analysis Exclusions  
 
4.4 
Data Completeness for Safety Data 
Purpose:  
To summarize data completeness according to the scheduled visits for infant safety data. 
 
Analysis Program Validation: 
Not required. 
 
Data:  
Infant observed visit data are from the following CRFs: LBW0093 (CHEMDT, CHEMOBT, 
HEMDT, HEMAOBT) for hematologies and liver chemistries, PE6831 (VISITDT) for 
signs/symptoms and PE6852 (VISITDT) for diagnoses. 
 
Analysis: 
a) Infant Safety Data Collection Schedule and Visit Windows for Cohort 1 and 2. 
Wide analysis visit windows which include all study visits will be used to summarize 
data completeness.  Upper limits for study visits weeks 6 and 24 will be used to define 
the safety endpoints for the primary and secondary safety objectives, respectively. 
Table 4: Infant Safety Data Collection Schedule for Cohort 1 
Evaluation 
Scheduled visits 
 
Visits with 
windows specified 
in SoE 
Entry (within 
48 hrs of birth) 
Day 3-4 of life 
Dose 2 Day 7-
10 of  life 2 
2 weeks of life 
(±2 days) 
6 weeks of life 
(± 1 week) 
24 weeks of life 
(± 4 weeks) 
After 24 weeks3 
Wide analysis 
window 
Days 1 
and 2 of 
life
Days 3-6 
of life 
Days 7-
11of life 
Days 12-
22 of life 
Days 23-
49 of life 
50-196 
days of 
life 
≥197 
days of 
life3 
Hematologies and liver 
chemistries (LBW0093) 
 
X  
X1 
X 
X 
X 
X 
 
Signs and Symptoms 
(PE6831) 
 
X 
X 
X 
X 
X 
X 
 
Diagnoses (PE6852) 
 
X 
X 
X 
X 
X 
X 
 
1 Only total and direct bilirubin required. 
2 Pre-dose. 
3 For safety evaluations done beyond the study specified follow-up for the neonates 
 
 
 
 
 
 


 
 
P1110 SAP Version 3.0                                                                                                             13  
 
Table 5: Infant Safety Data Collection Schedule for Cohort 2 
Evaluation 
Scheduled visits 
 
Visits with windows 
specified in SoE 
Entry (within 48 
hrs of birth) 
After second 
dose (2-4 days of 
life) 
Day 6-9 of life 
Day 15-18 of   
life  
Day 28-32 of life  
5-6 weeks of life  
8-10 weeks of 
life (± 1 weeks) 
24 weeks of 
life(± 4 weeks) 
After 24 weeks2 
Wide analysis window 
Days 1 and 
2 of life 
Days 3-5 of 
life 
Days 6-11 
of life 
Days 12-23 
of life 
Days 24-
33of life 
Days 34-49 
of life 
Days 50-84 
of life 
≥85 days of 
life 
≥197 days 
of life2 
Hematologies and liver 
chemistries (LBW0093) 
 
X 
X1 
X 
X 
X 
X 
X 
X 
 
Signs and Symptoms 
(PE6831) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Diagnoses (PE6852) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 Only total and direct bilirubin required. 
2 For safety evaluations done beyond the study specified follow-up for the neonates 
 
b) Data Completeness Summaries of Infant Safety Data 
Table: Frequency of infant expected and observed clinic visits with completed forms of 
IMPAACT P1097/P1110 Hematologies and Liver Chemistries (LBW0093), 
Signs/Symptoms (PE6831), and Diagnoses (PE6852).  
 
4.5 
RAL Adherence for Cohort 2 Infants 
Purpose:  
To summarize how compliant Cohort 2 infants were with study treatment.  Adherence for Cohort 
1 infants will be checked, but no summary table will be generated. 
Analysis Program Validation: 
Code review required. 
 
Data: 
Calculation of expected number of days on RAL will use data from the STATUS table 
(BIRTHDT, OFFSTDT and DOSE1DT). Calculation of actual number of days on RAL will use 
the data from TXW0276. Off-RAL reason will be from TXW0276 (RAL1RS AND RAL2RS). 
 
Analysis: 
Cohort 2 RAL adherence will be calculated using the following equation: 
 
 
% 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑅𝑅𝑅𝑅𝑅𝑅= 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑛𝑛𝑛𝑛𝑛𝑛b𝑒𝑒𝑒𝑒 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑅𝑅𝑅𝑅𝑅𝑅
𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑅𝑅𝑅𝑅𝑅𝑅 𝑥𝑥 100% 
 
Note: “expected number of days on RAL” will consider the off-study date. 
 


