Clinical trial NCT01818258
Conditions: HIV Positive Malnourished
Keywords: HIV Children HAART Malnourished
Sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Start date: 2015-10-26; Completion date: 2017-09-29
Enrollment: 52 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Children living with HIV from sub-Saharan Africa often present with severe malnutrition. In severe malnutrition, metabolic and/or gut structural derangement may lead to inadequate antiretroviral (ARV) absorption and/or erratic drug levels. The greater surface area to weight ratio in severely malnourished children could also place them at higher risk of under dosing compared to children with mild to moderate malnutrition. However, limited data are available on the pharmacokinetics of ARVs in severely malnourished children. This study addressed this critical gap in knowledge by evaluating the PK of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in severely malnourished children living with HIV, compared to children with normal nutrition to mild malnutrition living with HIV.

Detailed description:
P1092 was a prospective, non-randomized Phase IV open label study of antiretroviral drugs zidovudine (ZDV), lamivudine (3TC), and ritonavir boosted lopinavir (LPV/r) in children living with HIV aged 6 to less than 36 months grouped by nutritional status. The study's primary objectives were to characterize the pharmacokinetics (PK), safety, and tolerability of antiretroviral (ARV) regimens in severely acute malnourished (SAM) children following the initiation of nutritional rehabilitation and compare results to mildly malnourished or normally nourished children in order to determine if current recommended doses are optimal in severely malnourished children.

Two cohorts of children were enrolled based on nutritional status at screening: severely acute malnourished children and children with mild malnutrition or normal nutrition (non-SAM cohort). SAM participants were recruited from nutritional rehabilitation clinics while non-SAM participants were enrolled from HIV treatment centers. SAM participants were required to complete a 10 to 18 day nutritional rehabilitation program before entering the study. A World Health Organization (WHO, 2013) approach to management of SAM was used. All participants were to receive an antiretroviral regimen of ZDV+3TC+LPV/r. ARVs were dosed based on WHO weight band dosing and were to be administered twice per day in a pediatric liquid formulation. ZDV was allowed to be replaced with abacavir at the discretion of the site investigator/clinician in cases of grade 3 or higher hematologic toxicity on a ZDV-inclusive regimen or ZDV intolerance. Participants were followed for 48 weeks.

Arms: arm 1: ZDV+3TC+LPV/r Zidovudine (ZDV, Retrovir®) 10 mg/ml oral syrup administered twice daily at WHO weight band dose for 48 weeks; Lamivudine (Epivir®, 3TC) 10 mg/ml for oral solution administered twice daily at WHO weight band dose for 48 weeks; Lopinavir/ritonavir (Kaletra®, LPV/r) 80/20 mg/ml oral solution administered twice daily at the WHO weight band dose for 48 weeks arm 2: ZDV+3TC+LPV/r Zidovudine (ZDV, Retrovir®) 10 mg/ml oral syrup administered twice daily at WHO weight band dose for 48 weeks; Lamivudine (Epivir®, 3TC) 10 mg/ml for oral solution administered twice daily at WHO weight band dose for 48 weeks; Lopinavir/ritonavir (Kaletra®, LPV/r) 80/20 mg/ml oral solution administered twice daily at the WHO weight band dose for 48 weeks
Interventions: intervention 1: ZDV+3TC+LPV/r
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_ICF_000.pdf: 
 
 
 
P1092 
Phase IV Evaluation  
of the Steady State Pharmacokinetics of  
Zidovudine, Lamivudine, and Lopinavir/Ritonavir  
in Severely Malnourished HIV-1-Infected Children 
 
 
DAIDS ES #11689 
 
 
 
This file contains the current IMPAACT P1092 protocol, 
which is comprised of the following documents, 
presented in reverse chronological order: 
 
• Clarification Memorandum #4, dated 3 August 2017 
• Clarification Memorandum #3, dated 25 August 2016 
• Letter of Amendment #1, dated 12 April 2016 
• Clarification Memorandum #2, dated 10 November 2015 
• Clarification Memorandum #1, dated 24 April 2015 
• Protocol Version 2.0, dated 11 February 2015 
 
 


Clarification Memorandum #4 
 
Page 1 of 1 
3 August 2017 
IMPAACT P1092 Protocol Version 2.0 
Clarification Memorandum #4 for: 
 
IMPAACT P1092 
Phase IV Evaluation of the Steady State Pharmacokinetics of  
Zidovudine, Lamivudine, and Lopinavir/Ritonavir  
in Severely Malnourished HIV-1-Infected Children  
 
Version 2.0, dated 11 February 2015 
 
DAIDS ES #11689 
 
Clarification Memorandum Date:  3 August 2017 
 
 
Summary of Clarifications 
 
This Clarification Memorandum (CM) clarifies the study evaluations in the protocol Schedule of 
Evaluations that are considered routine tests as referenced in the Sample Informed Consent form. 
 
 
Implementation 
 
This CM has been approved by the NIAID and NICHD Medical Officers.  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 this CM to IRBs/ECs for their information or, if required 
by the IRBs/ECs, for their approval prior to implementation. 
 
The content of this CM clarifies the study evaluations that are considered routine tests referenced in 
protocol Appendix V: Sample Informed Consent Form (ICF) for study participation. This CM does not 
modify the ICF and does not impact the benefit-to-risk ratio for study participants.  
 
This CM should be maintained in each site’s essential documents file for IMPAACT P1092.  It is the 
responsibility of each site Investigator of Record to ensure that all study staff are made aware of this 
CM.  The content of this CM will be incorporated into any future amendment of the IMPAACT P1092 
protocol.  
 
Clarification of study evaluations in the Schedule of Evaluations that are considered routine tests  
 
This CM serves to clarify that the evaluations for hematology, chemistries, total protein/albumin, lipid 
profile, and the micronutrients: zinc and selenium in protocol Appendix I, Schedule of Evaluations, are 
considered routine tests for the study.  


Clarification Memorandum #3  
     Page 1 of 2 
25 August 2016 
IMPAACT P1092 Protocol Version 2.0 
 
Clarification Memorandum #3 for: 
 
IMPAACT P1092 
Phase IV Evaluation of the Steady State Pharmacokinetics of  
Zidovudine, Lamivudine, and Lopinavir/Ritonavir  
in Severely Malnourished HIV-1-Infected Children  
 
Version 2.0, dated 11 February 2015 
 
DAIDS ES #11689 
 
Clarification Memorandum Date:  25 August 2016 
 
 
Summary of Clarifications 
 
This Clarification Memorandum (CM) clarifies expectations for evaluating lymphocyte 
subsets at study Week 36. 
 
 
Implementation 
 
This CM has been approved by the NIAID and NICHD Medical Officers.  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 this CM to IRBs/ECs for their 
information or, if required by the IRBs/ECs, for their approval prior to implementation. 
 
The content of the CM does not impact the sample informed consent forms for the study or 
the benefit-to-risk ratio for study participants.  
 
This CM should be maintained in each site’s essential documents file for IMPAACT P1092.  
It is the responsibility of each site Investigator of Record to ensure that all study staff are 
made aware of this CM.  The content of this CM will be incorporated into any future 
amendment of the IMPAACT P1092 protocol.  
 
 
 


Clarification Memorandum #3  
     Page 2 of 2 
25 August 2016 
IMPAACT P1092 Protocol Version 2.0 
 
Clarification of expectations for evaluating lymphocyte subsets at study Week 36 
 
The IMPAACT P1092 Schedule of Evaluations (SoE), provided in protocol Appendix I, 
specifies that lymphocyte subsets (i.e., CD4 and CD8 cell counts and percentages), be 
evaluated at Screening; at Weeks 12, 24, 36, and 48; and at Off Treatment/On Study visits.  
The SoE also specifies that complete blood counts (CBCs) be evaluated at Screening; at 
Weeks 12, 24, and 48; and at Off Treatment/On Study visits; however, a CBC is not required 
per protocol at Week 36.   
 
This CM serves to clarify that a CBC may be needed at some study sites to meet protocol 
requirements to evaluate CD4 and CD8 cell counts and percentages at Week 36. Specifically, 
at sites that utilize dual-platform lymphocyte testing methods, a CBC must be performed in 
order for both absolute counts and percentages to be obtained.  At these sites, a CBC should 
be performed at Week 36 to permit evaluation of both absolute counts and percentages.  The 
1 mL of blood needed to perform a CBC at Week 36 does not exceed the blood draw 
volumes permitted in the sample informed consent form provided in protocol Appendix V.  
The results of any CBCs performed at Week 36 should be recorded on study case report 
forms.  
 


Letter of Amendment #1  
     Page 1 of 2  
12 April 2016 
IMPAACT P1092 Protocol Version 2.0 
Letter of Amendment #1 for: 
 
IMPAACT P1092 
Phase IV Evaluation of the Steady State Pharmacokinetics of  
Zidovudine, Lamivudine, and Lopinavir/Ritonavir  
in Severely Malnourished HIV-1-Infected Children  
Version 2.0, dated 11 February 2015 
 
DAIDS ES #11689 
 
Letter of Amendment Date:  12 April 2016 
 
 
Information/Instructions to Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) impacts the oversight and 
management of the IMPAACT P1092 study 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 information contained in this LoA does not impact the study informed 
consent forms or participant management at participating study sites.  Nonetheless, IRB/EC 
approval of this LoA is required.  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, this 
LoA should be implemented immediately.  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.   
 
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 
P1092. 
 
If the IMPAACT P1092 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 2  
12 April 2016 
IMPAACT P1092 Protocol Version 2.0 
Summary of Revisions and Rationale 
 
In consultation with the IMPAACT Study Monitoring Committee (SMC), during a routine 
review of the study, the Protocol Team determined that protocol Section 8.51, Rules for 
Suspending Accrual to Assess Safety Following an Adverse Event, should be modified to 
allow for management of expected hematologic toxicities for participants on zidovudine per 
the toxicity management guidelines provided in protocol Section 6.22.  This section of the 
protocol provides detailed guidance for the management of expected hematologic events, 
including substitution of abacavir for zidovudine when indicated.  The modifications 
specified in this LoA will prevent unwarranted suspensions of participant accrual.  
 
 
Implementation 
 
Modifications of protocol Section 8.51, Rules for Suspending Accrual to Assess Safety 
Following an Adverse Event, are shown below, using strikethrough for deletions and bold 
type for additions. 
 
8.51 
Rules for Suspending Accrual to Assess Safety Following an Adverse Event 
 
Accrual will be temporarily suspended* if: 
 
 
Any subject has a life threatening adverse event that is judged to be probably or 
definitely attributable to study drug or Grade 4 event that may not be judged to be 
life-threatening but is judged to be probably or definitely attributable to study 
drug. 
 
Or if more than six out of the first 20 subjects or at least 30% of subjects 
thereafter have Grade 3 or greater toxicity that is judged to be definitely related to 
study drug. 
 
*Grade 3/4 hematologic events that meet the above definitions may not require 
temporary suspension of accrual and this determination can be made by the 
DAIDS/NICHD Medical Officers.  The SMC will be informed of all decisions. 
 
Following temporary suspension of accrual, the protocol 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 protocol team, including the study chair and the DAIDS 
medical officer of record agree that the study drug is likely to be safe for additional 
subjects, they the DAIDS/NICHD Medical Officers may allow accrual to resume, 
and the SMC will be informed.  If the protocol team, including the Medical 
Officers, determines that accrual should remain suspended for an ad hoc SMC 
review, the SMC will be notified.  Regulatory agencies (IRB/EC) will be notified of 
the event and the protocol team’s decision after this review of the safety data has 
taken place. 
 


Clarification Memorandum #2  
     Page 1 of 4 
10 November 2015 
IMPAACT P1092 Protocol Version 2.0 
 
Clarification Memorandum #2 for: 
 
IMPAACT P1092 
Phase IV Evaluation of the Steady State Pharmacokinetics of  
Zidovudine, Lamivudine, and Lopinavir/Ritonavir  
in Severely Malnourished HIV-1-Infected Children  
 
Version 2.0, dated 11 February 2015 
 
DAIDS ES #11689 
 
Clarification Memorandum Date:  10 November 2015 
 
 
Summary of Clarifications 
 
This Clarification Memorandum (CM) clarifies the required timing of Stage 2, Study Entry, 
for Cohort 2, in which children with normal nutrition to mild malnutrition will be enrolled.  
For children who are eligible for this cohort, entry must occur within 14 days after initiating 
the study screening process.  
 
This CM also updates the Protocol Team Roster. 
 
 
Implementation 
 
This CM has been approved by the NIAID and NICHD Medical Officers.  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 this CM to IRBs/ECs for their 
information or, if required by the IRBs/ECs, for their approval prior to implementation. 
 
The content of the CM does not impact the sample informed consent forms for the study or 
the benefit-to-risk ratio for study participants.  
 
This CM should be maintained in each site’s essential documents file for IMPAACT P1092.  
It is the responsibility of each site Investigator of Record to ensure that all study staff are 
made aware of this CM.  The content of this CM will be incorporated into any future 
amendment of the IMPAACT P1092 protocol.  
 
 
 


Clarification Memorandum #2  
     Page 2 of 4 
10 November 2015 
IMPAACT P1092 Protocol Version 2.0 
 
Clarification of the required timing of Stage 2, Study Entry, for Cohort 2, children with 
normal nutrition to mild malnutrition 
 
Protocol Sections 3.2 and 4.4, the Study Flow Chart, and Appendix I provide information 
about the timing of study entry for Cohort 2.  
 
Prior to study entry, children screened for Cohort 2 must be assessed as clinically stable per 
eligibility criterion 4.17 and eligible for antiretroviral therapy per eligibility criterion 4.14. 
They must also meet all other eligibility requirements applicable to Cohort 2.  “Within 7-14” 
days reflects the generally expected timeframe for completing the study screening and 
eligibility process for this cohort.  For children confirmed to meet all applicable eligibility 
criteria, entry into Cohort 2 may occur at any time within 14 days after initiating the 
study screening process.  This was the original intent for the protocol and is further clarified 
in the following protocol sections: 
 
Section 3.2, Stage 2: Entry, Criteria for Stage 2 Entry 
Cohort 2: Normal nutrition–mild malnutrition children  
For children with normal nutrition-mild malnutrition who are found to be eligible, entry into 
the study will occur after written informed consent has been obtained and within 14 days 
after screening. [paragraph continues] 
 
Section 4.4, Enrollment Procedures, seventh paragraph 
Minimum age at enrollment is six months (180 days).  However, screening evaluations may 
be performed within 14 days (for children with normal nutrition to mild malnutrition) or 10-
18 days (for children with severe malnutrition) prior to six months (180 days) of age, as long 
as the entry visit does not occur earlier than six months (180 days) of age. 
 
In the Study Flow Chart, Panel Cohort 2 
SCREENING 
within 14 days  
 
In addition to the above, the labeling of each panel in the chart is corrected; for ease of 
reference, the clarified version of the chart is provided in its entirety on page 3 of this CM. 
 
 
 


Clarification Memorandum #2  
     Page 3 of 4 
10 November 2015 
IMPAACT P1092 Protocol Version 2.0 
 
Study Flow Chart: 
 
 
Cohort 1:  Severe Malnutrition 
 
 
 
 
 
Cohort 2:  Normal Nutrition-Mild Malnutrition 
 
 
 
 
 
 
 
 


Clarification Memorandum #2  
     Page 4 of 4 
10 November 2015 
IMPAACT P1092 Protocol Version 2.0 
 
Update of Protocol Team Roster 
 
Contact information for the NICHD Medical Officer is updated as follows:  
 
NICHD Medical Officer 
John Moye, MD 
Maternal and Pediatric Infectious Disease Branch 
Eunice Kennedy Shriver National Institute of Child Health and Human Development 
6100 Executive Boulevard, Room 3A01 
Bethesda, MD 20892-7510 
Phone: (301) 594-8624 
Email: moyej@exchange.nih.gov 
 
 
 
 


Clarification Memorandum #1  
     Page 1 of 4 
24 April 2015 
IMPAACT P1092 Protocol Version 2.0 
 
Clarification Memorandum #1 for: 
 
IMPAACT P1092 
Phase IV Evaluation of the Steady State Pharmacokinetics of  
Zidovudine, Lamivudine, and Lopinavir/Ritonavir  
in Severely Malnourished HIV-1-Infected Children  
 
Version 2.0, dated 11 February 2015 
 
DAIDS ES #11689 
 
Clarification Memorandum Date:  24 April 2015 
 
 
Summary of Clarifications and Implementation 
 
The purpose of this Clarification Memorandum (CM) is to update the listing of study 
sites and site investigators in the IMPAACT P1092 protocol team roster. The name and 
number of the site in Harare, Zimbabwe, are updated and sites in Blantyre and Lilongwe, 
Malawi, are added.  In addition, other listings in the protocol team roster are updated to 
reflect current team membership and contact details.  
 
This CM has been approved by the NIAID and NICHD Medical Officers.  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 this CM to IRBs/ECs 
for their information or, if required by the IRBs/ECs, for their approval prior to 
implementation. 
 
The content of the CM does not impact the sample informed consent forms for the study 
or the benefit-to-risk ratio for study participants.  
 
This CM should be maintained in each site’s essential documents file for IMPAACT 
P1092.  It is the responsibility of each site Investigator of Record to ensure that all study 
staff are made aware of this CM.  The content of this CM will be incorporated into any 
future amendment of the IMPAACT P1092 protocol.  
 
 
 
 


 
Clarification Memorandum #1  
     Page 2 of 4 
24 April 2015 
IMPAACT P1092 Protocol Version 2.0 
 
Site 30293, Makerere University-Johns 
Hopkins University (MU-JHU) Research 
Collaboration Clinical Research Site    
Linda Barlow, MD, MPH 
MU-JHU Research Collaboration 
PO Box 23491  
Old Mulago Hill Road 
Kampala, Uganda 
Phone:  +256 071 2703994 
Email:  lbarlow@mujhu.org 
 
Irene Lubega, MBChB, MMed 
MU-JHU Research Collaboration  
PO Box 23491  
Old Mulago Hill Road  
Kampala, Uganda 
Phone: +256 712 222290 
Email: ilubega@mujhu.org 
 
Phionah Kibalama, MBChB 
MU-JHU Research Collaboration 
PO Box 23491  
Old Mulago Hill Road 
Kampala, Uganda 
Phone: +256 041 4541044 
Email: pkibalama@mujhu.org 
 
Philippa Musoke, MBChB, PhD 
Principal Investigator, Mulago Hospital  
MU-JHU Research House  
PO Box 23491,  
Old Mulago Hill Road  
Kampala, Uganda 
Phone: +256 414 541044 
Email:  pmusoke@mujhu.org 
 
Maxensia Owor, MBChB, MMED, MPH 
Clinic Director  
MU-JHU Research Collaboration  
PO Box 23491,  
Old Mulago Hill Road  
Kampala, Uganda 
Phone:  +256 414 541044 
Email:  maxowor@mujhu.org  
 
Site 31890, Harare Family Care Clinical 
Research Site 
Mutsa Bwakura-Dangarembizi, MBChB, 
MMed, MSc 
University of Zimbabwe College of Health 
Sciences 
PO Box A178 
Avondale, Harare, Zimbabwe 
Phone: +263 772 601735 
Email: dangas@zol.co.zw 
  
Hilda Mujuru, MBChB, MMed, MSc 
University of Zimbabwe College of Health 
Sciences 
PO Box A178 
Avondale, Harare, Zimbabwe 
Phone: +263 470 0877 
Email: hmujuru@mweb.co.zw 
 
Kusum J Nathoo, MBChB, DCH, MSc 
University of Zimbabwe College of Health 
Sciences 
Department of Paediatrics and Child Health  
PO Box A178 
Avondale, Harare, Zimbabwe 
Phone: +263 4 791631/731000 
Email: knathoo@mweb.co.zw; 
knathoo@medsch.uz.ac.zw 
 
Site 5118, Kilimanjaro Christian Medical 
Centre Clinical Research Site 
Blandina Theophil Mmbaga, MD, MMed, 
PhD 
Kilimanjaro Christian Medical Centre 
Paediatric Department 
Box 3010  
Moshi, Tanzania  
Phone: +25 576 843 5116  
Email:  blaymt@yahoo.com; 
blaymt@gmail.com  
 
James Samwel Ngocho, MD, MSc 
Kilimanjaro Christian Medical Centre 
KCMC-Duke Collaboration 
Box 3010 
Moshi, Tanzania  
Phone: +25 578 464 0164 
Email:  jamesngocho08@gmail.com


 
Clarification Memorandum #1  
     Page 3 of 4 
24 April 2015 
IMPAACT P1092 Protocol Version 2.0 
 
Site 12001, University of North Carolina Project  
Lilongwe Clinical Research Site 
Portia Kamthunzi, MBBS, MTroPaed, DTCH 
UNC Project 
Private Bag A-104 
Lilongwe, Malawi 
Phone: +265 1 755056 
Email: pkamthunzi@unclilongwe.org 
 
Noel Mumba, Diploma in Clinical Medicine 
UNC Project 
Private Bag A-104 
Lilongwe, Malawi 
Phone: +265 1 755056 
Email: nmumba@unclilongwe.org 
 
Site 30301, Johns Hopkins Project  
Blantyre Clinical Research Site 
Rachel Chamanga, MBBS 
Johns Hopkins Project  
Queen Elizabeth Central Hospital 
Chipatala Avenue 
Blantyre, Malawi 
Phone: +265 1875 129 
Email: rchamanga@jhu.medcol.mw  
 
Sufia Dadabhai, MHS, PhD 
Johns Hopkins Bloomberg School of Public Health 
Department of Epidemiology 
Baltimore, MD 21205 
Phone: 410 502 9304 
Email: sufia@jhu.edu 
 
Newton Kumwenda, MPH, PhD 
Johns Hopkins Project  
Queen Elizabeth Central Hospital 
Chipatala Avenue 
Blantyre, Malawi 
Phone: +265 1875 129 
Email: nikumwenda@jhu.medcol.mw 
 
Macpherson Mallewa BMedSc, MBBS, MRCP, 
MRCPCH, DTM&H, PhD 
University of Malawi College of Medicine 
Department of Paediatrics 
Private Bag 360, Chichiri 
Blantyre, Malawi 
Phone:  +265 1875 129 
Email: macphers@liverpool.ac.uk; 
mmallewa@mlw.medcol.mw 
 
 


 
Clarification Memorandum #1  
     Page 4 of 4 
24 April 2015 
IMPAACT P1092 Protocol Version 2.0 
 
Protocol Pharmacist 
Lynette Purdue, PharmD 
DAIDS/NIAID/NIH/DHHS 
5601 Fishers Lane, Room 9E28 
Rockville, MD  20852 
Phone:  (240) 627-3061 
Email:  lpurdue@niaid.nih.gov 
 