 
 
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Table: Summary statistics of % of days on RAL. 
       Table: Summary of reasons of permanent discontinuation and temporary holds of RAL.  
 
4.6 
Safety Analysis for SDAC Final Reports 
Purpose: 
To list the endpoints and tables of primary and secondary safety analyses for the SDAC final 
reports.  
 
Analysis Program Validation: 
Code review required.  Primary analysis for primary safety endpoints will require double coding. 
 
Data: 
Infant safety data are adverse clinical and laboratory events reported on the following CRFs: 
Hematology and Liver Chemistries (LBW0093), Signs/Symptoms (PE6831), Diagnosis 
(PE6852) and Death (PE1414). (The following variables in the SDAC SAS datasets will be used:  
EVENTDSC, EVNGRDE, FORMNM and FORMTYP in EVENTS table; and TBILCV, 
BILPHOTO, BILTRANS, BILOTH and BILOTHSP in LBW0093).  
 
Analysis: 
There will be two final SDAC reports. The first report will focus on Cohort 1(both RAL-naïve 
and exposed groups) and Cohort 2 RAL-naïve group. The second report will include Cohort 2 
(both RAL-naïve and exposed groups). The safety analyses will include all infants who have had 
at least one dose of RAL.  For Cohort 2, if there was dose adjustment after the interim analysis, a 
sensitivity analysis will be performed on infants who were enrolled after dose adjustment and 
only took the adjusted dose. Adverse Events (AEs) and Suspected Adverse Drug Reactions 
(SADRs) will exclude events classified by the team as “baseline” or “ongoing baseline” events. 
 
• Safety endpoints for Cohorts 1 and 2 in SDAC final reports 
• Primary safety endpoint for the final analysis:  
o Adverse events of Grade 3 or 4 severity in the EVENTS table or death 
reported in the Death CRF with onset date at or after study entry through 6 
weeks (i.e. through 49 days of age) of life 
• Secondary safety endpoints for the final analysis:  
o Adverse events of Grade 3 or 4 severity in the EVENTS table or death  
reported in the Death CRF with onset date at or after study entry through 24 
weeks of life (through 196 days of age) 
o Suspected adverse drug reaction (SADR*) of Grade 3 or 4 severity or death 
with onset date at or after study entry through 6 weeks (through 49 days of 
age) of life 
o Suspected adverse drug reaction (SADR*) of Grade 3 or 4 severity or death 
with onset date at or after study entry through 24 weeks of life (i.e. through 
196 days of age) 
 
* For the SDAC final report, SADRs will include the following attribution to drug:  11 – 
“Definitely related”; 12 – “Probably related”; and 13 – “Possibly related”.  
 
• Summary tables for Cohorts 1 and 2 in the SDAC final reports (Analysis for primary and 


 
 
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secondary safety endpoints for final analysis)  
Note: Summary tables will include statistics for infant subgroups and overall and listing 
will include information on infant in utero RAL exposure and RAL dosing. 
 
Table:  Summary tables showing number (%) and the 2-sided 90% confidence interval 
(CI) using the Clopper-Pearson exact method estimates of the proportion of 
infants meeting the primary and secondary safety endpoints(will provide as 
footnote number of infants with missing data).  The primary analysis will be on 
the primary safety endpoint. 
 
Table 6:  Proportion of Infants Meeting the Primary Safety Endpoint (mock-up table) 
RAL-naïve  
RAL-exposed 
Overall 
3mg/kg-3mg/kg 
2mg/kg- 3mg/kg 
Overall 
1.5mg/kg-3mg/kg 
N (%) [90% CI] 
N (%) [90% CI] 
 N (%) [90% CI] 
N (%) [90% CI] 
N (%) [90% CI] 
 
Note: Similar table will be generated for Cohort 2 with appropriate column labels 
appropriate for Cohort 2 subgroups of infants. 
 
Table:  Summary tables of worst adverse events (laboratory, signs/symptoms and 
diagnoses) for each of the primary and secondary safety endpoint. 
 
Table:  Summary of worst grade baseline events (laboratory, signs/symptoms and 
diagnoses). 
 
Table:  Listing of reasons for infant death and age (weeks) at death. 
 
Table:  Summary table showing number (%) and the 2-sided 90% confidence interval 
(CI) using the Clopper-Pearson exact method estimates of the proportion of 
infants who had total bilirubin exceeding 16.0 mg/dL, or received phototherapy, 
transfusion therapy or other therapies for hyperbilirubinemia.  
 
The following SDAC internal listings will be generated to facilitate the write-up of the SDAC 
final report.  The listings will also be provided to the manuscript writing team.   SDAC public 
IDs will be used and no identifying dates will be provided. 
a. Per infant listings of baseline events, AEs and SADRs with site and team 
assessment of drug attribution. 
b. Per infant listing of ARVs from TXW0276 and PE0421.   
 
4.7 
Safety Analysis for Dose Finding and Possible Early Study Discontinuation  
Purpose: 
To list the endpoints and summary tables of safety analysis for dose finding and possible early 
study discontinuation. Reports will be generated at full accrual to cohort 1 and at interim and full 
accrual to cohort 2.  
 


 
 
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Analysis Program Validation: 
Code review required. Primary analysis will require double coding. 
 
Data: 
Infant Safety Data are adverse clinical and laboratory events reported in Hematology and Liver 
Chemistries ((LBW0093), Signs/Symptoms (PE6831), Diagnosis (PE6852) and Death (PE1414) 
CRFs. (The following variables in the SDAC SAS datasets will be used:  EVENTDSC, 
EVNGRDE, FORMNM and FORMTYP in EVENTS table; TRACKCD and RELATSP  in 
TRAC table; and RAL1ST, RAL1RS, RAL2ST, RAL2RS in TXW0276 CRF).  
 
Analysis: 
Infants who have been excluded from the PK analyses, due to evidence of problematic exposure 
to the study medication, will be excluded from evaluation of the safety guidelines.  AEs and 
SADRs will exclude events classified by the team as “baseline” or “ongoing baseline” events. 
 
a) Safety endpoints for Cohorts 1 and 2 in dose finding and possible early study 
discontinuation 
• Safety endpoints  
-based on data through 6 weeks (i.e. through 49 days) of life:  
i. 
Life threatening event or death judged to be a SADR or Grade 4 event that 
is judged to be probably or definitely attributable to the study medication 
ii. 
Treatment discontinuation due to non-life threatening Grade 3 or 4 
severity SADR, judged to be at least possibly treatment related 
Notes:  During the regular monitoring, the team will assess whether an AE is life 
threatening and the assessment will be entered in the TRAC table.  Treatment 
discontinuation due to an AE will be on the TXW0276 CRF. 
 
b) Summary table for the interim and cohort full accrual safety reports (analysis for dose 
finding and possible early study discontinuation).  
Note: Only the overall summary will be provided since we are expecting very few infants 
meeting the safety endpoint.  
 
Table:  Summary table showing number (%) of the proportion of infants who meet the 
safety endpoints for dose finding and possible early study discontinuation. 
 
Table 7: Summary of Infants Meeting the Safety Endpoints for Dose Finding and Possible 
Early Study Discontinuation 
Endpoint 
Number and Proportion 
Life threatening adverse event or death judged to be a SADR or 
Grade 4 event that is judged to be probably or definitely attributable 
to the study medication 
 
Treatment discontinuation due to non-life threatening Grade 3 or 4 
severity SADR, judged to be at least possibly treatment related 
 
Meeting any of the two safety guideline endpoints 
 
 
 


 
 
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4.8 
 Infant Infection Testing 
Purpose:  
To describe the infant HIV infection status. 
 
Analysis Program Validation: 
Not required. 
 
Data:  
INFECT2 table holds the infection status of the participants while on study follow-up.  Site 
assessment of infant infection status will be in INFECT2.  HIV DNA test results will be in 
DNALDMS, and HIV RNA results will be in L_RNAFIN and F3109. 
 
Analysis: 
Table: Tabulation of infection status of the infants from the INFECT2 table. 
 
4.9 
Genotype Analysis 
Purpose: 
To list the tables for investigating the relationship between neonatal RAL elimination (as 
reflected in CL/F) and UGT1A-1 genotype, and the relationship between UGT1A-1and 
SLCO1B3 with hyperbilirubinemia. 
 
Analysis Program Validation: 
Code review required.   
 
Data: 
HUMGENO table and LBW0093 CRF (TBILCV, BILPHOTO, BILTRANS, BILOTH and 
BILOTHSP). 
Analysis: 
a) Response variables for genotype analysis: 
o UGT1A-1 genotype (presence or absence of *28/*28 genetic variant): 
    Wild-type: (TA)6(TA)6; mutation: (TA)5(TA)6,  (TA)6(TA)7 and (TA)7(TA)7 
o SLCO1B3 (rs2117032-C/T) genotype: 
     C/C, C/T and T/T 
o Hyperbilirubinemia defined as total bilirubin exceeding 16.0 mg/dL or infant 
requiring exchange transfusion for hyperbilirubinemia 
 
 
 
 
 
 
 
 
 
 


 
 
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b) Output tables: 
Table:  Summary descriptive statistics (N, geometric mean, median, 25th and 75th percentiles, min, and max) on CL/F will be 
generated for the subgroups of participants depending on whether they exhibit the UGT1A-1 polymorphism.  
 