Protocol Data Managers 
Bobbie Graham, BS 
Frontier Science & Technology Research Foundation  
4033 Maple Road  
Amherst, NY  14226-1056 
Phone:  (716) 834-0900 x7265 
Email:  graham.bobbie@fstrf.org 
 
Amanda Golner, BA, BS  
Frontier Science & Technology Research Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x7382 
Email: golner@fstrf.org 
 
 


 
IMPAACT P1092 
 
PHASE IV EVALUATION OF THE STEADY STATE PHARMACOKINETICS 
OF ZIDOVUDINE, LAMIVUDINE, AND LOPINAVIR/RITONAVIR  
IN SEVERELY MALNOURISHED HIV-1-INFECTED CHILDREN  
 
 
A Multicenter Trial of the  
International Maternal Pediatric Adolescent AIDS  
Clinical Trials Group (IMPAACT) 
 
 
Sponsored by: 
 
The National Institute of Allergy and Infectious Diseases (NIAID), 
the Eunice Kennedy Shriver National Institute of Child Health  
and Human Development (NICHD), and 
the National Institute of Mental Health (NIMH) 
 
 
Pharmaceutical Support Provided by: 
 
ViiV Healthcare Ltd 
Abbott Laboratories 
 
Non-IND Study 
DAIDS ES #11689 
 
IMPAACT HIV Treatment  
 
Scientific Committee Chair:  
Elaine Abrams, MD 
 
 
Protocol Chair: 
Maxensia Owor, MB, CHB, MMed, MPH  
  
Protocol Vice Chair: 
Philippa Musoke, MB, CHB, PhD 
 
NIAID Medical Officer: 
Renee Browning, RN, MSN 
 
NICHD Medical Officer: 
George Siberry MD, MPH 
 
Clinical Trials Specialists: 
Anne Coletti, MS 
 
Sarah Bradford, MPH 
 
 
FINAL VERSION 2.0 
11 February 2015


 
IMPAACT P1092 
FINAL Version 2.0 
11 February 2015 
 
IMPAACT P1092 PROTOCOL TEAM ROSTER 
 
1 
 
 
Protocol Chair 
Maxensia Owor, MB, ChB, MMED, MPH 
Clinic Director  
MU-JHU Research Collaboration  
PO Box 23491,  
Old Mulago Hill Road  
Kampala, Uganda 
Phone:  (256) 414-541044 
Email:  maxowor@mujhu.org  
 
Protocol Vice Chair 
Philippa Musoke, MB ChB, PhD 
Principal Investigator, Mulago Hospital  
MU-JHU Research House  
PO Box 23491,  
Old Mulago Hill Road  
Kampala, Uganda 
Phone: (256) 414-541044 
Email:  pmusoke@mujhu.org 
 
Investigator 
Kusum J Nathoo, MBChB, DCH, MSc 
University of Zimbabwe College of Health 
Sciences 
Department of Paediatrics and Child Health  
PO Box A178 
Avondale, Harare, Zimbabwe 
Phone: +263 4 791631/731000 
Email: knathoo@mweb.co.zw; 
knathoo@medsch.uz.ac.zw 
 
Protocol Nutritionist 
Elizabeth Kiboneka, MB, CHB MMed 
Dept of Pediatrics and Child Health 
PO Box 7072 
Kampala, Uganda 
Phone: (256) 071-2703994 
Email: elizakiboneka2000@yahoo.com 
 
 
NIAID Medical Officer  
Renee Browning, RN, MSN 
Medical Officer  
Maternal Adolescent and Pediatric Research 
Branch, PSP, DAIDS, NIAID, NIH  
5601 Fishers Lane, Room 8B29 
Rockville, MD  20852 
Phone (240) 292-4781 
Email: browningr@niaid.nih.gov 
 
NICHD Medical Officer 
George Siberry, MD, MPH 
Maternal and Pediatric Infectious Disease 
Branch  
Eunice Kennedy Shriver National Institute 
of Child Health and Human Development   
6100 Executive Boulevard, Room 4B11H   
Bethesda, MD  20892-7510 
Phone: (301) 496-7350 
Email: siberryg@mail.nih.gov  
 
Clinical Trials Specialists 
Anne Coletti, MS 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: (919) 544-7040 x11238 
Email: acoletti@fhi360.org 
 
Sarah Bradford, MPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: (919) 544-7040, x11685 
Email: sbradford@fhi360.org 
 
 
 
 
 
 
 
 
Please refer to the Manual of Procedures for guidance on  
study-related communications with protocol team members.  
Contact details for subject management are also provided in Section 6 of this protocol. 


 
IMPAACT P1092 
FINAL Version 2.0 
11 February 2015 
 
IMPAACT P1092 PROTOCOL TEAM ROSTER 
 
2 
 
Protocol Pharmacist 
Lynette Purdue, PharmD 
NIH, NIAID, DAIDS, PAB  
6700-B Rockledge Drive MSC 7620  
Bethesda, MD  20892-7620 
Phone:  (301) 435-3744 
Email:  lpurdue@niaid.nih.gov 
 
Protocol Pharmacologists 
Francesca Aweeka, PharmD 
Professor of Pharmacy  
University of California, San Francisco  
PO Box 0622  
521 Parnassus Avenue  
San Francisco, CA  94143-0622 
Phone:  (415) 476-0339 
Email:  faweeka@sfghsom.ucsf.edu 
 
Lubbe Wiesner, PhD 
UCT PK Laboratory Director 
Division of Clinical Pharmacology 
Department of Medicine 
University of Cape Town 
Cape Town, South Africa 
Phone:  +27 21 406 6472 
Email: lubbe.wiesner@uct.ac.za 
 
Protocol Immunologist 
Elizabeth McFarland, MD 
Professor of Pediatrics  
University of Colorado Denver  
Pediatric Infectious Diseases  
The Children's Hospital  
13132 E. 16th Avenue, B055  
Aurora, CO  80045 
Phone:  (303) 724-3447 
Email: betsy.mcfarland@ucdenver.edu 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Statisticians 
Vincent Carey, PhD 
Statistical & Data Analysis Center  
Harvard School of Public Health  
Building 3-505C, Channing Laboratory  
677 Huntington Avenue  
Boston, MA  02115-5821 
Phone:  (617) 525-2265 
Email:  vincent.carey@channing.harvard.edu 
 
Min Qin, PhD 
Statistical & Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 534A 
677 Huntington Avenue 
Boston, MA 02115 
Phone: (617) 432-2480 
Email: mqin@sdac.harvard.edu 
 
Protocol Data Managers 
Bobbie Graham, BS 
Frontier Science & Technology Research 
Foundation  
4033 Maple Road  
Amherst, NY  14226-1056 
Phone:  (716) 834-0900 x7265 
Email:  graham.bobbie@fstrf.org 
 
Stephanie Popson, PhD 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x 7356 
Email: popson@fstrf.org 
 
Laboratory Data Coordinator 
Amanda Zadzilka, BS 
Frontier Science and Technology Research 
Foundation  
4033 Maple Road  
Amherst, NY  14226 
Phone: (716) 834-0900 x7282 
Email: zadzilka@fstrf.org 
 
 
 
 
 


 
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Laboratory Center Specialist 
Carolyn Yanavich, MS, RAC 
IMPAACT Laboratory Center 
Children's Hospital Los Angeles 
Smith Research Tower  
4546 Sunset Boulevard, Room 902 
Los Angeles, CA 90027 
Phone: (443) 249-3851 
Email: Cyanavich@impaactlabcenter.org 
 
Laboratory Technologist 
Nancy Tustin, MLT (ASCP) (HEW) 
The Children's Hospital of Philadelphia 
Research Institute 
Abramson Research Center 1204B 
34th Street and Civic Center Blvd. 
Philadelphia, PA 19104 
Phone (215) 590-2043 
Email: tustin@email.chop.edu 
 
Pharmaceutical Industry Representative 
Wendy Snowden, PhD 
ViiV Healthcare UK Limited 
Mailstop CN12, GSK House 
980 Great West Road 
Brentford, Middlesex 
TW8 9GS, UK 
Phone: +44 (0)208 380 6311 
Email: wendy.x.snowden@viivhealthcare.com 
 


 
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Site 30293, Makerere University-Johns 
Hopkins University (MU-JHU) Research 
Collaboration   
Linda Barlow, MD, MPH 
MU-JHU Research Collaboration 
PO Box 23491  
Old Mulago Hill Road 
Kampala, Uganda 
Phone:  256 071 2703994 
Email:  lbarlow@mujhu.org 
 
Irene Lubega, MBCHB, MMed 
MU-JHU Research Collaboration  
PO Box 23491  
Old Mulago Hill Road  
Kampala, Uganda 
Phone: 256 712 222290 
Email: ilubega@mujuh.org 
 
Phionah Kibalama, MBChB 
MU-JHU Research Collaboration 
PO Box 23491  
Old Mulago Hill Road 
Kampala, Uganda 
Phone: 256 041 4541044 
Email: pkibalama@mujhu.org 
 
Philippa Musoke, MB ChB, PhD 
Principal Investigator, Mulago Hospital  
MU-JHU Research House  
PO Box 23491,  
Old Mulago Hill Road  
Kampala, Uganda 
Phone: (256) 414-541044 
Email:  pmusoke@mujhu.org 
 
Maxensia Owor, MB, ChB, MMED, MPH 
Clinic Director  
MU-JHU Research Collaboration  
PO Box 23491,  
Old Mulago Hill Road  
Kampala, Uganda 
Phone:  (256) 414-541044 
Email:  maxowor@mujhu.org  
 
Site 30313, University of Zimbabwe 
Parirenyatwa 
Mutsa Bwakura-Dangarembizi, MBChB, 
MMed 
University of Zimbabwe College of Health 
Sciences 
PO Box A178 
Avondale, Harare, Zimbabwe 
Phone: +263 772 601735 
Email: dangas@zol.co.zw 
  
Hilda Mujuru, MBChB, MMed, MSc 
University of Zimbabwe College of Health 
Sciences 
PO Box A178 
Avondale, Harare, Zimbabwe 
Phone: +263 470 0877 
Email: hmujuru@mweb.co.zw 
 
Kusum J Nathoo, MBChB, DCH, MSc 
University of Zimbabwe College of Health 
Sciences 
Department of Paediatrics and Child Health  
PO Box A178 
Avondale, Harare, Zimbabwe 
Phone: +263 4 791631/731000 
Email: knathoo@mweb.co.zw; 
knathoo@medsch.uz.ac.zw 
 
Site 5118, Kilimanjaro Christian Medical 
Centre 
Blandina Theophil Mmbaga, MD, MMed, 
PhD 
Kilimanjaro Christian Medical Centre 
Paediatric Department 
Box 3010  
Moshi, Tanzania  
Phone: +25 576 843 5116  
Email:  blaymt@yahoo.com; 
blaymt@gmail.com  
 
James Ngocho, MD  
Kilimanjaro Christian Medical Centre 
KCMC-Duke Collaboration 
Box 3010 
Moshi, Tanzania  
Phone: +25 578 464 0164 
Email:  jamesngocho08@gmail.com


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TABLE OF CONTENTS 
 
1.0 
INTRODUCTION .................................................................................................11 
1.1 
Background ................................................................................................11 
1.2 
Rationale ....................................................................................................15 
2.0 
STUDY OBJECTIVES ..........................................................................................23 
2.1 
Primary Objectives.....................................................................................23 
2.2 
Secondary Objectives.................................................................................23 
3.0 
STUDY DESIGN...................................................................................................24 
3.1 
Stage 1: Pre-Entry/Screening .....................................................................24 
3.2 
Stage 2: Entry .............................................................................................29 
3.3 
Criteria for Continued Participation in Pharmacokinetics Testing ............31 
3.4 
Pharmacokinetics .......................................................................................31 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS ..........................................32 
4.1 
Inclusion Criteria .......................................................................................32 
4.2 
Exclusion Criteria ......................................................................................35 
4.3 
Concomitant Medication Guidelines .........................................................36 
4.4 
Enrollment Procedures ...............................................................................36 
4.5 
Co-enrollment Procedures .........................................................................37 
5.0 
STUDY TREATMENT .........................................................................................38 
5.1 
Drug Regimens, Administration and Duration ..........................................38 
5.2 
Drug Formulation and Storage...................................................................39 
5.3 
Drug Supply, Distribution and Pharmacy ..................................................39 
6.0 
SUBJECT MANAGEMENT .................................................................................40 
6.1 
Team Communications ..............................................................................40 
6.2 
Toxicity Management ................................................................................40 
6.3 
Endpoints ...................................................................................................48 
6.4 
Criteria for Treatment Discontinuation ......................................................49 
6.5 
Criteria for Deferral of PK Evaluations .....................................................49 
6.6 
Criteria for Discontinuation of PK Evaluations .........................................50 
6.7 
Criteria for Study Discontinuation .............................................................50 
7.0 
EXPEDITED ADVERSE EVENT REPORTING.................................................50 
7.1 
Adverse Event Reporting to DAIDS ..........................................................50 
7.2 
Reporting Requirements for this Study......................................................51 
7.3 
Grading Severity of Events ........................................................................51 
7.4 
Expedited AE Reporting Period.................................................................52 
7.5 
CRF Recording Requirements for Laboratory Test Results, Signs, 
Symptoms, and Diagnoses .........................................................................52 
8.0 
STATISTICAL CONSIDERATIONS...................................................................52 
8.1 
General Design Issues ................................................................................52 
8.2 
Outcome Measures.....................................................................................52 
8.3 
Randomization and Stratification ..............................................................53 
8.4 
Sample Size and Accrual ...........................................................................53 
8.5 
Monitoring .................................................................................................55 
8.6 
Analyses .....................................................................................................57 


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9.0 
CLINICAL PHARMACOLOGY PLAN ...............................................................57 
9.1 
Pharmacology Objectives ..........................................................................57 
9.2 
Primary and Secondary Data .....................................................................58 
9.3 
Study Design, Modeling and Data Analysis ..............................................58 
9.4 
Anticipated Outcomes ................................................................................59 
10.0 
HUMAN SUBJECTS ............................................................................................59 
10.1 
Institutional Review Board and Informed Consent ...................................59 
10.2 
Subject Confidentiality ..............................................................................60 
10.3 
Study Discontinuation ................................................................................60 
11.0 
PUBLICATION OF RESEARCH FINDINGS .....................................................60 
12.0 
BIOHAZARD CONTAINMENT ..........................................................................60 
13.0 
REFERENCES ......................................................................................................61 
 
APPENDICES: 
 
APPENDIX I:  
SCHEDULE OF EVALUATIONS 
 
APPENDIX II:  WORLD HEALTH ORGANIZATION APPROACH TO THE 
MANAGEMENT OF SEVERE ACUTE MALNUTRITION 
 
APPENDIX III:  PHARMACOKINETIC SPECIMEN PROCESSING 
 
APPENDIX IV:  SAMPLE INFORMED CONSENT – SCREENING 
 
APPENDIX V:    SAMPLE INFORMED CONSENT – ENROLLMENT 
 
  
 


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GLOSSARY 
 
3TC  
Lamivudine, Epivir 
AAG  
 
Alpha -1 acid glycoprotein 
ABC  
 
Abacavir 
AE 
 
 
Adverse Event 
ALT  
 
Alanine aminotransferase 
ART  
 
Antiretroviral therapy 
ARV  
 
Antiretroviral  
AST  
 
Aspartate aminotransferase 
AUC  
 
Area under the curve 
BID 
 
 
Twice a day 
BLQ  
 
Below the limit of quantification 
BMI  
 
Body Mass Index 
Cmax  
 
Peak plasma concentration 
Ctrough  
 
Minimum concentration 
CBC  
 
Complete blood count 
CHER  
 
Children with Early HIV Antiretroviral Therapy 
CL/F  
 
Clearance 
CLIA  
 
Clinical Laboratory Improvement Amendments 
CI  
 
 
Confidence Interval 
CRF  
 
Case report form 
CRPMC  
NIAID Clinical Research Products Management Center 
CYP  
 
Cytochrome 
DAERS 
 
DAIDS Adverse Experience Reporting System 
DAIDS 
 
Division of AIDS 
DAIDS PRO DAIDS Protocol Registration Office 
DMC  
 
Data Management Center 
DNA  
 
Deoxyribonucleic Acid 
EAE  
 
Expedited Adverse Event 
 
EC 
 
 
Ethics Committee 
EIA 
 
 
Enzyme immunoassay 
EKG  
 
Electrocardiogram 
F75 
 
 
High energy milk (75 kilocalories/100ml) 
F100  
 
High energy milk (100 kilocalories/100ml) 
FDA  
Food and Drug Administration 
HAART 
Highly active antiretroviral therapy 
HIV/AIDS 
Human Immunodeficiency Virus/ Acquired Immunodeficiency Syndrome 
ICF 
 
Informed consent form 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IRB 
 
Institutional review board 
LAR  
Legally authorized representative 
LC-MS 
Liquid chromatography-Mass spectroscopy 
LFT  
Liver function test 
LTFU  
Loss to follow-up 
LPV/r  
Lopinavir/ritonavir, Kaletra 


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MUAC 
Middle upper arm circumference 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Development 
NIH  
National Institutes of Health 
NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
NRTI  
Nucleoside reverse transcriptase inhibitor 
NVP  
Nevirapine, Viramune 
OHRP  
Office for Human Research Protections 
PACTG 
Pediatric AIDS Clinical Trials Group 
PCR  
Polymerase chain reaction 
PENTA 
Pediatric European Network for Treatment of AIDS 
PI 
 
Protease inhibitor 
PID 
 
Participant identification number 
PK 
 
Pharmacokinetic 
RNA  
Ribonucleic Acid 
RSC  
Regulatory Support Center 
RTV  
Ritonavir 
RUTF  
Ready to use therapeutic feed 
SAE  
Serious adverse event 
SAM  
Severe acute malnutrition 
SES 
 
Subject Enrollment System 
SID 
 
Study identification number 
SMC  
Study Monitoring Committee 
SUSAR 
Suspected unexpected serious adverse reactions 
TID 
 
Three times a day 
Tmax 
 
Time to reach Cmax 
US HHS 
United States Department of Health and Human Services 
WHO  
World Health Organization 
WHZ  
Weight for height z score 
ZDV  
Zidovudine, Retrovir 
 
 


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SCHEMA 
 
PHASE IV EVALUATION OF THE STEADY STATE PHARMACOKINETICS OF 
ZIDOVUDINE, LAMIVUDINE, AND LOPINAVIR/RITONAVIR IN SEVERELY 
MALNOURISHED HIV-1-INFECTED CHILDREN  
 
DESIGN: 
Phase IV, multicenter, open-label, intervention 
pharmacokinetic trial 
 
SAMPLE SIZE:  
50 (25 per cohort) to achieve 34 evaluable  
(17 per cohort) 
 
POPULATION: 
Cohort 1: HIV-1-infected children ages ≥6 months 
(≥180 days) to <36 months with severe malnutrition 
 
Cohort 2: HIV-1-infected children ages ≥6 months 
(≥180 days) to <36 months with normal nutrition–mild 
malnutrition 
 
STRATIFICATION: 
Two strata: Age <18 months and ≥18 months  
 
   
 
REGIMEN: 
Cohort 1 (severe malnutrition)  
Arm A: <18 months: ZDV+3TC+LPV/r   
 
Arm B: ≥18 months: ZDV+3TC+LPV/r  
 
 
 
 
Cohort 2 (normal nutrition/mild malnutrition) 
Arm C: <18 months: ZDV+3TC+LPV/r   
 
Arm D: ≥18 months: ZDV+3TC+LPV/r  
 
TREATMENT DURATION: 
48 weeks after initiation of HAART 
 
PRIMARY OBJECTIVES: 
 
1. To compare the PK exposure (as estimated by the area under the plasma 
concentration versus time curve, AUC) and clearance of ZDV, 3TC, and LPV/r under 
steady-state conditions between severely malnourished children and children with 
normal nutrition – mild malnutrition at 1, 12 and 24 weeks following study entry.  
 
2. To evaluate the safety and tolerability of ZDV, 3TC, and LPV/r in severely 
malnourished children and children with normal nutrition – mild malnutrition at 24 
weeks following study entry. 
 


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SECONDARY OBJECTIVES: 
 
1. To compare the minimum concentration (Ctrough) of LPV/r between severely 
malnourished children and children with normal nutrition – mild malnutrition at 1, 4, 
8, 12,16, 24, 36 and 48 weeks following study entry. 
 
2. To investigate the impact of malnutrition on LPV protein binding by comparing the 
free fraction of LPV in severely malnourished children and children with normal 
nutrition – mild malnutrition at 1, 12 and 24 weeks following study entry. 
 
3. To compare the viral loads between severely malnourished children and children 
with normal nutrition – mild malnutrition at baseline, 12, 24, 36 and 48 weeks 
following study entry. 
 
4. To compare CD4 cell percent between severely malnourished children and children 
with normal nutrition – mild malnutrition at baseline, 12, 24, 36 and 48 weeks 
following study entry.    
 
5. To describe the recovery of lean body mass and linear growth in severe acute 
malnutrition at 24 and 48 weeks following study entry. 
 
 
 


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1.0 
INTRODUCTION 
 
1.1 
Background  
 
1.11 
Severe Acute Malnutrition (SAM) 
 
Malnutrition is a major problem of children living in resource-limited 
settings and is responsible for over one million deaths per year in children 
under five years of age (1).  Severe malnutrition remains one of the most 
common presentations of HIV infection in African infants and children, 
with wasting being recognized as a risk factor for mortality (2, 3).  Lean 
body mass has been closely associated with, and predictive of survival in 
both adults and children living with HIV even when on antiretroviral 
therapy. Severe acute malnutrition (SAM) in children age 6-59 months is 
defined anthropometrically by the World Health Organization (WHO) 
(2013) as a weight for height less than -3 Z score using the WHO growth 
standards, or a mid-upper arm circumference (MUAC) less than 115mm 
(11.5cm), or any degree of bilateral edema (4). A systematic review and 
meta-analysis of children presenting with SAM in sub-Saharan Africa 
reported an average HIV seroprevalence of 29%, with an urban large 
referral hospital having the highest burden of disease (5).   The urban 
nutritional treatment centers had HIV prevalence rates as high as 50%, 
with mortality of 30% in HIV-infected children. 
 
The clinical presentation of severe acute malnutrition includes severe 
visible wasting (marasmus), nutritional edema (kwashiorkor) or a mixed 
picture (marasmic–kwashiorkor). In sub-Saharan Africa, marasmus occurs 
more commonly than kwashiorkor in HIV-infected children (6).  It is 
unclear why HIV-infected children are more prone to marasmus than to 
kwashiorkor. In the earlier years of the HIV epidemic in North America, 
HIV- infected children also presented with HIV-related wasting that was 
associated with profound anorexia and weight loss. In African settings, it 
is generally not possible to differentiate clinically between HIV-related 
wasting and marasmus that affects HIV uninfected children from the same 
communities. Both HIV-infected and uninfected children presenting with 
SAM suffer recurrent infectious diseases, persistent diarrhea (usually due 
to villous atrophy and disaccharide or even monosaccharide intolerance) 
and oral candidiasis which contributes to anorexia and poor oral intake. 
Micronutrient deficiencies are common and may contribute to growth 
failure and disease progression. However micronutrient supplements alone 
do not necessarily restore body stores or result in improved weight gain or 
linear growth. While vitamin A supplements have been shown to reduce 
all-cause mortality in HIV-infected children, systematic reviews have not 
concluded that micronutrient supplements improve survival in HIV-
infected children or adults although these reviews have not disaggregated 
outcomes by nutritional status such as severe malnutrition. 
 


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Among HIV-infected children with SAM mortality has been reported to be 
three times higher than in those without HIV infection (5).  HIV-infected 
children with SAM are often admitted with multiple complex pathologies 
such as persistent diarrhea, tuberculosis, septicemia and oral thrush which 
make it more difficult to respond to the standard nutritional rehabilitation. 
Severely malnourished HIV-infected children generally have a prolonged 
hospital stay with inadequate and slow weight gain and increased risk of 
death especially in the first two weeks of admission.  In Uganda, Bachou 
et al reported a mortality of 24% in a cohort of 220 children admitted with 
SAM and the majority of deaths occurred within the first week of 
admission (7). However, there have been some reports of HIV-infected 
children who survive having similar weight gain following nutritional 
rehabilitation when compared to the HIV-uninfected children with SAM 
(8).   
 
In any child suffering severe malnutrition, normal physiological 
mechanisms adapt to low food intake in a process called reductive 
adaptation.  These changes affect every physiological function in the body 
to decrease energy and nutrient demands and mobilize energy and 
nutrients from other reserves; adaptations include reduced cardiac output, 
glomerular filtration and hepatic perfusion. This is initially beneficial but 
eventually becomes detrimental to the child as the body is unable to 
handle stress and control normal physiological functions leading to poor 
homeostasis and serious infections.  
 
Complicated SAM is associated with important biochemical and 
electrolyte abnormalities, including hypoglycemia, hypokalemia, 
hyponatremia, and micronutrient deficiencies such as zinc, magnesium 
and phosphate. Immune function even in HIV-uninfected children is also 
compromised in SAM and has given rise to the term “nutrition acquired 
immunodeficiency”.  HIV-infected children with SAM have lower total 
white cell counts, lymphocyte counts and CD4 cell counts and impaired 
cell mediated immunity with additional risk of miliary tuberculosis, 
invasive salmonellosis and candidiasis. Bacteremia occurs in 20% of 
children admitted with SAM and is more common in those with SAM and 
HIV and is associated with higher mortality.   The majority of the 
pathogens are Gram-negative enteric bacteria probably due to the break 
down in the intestinal barrier (7,9). 
 


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Nutritional Rehabilitation 
 
The World Health Organization recommends a ten step approach to the 
management of SAM which is described in Appendix II (10). This 
involves a stabilization and rehabilitation phase. The stabilization phase 
which usually lasts up to two weeks includes feeding with management of 
the acute medical conditions and initiation of therapeutic feeding (high 
energy milk F75 and F100). This involves providing standard antibiotic 
coverage for bacterial infections, prevention of and treatment for 
hypoglycemia, hypothermia and dehydration if present. Electrolyte and 
micronutrient deficiencies are managed by supplementing potassium and 
magnesium, while multivitamins, zinc and folic acid are added to the 
feeds. Iron is replaced only in the rehabilitation phase because of the pro-
oxidative effects and potential complication of worsening infections.    
 
 
1.12 
Pharmacokinetics 
 
In recent years, there has been increased access to highly active 
antiretroviral therapy (HAART) for HIV-infected children with improved 
morbidity and mortality outcomes (11). The goal of antiretroviral therapy 
is to sustain immunologic health by achieving a sustained control of viral 
replication which is dependent upon adequate drug exposure. 
   
Multiple factors significantly influence pharmacokinetic (PK) processes of 
drugs including disease states like malnutrition, age, sex, genetic 
variations and variations in physiological processes such as absorption and 
drug metabolism (12).  In the general population, variations in gastric pH, 
emptying time, integrity of gut absorptive surface area and permeability 
have been determined to influence absorption while variations in body 
composition, total body water, fat content, body mass and levels of 
binding protein have been found to influence distribution of drugs within 
the body compartments (12).   
 
Any disease state that disrupts drug absorption and metabolism will also 
affect the PK of drugs. Malnourishment has been associated with villous 
atrophy of the gut, reduced gastric acidity, prolonged emptying time and 
reduced binding of some drugs due to reduced albumin levels causing PK 
changes in the malnourished children (13,14). Decreased gastric acidity 
(higher gastric pH) associated with malnutrition can result in increased 
absorption of acid labile drugs and decreased absorption of drugs requiring 
lower gastric pH for stability (15). The protease inhibitors [PIs, e.g. LPV/r 
(lopinavir/ritonavir)] and the non-nucleoside reverse transcriptase 
inhibitors [NNRTIs, e.g. nevirapine (NVP)] prefer an acidic environment 
for absorption and thus, may exhibit diminished absorption in the 
malnourished child (16). In contrast, the nucleoside reverse transcriptase 
inhibitors [NRTIs, e.g. zidovudine (ZDV) and lamivudine (3TC)] are acid 


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labile and thus may exhibit increased absorption with the increase in 
gastric pH consistent with malnutrition. 
 
Malnutrition may also affect drug metabolism.  Drugs like antipyrine, anti-
tuberculosis drugs and antibiotics exhibit altered metabolism in severely 
malnourished children due to altered hepatic oxidative drug 
biotransformation via the cytochrome P450 (CYP) enzymatic system.  In 
early animal studies, it was shown that as protein was restricted in the diet, 
the microsomal P450 content and activity was lowered which was 
confirmed using several drugs as substrates. Diminished metabolism, 
reduced elimination of conjugates and reduced elimination of renally 
excreted drugs seemingly increases the risk of toxicity in malnourished 
children (17,18).   The protease inhibitors and non-nucleoside reverse 
transcriptase inhibitors undergo CYP metabolism by the isozymes 
CYP3A4 and CYP2B6 and thus may exhibit diminished metabolism in the 
context of malnourishment.   
 
While the PK of several drugs has been studied in the malnourished child, 
very few studies have investigated the effect of severe malnutrition on the 
PK of ARVs.   Ellis et al found an independent association between lower 
NVP concentrations and lower height-for-age (indicating stunting, p=0.05) 
and higher body mass index (BMI) for age (indicating lack of wasting, 
p=0.03) (19).  This study conducted in 56 Zambian and 71 Malawian 
children was designed to investigate the PK of NVP in subjects receiving 
fixed-dose generic agents. In another study in Malawi, children with 
moderate malnutrition had a trend toward lower NVP levels.  This study 
also measured unbound NVP and reported no apparent change in the 
percentage of unbound NVP, a finding expected since NVP is only 60% 
bound to plasma proteins (while changes in the binding of LPV/r which is 
98-99% bound are more likely).  Younger children independent of 
nutrition status had an increased risk of sub-therapeutic NVP 
concentrations (20). 
 
In general, PK of ARV drugs in children is less predictable than adults. 
For several ARVs, age-dependent PK parameters have been reported (21, 
22).  Furthermore, high inter-individual variability in PK of ARV drugs 
may occur within age brackets. Variations in weight among children may 
affect drug disposition as shown in the Zambian study where children ≥6 
kg exhibited appropriate concentrations of NVP with Triomune® junior 
and baby formulations.  However, more information as to appropriateness 
of dosing was needed for children < 6kg (23).   
 
When ARVs are administered orally, they are absorbed from the intestinal 
epithelial cells into the systemic circulation.  They are then distributed into 
tissues depending on their affinity for the tissues relative to plasma 
proteins.  ARVs are variably bound to plasma proteins (<5% to >99%) 
(24). NRTIs are not highly protein bound with binding ≤40% in most 


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cases. Protease inhibitors, with the exception of indinavir, are >90% 
protein bound, mainly to α1-acid glycoprotein (AAG). In particular, 
lopinavir is highly protein bound in plasma (98-99%); mainly to AAG for 
which it has the highest affinity, and albumin.  Since malnutrition may 
lead to lower plasma albumin and AAG levels, the fraction of lopinavir 
that is unbound (pharmacological active) may be increased (25).  The 
actual concentration of unbound drug is unlikely to change at steady-state; 
however, the fraction of unbound drug (relative to total drug) may change.  
Thus, an estimate of the fraction of unbound drug for highly bound drugs 
in the malnourished state is helpful for interpreting the results for total 
drug levels generated in this study.  In other words, if a difference in total 
drug exposure is detected in the severely malnourished child compared to 
a child that is not severely malnourished, this change should be interpreted 
in the context of any change in fraction unbound.  For example, a 40% 
decrease in total drug exposure may be partially offset by an increase in 
the fraction unbound. 
 
The overall goals of this study are to characterize the PK of ARVs (ZDV, 
3TC, and LPV/r) in severely malnourished children following the 
initiation of nutritional rehabilitation and to compare results to normal – 
mildly malnourished children to determine if dosage adjustments in the 
severely malnourished child are warranted.   Since PK is being studied at 
specific time points following study entry, PK results also will aid in 
determining if initiation of HAART early in SAM leads to adequate drug 
levels.  It is hypothesized that children with severe acute malnutrition will 
have reduced absorption of antiretroviral drugs compared to those with 
normal nutrition-mild malnutrition. 
    
1.2 
Rationale 
 
1.21 
Pharmacokinetics in severe malnutrition 
 
Severe malnutrition that is not responding to nutritional rehabilitation 
(WHO clinical stage IV) is an indication to initiate HAART. A PK study 
of adult Triomune® given to children with mild to moderate malnutrition 
in Malawi revealed antiretroviral therapy (ART) dosing in the children 
was too low, but did not detect an effect of malnutrition on total drug 
exposure or the unbound fraction of NVP. In severe malnutrition, 
however, metabolic and or gut structural derangement may lead to 
inadequate ARV absorption and or erratic drug levels. The greater surface 
area to weight ratio in these children also could place them at higher risk 
of under dosing compared to the group with mild to moderate 
malnutrition.  The paucity of ARV PK data in these vulnerable, severely 
malnourished children speaks to the need to determine the PK of ARVs in 
this group with the aim of informing future dosing guidelines for this 
particular group of patients.   
 


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1.22 
Pharmacokinetics in moderate malnutrition 
 
In Malawi, HIV-1-infected children initiated on HAART using a FDC 
Triomune® 30 had similar total AUC0-12hr in the mild to moderately 
malnourished children (70-85% weight for height) compared to children 
of normal nutritional status (> 85% weight for height).  Mean (90% CI) 
AUC0-12hr in malnourished children (n=12) was 60,082 (35,328 -
166,629) ng*h/mL compared to 79,861 (43922-146376) ng*h/mL in the 
normal group (n=25) [p=0.17].  However there was a trend towards lower 
total nevirapine Cmax (29%) in the malnourished children [6719 (3401 -
18947) ng/mL] versus the normal children [9483 (5099 – 22453) ng/mL] 
(p=0.089).  There was no difference in Ctrough (p=0.327).  Age and dose 
were the main predictors of achieving a therapeutic Ctrough in the univariate 
model and, in the multivariate model, age was found to be independent of 
dose. The authors’ conclusion was that malnutrition did not seem to have a 
significant impact on NVP PK (26).  However, children with acute severe 
malnutrition were not included in this study (4). 
 
The current study will utilize the recommended weight band dosing which 
simplifies dosing in resource limited settings and is the approach used in 
the WHO pediatric ARV dosing guidelines. It will also use pediatric 
formulations which have not been studied before in severely malnourished 
children. 
 
1.23 
Virology and immunology 
 
Children who acquired HIV infection through mother-to-child 
transmission develop high peak levels of circulating virus within the first 
six months of life with a plateau and slow decline over the next 18 
months.  Complete viral suppression is critical to effective treatment and 
survival.  HAART has been shown to reduce HIV-1 RNA levels 
dramatically with the most rapid reduction in viremia occurring during the 
first two weeks with a slower decline thereafter.  Adequate ARV drug 
levels ensure complete viral suppression and delay emergence of HIV-1 
resistant mutations. By measuring HIV-1 RNA levels at baseline and at 12 
and 24 weeks after initiating dosing, it will be possible to ascertain 
whether the study drug levels achieved as measured by pharmacokinetics 
are effective in reducing viremia. 
 
HIV-1-infected children presenting with severe malnutrition are at a high 
risk of mortality during nutritional rehabilitation - 35% mortality in a 
study in Malawi (8).  In a study of severely malnourished Zambian 
children, CD4 percentages were lower among HIV-1-infected children 
compared to uninfected children, with 46% of the HIV-1-infected children 
having a CD4 percent <15% (27).  The difference in CD4 percent is even 
more pronounced in children with SAM and lacking edema, with 
approximately 80% having CD4 < 15%.  Despite successful nutritional 


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rehabilitation among those children who survived, CD4 percent did not 
increase.  On the contrary, at the time of complete nutritional recovery, an 
increased proportion of the children (85%) had CD4 percent <15% (27).  
This observation argues for initiation of ART since nutritional treatment 
alone did not result in CD4 recovery.   However, studies demonstrating the 
effect of ART and nutritional rehabilitation on CD4 parameters are 
lacking.  It is not known whether severely malnourished children will have 
CD4 recovery similar to those with more normal nutrition.  A study of 
adults in Singapore examined the CD4 count increases following ART 
initiation (28).  The study did not demonstrate a significant difference 
between adults presenting with a BMI <17 vs. higher BMI.  However this 
study was performed in adults and the degree of malnutrition was not 
detailed.  In children production of naïve cells by the thymus is thought to 
be an important contributor to CD4 recovery with ART.  Severe 
malnutrition results in thymic atrophy (29).  It is possible that HIV-
infected children with severe malnutrition will have greater thymic 
compromise which might lead to delayed or inadequate increases in CD4 
parameters.  Therefore a secondary objective of this study will investigate 
the hypothesis that change from baseline for CD4 percent at 12 and 24 
weeks will be lower for the cohort with severe malnutrition at baseline.   
 
1.24 
Extended follow-up to 48 weeks 
 
The primary objectives of the study are to compare the pharmacokinetic 
characteristics of severely malnourished and normally nourished HIV-
infected children starting lifelong antiretroviral therapy. However, there is 
very limited well-documented, comparative, clinical data about these 
groups of children, and hence there would be significant benefit in 
monitoring the outcomes of study children for a period of 48 weeks total. 
While the sample size would not be predicated on answering other clinical 
questions, valuable observational data could be derived on differences in 
the two groups of children on: 
 
 Recovery of lean body mass (proxy = weight for height and middle 
upper arm circumference (MUAC)  
 Linear growth  
 Rate of metabolic complications 
 
Such information, even if not definitive, would contribute to the emerging 
body of knowledge about how to manage these children and the benefits 
of doing so, and may serve as preliminary data for subsequent research 
proposals.  
 


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Outcomes to be monitored over 48 weeks of follow-up: 
 Vital status 
 Weight, height and MUAC 
 Glucose and lipid profile 
 Skin fold thickness  
 Viral load and CD4 count 
 
1.25 
Summary 
 
The primary objectives of the study are to compare the pharmacokinetic 
characteristics of severely malnourished and normally nourished to mildly 
malnourished HIV-infected children starting lifelong antiretroviral 
therapy. Whether or not it is better to wait for some nutritional recovery 
before initiation of ART is not known. There is the potential for the ARVs 
to cause adverse events in a child who is metabolically unstable, has 
reduced hepatocellullar function and has low antioxidant capacity.  
However, slow weight gain and recovery associated with high mortality 
makes it difficult to wait for complete nutritional recovery before initiating 
HAART. Therefore developing a better understanding of the PK in these 
severely malnourished children will better inform future research as to the 
best timing of HAART initiation in severely malnourished children. 
 
Furthermore, the findings of this study will provide information on the PK 
of HAART in severely malnourished children compared to children with 
normal nutrition–mild malnutrition.  It will inform us whether or not 
current recommended doses are optimum for treating severely 
malnourished children.   Results from this study will also have important 
implications for how best to administer new ARVs to severely 
malnourished children as new ARVs become available. 
 
1.26 
Pediatric Antiretroviral Drug Regimens  
 
 
 
 
1.261 Zidovudine (ZDV, Retrovir®) 
 
Zidovudine, a nucleoside analog, is an FDA-approved antiretroviral agent 
for the treatment of HIV infection (initially approved in March 1987).  It is 
indicated for treatment of HIV-infected adults and children who have 
impaired immunity. Separate placebo-controlled studies evaluated 
zidovudine therapy in adults with asymptomatic HIV infection, early 
symptomatic disease and advanced symptomatic disease (30-32).  In 
patients with advanced HIV disease, zidovudine therapy provided 
significant benefits in terms of reduced morbidity and decreased mortality. 
In those with less advanced HIV disease, zidovudine therapy was 
associated with a decrease in the rate of disease progression.  Moderate 
antiviral activity has been documented for all stages of HIV disease.  


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Zidovudine is also indicated for the treatment of children with 
symptomatic HIV disease or those with laboratory evidence of significant 
immune deficiency.  Zidovudine is commonly used as one of two 
“backbone” NRTI agents within HAART.  The WHO currently 
recommends lopinavir/ritonavir plus an NRTI backbone of either 
zidovudine or abacavir (ABC) paired with lamivudine as the first line 
regimen for children less than three years of age.  HIV-infected infants 
have a high mortality regardless of CD4 cell count, and this also was 
confirmed by the CHER study of HIV-infected children who received late 
HAART (33).  Therefore the new WHO guidelines recommend that all 
HIV-infected infants should be initiated on HAART regardless of CD4 
cell count or clinical state (4). PACTG 076 demonstrated that zidovudine 
therapy, initiated during the second or third trimester of pregnancy, can 
reduce the risk of perinatal transmission of HIV by approximately two-
thirds.  
 
In general, the frequency and severity of adverse events associated with 
the use of zidovudine are greater in patients with advanced disease at the 
time of initiation of therapy.  The most frequently reported adverse events 
are hematologic abnormalities including anemia and granulocytopenia.  
Some investigators are concerned that an increased incidence of anemia 
may occur among ZDV-treated infants and children in resource-poor 
settings where malnutrition and multiple infections may so predispose 
them.  For this reason, hematology values will be monitored frequently. In 
placebo-controlled trials, the clinical side effects reported more by 
zidovudine than placebo recipients were nausea, insomnia, myalgia, 
severe headache, asthenia, dyspepsia, vomiting, anorexia, malaise, 
dizziness and constipation.  The development of myositis, with and 
without elevated CPK levels, has been reported for some patients with 
advanced HIV disease receiving long-term zidovudine therapy. 
 
Twice daily ZDV dosing is a common clinical practice for ease of 
administration and to promote adherence (34).  Current WHO pediatric 
treatment guidelines for resource-limiting settings also recommend BID 
dosing.  In a small pharmacokinetic study of six HIV-infected children, 
ZDV plasma pharmacokinetic parameters (AUC0-24 and Cmax) were not 
significantly different when comparing BID vs. TID dosing (35). 
 
Please refer to the Retrovir® package insert for complete prescribing 
information. 
 


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1.262 Lamivudine (3TC, Epivir®) 
 
Lamivudine (3TC) was approved in November 1995 for use in infants 
greater than 3 months of age and in children based on efficacy studies in 
adults in conjunction with safety and PK studies in children.  3TC is the 
negative enantiomer of a synthetic cytidine analogue. 3TC requires 
intracellular phosphorylation to become active and does so preferentially, 
like ddI and zalcitabine (ddC), in resting cells.  3TC has activity against 
HIV-1 and HIV-2, as well as Hepatitis B virus (36).  The CSF/plasma 
ratio in children is relatively low (0.11) compared with that of ZDV 
(0.25), but higher than that of ddI (0.05) (37).  The bioavailability is 
approximately 66% in children and 86% in adolescents and adults.  Its 
plasma half-life is 2 hours and its intracellular half-life is 10-15 hours, 
allowing for twice daily dosing.  
 
When 3TC is administered as monotherapy, resistance emerges rapidly 
and is associated with a single genotypic mutation at codon 184.  
Resistance also develops rapidly (within weeks) when 3TC is used in non-
suppressive combination antiretroviral regimens, such as dual NRTI 
therapy with ZDV/3TC (38). Therefore, optimal use of 3TC is within a 
combination of at least three ARV medications capable of providing full 
suppression of viral replication.  3TC-resistant virus may be partially 
cross-resistant to ddI and ddC.  In vitro, development of the codon 184 
3TC resistance mutation is associated with increased fidelity of the viral 
RT enzyme for its substrate (39).  It is speculated that this could influence 
the evolution of the virus and may prevent or delay the generation of drug 
resistant variants.  For example, the 184 mutation is reported to suppress 
ZDV resistance in vitro and when introduced into the background of a 
ZDV-resistant reverse transcriptase gene to suppress the effect of some 
ZDV resistance mutations (40).  Additionally, the M184V mutation is 
associated with diminished viral replicative fitness (41). 
Pediatric Experience     
A phase I/II study of 3TC showed that the agent could decrease viral 
burden by 0.77 logs when used as monotherapy (37).  In PACTG 300, 
children receiving ZDV and 3TC had a lower risk of HIV disease 
progression or death than those receiving ddI alone (42). In the European 
PENTA-4 double-blind, randomized trial of the addition of 3TC or 
placebo to NRTI therapy in pediatric patients with advanced disease, 3TC 
was well-tolerated when coupled with ZDV, ddI or ZDV plus ddC (43).  
In PACTG 338, 42% of previously treated children receiving triple 
combination ZDV, 3TC plus RTV had undetectable HIV-RNA at week 48 
compared with 27% receiving a single NRTI plus RTV (44).  