Table 8:  Summary of Infant RAL CL/F between UGT1A1 Genotype Groups for Cohort 1 
 (mock-up table) 
 
 
 
UGT1A1 Genotypes 
 
Wild-type 
Mutation 
Overall 
p-valuea for 
all 
genotypes 
p-valueb for 
wild-type vs. 
mutation  
(TA)6(TA)6 
(TA)5(TA)6 
(TA)6(TA)7 
(TA)7(TA)7 
Overall 
CL/F of RAL-naïve Infants 
N 
 
 
 
 
 
 
 
mean 
 
 
 
 
 
 
 
median 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
CL/F of RAL-Exposed Infants 
N 
 
 
 
 
 
 
 
mean 
 
 
 
 
 
 
 
median 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
CL/F of All Infants 
N 
 
 
 
 
 
 
 
mean 
 
 
 
 
 
 
 
median 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
a Comparison of median among different genotypes will use Kruskal–Wallis test for CL/F of all infants only. The formal comparison will be 
done only if we have enough infants in the listed genotype groups. 
b Comparison of median between wild-type vs. mutation will use Wilcoxon Rank Sum Test for CL/F of all infants only. The formal 
comparison will be done only if we have enough infants in the listed genotype groups. 
 
 
 


 
 
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Table 9:  Summary of Infant RAL CL/F between UGT1A1 Genotype Groups for Cohort 2 
 (mock-up table) 
 
 
 
UGT1A1 Genotypes 
Wild-type 
Mutation 
Overall 
(TA)6(TA)6 (TA)5(TA)6 (TA)6(TA)7 (TA)7(TA)7 Overall 
CL/F from the 1st intensive PK 
analysis 
N 
 
 
 
 
 
 
mean 
 
 
 
 
 
 
median 
 
 
 
 
 
 
… 
 
 
 
 
 
 
CL/F from the 2nd intensive 
PK analysis 
N 
 
 
 
 
 
 
mean 
 
 
 
 
 
 
median 
 
 
 
 
 
 
… 
 
 
 
 
 
 
Note: This table is for Cohort 2 RAL-naïve group only and should we have data on Cohort 2 RAL-exposed group, additional columns 
for: (i) RAL-exposed group, and (ii) Overall Cohort 2, will be added. Formal comparisons for all Cohort 2 infants will be done 
by then. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Table:  Association between UGT1A-1 genotypes and hyperbilirubinemia (yes/no) with Fisher’s Exact Test.  
 
Table 10: Summary of Cohort 1 Infant Hyperbilirubinemia between UGT1A1 Genotype Groups (mock-up table) 
 Characteristic 
 
Wild-type 
Mutation 
Overall 
(N=0) 
P-value* for 
all genotype 
groups 
P-value* for 
Wild-type vs. 
Mutation 
 
 
(TA)6(TA)6 
(TA)5(TA)6 
(TA)6(TA)7 
(TA)7(TA)7 
Overall 
Hyperbilirubinemia Yes 
0 
0 
0 
0 
0 
0 
0.000 
0.000 
 
No 
0 
0 
0 
0 
0 
0 
*Fisher’s Exact Test. The power of test will depend upon the distributions of the variables to be analyzed, but will be extremely limited due to the 
small sample size. 
 Note: Similar table will be created for Cohort 2 infants. 
 
 
 
Table:  Association between SLCO1B3 genotypes and hyperbilirubinemia (yes/no) with Fisher’s Exact Test.  
 
Table 11: Summary of Cohort 1 Infant Hyperbilirubinemia among SLCO1B3 Genotype Groups (mock-up table) 
 Characteristic 
 
C/C 
(N=0) 
C/T 
(N=0) 
T/T 
(N=0) 
Total 
(N=0) 
P-Value* 
Hyperbilirubinemia Yes 
0 
0 
0 
0 
0.000 
 
No 
0 
0 
0 
0 
 
*Fisher’s Exact Test. The power of test will depend upon the distributions of the variables to be analyzed, but 
will be extremely limited due to the small sample size. 
Note:  Similar table will be created for Cohort 2 infants.