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Adverse Effects 
 
3TC is very well-tolerated.  The major reported toxicities are pancreatitis 
and peripheral neuropathy (37).  Headache, fatigue and gastrointestinal 
upset also have been described. Lactic acidosis and severe hepatomegaly 
with steatosis, including fatal cases, have been reported with the use of 
nucleoside analogues alone or in combination, including 3TC. 
In 175 pediatric patients treated with 3TC, 10 cases of clinical pancreatitis 
and six cases of chemical pancreatitis have been reported.  Patients have 
ranged from 29 months to 18 years of age.  Total daily dose ranged from 
64 mg to 350 mg and duration of treatment prior to the event varied from 
five weeks to 13 months.  In 14 of these cases, causality was judged 
possibly related to 3TC or unknown.  Ten of these 14 cases have possibly 
confounding factors including previous pancreatitis, 
cholecystitis/cholelithiasis, recent mumps vaccine, hemophilia, 
mycobacterium infection, and HIV progression.  Concomitant medications 
listed for these patients that also may be linked to pancreatitis are 
cotrimoxazole, ddI, pentamidine, and ZDV.  Only one patient had never 
received prior ART.  None of the 16 patients died as a result of the 
pancreatitis (42,43).   
Please refer to the Epivir® package insert for complete prescribing 
information. 
1.263 Lopinavir/ritonavir (LPV/r, Kaletra®) 
 
LPV/r is a fixed combination of LPV (133.3 mg) plus RTV (33.3 mg).  
LPV/r received FDA approval in 2000 for combination with other 
antiretroviral agents for the treatment of HIV-1 infection in adults and 
pediatric patients age six months and older.  It is available in both liquid 
and solid formulations.  Like other PIs, LPV/r is metabolized by the 
hepatic cytochrome P450 system and multiple drug interactions are 
possible (45).  Administration of LPV/r with food increases plasma 
concentrations; to enhance bioavailability and minimize PK variability, 
LPV/r should be taken with food.   Resistance to LPV/r has been 
associated with genotypic mutations at 11 positions of the protease 
enzyme including codons 10, 20, 24, 46, 53, 54, 63, 71, 82, 84, and 90.  
Importantly, high-level resistance generally requires at least six mutations.  
Cross-resistance among PIs is likely.  


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Pediatric Experience 
The use of dual protease inhibitors that include RTV have been studied in 
adults.  In these combinations, rather than being used for its ARV activity, 
RTV acts as a PK enhancer by inhibiting the metabolism of other PIs and 
therefore increasing its plasma concentrations. RTV inhibits the 
metabolism of LPV and thus increases its plasma concentration. Data on 
combination PIs in children is more limited.  Abbott Study M98-940 is a 
phase I/II open-label study that evaluated the PK profile, tolerability, 
safety, and efficacy of LPV/r oral solution and either two NRTIs or NVP 
plus up to two NRTIs in 100 pediatric patients aged six months to 12 years 
of age at two doses, 230/57.5 mg/m2 BID and 300/75 mg/m2 BID.  
Treatment-naïve subjects also were taking d4T and 3TC and treatment-
experienced subjects also were taking NVP and one to two NRTIs.  PK 
profiles at study week three indicated that both the 230/57.5 mg/m2 BID 
dose given without enzyme-inducing NVP and the 300/75 mg/m2 BID 
dose given with NVP approximated adult exposures observed in the M98-
720 study.  Consequently, the dose for all subjects was changed to 300/75 
mg/m2 BID (46).   
Children receiving LPV/r 300/75 mg/m2 in combination with NVP and 
one or two NRTIs yielded a Ctrough of 5.6 g/mL (+/-3.3).  Through 24 
weeks of therapy, the proportion of patients with HIV RNA <400 
copies/mL was 82% for antiretroviral-naïve patients and 66% for 
antiretroviral-experienced patients. Follow-up at 60 weeks was 77% and 
70% for naïve and experienced patients, respectively (47).  The mean 
increase from baseline in CD4+ cell count was 328 cells/mm3 for 
antiretroviral-naïve and 335 cells/mm3 for antiretroviral-experienced 
patients treated through 24 weeks.  This increased to 404 cells/mm3 for 
naïve patients and 238 cells/mm3 for treatment-experienced patients at 
week 60.  
In PACTG P1030, HIV-1-infected infants less than 6 months of age were 
treated with LPV/r 300/75 mg/m2 twice daily plus two nucleoside reverse 
transcriptase inhibitors (48).  Results available at 24 weeks indicated that, 
although apparent clearance of LPV/r was slightly higher than in older 
children, the median area under the concentration-time curve 0-12 h 
(67.5μg.h/ml) was in the range reported from older children taking the 
recommended dose of 230/57.5 mg/m2.  Longer-term results indicated 
that, at 12 months of age, median LPV area under the curve was similar to 
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Adverse Effects 
The most common side effects associated with LPV/r have been diarrhea, 
asthenia, and triglyceride and cholesterol elevations.  Pancreatitis has been 
reported in adult patients taking LPV/r. High triglyceride levels may be a 
risk factor for pancreatitis to develop.  As with all agents in this class, new 
onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, 
hyperglycemia, and diabetic ketoacidosis may occur.  In the phase I/II 
Abbott Study M98-940, only one subject discontinued therapy due to a 
study drug-related adverse event (pancreatitis).  Grade 3 or higher clinical 
adverse events included vomiting (1%) and rash (2%) (47).   
Please refer to the Kaletra® package insert for complete prescribing 
information. 
 
2.0 
STUDY OBJECTIVES 
 
2.1  
Primary Objectives 
 
2.11 
To compare the PK exposure (as estimated by the area under the 
plasma concentration versus time curve, AUC) and clearance of 
ZDV, 3TC, and LPV/r under steady-state conditions between 
severely malnourished children and children with normal nutrition 
– mild malnutrition at 1, 12 and 24 weeks following study entry 
 
 
 
 
2.12 
To evaluate the safety and tolerability of ZDV, 3TC, and LPV/r in 
severely malnourished children and children with normal 
nutrition-mild malnutrition at 24 weeks following study entry 
 
2.2  
Secondary Objectives 
 
2.21 
To compare the minimum concentration (Ctrough) of LPV/r 
between severely malnourished children and children with normal 
nutrition - mild malnutrition at 1, 4, 8, 12, 16, 24, 36 and 48 weeks 
following study entry 
 
2.22 
To investigate the impact of malnutrition on LPV protein binding 
by comparing the free fraction of LPV in severely malnourished 
children and children with normal nutrition – mild malnutrition at 
1, 12 and 24 weeks following study entry   
 
 
 
 
 
2.23 
To compare the viral loads between severely malnourished 
children and children with normal nutrition – mild malnutrition at 
baseline, 12, 24, 36 and 48 weeks following study entry 
 


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2.24 
To compare CD4 cell percent between severely malnourished 
children and children with normal nutrition – mild malnutrition at 
baseline, 12, 24, 36 and 48 weeks following study entry 
 
2.25 
To describe the recovery of lean body mass and linear growth in 
severe acute malnutrition at 24 and 48 weeks following study 
entry 
 
 
3.0 
STUDY DESIGN  
 
This is a Phase IV open label study to evaluate the pharmacokinetics (PK), safety, 
and tolerability of ZDV, 3TC, and LPV/r syrup in HIV-1-infected infants and 
children aged ≥6 months (≥180 days) to <36 months with severe malnutrition and 
with normal nutrition-mild malnutrition.  Two cohorts of children will be enrolled 
in the study: Cohort 1: 25 HIV-1-infected children who are severely 
malnourished and are eligible for HAART as defined by the WHO pediatric 
algorithm and Cohort 2: a control group of 25 HIV-1-infected children with 
normal nutrition-mild malnutrition who are also eligible for HAART.  Children 
with severe malnutrition will undergo an approximate two week nutrition 
rehabilitation program before entering the study.  
 
Children in each cohort will be assigned to receive ZDV+3TC+ LPV/r.  All 
subjects will continue on treatment and on study for 48 weeks after the initiation 
of HAART. Post study access to study HAART regimen: once the study is over, 
all children will be referred to their country national care program where they will 
be eligible to receive the standard of care in their country.  
 
The study will be conducted in two stages. 
 
3.1 
Stage 1: Pre-Entry/Screening 
 
Cohort 1: Severely malnourished children  
Severe acute malnutrition (SAM) in children age 6-59 months is defined 
by WHO (2013) as a weight-for-height less than -3 Z score using the  
WHO growth standards or a MUAC less than 115 mm (11.5 cm), or any 
degree of bilateral edema (49). 
          
Sites will identify severely malnourished children admitted to the nutrition 
rehabilitation unit; however, children with edematous malnutrition will not 
be included in this study.  All sites will manage these children according 
to WHO (2013) guidelines on managing children with severe malnutrition. 
 


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Study Flow Chart:   
 
 
Normal Nutrition-Mild Malnutrition 
 
 
 
 
 
 
 
Severe Malnutrition 
 
 
 


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Nutritional Rehabilitation 
 
The World Health Organization recommends a ten step approach to the 
management of SAM as described in Table 1 (10). This involves a 
stabilization and rehabilitation phase. The stabilization phase which 
usually lasts up to two weeks includes feeding with management of the 
acute medical conditions and initiation of therapeutic feeding. This 
involves providing standard antibiotic coverage for bacterial infections, 
prevention of and treatment for hypoglycemia, hypothermia and 
dehydration if present. Electrolyte and micronutrient deficiencies are 
managed by supplementing potassium and magnesium, while multi-
vitamins, zinc and folic acid are added to the feeds. Iron is replaced only 
in the rehabilitation phase because of the pro-oxidative effects and 
potential complication of worsening infections.    
 
The initial feeds are small and frequent given every 2 to 3 hours and 
provide total of about 100kcal/kg/day. The World Health Organization 
recommends local hospitals to prepare milk referred to as F75 that is 
fortified with vitamins, electrolytes and micronutrients and contains 75 
kcal/100ml and 0.9g of protein.    
 
Children with SAM may also require vitamin A, zinc, and antibiotics; all 
study sites will follow WHO guidelines related to provision of these 
therapies. Also consistent with WHO guidelines, fluid management will 
depend on the extent of dehydration, whether the child is in shock, and 
whether the child has cholera or profuse watery diarrhea. 
 
Children will be carefully monitored throughout the stabilization phase as 
they are particularly susceptible to fluid overload and cardiac failure. 
Monitoring will include: 
 
 Respiratory rate 
 Vomiting 
 Temperature 
 Glucose level 
 Stool frequency and consistency 
 Amount of feed offered and left over. Note: while feeds need to be 
started in the stabilization phase, significant weight gain is not 
expected until underlying sepsis and electrolyte disturbances are 
treated and resolved.  
 Weight gain 
 
If children survive the immediate stabilization phase, the focus of care and 
management is to initiate and sustain catch up growth. However, full 
recovery and reaching expected weight-for-height will take about 6-8 
weeks and therapeutic feeds therefore need to be continued at home. 


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Increase in appetite is one of the most important signs indicating that the 
child is entering the rehabilitation phase. In HIV uninfected children this 
usually takes about one week following admission and appropriate 
management of sepsis and electrolyte disturbances. Once children are 
stabilized and have appetite, they are ready to move into the rehabilitation 
phase, and should be transitioned from F75 to another milk formulation 
called F100 or an equivalent non-milk therapeutic food called Ready-to-
Use Therapeutic Feed (RUTF).  The transition should occur over 2-3 days 
as tolerated and the recommended energy intake during this period is 100-
135 kcal/kg/day.  
 
 F100 is a milk-based preparation with added vitamins and trace 
elements which has 100kcal/100 ml and 2.9g protein per 100ml. The 
volume of milk is increased to about 130ml/kg day while other foods 
are introduced and increased 
 RUTF is an energy dense food usually containing peanut butter, milk 
powder, oil, sugar and micronutrients with an equivalent nutritional 
content to F100. The major advantage of RUTF over milk F100 is that 
it can be given to the mother to take and safely use at home whereas 
F100, being a milk preparation that is easily contaminated unless 
prepared in hygienic conditions, is reserved for hospital use only.  
 In the rehabilitation phase, children recovering from SAM will 
consume about 200-230 kcal/kg/day and between 5-7gm 
protein/kg/day. 
 Expected daily weight gain of HIV uninfected children in 
rehabilitation phase of Severe Acute Malnutrition: 
 Poor: < 5g/kg/day 
 Moderate:  5-10 g/kg/day 
 Good: > 10g/kg/day 
 
HIV-infected children with SAM should be managed with the same 
therapeutic feeding approaches as children who are HIV-uninfected. 
However, while resolution of clinical signs such as edema and anorexia 
are similarly expected, early weight recovery may not be as significant as 
for HIV uninfected children. 
 
 
 Discharge criteria 
Readiness for discharge from hospital should be based on the 
anthropometric indicator that was used to identify SAM when the child 
was admitted:  


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 If SAM was identified based on weight-for-height, discharge should be 
considered when the Z score is ≥-2 and the child has had no edema for 
at least two weeks 
 If SAM was identified based on mid-upper arm circumference, 
discharge should be considered when mid-upper arm circumference is 
≥125 mm (12.5 cm) and the child has had no edema for at least two 
weeks 
 
Play and emotional stimulation are also essential elements of management 
in this phase as these can directly influence clinical outcomes including 
growth. Attending to maternal needs and preparing her to look after her 
child once discharged are similarly important. 
 
Table 1. The WHO ten-step approach to management of severe 
malnutrition  
  
 
Treat/Prevent hypoglycaemia 
 
Treat/Prevent hypothermia 
 
Treat/Prevent dehydration 
 
Correct electrolyte imbalance 
 
Treat/Prevent infection 
 
Correct micro deficiencies 
 
Initiate refeeding 
 
Facilitate catch up growth 
 
Provide sensory stimulation and emotional support 
 
Prepare for follow up and recovery 
 
 
 
 
Stage 1: Pre-Entry/Screening (continued)  
 
 
 
Cohort 2: Normal nutrition–mild malnutrition children 
HIV-infected children with normal nutrition–mild malnutrition as defined 
by: 
 
Normal nutrition = WHZ score >-1  
Mild malnutrition =WHZ score >-2 <-1  
 
Cohort 1 and Cohort 2 
Sites will identify severely malnourished children admitted to the 
nutrition rehabilitation unit and will identify children with normal 
nutrition or mild malnutrition from HIV treatment centers. For both 
cohorts, when a potentially eligible child is identified, the child’s parent 
or legal guardian will be informed about the study and asked to provide 
written informed consent for the child to be screened for eligibility.  If 
informed consent is provided, the child will be assigned a participant 
identification number (PID) and a study-specific screening number will be 
obtained through the DMC Subject Enrollment System (SES). After 
informed consent is obtained, screening evaluations will be performed.  
Screening evaluations may be repeated during the screening period at the 


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discretion of the site investigator, with the latest value used for eligibility 
determination. For children found to be eligible, the parent or legal 
guardian will be asked to provide written informed consent for study 
participation (refer to Section 3.2 for more information about the study 
enrollment process). For children found to be ineligible, or who do not 
enroll in the study for any reason, a case report form (CRF) will be 
completed to record the screening outcome. Children who are not enrolled 
will be referred to the nutritional rehabilitation unit and/or non-study HIV 
treatment programs for ongoing care and treatment as needed. 
 
3.2 
Stage 2: Entry  
 
 
Stage 2 begins with the study entry visit and initiation of the study 
HAART regimen. 
 
 
Criteria for Stage 2 Entry: 
             
Cohort 1: Severely malnourished children  
For children with severe malnutrition who are found to be eligible, entry 
into the study will occur after informed consent for study participation has 
been obtained and within 10-18 days after the day of admission to the 
nutritional rehabilitation unit.  Before these children can advance to Stage 
2, they must be judged by their clinician to have improved clinically and 
be eligible to begin the study HAART regimen.  Clinical improvement 
will be indicated by: 
 
 Appetite returned and eating better - child shows interest in food even 
if does not complete amount given 
 No edema and no recurrence of edema 
 No recurrence of diarrhea (if present earlier) 
 Normalized sodium and potassium defined as severity grade 1 or 
lower 
 No evidence of cardiac failure 
 No hypothermia or pyrexia - temperature stable at >35.0 to <38.0° C 
(non-axillary) or >34.4 to <37.4° C (axillary) 
 Ideally, HIV-infected children will show weight gain of about 3-
5gm/kg body weight/day for 1-2 days as expected among recovering 
HIV- uninfected children. However, HIV-infected children will still 
be enrolled as long as the criteria above are fulfilled and there is no 
further weight loss. 
 


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Cohort 2: Normal nutrition–mild malnutrition children  
For children with normal nutrition-mild malnutrition who are found to be 
eligible, entry into the study will occur after written informed consent has 
been obtained and within 7-14 days after screening. Before these children 
can advance to Stage 2, they must be judged by their clinician to be 
clinically stable and eligible to begin the study HAART regimen. Clinical 
stability will be indicated by: 
 
 Normalized sodium and potassium defined as severity grade 1 or 
lower 
 No evidence of cardiac failure 
 No hypothermia or pyrexia - temperature stable at >35.0 to <38.0° C 
(non-axillary) or >34.4 to <37.4° C (axillary) 
 
Other Requirements for Cohort 1 and Cohort 2 
For children in both cohorts, entry evaluations are expected to be 
performed on the day of enrollment into the study, with enrollment 
defined as successful entry of required eligibility data into the SES.  
Successful entry into the SES will generate a study identification number 
(SID) and prescribing information for the study HAART regimen.  The 
study HAART regimen should be initiated on the day of enrollment; 
however, if necessary, initiation of the study HAART regimen may be 
deferred up to 72 hours after enrollment.  The P1092 Core Team should 
be notified of all instances in which the study HAART regimen is not 
initiated on the day of enrollment. 
 
Eligible and enrolled children will initiate the study HAART regimen 
with doses prescribed based on weight bands. Severely malnourished 
children will remain inpatients until they stabilize on the ARVs.  
 
At specified time points during the study, trough and intensive PK 
sampling will be performed, nutritional assessment, and adverse event 
monitoring will be carried out. 
 


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3.3 
Criteria for Continued Participation in Pharmacokinetics Testing 
 
Prior to conducting the intensive pharmacokinetic measurements at 1, 12 
and 24 weeks, the severely malnourished children must be judged by their 
clinician to be nutritionally and clinically improved. If a child’s condition 
is not improving or if there are signs of clinical deterioration including 
weight loss or development of edema at any time during the study period, 
the child should be readmitted and managed according to WHO 
guidelines. All children who develop edema during the course of the 
study will be discontinued from the PK component but continue on 
study/off study drug. Those with only weight loss, but no edema will 
have their PK evaluations done but blood volumes drawn will be 
according to their current weight. In addition, the subject’s most recent 
hemoglobin preceding the intensive PK study visit must be ≥ 7.5 g/dl.  If 
any child’s parent/guardian withdraws consent for PK evaluations, the 
child will be discontinued from the PK component but continue on 
study/off study drug. 
 
3.4 
Pharmacokinetics 
 
At 1, 12 and 24 weeks after initiation of HAART, intensive PK sampling 
will be carried out in the context of a morning dose of ARVs. The 
caregiver will be asked to hold the child’s morning dose so that a pre-
dose sample can be collected. Serial samples will be collected just prior to 
an observed morning dose and at 1, 2, 4, 8 and 12 hours post-dosing. To 
assure that the PK samples are collected under steady-state conditions, 
every effort will be made to assure doses are administered approximately 
every 12 hours for the 48 hours preceding the intensive sampling period.  
 
For those in Cohort 1 (severely malnourished children), at week 1, 
intensive PK sampling is done as the child is an inpatient at 7-10 days 
following study entry, and the child’s inpatient providers will be asked to 
hold the child’s morning dose of ARVs so that a pre-dose sample can be 
collected.  At weeks 12 and 24, children will return to the clinical research 
center in the morning or prior evening for intensive sampling.  At weeks 
12 and 24, the caregiver will be asked to hold the child’s morning dose of 
ARVs so that a pre-dose sample can be collected.  
 
For those in Cohort 2, at weeks 1, 12 and 24, children will come to the 
clinical research center in the morning or prior evening for intensive 
sampling.  The caregiver will be asked to hold the child’s morning dose of 
ARVs so that a pre-dose sample can be collected.  
 
There will be standardization of food intake around the PK sampling at 
week 1 at all study sites. The meal will be similar to RUTF or F100 for 
children with normal – mild malnutrition. 
 


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For weeks 1, 12 and 24, an additional sample generating 1 mL of plasma 
will be collected at the 2 hour time point.  This will be done to determine 
the free fraction of lopinavir at the time of the peak concentration. 
 
At weeks 4, 8, 16, 36, 48, a trough PK sample will be collected for the 
ARVs just prior to the morning dose of drug.  Again, caregivers will be 
asked to hold the child’s morning dose of ARVs.  These values will be 
analyzed in combination with trough samples collected just prior to 
dosing and as part of intensive sampling on weeks 1, 12 and 24. 
 
 
 
In all cases for the PK visits, it is imperative that the precise time of the 
morning dose administration is recorded as well as the precise time for all 
samples collected.  
 
Refer to Appendix I, Schedule of Evaluations, for a complete description 
of the clinical and laboratory evaluations to be performed. 
 
 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 
Inclusion Criteria 
 
4.11 
Age ≥6 months (defined as ≥180 days) to <36 months at entry 
 
4.12 
Documentation of HIV-1 infection defined as positive results from 
two samples collected at different time points. All samples tested 
must be whole blood, serum or plasma using methods approved by 
the IMPAACT Laboratory Center. 
 
For subjects less than 2 years of age or have not ceased 
breastfeeding for at least 4 weeks, Sample #1 and Sample #2 may 
be tested using any of the following: 
 
 
One HIV DNA PCR 
 
One quantitative HIV RNA PCR (above the limit of detection) 
 
One qualitative HIV RNA PCR 
 
One total HIV nucleic acid test 
 
For these subjects, at least one of the two samples must be tested 
in the study site’s designated VQA-certified laboratory.  For tests 
performed in other (non-VQA-certified) settings, adequate source 
documentation, including the date of specimen collection, date of 
testing, test performed, and test result, must be available. 
 


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For subjects 2 years of age and older who have ceased 
breastfeeding for at least 4 weeks, Sample #1 may be tested using 
any of the following: 
 
 
Two rapid antibody tests from different manufacturers or based 
on different principles and epitopes 
 
One EIA or Western Blot OR immunofluorescence OR 
chemiluminescence 
 
One HIV DNA PCR 
 
One quantitative HIV RNA PCR (above the limit of detection) 
 
One qualitative HIV RNA PCR) 
 
One total HIV nucleic acid test 
 
For subjects 2 years of age and older who have ceased 
breastfeeding for at least 4 weeks, Sample #2 may be tested using 
any of the following: 
 
 Rapid antibody test. If this option is used in combination with 
two rapid tests for Sample #1, at least one of the three rapid 
tests must be FDA-approved and the third rapid test must be 
from a third manufacturer or based on a third principle or 
epitope. 
 One EIA OR Western Blot OR immunofluorescence OR 
chemiluminescence 
 One HIV DNA PCR 
 One quantitative HIV RNA PCR (above the limit of detection) 
 One qualitative HIV RNA PCR 
 One total HIV nucleic acid test 
 
For these subjects, if both samples are tested using antibody tests, 
at least one of the samples should be tested in a laboratory that 
operates according to 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 the study 
site’s designated VQA-certified laboratory.  For tests performed in 
other (non-VQA-certified or non-GCLP-compliant) settings, 
adequate source documentation, including the date of specimen 
collection, date of testing, test performed, and test result, must be 
available. 
 
Note:  HIV RNA PCR is a required screening evaluation that must 
be performed in a VQA-certified laboratory (refer to Appendix I).  
Assuming the result of this test is above the limit of detection of 
the assay, this test may serve as one of the two tests required for 
documentation of HIV infection.  
 


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4.13 
Meets WHO classification for severe malnutrition 
(non-edematous), normal nutrition status, or mild 
malnutrition as described below: 
 Severe non-edematous malnutrition defined as weight for 
height z (WHZ) score <-3 or MUAC <115 mm 
 Normal nutrition status defined as weight for height z (WHZ)  
score >-1 
 Mild malnutrition defined as weight for height z (WHZ)    
score >-2 ≤-1 
 
 
4.14 
Eligible for HAART:  as defined by WHO 2013 pediatric 
guidelines, ART should be initiated in all children infected with 
HIV below five years of age, regardless of WHO clinical stage or 
CD4 cell count.  
4.15 
Parent or legal guardian able and willing to provide signed 
informed consent, remain within the study area during the study 
period and agree to have subject followed at the clinical site 
 
4.16 Qualifying laboratory values obtained from specimens collected 
within the study-specific screening period: 
Hematology testing indicates 
 Hemoglobin ≤ Grade 2  
 White blood cells ≤  Grade 2  
 Neutrophils (absolute count) ≤ Grade 2  
 Platelets ≤ Grade 1  
 
Chemistry testing indicates 
 AST ≤ Grade 2  
 ALT ≤ Grade 2  
 Creatinine ≤ Grade 1  
 Sodium ≤ Grade 1  
 Potassium ≤ Grade 1  
 Bicarbonate ≤ Grade 1  
 
4.17 For severely malnourished children: An inpatient in a nutrition 
rehabilitation unit. Clinical improvement after 10-18 days on 
nutrition rehabilitation defined as: Appetite returned and eating 
better – child shows interest in food even if does not complete 
amount given: 


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 No further weight loss  
 Normalized sodium and potassium defined as severity grade 1 
or lower 
 No evidence of cardiac failure 
 Loss of apathy and starting to play  
 No hypothermia or pyrexia - temperature stable at >35.0 to 
<38.0° C (non-axillary) or >34.4 to <37.4° C (axillary) 
 
For children with normal – mild malnutrition, clinical stability will 
be indicated by: 
 
 Good appetite 
 Normalized sodium and potassium defined as severity grade 1 
or lower 
 No hypothermia or pyrexia - temperature stable at >35.0 to 
<38.0° C (non-axillary) or >34.4 to <37.4° C (axillary) 
 
4.2 
Exclusion Criteria 
 
4.21  Edematous malnutrition at the time of study entry 
 
4.22 
≥ Grade 3 respiratory distress or presence of cardio respiratory 
compromise within 3 days prior to entry 
 
4.23 
Chemotherapy for malignancy 
 
4.24 
Acute infection for which the child has received appropriate 
antimicrobial treatment for <5 days 
 
4.25 
Tuberculosis disease 
 
4.26 
Clinical hepatitis as evidenced by jaundice and hepatomegaly 
 
4.27 
Taking any disallowed medications (see Section 4.32) 
 
4.28 
Any condition, situation, or clinical finding that in the opinion of 
the investigator would place the child at an unacceptable level of 
risk for injury, or render the child/caregiver(s) unable to meet the 
requirements of the study, interfere with study participation, or in 
the interpretation of study results. 
 


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4.3 
Concomitant Medication Guidelines 
 
4.31 
Precautionary Medications 
Please refer to the study medications’ most recent package inserts, 
Investigator's Brochures, or updated information from DAIDS 
(RSC) to obtain the most current information on drug interactions, 
contraindications, and precautions. 
4.32 
Disallowed Medications 
 
The following medications are disallowed while on study: 
 
 
Use of known inducers or inhibitors of cytochrome P450, such 
as rifampicin, ketoconazole, anticonvulsants  
 
Herbal medications 
 
Antihyperlipidemic agents 
 
Rifabutin 
 
Flecainamide 
 
Propafenone 
 
Astemizole 
 
Terfenadine 
 
Diydroergotamine 
 
Ergonovine 
 
Ergotamine 
 
Methylergonovine 
 
Cisapride 
 
Pimozide 
 
Midazolam (allowed if used in a monitored setting for 
procedures)  
 
Triazolam 
 
4.4 
Enrollment Procedures 
 
Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol informed 
consent form(s) approved, as appropriate, by their local institutional 
review board (IRB)/ethics committee (EC) and any other applicable 
regulatory entity (RE). Upon receiving final approval, sites will submit all 
required protocol registration documents to the DAIDS Protocol 
Registration Office (DAIDS PRO) at the Regulatory Support Center 
(RSC).  The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received.   
 


IMPAACT P1092 
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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. 
 
A Site Implementation Plan is required from each site participating in the 
study. The plan must be submitted to the Protocol Team for review and 
approval before protocol registration can occur.   
 
Written informed consent must be obtained before any study related 
procedures are performed.  Informed consent will first be obtained for 
screening (prior to performing any study-specific screening procedures); 
for children found to be eligible, informed consent for study participation 
will be obtained separately (prior to performing any on-study procedures). 
 
Minimum age at enrollment is six months (180 days).  However, screening 
evaluations may be performed 7-14 days (for children with normal 
nutrition to mild malnutrition) or 10-18 days (for children with severe 
malnutrition) prior to six months (180 days) of age, as long as the entry 
visit does not occur earlier than six months (180 days) of age. 
 
Refer to Sections 3.1 and 3.2 for additional information on use of the 
DMC Subject Enrollment System (SES) for this study.  
 
4.5 
Co-enrollment Procedures 
 
Co-enrollment into other studies will be considered on a case by case basis 
and requires the approval of the protocol chairs of P1092 and the co-
enrollment protocols. 
 
 


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5.0 
STUDY TREATMENT 
 
5.1 
Drug Regimens, Administration and Duration 
 
For purposes of this study, LPV/r, ZDV and 3TC are all considered to be 
study drugs.  
 
All children will receive the same starting regimen: a LPV/r-based 
regimen, with ZDV/3TC as the backbone. At each visit, dosing will be 
adjusted to the current WHO weight band dose (see Dosing Table below).  
The study treatment duration is 48 weeks. 
 
Arms A, B, C, D 
Day 0-Week 48 
Lopinavir/Ritonavir two times daily orally at the WHO weight band dose 
Zidovudine two times daily orally at the WHO weight band dose 
Lamivudine two times daily orally at the WHO weight band dose 
 
Lopinavir/Ritonavir Administration 
Administer lopinavir/ritonavir every 12 hours according to weight band 
dosing. Lopinavir/ritonavir must be taken with food.  The Dosing Table 
presents dosing guidelines for zidovudine, lamivudine, and 
lopinavir/ritonavir oral solution based on body weight.   
 
All liquid doses should be administered using a calibrated dosing syringe. 
Contact the protocol pharmacist for information regarding purchasing 
calibrated dosing syringes. 
 
Dosing Table  
 
Drug 
Strength 
Dose Volume by Weight Band for 
Study-Supplied LIQUID Formulations (twice daily) 
3.0-5.9 kg 
6.0-9.9 kg 
10.0-13.9 kg 
14.0-19.9 kg 
20.0-24.9 kg 
ZDV 
10 mg/mL 
6 mL 
9 mL 
12 mL 
15 mL 
18 mL 
3TC 
10 mg/mL 
3 mL 
4 mL 
6 mL 
8 mL 
10 mL 
LPV/r 
80/20 mg/mL 
1 mL 
1.5 mL 
2 mL 
2.5 mL 
3 mL 
 
If a subject vomits within 30 minutes of dosing, he or she should be re-
dosed one time to replace the vomited dose.  If the vomiting occurs on a 
day of PK sampling, the sampling may proceed if the subject vomited 
within 30 minutes of the first dose and can be re-dosed with a full dose 
that is not subsequently vomited.  Otherwise, the PK sampling should 
occur on the following day. 
 


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5.2 Drug Formulation and Storage    
 
This protocol will use pediatric liquid formulations.  
 
Zidovudine 
Zidovudine (ZDV, Retrovir) will be available as a strawberry-flavored 
clear colorless to pale yellow syrup in a glycerin/sucrose base at a 
concentration of 10 mg/ml.  The ZDV syrup will be supplied in opaque 
plastic bottles with child resistant closures. Store at room temperature, 
15°-25°C (59°-77°F). 
 
Lamivudine 
Lamivudine oral solution (Epivir®, 3TC) is for oral administration. One 
milliliter (1 mL) of lamivudine oral solution contains 10 mg of lamivudine 
(10 mg/mL) in an aqueous solution and the inactive ingredients artificial 
strawberry and banana flavors, citric acid (anhydrous), methylparaben, 
propylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose. 
Store in tightly closed bottles at 25°C (77°F). See USP Controlled Room 
Temperature. 
 
Lopinavir/ritonavir 
Lopinavir 80 mg/ritonavir 20 mg per milliliter oral solution (Kaletra®, 
LPV/r) contains 42.4% alcohol by volume.  Inactive ingredients: 
acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, 
glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, 
natural and artificial vanilla flavor, peppermint oil, polyoxyl 40 
hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, 
sodium chloride, sodium citrate, and water.   
 
Store lopinavir 80 mg/ritonavir 20 mg oral solution at 2- 8C (36-46F) 
until dispensed to subject. Avoid exposure to excessive heat. Refrigerated 
lopinavir 80 mg/ritonavir 20 mg oral solution remains stable until the 
stated expiration date.  For subject use, if the lopinavir 80 mg/ritonavir 20 
mg oral solution is stored at room temperature, up to 25C (77F), it 
should be used within 2 months. 
 
5.3 
Drug Supply, Distribution and Pharmacy   
 
Zidovudine 10 mg/mL syrup and lamivudine 10 mg/mL oral solution will 
be supplied by ViiV Healthcare Ltd. Lopinavir 80 mg/ritonavir 20 mg per 
milliliter oral solution will be supplied by Abbott Laboratories.  
 


IMPAACT P1092 
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40 
 
Each drug is manufactured by the company that is supplying the drug. 
Study products will be available through the NIAID Clinical Research 
Products Management Center (CRPMC). The site pharmacist can obtain 
the study products for this protocol by following the instructions in the 
manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks in the Section Study Product Management Responsibilities. 
 
Abacavir (ABC) will not be provided by the study and must be obtained 
from the subject’s clinical care provider; WHO weight band dosing is 
provided in the tables below.  Serious and sometimes fatal hypersensitivity 
reactions have been associated with ABC containing products. Please refer 
to the ABC package insert for complete prescribing information. 
 
Drug 
Strength 
Dose Volume by Weight Band  
for LIQUID Formulation (twice daily) 
3.0-5.9 kg 
6.0-9.9 kg 
10.0-13.9 kg 
14.0-19.9 kg 
20.0-24.9 kg 
ABC 
20 mg/mL 
3 mL 
4 mL 
6 mL 
— 
— 
 
Drug 
Strength 
Number of Tablets by Weight Band for  
DISPERSIBLE TABLET Formulation (twice daily) 
3.0-5.9 kg 
6.0-9.9 kg 
10.0-13.9 kg 
14.0-19.9 kg 
20.0-24.9 kg 
ABC 
60 mg 
1 
1.5 
2 
2.5 
3 
 
 
6.0 
SUBJECT MANAGEMENT 
 
6.1 
Team Communications  
 
Questions concerning clinical management of study subjects and all 
communication regarding adverse events (AEs) should be addressed to the 
P1092 Core Team at impaact.corep1092@fstrf.org.  Include the subject’s 
PID when applicable. The appropriate team member will respond via e-
mail, generally within 24 hours (Monday-Friday).   
 
6.2 
Toxicity Management 
 
The Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events, (DAIDS AE Grading Table), Version 2.0, dated 
November 2014, must be used for screening eligibility and for grading all 
adverse events, and is available on the RSC website (http://rsc.tech-
res.com/safetyandpharmacovigilance/).  The only exception to this 
requirement pertains to axillary-measured fever, which will be graded as 
follows: 
 
Grade 1:  
37.4 to < 38.0o C  
Grade 2: 
38.0 to < 38.7o C  
Grade 3: 
38.7 to < 39.4o C  
Grade 4: 
 39.4o C 


IMPAACT P1092 
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Management of AEs will be according to the best clinical practice and the 
judgment of the site investigator. Alternate explanations for clinical and 
laboratory abnormalities must be sought. Laboratory normals will be the 
institutional values. Abnormal clinical and laboratory findings should be 
followed until resolution to < Grade 2.  For all grade 3 and 4 laboratory 
values, sites should attempt to repeat the test within 3 days and should 
notify the Core Team for exceptions (longer period of time needed) up to 
7 days. 
 
The toxicity management guidelines are for AEs for which a relationship 
to study drugs cannot be excluded. Clinical or laboratory AEs that are 
definitely unrelated to study drug(s) may not result in study drug 
interruption. 
 
Study drug doses will not be modified for toxicity; drugs will either be 
continued at protocol-specified doses or discontinued/replaced.  For 
hematologic toxicity on a ZDV-inclusive regimen and ZDV intolerance 
(Section 6.22), the site investigator or designee must notify the Core Team 
in the following situations: 
ZDV replacement with ABC 
ZDV may be replaced with ABC at the discretion of the 
site investigator/clinician in cases of > Grade 3 
hematologic toxicity on a ZDV-inclusive regimen or ZDV 
intolerance. Refer to Section 6.22. Notify Core Team 
within 3 business days. 
Grade 4 adverse events that are 
definitely not related to study drugs 
Notify Core Team and provide management plan within 3 
business days. 
Study drug related Grade 4 adverse 
events  
ZDV should be replaced with ABC. Notify Core Team 
and provide management plan within 3 business days. 
 
DMC-generated reports of all Grade 2 LFTs, and Grade 3 and 4 AEs for 
which a relationship to study drugs cannot be excluded will be reviewed 
by the P1092 Core Team on a regular basis. 
 
Subjects who prematurely discontinue study treatment will be placed in an 
off drug/on study category and continue to be followed for the duration of 
the study. 
 
6.21 
General Toxicity Management Guidelines 
 
Grade 1 Toxicity:   
Continue study drugs. 
 
Grade 2 Toxicity:   
Continue study drugs. 
 


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Grade 3 Toxicity:  
Notify the Core Team within 3 business days. Study drugs can be 
continued at the discretion of the site investigator/clinician for 
clinical events, or while awaiting a repeat assessment/confirmation 
of an abnormal laboratory test as soon as possible (at most within 
one week) except for hepatotoxicities (for Grade 3 
hepatotoxicities, study drugs should be held as specified in Section 
6.23 below).  If repeat assessment confirms Grade 3 toxicity, hold 
all study drugs and follow abnormal laboratory values weekly.  If 
toxicity resolves to < Grade 2 within 14 days, all study drugs can 
be restarted. If Grade 3 toxicity persists for >14 days, or recurs to > 
Grade 3 after reintroduction of study drugs, all study drugs must be 
permanently discontinued.  Alternatively, if the toxicity is clearly 
attributed to an individual study drug, that study drug may be 
permanently discontinued and replaced, with continuation of other 
drugs in the regimen. 
 
Grade 4 Non-Life-Threatening Toxicity:   
All study drugs should be held and the Core Team should be 
notified within 3 business days.  For abnormal laboratory test, 
repeat assessment/confirmation should be done as soon as possible 
(at most within 1 week).  If repeat assessment confirms Grade 4 
toxicity, all study drugs should be permanently discontinued.  If 
repeat assessment shows Grade 3 toxicity, continue to hold all 
study drugs and follow abnormal laboratory values weekly.  If 
toxicity resolves to < Grade 2 within 14 days, all study drugs can 
be restarted after approval from the Core Team.  If > Grade 3 
toxicity recurs after reintroduction of study drugs, all study drugs 
must be permanently discontinued. 
 
Grade 4 Life-Threatening Toxicity:   
All study drugs should be permanently discontinued and the Core 
Team should be notified within 3 business days.  
 
6.22 
Hematologic Toxicity on a ZDV-Inclusive Regimen and ZDV 
Intolerance  
 
NOTE: For subjects not receiving ZDV, follow general toxicity 
management guidelines in Section 6.11. 
 
Grade 1 Hematologic Toxicity 
Continue study drugs. 
 
Grade 2 Hematologic Toxicity 
Continue study drugs. 
 


IMPAACT P1092 
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43 
 
Grade 3 Hematologic Toxicity 
For Grade 3 hematologic toxicity — involving hemoglobin level, 
white blood cell count, absolute neutrophil count, or platelet count 
— on a ZDV-inclusive regimen, continue study drugs at the 
discretion of the site investigator/clinician while awaiting a repeat 
assessment/confirmation of the abnormal laboratory test as soon as 
possible (at most within 1 week). Notify the Core Team within 3 
business days. If repeat assessment confirms Grade 3 toxicity, the 
site investigator/clinician may replace ZDV with ABC and restart 
study drugs at this point (if held). Abnormal laboratory value(s) 
should be followed weekly until resolution to < Grade 2.  If 
trimethoprim/sulfamethoxazole is being administered for 
prophylaxis, the site investigator/clinician may decide to continue 
or discontinue this in the presence of Grade 3 hematologic toxicity.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
*Site clinician may choose to continue the child on non-study HAART based on local treatment standards and the best 
interest of the child. 
 
If toxicity resolves to ≤ Grade 2 
within 14 days from date of 
intervention (holding drug or 
replacing ZDV with ABC): 
 Restart study drugs (if held) 
 Continue routine monitoring 
Grade 3 toxicity confirmed: 
 Replace ZDV with ABC (resume other study drugs if 
previously held) 
 Otherwise hold all study drugs 
 Notify Core Team and follow abnormal labs weekly until 
resolution to ≤ Grade 2 
Grade 3 toxicity not confirmed (or 
resolved to ≤ Grade 2): 
 Continue routine monitoring 
If Grade 3 toxicity persists for  
≥ 14 days from date of 
intervention (holding drug or 
replacing ZDV with ABC): 
 Permanently discontinue all 
study drugs*  
If ≥ Grade 3 toxicity recurs after 
reintroduction of study drugs: 
 Permanently discontinue all 
study drugs* 
 Notify Core Team 
 Continue study drugs at 
discretion of site 
investigator/clinician  
 Repeat assessment (as soon as 
possible, at most within 1 week) 
Grade 3 hematologic toxicity 


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44 
 
Grade 4 Hematologic Toxicity  
For Grade 4 hematologic toxicity — involving hemoglobin level, 
white blood cell count, absolute neutrophil count, or platelet count 
— on a ZDV-inclusive regimen, ZDV should be discontinued and 
substituted with ABC. Notify the Core Team within 3 business 
days.  If trimethoprim/sulfamethoxazole is being administered for 
prophylaxis, it should be temporarily held.  Repeat assessment 
should be done as soon as possible (at most within one week).  If 
repeat assessment confirms Grade 4 non-life threatening 
hematologic toxicity and this persists for more than 14 days, study 
drugs should be permanently discontinued. Abnormal laboratory 
value(s) should be followed weekly.  The child may remain on 
study drugs/on study if the toxicity resolves to < Grade 2 within 14 
days.  If resolution to < Grade 2 does not occur within 14 days or ≥ 
Grade 3 toxicity recurs, all study drugs must be permanently 
discontinued. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
*Site clinician may choose to continue the child on non-study HAART based on local treatment standards and the best 
interest of the child. 
 
 
 
 
If ≤ Grade 2 toxicity on repeat 
assessment: 
 Continue routine monitoring 
 Restart TMX, if applicable 
Grade 3 or 4 toxicity on repeat assessment: 
 Continue previous management action 
 Follow abnormal labs weekly  
Grade ≤ 2 toxicity on repeat assessment: 
 Restart TMX, if applicable 
 Repeat assessment within 14 days  
If Grade 3 or 4 toxicity persists 
for ≥ 14 days from date of 
intervention (holding drug or 
replacing ZDV with ABC): 
 Permanently discontinue all 
study drugs*  
If ≥ Grade 3 toxicity recurs after 
reintroduction of study drugs: 
 Permanently discontinue all 
study drugs* 
 Discontinue ZDV; replace with ABC 
 Temporarily hold TMX if being used 
 Repeat assessment (as soon as 
possible, at most within 1 week)  
 Notify Core Team. 
Grade 4 hematologic toxicity 


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6.23 
Symptomatic and Asymptomatic Hepatitis in Subjects on Study 
Drug  
6.231 Clinical (Symptomatic) Hepatitis 
Subjects taking study drug should be monitored for the 
development of a clinical hepatitis syndrome.  Symptoms 
of hepatitis include the following: fatigue, malaise, 
anorexia, nausea, acholic stools, bilirubinuria, jaundice, 
liver tenderness, or hepatomegaly.  Subjects with signs and 
symptoms suggestive of clinical hepatitis must seek 
medical attention immediately and have liver function tests 
(LFTs) and screening for hepatitis A and B performed.   
Management of hepatitis will be according to the grading 
of AST/ALT stipulated below. 
6.232 AST/ALT Elevations  
If AST and ALT are of different severity grades, follow the 
management guidance for the higher of the two grades. 
 
Grade 1 
If grade 1 at entry, no additional evaluation is required; if 
normal at entry, follow guidance in this section: 
 
AST and ALT must be repeated as soon as possible (at 
most within one week). 
 
Study drugs may be continued while repeating AST and 
ALT as long as the subject is asymptomatic.  Subjects 
with a confirmed Grade 1 AST or ALT who are 
asymptomatic may continue study drugs with continued 
close observation. 
 
For study subjects with Grade 0 AST and/or ALT at 
study entry, an increase to Grade 1 AST and/or ALT 
even in an asymptomatic subject may be of concern. 
 
Subjects should be evaluated for a cause of the LFT 
abnormality, and should be observed for worsening 
LFT elevation or development of clinical hepatitis.  
Careful assessments should be undertaken for non-
study drug-related toxicity, the lactic acidosis 
syndrome, and viral hepatitis as the cause of the 
transaminase elevation.   
 
Grade 2 
If grade 2 at entry, no additional evaluation is required; if 
normal or Grade 1 at entry, follow guidance in this section: 
 
AST/ALT must be repeated as soon as possible (at most 
within one week) and then be followed weekly until 
levels are < Grade 1. 


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 
Study drugs may be continued while repeating AST and 
ALT as long as the subject is asymptomatic.  Subjects 
with a confirmed Grade 2 AST or ALT who are 
asymptomatic may continue study drugs with continued 
close observation.     
 
Subjects should be evaluated for a cause of the LFT 
abnormality, and should be observed for worsening LFT 
elevation or development of clinical hepatitis.  Careful 
assessments should be undertaken for non-study drug-
related toxicity, the lactic acidosis syndrome, and viral 
hepatitis as the cause of the transaminase elevation.  
 
If the AST/ALT elevation is considered most likely due to 
concomitant illness or medication, then standard 
management, including discontinuation of the likely 
causative medication, should be undertaken. 
Grades 3 and 4  
 
Hold study drugs while awaiting a repeat 
assessment/confirmation of the abnormal laboratory test 
as soon as possible but at most within 7 days. 
 
AST/ALT should be repeated as soon as possible (at most 
within 7 days) and then be followed weekly until levels 
are < Grade 1. Other LFTs also may be performed at the 
discretion of the site investigator if considered useful for 
diagnostic or clinical management purposes. 
 
Notify the P1092 Core Team of Grades 3 or 4 toxicity 
within 3 business days. 
 
If the AST/ALT elevation does not improve to < Grade 2 
within two weeks of discontinuing study drug, all study 
drugs should be permanently discontinued.   
 
If an alternate cause of the AST/ALT elevation can be 
established (i.e. confirmed diagnosis Hepatitis A) Study 
drugs may be restarted after resolution of AST/ALT to < 
Grade 2 and within 21 days of the initial elevation. If the 
AST/ALT does not resolve to < Grade 2 within 21 days, 
all study drugs must be permanently discontinued.  If > 
Grade 3 elevation in AST/ALT recurs after reintroduction 
of study drugs, all study drugs must be permanently 
discontinued. The protocol team will be notified to discuss 
further management. 
 
Subjects should be evaluated for development of clinical 
hepatitis. Careful assessments should be undertaken for 
non-study drug-related toxicity, the lactic acidosis 
syndrome, and viral hepatitis as the cause of the 
transaminase elevation. 


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6.24 
Rash 
 
 
 
 
Grade 1 or 2, on Abacavir 
Study drugs may need to be held depending on rash distribution 
and relatedness assessment. 
 If the rash is generalized and there is no specific alternative 
explanation for the rash: 
 Hold entire regimen, 
 Test ALT within 3 business days, and 
 Evaluate for symptoms of clinical hepatitis and 
hypersensitivity reaction.  
If any clinical symptoms of hepatitis or ALT elevation or 
hypersensitivity reaction, permanently discontinue abacavir 
and consult with the Core Team on alternative ARV regimens. 
 If the rash is not generalized or if there is a specific alternative 
explanation for the rash (e.g., varicella), study drugs — 
including abacavir — may be continued with no additional 
evaluation required.   
 
Grade 1 or 2, Not on Abacavir 
 Continue study drugs. 
 Rash may be treated symptomatically, but should be monitored 
closely by the site investigator. 
 
Grade 3 
 
Hold entire regimen unless the rash is determined to be 
unrelated to study drug 
 
Notify the Core Team within 3 business days. 
 
If there is no specific alternative explanation for the rash (e.g., 
varicella), test ALT and manage per the ALT/AST guidelines 
in Section 6.23.  
 
If on abacavir, permanently discontinue abacavir.  When the 
rash resolves, study drug may be resumed with an alternate 
regimen that does not include abacavir; consult with the Core 
Team on alternative regimens.  
 
Grade 4 
 Hold entire regimen. 
 Notify and consult with the Core Team on alternative ARV 
regimens within 3 business days. 
 
Note:  Abacavir should never be restarted following a 
hypersensitivity reaction. 
 


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6.3 
Endpoints 
 
6.31 
Toxicity Endpoints   
 
Any one of the following constitutes a toxicity endpoint: 
 
 
Persistent (lasting > 14 days) or recurrent treatment-related 
Grade 3 toxicity 
 
Persistent (lasting ≥14 days), non-life-threatening, treatment-
related Grade 4 toxicity (confirmed within 7 days) or 
recurrence to Grade ≥ 3 
 
EXCEPTION: in the setting of ZDV and Grade 4 hematologic 
toxicity - persistent (lasting ≥ 14 days) treatment-related Grade 
4 toxicity 
 
Single, treatment-related, life-threatening Grade 4 toxicity 
  
Subjects who achieve any of the above toxicity endpoints will be 
placed in an off drug/on study category and continue to be 
followed for the duration of the study. 
 
6.32 
Virologic Endpoints 
 
The following constitutes a virologic endpoint: confirmed plasma 
HIV-1 RNA level >400 copies/mL at 24 weeks.  Virologic criteria 
must be confirmed before the subject will be considered to have 
met a virologic endpoint.  
 
At each scheduled viral load testing time point during follow-up, if 
an HIV-1 RNA level >400 copies/mL is identified, the subject will 
be recalled to the clinic within 4 weeks for confirmatory testing. 
 
Subjects who achieve virologic endpoint will be allowed to 
continue therapy if the subject is clinically stable. If viral load is 
>1000 copies/ml, the site investigator will intensify work with the 
subject’s family to ensure adherence and if need be effect a change 
in ARV therapy. 
 


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6.33 
Pharmacokinetic Endpoint 
 
The primary pharmacokinetic endpoint is the area under the 
plasma concentration time curve from 0-12 hrs (AUC0-12h) of 100 
micrograms*hr/mL which will be estimated under steady-state 
conditions and PK trough of > 1 micrograms/mL  
 
Additional parameters to be investigated include plasma clearance 
(CL/F), Ctrough (collected just prior to the morning ARV dose), Cmax 
(peak plasma concentration) and Tmax (the time to reach Cmax).  
 
6.4 
Criteria for Treatment Discontinuation 
 
 Treatment with disallowed medications as described in Section 4.32. 
 Drug toxicity that requires permanent study drug discontinuation as 
defined in Section 6.0 
 
Subjects who permanently discontinue all study drugs will remain in 
follow-up for the protocol-specified duration, however evaluations will be 
performed per the Off treatment/On study column of the Schedule of 
Evaluations.  For these subjects, the site investigator/clinician may choose 
to continue the child on non-study HAART based on local treatment 
standards and the best interest of the child. 
 
6.5 
Criteria for Deferral of PK Evaluations 
 
 
Intensive PK testing should be deferred (up to 5 days) if the subject: 
  
 Missed any doses of study drug within the prior 72 hours.  Intensive PK 
testing should be done as soon as all doses have been taken for 72 
hours. 
 Had a hemoglobin value < 7.5 g/dl at the most recent prior evaluation.  
Hemoglobin can be repeated and, if ≥7.5 g/dl, the intensive PK testing 
should be performed.  
 Has diarrhea.  Intensive PK testing should be done as soon as possible 
after the diarrhea has resolved.  
 
For all of the above, if the intensive PK testing is not done within five 
days after the close of the allowable window for the evaluations, the 
evaluations will be considered missed for that visit.   
 


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As noted in Section 5.1, if a subject vomits within 30 minutes of dosing, 
he or she should be re-dosed one time to replace the vomited dose.  If the 
vomiting occurs on a day of PK sampling, the sampling may proceed if the 
subject vomited within 30 minutes of the first dose and can be re-dosed 
with a full dose that is not subsequently vomited.  Otherwise, the PK 
sampling should occur on the following day. 
 
6.6 
Criteria for Discontinuation of PK Evaluations 
 
 Clinical deterioration during the study including development of 
edema.  The subject should discontinue the PK component of the study.  
 Subject is non-adherent to study treatment and the investigator believes 
that adherence is unlikely to improve. 
 
Subjects who have only one week of PK data will be replaced. 
 
6.7 
Criteria for Study Discontinuation 
 
 The parent or legal guardian refuses further treatment and/or follow-up 
evaluations. 
 The investigator determines that further participation would be 
detrimental to the subject’s health or well-being. 
 The subject fails to comply with the study requirements so as to cause 
harm to him/herself or seriously interfere with the validity of the study 
results 
 
 
7.0 
EXPEDITED ADVERSE EVENT REPORTING  
 
7.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, 
which is available on the RSC website at http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 
The 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 or technical difficulties, expedited 
AEs may be submitted via the DAIDS EAE Form.  For questions about 
DAERS, please contact DAIDS-ES at DAIDS-ESSupport@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/safetyandpharmacovigilance/.  


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For questions about EAE reporting, please contact the RSC 
(DAIDSRSCSafetyOffice@tech-res.com or call 1-800-537-9979 or  
301-897-1709 or fax 1-800-275-7619 or 301-897-1710). 
 
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 agents for which relationship assessments are required are 
zidovudine, lamivudine, and lopinavir/ritonavir.  In addition, for subjects 
who may receive abacavir due to intolerance to zidovudine, relationship 
should also be assessed for abacavir. 
 
In addition to reporting all SAEs as defined above, other events that sites 
must report in an expedited fashion include all malignancies, seizures and 
Grade 3 and 4 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. 
  
The death of any subject 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 2.0, dated 
November 2014, must be used and is available on the RSC website at  
http://rsc.tech-res.com/safetyandpharmacovigilance/ 
 


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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 subject (from study enrollment until study 
completion or discontinuation of the subject 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). 
 
7.5 
CRF Recording Requirements for Laboratory Test Results, Signs, 
Symptoms, and Diagnoses 
 
The results of all laboratory tests performed at screening, entry, and post-
entry must be recorded on CRFs, regardless of severity grade. 
 
All abnormal (severity grade 1 and higher) signs, symptoms, and 
diagnoses occurring within 30 days prior to study entry must be recorded 
on CRFs.  All abnormal (severity grade 1 and higher) signs, symptoms, 
and diagnoses occurring post-entry must also be recorded on CRFs at all 
visits.   
 
 
8.0 
STATISTICAL CONSIDERATIONS 
 
8.1 
General Design Issues  
 
This is a Phase IV, multicenter, open label, intervention pharmacokinetic 
study to compare the pharmacokinetics, safety and tolerance of 
ZDV+3TC+LPV/r in severely malnourished and normal – mildly 
malnourished children.  Two cohorts will be formed (severely 
malnourished and normal – mildly malnourished) and age-based strata 
(threshold 18 months of age) will be formed within each cohort.  Within 
each stratum in each cohort, patients will be assigned to 
ZDV+3TC+LPV/r.  Because it is desired that the two cohorts have 
comparable age distributions, upper bounds on stratum arm enrollments 
will be established, as described in section 8.3.   
 
8.2 
Outcome Measures   
 
All components of treatment regimens will be evaluated in six conditions 
(two initial nutritional states and three follow-up times: 1, 12 and 24 
weeks following study entry).   
 


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Primary Outcome Measures  
 
 Steady-state AUC and plasma clearance (CL/F) for ZDV, 3TC, and 
LPV/r 
 Safety and tolerability measures, which include numbers and percent 
of subjects with at least Grade 3 adverse events related to study drugs 
and at least Grade 3 adverse events regardless of the relationship to 
study drugs. 
Secondary outcome measures include: 
 
 The minimum concentration (“trough”) of LPV/r in the two cohorts, at 
Weeks 1, 4, 8, 12, 16, 36 and 48 
 The measures of LPV protein binding in the two cohorts at weeks 1, 
12 and 24 
 The HIV-RNA load and CD4 percent in the two cohorts at study entry 
and Weeks 12, 24, 36 and 48 
 Description of the recovery of the lean body mass by assessment of 
weight to height z-score (WHZ) and mid-upper arm circumference 
(MUAC) in children in severe acute malnutrition at Weeks 24 and 48  
 
Assessment of height and change in height over time in severe acute 
malnutrition.     
8.3 
Randomization and Stratification 
 
There will be no randomization in this study.  Eligible HIV-infected 
severely malnourished children and HIV-infected children with normal 
nutritional status–mild malnutrition will be enrolled into this study.  
Children with severe malnutrition will be enrolled to Cohort 1, and 
children with normal – mild malnutrition will be enrolled to Cohort 2.  
Within cohorts, age strata will be defined with threshold 18 months, and 
children will be assigned to LPV/r-containing arms with common 
ZDV+3TC backbone. An initial upper bound of 13 patients per stratum 
arm combination will be established.  Once this bound is reached, no more 
patients will be enrolled to that study cell.  If, as the study matures and 2 
of 4 cells have reached capacity, the team may reevaluate the values of 
upper bounds, recognizing that PK analysis can accommodate imbalances 
of approximately 20% between groups without sacrificing interpretability. 
 
8.4 
Sample Size and Accrual  
 
 
The primary objective is to compare severely malnourished and normal–
mildly malnourished children on HAART with respect to pharmacokinetic 
exposures quantified as concentration AUCs.  The coefficient of variation 
of AUC for LPV was estimated to be approximately 0.40 in similarly aged 
children (50).  The protocol team considers a 40% difference between 
groups with respect to LPV AUC to be clinically important.  A parallel-


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arm study with two groups would require N=17 patients per group to 
detect a 40% difference between groups in the LPV AUC with 80% power 
and a two-sided Type I error of 5% for a CV of 0.4. In addition, a 10% 
LTFU and 20% mortality rate (current mortality rate in the malnutrition 
unit) is considered for the estimate.  This yields a necessary sample size of 
17 children + 30% for a total of 23 children required per treatment group.  
Because of uncertainties in the estimation of AUC CV and possible 
heterogeneity in variance associated with differential malnutrition status, 
we suggest a further 10% inflation to 25 children per nutrition status 
stratified by age. 
 
The following table gives the 90% confidence intervals (CI) associated 
with various potential rates.  This will provide 95% confidence that the 
rate of severe adverse effects is not greater than the upper limit of the CI. 
These intervals are computed for a sample of 17 evaluable subjects per 
group.  Because of the small sample sizes, these intervals will be 
calculated using exact methods, rather than normal distribution 
approximations. 
 
Table 2:  90% Confidence Intervals for Potential Rates of Severe Adverse 
Events 
 
Proportion of Subjects with 
Severe Adverse Events 
90% Confidence Limits 
Lower 
Upper 
0.000 (0/17) 
0.000 
0.162 
0.059 (1/17) 
0.003 
0.250 
0.118 (2/17) 
0.021 
0.326 
0.176 (3/17) 
0.050 
0.396 
0.235 (4/17) 
0.085 
0.461 
0.294 (5/17) 
0.124 
0.522 
0.353 (6/17) 
0.166 
0.580 
0.412 (7/17) 
0.212 
0.636 
0.471 (8/17) 
0.260 
0.689 
0.529 (9/17) 
0.311 
0.740 
0.588 (10/17) 
0.364 
0.788 
0.647 (11/17) 
0.420 
0.834 
0.706 (12/17) 
0.478 
0.876 
0.765 (13/17) 
0.539 
0.915 
0.824 (14/17) 
0.604 
0.950 
0.882 (15/17) 
0.674 
0.979 
0.941 (16/17) 
0.750 
0.997 
1.000 (17/17) 
0.838 
1.000 
 
This table shows that if 4 of 17 subjects (23.5%) in a group experience 
adverse events, with 95% confidence the true rate in the population 
represented by this sample is very likely no greater than 0.461.  The 
relatively wide range in the confidence interval reflects imprecision due to 
the small sample size.  
 


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An N of 25 is our best guess of the number needed to get 17 evaluable; if 
because of the unusual nature of this population a greater loss to follow-up 
is encountered or data is deemed unevaluable enrollment may be extended 
beyond 25 to reach 17 evaluable.  
 
Therefore, a total of 50 children, (25 severely malnourished and 25 normal 
nutrition–mildly malnourished) are required for study completion.  
 
Evaluable participants: The goal of the study is to have all subjects have 
intensive PK parameters available for weeks 1, 12 and 24 following 
initiation of HAART. Therefore, in order for a subject to be evaluable, the 
subject must have results for the week 1 intense PK evaluations and either 
week 12 or 24 intense PK results.    
 
8.5 
Monitoring 
 
Site investigators are responsible for close safety monitoring of all study 
participants, reporting of safety information at the participant level, and 
alerting the Core Team if unexpected concerns arise.  Site investigators are 
also responsible for safety-related communications with their IRBs/ECs, 
per IRB/EC policies and procedures.  
 
Site monitors under contract to the NIAID or NICHD may visit 
participating clinical research sites to review the individual participant 
records including consent forms, CRFs, supporting data, laboratory 
specimen records, and medical records (physicians’ progress notes, 
nurses’ notes, individuals’ hospital charts), to ensure protection of study 
participants, compliance with the protocol and accuracy and completeness 
of records. The monitors also will inspect sites’ regulatory files to ensure 
that regulatory requirements are being followed. The site investigator will 
make study documents readily available for inspection by the local IRB, 
site monitors, NIAID, NICHD, and the Office for Human Research 
Protections (OHRP). 
 
It is the responsibility of the protocol team to interpret safety data, and 
make decisions regarding serious adverse events that are needed to protect 
subjects from undue risk. The safety and tolerability of the study agent 
will be monitored by means of adverse events reports and toxicity reports 
summarizing laboratory and clinical events. It is required that the data 
required for the toxicity reports be entered into the database within 48 
hours of the time at which the results of the laboratory tests or clinical 
examinations become available. Reports compiled by the DMC will be 
reviewed and discussed by the protocol team on conference calls held at 
least every two to four weeks. Data on accrual, pharmacokinetics, and 
toxicity will be reviewed.   The IMPAACT Study Monitoring Committee 
(SMC) will review the study regularly — at least annually — and on a 
more frequent or ad hoc basis for safety issues and any other concerns. 


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Other study implementation issues, such as participant accrual, participant 
retention, and data quality, will also be monitored by the SMC. 
 
If the protocol team identifies any potentially treatment-related toxicities, 
which may compromise subject safety, it will determine whether the study 
needs to be suspended or modified.    
 
8.51   Rules for Suspending Accrual to Assess Safety Following an 
Adverse Event  
Accrual will be temporarily suspended if: 
 
Any subject has a life-threatening adverse event that is judged 
to be probably or definitely attributable to study drug or Grade 
4 event that may not be judged to be life-threatening but is 
judged to be probably or definitely attributable to study drug.  
 
Or if more than six out of the first 20 subjects or at least 30% 
of subjects thereafter have Grade 3 or greater toxicity that is 
judged to be definitely related to study drug. 
Following temporary suspension of accrual, the protocol 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 
protocol team, including the study chair and the DAIDS medical 
officer of record agree that the study drug is likely to be safe for 
additional subjects, they may allow accrual to resume. Regulatory 
agencies (IRB/EC) will be notified of the event and the protocol 
team’s decision after this review of the safety data has taken place.   
8.52 
Accrual Rate Evaluation  
 
Accrual to this study will be monitored by the IMPAACT 
leadership in accordance with standard operating procedures. 
Initially, the protocol team will monitor site registration and site   
activation monthly to ensure that an adequate number of sites have 
registered to complete the protocol.  The expected period of 
enrollment will be over 12 months, but should allow up 18 months 
since the malnourished may be hard to accrue quickly.  Once 2 
sites are activated, we would expect to enroll about 14-15 children 
per site and expect 7-8 children enrolled within 6 months and 10-
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Monthly conference calls will be held by the study team to assess 
accrual of both severely malnourished and normal–mildly 
malnourished subjects, and follow-up statistics will be reported to 
the team by the data management group on a monthly basis.  Rate 
of enrollment will be closely monitored with input provided from 
team members and participating sites.  If any group has not 
accrued half of its subjects within 12 months after opening of the 
protocol, the team will identify the reasons for lack of accrual and 
take corrective actions to speed enrollment if needed.   
8.6 
Analyses   
 
Details on pharmacokinetic analyses are given in sections 9.1 and 9.3 
below.  Analysis of safety and tolerability data will take the form of 
detailed tabulation of all adverse events and computation of confidence 
intervals for incidence of severe adverse events by month of study follow-
up.   
 
Comparison of LPV protein binding characteristics and HIV RNA viral 
load and CD4 percent will occur through standard two-sample analyses.  
Pre-specified null hypotheses will be tested individually at the 0.05 level 
of significance.  Ad hoc analysis of data within subgroups will be 
presented with caveats and attention to multiple testing corrections. 
 
 
9.0 
CLINICAL PHARMACOLOGY PLAN 
 
9.1 
Pharmacology Objectives 
 
 To compare the PK exposure (as estimated by the area under the 
plasma concentration versus time curve, AUC) and clearance of ZDV, 
3TC, and LPV/r under steady-state conditions between severely 
malnourished children and children with normal nutrition-mild 
malnutrition at 1, 12 and 24 weeks following study entry (steady state 
is achieved or nearly achieved by 7 days of study drug initiation; 
therefore, the week 1 evaluations will be performed between days 7-
10). 
 To compare the minimum concentration (Ctrough) of LPV/r between 
severely malnourished children and children with normal nutrition - 
mild malnutrition at 1, 4, 8, 12, 16, 36 and 48 weeks following study 
entry. 
 To investigate the impact of malnutrition on LPV protein binding by 
comparing the free fraction of LPV in severely malnourished children 
and children with normal nutrition – mild malnutrition at 1, 12 and 24 
weeks following study entry.   
 


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9.2 
Primary and Secondary Data 
 
Primary objectives concern:  PK AUCs to be analyzed. Non- 
compartmental analysis will be performed for individual PK estimates via 
the linear up-log down trapezoidal rule in conjunction with an oral input 
model using WinNonlin 5.0.1 (Pharsight Corporation, Mountain View, 
USA).  Safety and tolerability analysis will consist of summaries of 
numbers of adverse and severe adverse events encountered in all strata 
with exact testing of hypotheses of equal rates of adverse events and rates 
of treatment cessation due to tolerability concerns.  Secondary objectives 
include comparison of Ctrough values of LPV/r at 1, 4, 8, 12, 16, 24, 36 and 
48 weeks, albumin concentrations, CD4 and HIV RNA viral load 
measures at baseline, 12, 24, 36 and 48 weeks and linear growth at 24 and 
48 weeks.  Week 1, 12 and 24 week trough measurements will be 
collected as part of the intensive PK assessments. Full descriptive statistics 
and appropriate tests of relationships between malnutrition status, drug 
exposure, and distributions of these clinical parameters will be provided. 
 
ZDV may be changed to ABC if hematologic toxicity dictates. In this case 
the subject may continue but analysis will be of 3TC and LPV/r.  
 
9.3  
Study Design, Modeling and Data Analysis 
 
Plasma PK data from intensive sampling visit will be analysed using non-
compartmental analysis to determine the following PK measures for ZDV, 
3TC, LPV and RTV. Ctrough (pre-dose sample concentration), Cmax (peak 
plasma concentration) and Tmax (the time to reach Cmax after drug 
ingestion) will be determined by inspection of the results. Drug 
concentrations below the limit of quantification (BLQ) will be handled 
using standard pharmacokinetic methods (e.g., 50% BLQ or ‘0’ value) to 
assure all data are handled in a consistent manner. 
 
Population PK analysis will be carried out utilizing the intensive PK data 
coupled with the trough measurements carried out throughout the 48 week 
study period. 
  
Protein binding and albumin:  Lopinavir free drug measurements will be 
carried out during the intensive PK sampling weeks when children are 
malnourished (week 1) and after they begin to improve nutritionally 
(weeks 12 and 24).  Due to limitations for blood collection volumes, 
markers for malnutrition such as albumin will be collected at different 
study weeks (e.g baseline), but should still represent the child's overall 
nutritional status at the time of PK collections (week 1).  Exploratory 
analysis relating malnutrition markers and the fraction of lopinavir binding 
will be carried out. 
  


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Target PK- The trough measurements collected in children will be 
compared to published measurements for lopinavir trough of >1 ng/mL.  
This latter trough estimate will be considered the target trough 
concentration for these children.   
  
9.4  
Anticipated Outcomes 
 
The overall goal of the study aims is to determine if current dosing 
guidelines for LPV/r based HAART are optimum for severely 
malnourished children by comparing PK data generated in severely 
malnourished children to PK data generated in children with normal 
nutrition-mild malnutrition.  The results from this study will also aid in 
determining appropriate timing of HAART initiation during nutritional 
rehabilitation in the severely malnourished children.    
 
 
10.0 
HUMAN SUBJECTS 
 
10.1 
Institutional Review Board and Informed Consent 
 
This protocol, the informed consent documents (Appendices IV and V), 
and any subsequent modifications must be reviewed and approved by the 
Institutional Review Board (IRB) or Ethics Committee (EC) responsible 
for oversight of the study. Written informed consent must be obtained 
from the parents or legal guardians of subjects who cannot consent for 
themselves, such as those below the legal age.  The informed consent will 
describe the purpose of the study, the procedures to be followed, and the 
risks and benefits of participation.  A copy of the consent form will be 
given to the parent or legal guardian. 
Each site which receives US HHS funding and follows the United States 
Code of Federal Regulations Title 45-Public Welfare, Part 46-Protection 
of Human Subjects (also known as the Common Rule) should have on 
record at the site a plan that detects and addresses any change in 
guardianship occurring in pediatric subjects and determines when a study 
subject must have a consent process which involves a legally authorized 
representative (LAR) other than a family member with guardianship. The 
plan will include how the site determines when a LAR is initially or no 
longer needed and how frequently the LAR re-signs the consent. The plan 
should follow all IRB/EC, local, state, national and/or host country 
guidelines. Confirmation of such a plan at a site should be submitted with 
protocol registration materials. 
 


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10.2 
Subject Confidentiality 
 
 
All laboratory specimens, evaluation forms, reports, and other records will 
be identified only by a coded number to maintain subject confidentiality.  
All records will be kept in a secured area.  All computer entry programs 
will be done with coded numbers only.  Clinical information will not be 
released without written permission of the subject’s parent or Legally 
Authorized Representative, except as necessary for monitoring by the 
Office for Human Research Protections (OHRP), the NIAID or other 
authorized governmental agencies, or the local IRB/EC. 
10.3 
Study Discontinuation 
 
 
The study may be discontinued at any time by IMPAACT, the NIAID, the 
IRB/EC, ViiV Healthcare Ltd, Abbott Laboratories, local regulatory 
authorities, the OHRP, or other governmental agencies as part of their 
duties to ensure that research subjects are protected.  
 
11.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by IMPAACT policies.  
 
Any presentation, abstract, or manuscript will be made available for review by the 
 
pharmaceutical sponsors prior to submission. 
 
 
12.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood borne pathogens can occur through 
contact with contaminated needles, blood, and blood products, appropriate blood 
and secretion precautions will be employed by all personnel in the drawing of 
blood and shipping and handling of all specimens for this study, as currently 
recommended by the Centers for Disease Control and Prevention. 
All infectious specimens will be sent using the ISS-1 SAF-T-PAK mandated by 
the International Air Transport Association Dangerous Goods Regulations-
Packing Instruction 602.  Refer to individual carrier guidelines (e.g., Federal 
Express or Airborne) for specific instructions. 
 
 
 


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13.0 
REFERENCES 
 
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Walker AS, Mulenga V, Sinyinza F, Lishimpi K, Nunn A, Chintu C, et al. 
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4. 
Organization WH. Guideline: Updates on the Management of Severe Acute 
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Fergusson P, Tomkins A. HIV prevalence and mortality among children 
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Bunn J. Severe acute malnutrition and HIV in African Children. HIV Ther. 
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7. 
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8. 
Fergusson P, Chinkhumba J, Grijalva-Eternod C, Banda T, Mkangama C, 
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10. 
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11. 
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Gilman RH, Partanen R, Brown KH, Spira WM, Khanam S, Greenberg B, et al. 
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Charman WN, Porter CJ, Mithani S, Dressman JB. Physiochemical and 
physiological mechanisms for the effects of food on drug absorption: the role of 
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16. 
Falcon RW, Kakuda TN. Drug interactions between HIV protease inhibitors and 
acid-reducing agents. ClinPharmacokinet. 2008;47(2):75-89. 
17. 
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a study with antipyrine. ArchDisChild. 1979;54(4):299-302. 
18. 
Eriksson M, Paalzow L, Bolme P, Mariam TW. Chloramphenicol 
pharmacokinetics in Ethiopian children of differing nutritional status. EurJ 
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19. 
Ellis JC, L'Homme RF, Ewings FM, Mulenga V, Bell F, Chileshe R, et al. 
Nevirapine concentrations in HIV-infected children treated with divided fixed-
dose combination antiretroviral tablets in Malawi and Zambia. AntivirTher. 
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20. 
Else LJ, Pollock L, Poekson G, Back DJ, Khoo SH, Fraser W, et al. Total and 
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International Workshop on Clinical Pharmacology of HIV Therapy. 2010. 
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Burger DM, Verweel G, Rakhmanina N, Verwey-Van Wissen CP, la Porte CJ, 
Bergshoeff AS, et al. Age-dependent pharmacokinetics of lamivudine in HIV-
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22. 
Verweel G, Burger DM, Sheehan NL, Bergshoeff AS, Warris A, van der Knaap 
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suboptimal in children aged 2 years and below. AntivirTher. 2007;12(4):453-8. 
23. 
L'Homme RF, Kabamba D, Ewings FM, Mulenga V, Kankasa C, Thomason MJ, 
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24. 
Boffito M, Back DJ, Blaschke TF, Rowland M, Bertz RJ, Gerber JG, et al. Protein 
binding in antiretroviral therapies. AIDS Res HumRetroviruses. 2003;19(9):825-
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Atcheson B, Taylor PJ, Pillans PI, Tett SE. Measurement of free drug and clinical 
end-point by high-performance liquid chromatography-mass spectrometry: 
Applications and implications for pharmacokinetic and pharmacodynamic studies. 
Analytica Chimica Acta. 2003(492):157-69. 
26. 
Pollock L, Else L, Poerksen G, Molyneux E, Moons P, Walker S, et al. 
Pharmacokinetics of nevirapine in HIV-infected children with and without 
malnutrition receiving divided adult fixed-dose combination tablets. J 
AntimicrobChemother. 2009;64(6):1251-9. 
27. 
Hughes SM, Amadi B, Mwiya M, Nkamba H, Mulundu G, Tomkins A, et al. CD4 
counts decline despite nutritional recovery in HIV-infected Zambian children with 
severe malnutrition. Pediatrics. 2009;123(2):e347-e51. 
28. 
Paton NI, Sangeetha S, Earnest A, Bellamy R. The impact of malnutrition on 
survival and the CD4 count response in HIV-infected patients starting 
antiretroviral therapy. HIV Med. 2006;7(5):323-30. 
29. 
Savino W, Dardenne M, Velloso LA, yse Silva-Barbosa S. The thymus is a 
common target in malnutrition and infection. BrJ Nutr. 2007;98 Suppl 1:S11-S6. 
30. 
Fischl MA, Richman DD, Causey DM, Grieco MH, Bryson Y, Mildvan D, et al. 
Prolonged zidovudine therapy in patients with AIDS and advanced AIDS-related 
complex. AZT Collaborative Working Group. Jama. 1989;262(17):2405-10. 
31. 
Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, 
et al. The efficacy of azidothymidine (AZT) in the treatment of patients with 
AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. 
NEnglJ Med. 1987;317(4):185-91. 
32. 
Fischl MA, Richman DD, Hansen N, Collier AC, Carey JT, Para MF, et al. The 
safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly 
symptomatic human immunodeficiency virus type 1 (HIV) infection. A double-
blind, placebo-controlled trial. The AIDS Clinical Trials Group. AnnInternMed. 
1990;112(10):727-37. 
33. 
Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, et al. Early 
antiretroviral therapy and mortality among HIV-infected infants. The New 
England journal of medicine. 2008;359(21):2233-44. 
34. 
Working Group on Antiretroviral T, Medical Management of HIVIC, Health R, 
Services A, National Institutes of H. Guidelines for the use of antiretroviral agents 
in pediatric HIV infection. 2005. 
35. 
Bergshoeff AS, Fraaij PL, Verweij C, van Rossum AM, Verweel G, Hartwig NG, 
et al. Plasma levels of zidovudine twice daily compared with three times daily in 
six HIV-1-infected children. J AntimicrobChemother. 2004;54(6):1152-4. 


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36. 
Coates JA, Cammack N, Jenkinson HJ, Jowett AJ, Jowett MI, Pearson BA, et al. 
(-)-2'-deoxy-3'-thiacytidine is a potent, highly selective inhibitor of human 
immunodeficiency virus type 1 and type 2 replication in vitro. AntimicrobAgents 
Chemother. 1992;36(4):733-9. 
37. 
Lewis LL, Venzon D, Church J, Farley M, Wheeler S, Keller A, et al. Lamivudine 
in children with human immunodeficiency virus infection: a phase I/II study. The 
National Cancer Institute Pediatric Branch-Human Immunodeficiency Virus 
Working Group. J InfectDis. 1996;174(1):16-25. 
38. 
Kuritzkes DR, Quinn JB, Benoit SL, Shugarts DL, Griffin A, Bakhtiari M, et al. 
Drug resistance and virologic response in NUCA 3001, a randomized trial of 
lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously 
untreated patients. AIDS. 1996;10(9):975-81. 
39. 
Wainberg MA. Increased fidelity of drug-selected M184V mutated HIV-1 reverse 
transcriptase as the basis for the effectiveness of 3TC in HIV clinical trials. 
Leukemia. 1997;11 Suppl 3:85-8. 
40. 
Nijhuis M, Schuurman R, de Jong D, van Leeuwen R, Lange J, Danner S, et al. 
Lamivudine-resistant human immunodeficiency virus type 1 variants (184V) 
require multiple amino acid changes to become co-resistant to zidovudine in vivo. 
JInfectDis. 1997;176(2):398-405. 
41. 
Devereux HL, Emery VC, Johnson MA, Loveday C. Replicative fitness in vivo of 
HIV-1 variants with multiple drug resistance-associated mutations. J Med Virol. 
2001;65(2):218-24. 
42. 
McKinney RE, Jr., Johnson GM, Stanley K, Yong FH, Keller A, O'Donnell KJ, et 
al. A randomized study of combined zidovudine-lamivudine versus didanosine 
monotherapy in children with symptomatic therapy-naive HIV-1 infection. The 
Pediatric AIDS Clinical Trials Group Protocol 300 Study Team. J Pediatr. 
1998;133(4):500-8. 
43. 
A randomized double-blind trial of the addition of lamivudine or matching 
placebo to current nucleoside analogue reverse transcriptase inhibitor therapy in 
HIV-infected children: the PENTA-4 trial. Paediatric European Network for 
Treatment of AIDS. AIDS. 1998;12(14):F151-F60. 
44. 
Nachman SA, Stanley K, Yogev R, Pelton S, Wiznia A, Lee S, et al. Nucleoside 
analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected 
children: a randomized controlled trial. Pediatric AIDS Clinical Trials Group 338 
Study Team. Jama. 2000;283(4):492-8. 
45. 
Abbott L. Kaletra package insert. November 2013. 


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46. 
Saez-Llorens X, Violari A, Deetz CO, Rode RA, Gomez P, Handelsman E, et al. 
Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in 
human immunodeficiency virus-infected children. Pediatr Infect DisJ. 
2003;22(3):216-24. 
47. 
Cahn P, Renz C, Saez-Llorens X, Violari A, Gomez P, Sun E, et al. Treatment of 
HIV-infected children with Kaletra (lopinavir/ritonavir) oral solution: 60 week 
follow-up. 1st International AIDS Society Conference on HIV Pathogenesis and 
Treatment, Buenos Aires, Argentina. 2001;Abstract 779. 
48. 
Chadwick EG, Pinto J, Yogev R, Alvero CG, Hughes MD, Palumbo P, et al. 
Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: 
pharmacokinetics and 24-week safety and efficacy. The Pediatric infectious 
disease journal. 2009;28(3):215-9. 
49. 
World Health Organization. Report of the WHO Technical Reference Group, 
Paediatric HIV/ART Care Guideline Group Meeting. Geneva, Switzerland: World 
Health Organization, 2008 April 10-11. Report No. 
50. 
Capparelli E, Pinto J, Robbins B, Alvero C, Yogev R, Palumbo P, et al. Lopinavir 
Pharmacokinetic (PK) maturational changes and variability in HIV-infected 
infants beginning Kaletra (LPV/r) therapy at <6 weeks (WK) of Age. Conference 
on Retroviruses and Opportunistic Infections; Boston, 2008. 2008. 
 
 
 


 
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APPENDIX I 
SCHEDULE OF EVALUATIONS  
 
 
Stage 1 
Stage 2 
 
Screening1 
Entry2 
Week 117 
(+ 3 days) 
Week 2 
(± 2 days) 
Week 4 
(± 7 days) 
Week 8 
(± 7 days) 
Week 12 
(± 7 days) 
Week 16 
(± 7 days) 
Week 20 
(± 7 days) 
Week 24 
(± 7 days) 
Week 36  
(±14 days) 
Week 48 
(±14 days) 
Off treatment/ 
On study18 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
History3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nutrition 
assessment5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology6 
1mL 
 
1mL 
 
1mL 
1mL 
1mL 
 
 
1mL 
 
1mL 
1mL 
Chemistries7 
2mL 
 
2mL 
 
2mL 
2mL 
 
 
 
2mL 
 
 
2mL 
Total 
protein/albumin 
 
2mL 
 
 
 
2mL 
 
2mL 
 
 
 
2mL 
2mL 
Glucose 
 
 
 
 
1mL 
 
 
 
 
 
 
1mL8 
 
Lipid profile9 
 
1mL 
 
 
 
 
 
1mL 
 
 
 
1mL 
 
Micronutrients10 
 
2mL 
 
 
 
 
 
 
 
 
 
2mL 
 
Documentation of 
HIV infection1  
0-3mL 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA 11 
1-3mL 
1-3mL 
 
 
 
 
1-3mL 
 
 
1-3mL 
1-3mL 
1-3mL 
1-3mL 
Lymphocyte 
subsets12 
1mL 
 
 
 
 
 
1mL 
 
 
1mL 
1mL 
1mL 
1mL 
Trough PK for 
weight ≥5kg13 
 
 
 
 
0.8mL 
0.8mL 
 
0.8mL 
 
 
0.8mL 
0.8mL 
 
Trough PK for 
weight <5kg13 
 
 
 
 
0.3mL 
0.3mL 
 
0.3mL 
 
 
0.3mL 
0.3mL 
 
Intensive PK for 
weight ≥5kg 14,16 
 
 
7 mL 
 
 
 
7mL 
 
 
7mL 
 
 
 
Intensive PK for 
weight <5kg15,16 
 
 
1.8 mL 
 
 
 
1.8 mL 
 
 
1.8 mL 
 
 
 
TOTAL BLOOD 
5-10mL 
6-8mL 
4.8- 
10 mL 
- 
4.3-
4.8mL 
5.3-
5.8mL 
4.8-
12mL 
3.3-
3.8mL 
- 
6.8-
14mL 
2.3-
4.8mL 
9.3-
11.8mL 
7-9mL 
 
 
 
 
 


 
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Appendix I Footnotes: 
 
1. Screening evaluations must be performed within 18 days prior to entry for Cohort 1 and within 14 days prior to entry for Cohort 2. For purposes of 
documentation of HIV infection for eligibility determination, if adequate documentation is available to fulfill the requirements of inclusion criterion 4.12, no 
HIV testing is required at Screening.  If testing is required to fulfill the requirements of inclusion criterion 4.12, the HIV RNA PCR required at Screening 
may serve as one of the two required tests, and additional blood (1-3 mL) may be collected as Sample #1 and/or Sample #2. 
2. Entry may occur when the subject is nutritionally stable.  Eligible subjects will be considered enrolled in the study upon successful entry into the DMC’s 
Subject Enrollment System (date of subject enrollment = day 0 for determining the target dates of all follow-up visits).  The study HAART regimen must be 
initiated within 72 hours of enrollment/entry. 
3. A complete history is required to be source documented at screening and at all follow-up visits; see Section 7.5 for CRF recording requirements for signs, 
symptoms, and diagnoses. All ARVs and concomitant medications taken within 30 days prior to study entry and throughout follow-up will be source 
documented and recorded on CRFs. 
4. Physical exam includes length, weight, head circumference, and vital signs (temperature, heart rate, respiratory rate).  Skin fold thickness (triceps) will be at 
entry, weeks 24 and 48. 
5. Nutritional assessment includes mid upper arm circumference. 
6. Hematology includes CBC with differential and platelet count.  
7. Chemistries include AST, ALT, creatinine, sodium, potassium, chloride, and bicarbonate.  
8. Obtain fasting if the subject is clinically stable.  For subjects 6-24 months, collect specimen at least 3 hours after last meal; for subjects >24 months, collect 
specimen at least six hours after last meal.  
9. Lipid profile includes triglycerides and total cholesterol.  
10. Micronutrients include zinc and selenium to be processed and stored until shipping to the central laboratory for testing. 
11. Must be performed at DAIDS VQA-certified laboratory. 
12. Lymphocyte subsets include CD3/CD4/and CD3/CD8 absolute counts and percentages. Must be performed at DAIDS IQA/UK NEQAS-certified laboratory. 
13. Obtain the specified blood volume based on subject weight (0.8 mL for children ≥5kg, 0.3 mL for children <5 kg) for trough PK sampling prior to morning 
dose of ARVs.  Caregivers will be asked to hold the child’s morning doses. 
14. For children weighing ≥5kg, obtain 0.8mL of blood at the following intensive PK sampling time points: pre-dose and 1, 2, 4, 8 and 12 hours post-dose.  An 
additional sample of 2.2 mL whole blood (generating 1 mL of plasma) will be collected at the 2 hour time point to determine the free fraction of lopinavir at 
the time of the peak concentration. 
15. For children weighing <5kg, obtain 0.3mL of blood at the following intensive PK sampling time points: pre-dose and 1, 2, 4, 8 and 12 hours post-dose. 
16. Obtain intensive PK sampling if hemoglobin is ≥7.5 g/dl at the most recent prior evaluation, the child does not have diarrhea, and the child has not missed 
any ARV doses within the prior 72 hours. 
17. Week 1 intensive PK must be completed 7-10 days following study entry (may defer up to day 15 if hemoglobin <7.5 g/dl or the child has diarrhea or the 
child missed ARV doses within the prior 72 hours). 
18. For children who permanently discontinue all study drugs, follow-up visits should be conducted per the schedule shown in the table above; however, 
evaluations performed should be limited to those indicated in the Off treatment/On study column of the table. 
Note:  NIH recommendations for maximum pediatric blood draw volumes will be followed in this study.  The volume of blood drawn at any study visit should 
not exceed 5 mL/kg in a single day and 9.5 mL/kg over any eight-week period. Priority of draw should be as follows: (1) Hematology, (2) Chemistries, (3) 
Pharmacokinetics, (4) HIV RNA, (5) Lymphocyte subsets. 
Note:  For all PK evaluations, record the precise date, time, and amount of the prior ARV dose, as well as the precise date and time of each specimen collection. 


 
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APPENDIX II 
WORLD HEALTH ORGANIZATION (2013) APPROACH TO THE MANAGEMENT 
OF SEVERE ACUTE MALNUTRITION 
 
The World Health Organization recommends local hospitals to prepare a milk referred to as 
F75 that is fortified with vitamins, electrolytes and micronutrients and contains 75 
kcal/100ml and 0.9g of protein.   The initial feeds are small and frequent given every 2 to 3 
hours and provide a total of about 100kcal/kg/day.  
 
Children with severe acute malnutrition (SAM) may also require vitamin A, zinc, and 
antibiotics. Children with SAM should be provided with about 5000 IU vitamin A daily, 
either as an integral part of therapeutic foods or as part of a multi-micronutrient formulation. 
Children with SAM do not require a high dose of vitamin A as a supplement if they are 
receiving F75, F100 or ready-to-use therapeutic food that comply with WHO specifications 
(and therefore already contain sufficient vitamin A), or vitamin A is part of other daily 
supplements. Children with SAM should be given a high dose of vitamin A (50 000 IU, 100 
000 IU or 200 000 IU, depending on age) on admission, only if they are given therapeutic 
foods that are not fortified as recommended in WHO specifications and vitamin A is not part 
of other daily supplements. Fluid management will depend on the extent of dehydration, 
whether the child is in shock, and whether the child has cholera or profuse watery diarrhea.   
 
Children with HIV and severe acute malnutrition should be given the same antiretroviral drug 
treatment regimen as HIV-infected children without severe acute malnutrition.  HIV-infected 
children with severe acute malnutrition should also be given the same therapeutic feeding as 
children with severe acute malnutrition that are not HIV-infected.   
 
Children need to be carefully monitored throughout the stabilization phase as they are 
particularly susceptible to fluid overload and cardiac failure. Monitoring should include: 
 
 
Respiratory rate 
 
Vomiting 
 
Temperature 
 
Glucose level 
 
Stool frequency and consistency 
 
Amount of feed offered and left over. Note: while feeds need to be started in the 
stabilization phase, significant weight gain is not expected until underlying sepsis and 
electrolyte disturbances are treated and resolved.  
 
If children survive the immediate stabilization phase, the focus of care and management is to 
initiate and sustain catch up growth. However, full recovery and reaching expected weight-
for-height will take about 6-8 weeks and therapeutic feeds therefore need to be continued at 
home. 
 
 
 


 
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Increase in appetite is one of the most important signs indicating that the child is entering the 
rehabilitation phase. Once children are stabilized, have appetite and reduced edema, they are 
ready to move into the rehabilitation phase, and should be transitioned from F75 to another 
milk formulation called F100 or an equivalent non-milk therapeutic food called Ready-to-
Use Therapeutic Feed (RUTF). The transition should occur over 2-3 days as tolerated and the 
recommended energy intake during this period is 100-135 kcal/kg/day.  
 
 
F100 is a milk-based preparation with added vitamins and trace elements which has 
100kcal/100 ml and 2.9g protein per 100ml. The volume of milk is increased to about 
130ml/kg day while other foods are introduced and increased 
 
RUTF is an energy dense food usually containing peanut butter, milk powder, oil, sugar 
and micronutrients with an equivalent nutritional content to F100. The major advantage 
of RUTF over milk F100 is that it can be given to the mother to take home whereas F100, 
being a milk preparation that is easily contaminated unless prepared in hygienic 
conditions, is usually reserved for hospital use.  
 
In the rehabilitation phase, children recovering from SAM will consume about 200-230 
kcal/kg/day and between 5-7gm protein/kg/day. 
 
Expected daily weight gain: 
- Poor: < 5g/kg/day 
- Moderate:  5-10 g/kg/day 
- Good: > 10g/kg/day 
 
Readiness for discharge from hospital should be based on the anthropometric indicator that 
was used to identify SAM when the child was admitted: 
 
 If SAM was identified based on weight-for-height, discharge should be considered when 
the Z score is -2 and the child has had no edema for at least two weeks 
 
 If SAM was identified based on mid-upper arm circumference, discharge should be 
considered when mid-upper arm circumference is 125 mm (12.5 cm) and the child has 
had no edema for at least two weeks 
 
Play and emotional stimulation are also essential elements of management in this phase as 
these can directly influence clinical outcomes including growth. Attending to maternal needs 
and preparing her to look after her child once discharged are similarly important. 
 
The WHO ten-step approach to management of severe malnutrition  
  
 
Treat/Prevent hypoglycaemia 
Treat/Prevent hypothermia 
Treat/Prevent dehydration 
Correct electrolyte imbalance 
Treat/Prevent infection 
Correct micro deficiencies 
Initiate refeeding 
Facilitate catch up growth 
Provide sensory stimulation and emotional support 
Prepare for follow up and recovery 


 
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APPENDIX III 
PHARMACOKINETIC SPECIMEN PROCESSING 
 
 
Processing of pharmacokinetic samples  
Pharmacokinetic blood samples will be sent to the laboratory within 30 minutes of 
collection for processing. Samples will be centrifuged at 1500 g for 10 minutes.  
Immediately after centrifugation, plasma is removed from cells and transferred to labeled 
screw cap cryovials and stored at -80o C until shipment for analysis, which is expected 
approximately every six months.  All samples will be logged into the Laboratory Data 
Management System.  
 
Determination of drug concentrations:  
Validated liquid chromatography mass spectrometry (LC-MS/MS) methods will be used 
to determine concentrations of LPV, RTV, ZDV and 3TC in plasma.  These assays will 
be carried out within the designated IMPAACT-funded Pharmacology Laboratory.  The 
laboratory will perform testing and assay validation in accordance with the Clinical 
Pharmacology Quality Assurance procedures, which are based on the principles of Good 
Laboratory Practices and FDA guidelines. 
 
 
 
 


 
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APPENDIX IV 
 
DIVISION OF AIDS  
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL 
TRIALS GROUP (IMPAACT) 
SAMPLE INFORMED CONSENT – SCREENING 
 
For protocol: 
 
PHASE IV EVALUATION OF THE STEADY STATE PHARMACOKINETICS OF 
ZIDOVUDINE, LAMIVUDINE AND LOPINAVIR/RITONAVIR IN SEVERELY 
MALNOURISHED HIV-1 INFECTED CHILDREN 
VERSION 2.0, DATED 11 FEBRUARY 2015 
 
INTRODUCTION 
 
You are being asked to allow your child to take part in screening tests to see if your child 
will be able to take part in the research study named above because your child is infected 
with Human Immunodeficiency Virus (HIV), the virus that causes AIDS (Acquired 
Immunodeficiency Syndrome).  This study is sponsored by the National Institutes of 
Health (NIH).  The doctor in charge of this study at this site is: (insert name of Principal 
Investigator).  Before you decide if you want your child to participate in the screening 
tests, we want you to know about the study.  
 
This is a consent form that gives you information about the screening tests. The study 
staff will talk with you about this information.  You are free to ask questions at any time.  
If you agree to allow your child to take part in screening tests, you will be asked to sign 
this consent form. You will get a copy to keep. 
 
WHAT SHOULD YOU KNOW ABOUT SCREENING FOR THIS STUDY? 
 
 Your permission to allow your child to participate in the screening is entirely 
voluntary. 
 You may decide not to allow your child to participate in the screening tests or to 
withdraw from the screening at any time without losing the benefits of your child’s 
standard medical care. 
 Even if you have agreed to allow your child to participate in the screening, it does not 
mean that you have agreed to allow your child to be in the research study. 
 If you consent to allow your child to be screened, you are saying that you are 
interested in allowing your child to be in this research study but you can change your 
mind before actually agreeing to allow your child to join the study. 
 If you decide not to allow your child to participate in the screening, your child cannot 
participate in this research study, but your child can join another research study later 
if one is available and your child qualifies. 
 


 
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WHY IS THIS STUDY BEING DONE? 
 
There are currently approved anti-HIV medicines and doses to treat HIV infection in 
children.  Based on strong data, children with severe malnutrition are expected to have 
differences in the levels of these anti-HIV drugs in their blood. The reason for this study 
is to find out if the approved HIV medications for the treatment of HIV infection in 
children will give adequate drug levels in the blood when given to infected children with 
severe malnutrition as compared to children with normal nutrition or mild malnutrition. 
The information from the study will be used in the future to recommend if the same dose 
or a different dose should be used in children with severe malnutrition who are starting a 
similar anti-HIV medicine. No changes will be made to your child’s doses based on these 
results.  In addition, the study will also find out how well the children take these drugs 
and if they are safe for the children. The purpose of this screening is to see if your child 
will be able to be in this research study. 
 
WHAT WILL HAPPEN IF YOU AGREE TO HAVE YOUR CHILD SCREENED? 
 
If you are interested in allowing your child to join this research study, we will first do 
some screening tests to see if your child is eligible.  If requested by the study doctor, 
some screening tests may be performed more than once. 
 
 We will ask about your child’s medical history including questions about your child’s 
health and what symptoms, medications, and illnesses your child has had. 
 We will do a physical exam including length, weight, mid upper arm measurement, 
head measurement, and vital signs (temperature, heart rate and respiratory rate). 
 We will ask you questions about what you are feeding your child and how well your 
child is eating, playing and behaving. 
 We will draw 5-10 mL (1-2 teaspoons) of blood for HIV testing and other routine 
tests. [Note to sites: add locally relevant description of blood volume] 
 This visit will take about ___to complete. [Note to sites: add locally relevant length 
of study visit] 
 
You will be asked to return to the clinic to get the results of these tests.  If the screening 
tests show that your child is able to join the research study, you will be given more 
detailed information about the research study and be asked to sign another consent form 
to allow your child to participate in the research study.  
 
WHY WOULD THE DOCTOR STOP MY CHILD’S SCREENING TESTS EARLY? 
 
Your child will be withdrawn from the screening if at any time the screening tests show 
that your child will not be able to be in the research study.  Your child may also be 
withdrawn from the screening if the study is cancelled or stopped. 
 


 
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WHAT ARE THE RISKS STUDY SCREENING? 
 
Drawing blood from a vein or heel stick can cause pain, bruising or bleeding at the place 
where the needle goes into the skin. There is also a small risk of inflammation or 
infection of the vein. If your child is screened for this study, some hospital staff and study 
staff will know that your child has HIV.  The study doctors and staff will protect 
information about your child’s participation in these screening tests to the best of their 
ability.  On your child’s screening records, a code will be used instead of your child’s 
name. Only the study staff will know the code. Study staff will make every possible 
effort to be sure that others do not learn your child’s HIV status.  However, sometimes if 
your child receives special treatment or attends a special clinic, it may make others 
wonder if your child has HIV. 
 
ARE THERE BENEFITS TO TAKING PART IN SCREENING TESTS? 
 
The screening tests may or may not be of direct benefit to your child.  The results of the 
screening tests will be shared with you and the medical staff providing your child’s care 
and may help them know more about what care your child needs. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your child’s personal information confidential.  We cannot 
guarantee absolute confidentiality.  Your child’s personal information may be disclosed if 
required by law.  Any publication of this study will not use your child’s name or identify 
child personally. 
 
Your child’s records may be reviewed by the [insert name of site] IRB/EC, National 
Institutes of Health (NIH), Office for Human Research Protections (OHRP), study staff, 
study monitors, ViiV Healthcare Ltd, Abbott Laboratories, IMPAACT, and local 
regulatory authorities. An IRB protects the rights and well-being of people in research. 
 
WHAT ARE THE COSTS TO ME? 
 
The screening tests (physical examination, blood tests) will be done free of charge at no 
cost to you but you will not receive any payment for having the screening tests done on 
your child. 
 


 
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WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about screening for this study or a screening-related injury, contact: 
 
[name of the investigator or other study staff] 
 
[telephone number of above]  
 
For questions about your child’s rights as a research subject, contact: 
 
[name or title of person on the Institutional Review Board (IRB), Ethics Committee 
(EC) or other organization appropriate for the site] 
 
[telephone number of above]   
 
 
SIGNATURE PAGE   
 
If you have read this screening consent form (or had it explained to you), all your 
questions have been answered and you agree to allow your child to take part in screening 
for this research study, please sign your name below. 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent or Legal Guardian Name  
Parent or Legal Guardian  
 
Date 
(print)  
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name  
 
 
Witness Signature 
 
 
Date 
 
 
 
 
 
 


 
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APPENDIX V 
 
DIVISION OF AIDS  
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL 
TRIALS GROUP (IMPAACT) 
SAMPLE INFORMED CONSENT - ENROLLMENT 
For protocol: 
 
PHASE IV EVALUATION OF THE STEADY STATE PHARMACOKINETICS OF 
ZIDOVUDINE, LAMIVUDINE AND LOPINAVIR/RITONAVIR IN SEVERELY 
MALNOURISHED HIV-1 INFECTED CHILDREN  
VERSION 2.0, DATED 11 FEBRUARY 2015 
 
INTRODUCTION 
 
You are being asked to allow your child to take part in this research study because your 
child is infected with Human Immunodeficiency Virus (HIV), the virus that causes AIDS 
(Acquired Immunodeficiency Syndrome) and the screening tests show that your child is 
eligible for the study.  This study is sponsored by the National Institutes of Health (NIH).  
The doctor in charge of this study at this site is: (insert name of Principal Investigator).  
Before you decide if you want your child to be a part of this study, we want you to know 
about the study.  
 
This is a consent form. It gives you information about this study.  The study staff will talk 
with you about this information.  You are free to ask questions about this study at any 
time.  If you agree to allow your child to take part in this study, you will be asked to sign 
this consent form. You will get a copy to keep. 
 
WHY IS THIS STUDY BEING DONE? 
 
There are currently approved anti-HIV medicines and doses to treat HIV infection in 
children.  Based on strong data, children with severe malnutrition are expected to have 
differences in the levels of these anti-HIV drugs in their blood. The reason for this study 
is to find out if the approved HIV medications for the treatment of HIV infection in 
children will give adequate drug levels in the blood when given to infected children with 
severe malnutrition as compared to children with normal nutrition or mild malnutrition. 
The information from the study will be used in the future to recommend if the same dose 
or a different dose should be used in children with severe malnutrition who are starting a 
similar anti-HIV medicine. No changes will be made to your child’s doses based on these 
results.  In addition, the study will also find out how well the children take these drugs 
and if they are safe for the children.  We will do this by measuring how much anti-HIV 
medicine is in your child’s blood.  Your child’s blood will be sent to laboratories in South 
Africa and the United States for analysis.  Two groups of children will be enrolled in this 
study; a group of severely malnourished children and a group of children with normal 
nutrition or who are mildly malnourished. 
 


 
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WHAT DOES MY CHILD HAVE TO DO IF HE/SHE IS IN THIS STUDY? 
 
Before the Study Starts: 
If you agree to allow your child to take part in this study, we will first need to confirm 
that your child is eligible.  For example, if your child is severely malnourished, he or she 
must be eating better, showing an interest in food, and gaining weight.  Your child also 
must be able to start taking the anti-HIV medications given by the study before he or she 
can be in the study.    
 
Entry Visit: 
If your child is eligible, you will be asked to bring your child to the clinic for an entry 
visit.  If your child is hospitalized, the entry visit may be done in the hospital.  The 
following tests will be done: 
 
 We will ask more questions about your child’s medical history including questions 
about your child’s health and what symptoms, medications, and illnesses your child 
has had.   
 We will do a physical exam including length, weight, mid upper arm measurement, 
head measurement, and vital signs (temperature, heart rate and respiratory rate). 
 We will ask you questions about what you are feeding your child and how well your 
child is eating, playing and behaving. 
 We will draw 6-8 mL (about 1-2 teaspoon) of blood for routine tests and to check the 
amount of HIV in your child’s blood. [Note to sites: add locally relevant description 
of blood volume] 
 If your child can start taking anti-HIV medications, your child will be started on 
zidovudine + lamivudine + lopinavir/ritonavir. Your child will take zidovudine two 
times daily + lamivudine two times daily + lopinavir/ritonavir two times daily by 
mouth for 48 weeks. 
 This visit will take about ___to complete. [Note to sites: add locally relevant length 
of study visit) 
 
On Study Visits: 
 You will be asked to bring your child to the clinic at least 10 times over 48 weeks.  
The visits will be at the beginning of the study (weeks 1, 2, and 4) and will then 
spread out to every 4 weeks (weeks 8, 12, 16, 20, 24) and then to every 12 weeks 
(weeks 36 and 48).   
 Most of these visits will take about ___ hours to complete.  [Note to sites: add locally 
relevant length of study visit] 
 At each visit, we will take a medical history, perform a physical exam, and ask you 
how well your child is eating. 
 At 5 of these visits, we will ask you how well your child is taking his/her anti-HIV 
medications. 


 
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 We will draw blood for routine tests and to check how well your child’s immune 
system is working and the amount of HIV in your child’s blood.  If the amount of 
HIV in your child’s blood is higher than expected, we will ask you to bring your child 
back to the clinic within 2-4 weeks for another test to confirm this result.  
 For 2 of these visits, less than one teaspoon of blood will be drawn for a glucose test 
(to see if there is sugar in the blood).   At one of these visits, your child may be ask to 
fast (not eat or drink) before the test.  
 For 5 of the visits less than one teaspoon of blood will be drawn right before your 
child takes the first dose of anti-HIV medications. [Note to sites: add locally relevant 
description of blood volume] You will be asked to hold your child’s first dose of anti-
HIV medications on the days of these visits. 
 For 3 of the visits, you will be asked to bring your child to the clinic to have blood 
drawn 6 times over 12 hours to measure the amount of anti-HIV medications in your 
child’s blood.  The total amount of blood to be drawn for these tests will be a little 
more than one teaspoon if your child weighs 10 pounds or more and less than one 
teaspoon if your child weighs less than 10 pounds. [Note to sites: add locally relevant 
description of blood volume and weight]. You will be asked to hold your child’s first 
dose of anti-HIV medications on the days of these visits. 
 A small plastic catheter (a needle that is placed in a vein for an extended period of 
time, so that blood can be drawn multiple times, without having to stick your child 
with a needle each time) will be placed in your child’s arm to draw these blood 
samples.  The needle will stay in place during the visit until all of the blood samples 
are drawn.   
 The total amount of blood drawn at the different study visits will vary from 2.3 mL to 
14 mL (less than one teaspoon to 3 teaspoons) depending on the type of test and how 
much your child weighs. [Note to sites: add locally relevant description of blood 
volume] 
 
It is important that you bring your child to the clinic for all study visits.  If you do not 
come for a study visit, or if a test result comes back abnormal, we will contact you to find 
out how your child is doing.  If your child becomes sick at any time, please contact the 
study nurse or doctor right away. 
 
The tests that might affect your child’s healthcare will be done soon after your child’s 
blood is drawn, and you will be given the results as soon as possible, usually at the next 
visit.  The tests of the amount of anti-HIV medications in your child’s blood will not be 
done right away; the blood will be kept for later testing and you will not be given the 
results of these tests. 
 
On the days when your child has blood drawn over 12 hours, if your child vomits within 
30 minutes after taking anti-HIV medications, we will try giving another dose of the 
medications.  If your child cannot be given another dose, or vomits again, we will not do 
the blood draws that day. We will ask you to bring your child back to the clinic to try 
again the next day. 
 


 
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If you allow your child to take part in this study, but then later decide that you do not 
want your child to have the blood draws over 12 hours, your child will stop taking the 
anti-HIV medications that are given by the study.  If your child stops taking the anti-HIV 
medications that are given by the study for this reason or other reasons before the study 
ends, you will be asked to continue to bring your child to the clinic for regular study 
visits until the study ends. At each of these visits, we will take a medical history, perform 
a physical exam, and draw blood for routine tests and to check how well your child’s 
immune system is working and the amount of HIV in your child’s blood. The total 
amount of blood drawn at this visit will be 7-9 mL (less than 2 teaspoons). [Note to sites: 
add locally relevant description of blood volume] If your child stops taking the anti-HIV 
medications that are given by the study, we will tell you about other options for treatment 
of your child’s HIV infection. 
 
HOW MANY CHILDREN WILL TAKE PART IN THIS STUDY?  
 
About 50 children will take part in this study; 25 children with severe malnutrition and 25 
children with normal nutrition/mild malnutrition. 
 
HOW LONG WILL MY CHILD BE IN THIS STUDY? 
 
Your child will be in this study for about 48 weeks. 
 
WHY WOULD THE DOCTOR TAKE MY CHILD OFF THIS STUDY EARLY? 
 
The study doctor may need to take your child off the study early without your permission 
if: 
 
 
The study is cancelled by the National Institutes of Health (NIH), ViiV Healthcare 
Ltd, Abbott Laboratories, IMPAACT, and local regulatory authorities, the Office for 
Human Research Protections (OHRP), or the site’s Institutional Review Board (IRB) 
or Ethics Committee (EC).  An IRB/EC is a committee that watches over the safety 
and rights of research subjects. 
 
Your child is not able to attend the study visits as required by the study. 
 
The study doctor may also need to take your child off the study drug(s) without your 
permission if: 
 
 
Continuing certain study procedures may be harmful to your child. 
 
Your child needs a treatment that your child may not take while on the study. 
 
Your child is not able to take certain study drugs as required by the study. 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Taking part in this study may involve some risks and discomfort. These include risks of 
study procedures, risks of study medicine and risks to your child’s privacy. 
 


 
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Risks of Study Procedures: 
 
Drawing blood from a vein or heel stick can cause pain, bruising or bleeding at the place 
where the needle goes into the skin. There is also a small risk of inflammation or 
infection of the vein. Because your child is small, infected with HIV and severely 
malnourished, these risks from drawing blood are greater than in children who are older 
or do not have these problems. 
 
Risks of Study Medicines: 
 
We are asking your child to participate in this study because we don’t know if young 
severely malnourished children with HIV are getting the best doses of anti-HIV 
medicine. If the dose of the treatment is not correct, treatment could fail, the HIV could 
become resistant to the medicines, or your child could be more likely to have serious side 
effects from the treatment. This study will help make sure that other young children in the 
future who are severely malnourished and infected with HIV get the best possible anti-
HIV treatment. 
 
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. 
 
Use of Combination Antiretroviral Drugs 
 
Immune Reconstitution Syndrome:  In some people with advanced HIV infection, signs 
and symptoms of inflammation from other infections may occur soon after anti-HIV 
treatment is started.   
 
The use of potent antiretroviral drug combinations may be associated with an abnormal 
placement of body fat and wasting. Some of the body changes include: 
 
 Increase in fat around the waist and stomach area 
 Increase in fat on the back of the neck  
 Thinning of the face, legs, and arms 
 Breast enlargement 
 
Nucleoside Reverse Transcriptase Inhibitor 
 
Lactic acidosis and severe hepatomegaly (enlarged liver) with steatosis (fatty liver) that 
may result in liver failure, other complications and death have been reported with the use 
of antiretroviral nucleoside analogues alone or in combination.  The liver complications 
and death have been seen more often in women on these drug regimens. Some 


 
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nonspecific symptoms that might indicate lactic acidosis include: unexplained weight 
loss, stomach discomfort, nausea, vomiting, fatigue, weakness, and shortness of breath. 
Zidovudine (RETROVIR®) 
ViiV Healthcare Ltd 
 
The following side effects have been associated with use of zidovudine: 
 
 Decrease in the number of white blood cells that help fight infection  
 Decrease in the number of red blood cells that may cause weakness, dizziness, and 
fatigue  
 Muscle aches, weakness, and wasting 
 Headache 
 Upset stomach  
 Vomiting  
 Decrease in appetite  
 Vague overall feeling of discomfort  
 Lack of energy  
 Feeling tired  
 Sleeplessness 
 Heartburn 
 
Lamivudine (3TC, EPIVIR®) 
ViiV Healthcare Ltd 
 
The following side effects have also been associated with use of lamivudine: 
If your child is infected with both Hepatitis B and HIV, you should be aware that your 
child’s liver function tests may increase, and symptoms associated with hepatitis (an 
acute inflammation of the liver) may worsen if lamivudine is stopped.  Although most of 
these cases have resolved without treatment, some deaths have been reported. 
 
 Headache 
 Feeling tired  
 Dizziness 
 Numbness, tingling, and pain in the hands or feet  
 Depression 
 Trouble sleeping 
 Rash 
 Upset stomach, vomiting, nausea, loose or watery stools  
 Pancreatitis (inflammation of the pancreas), which may cause death. If your child  
develop pancreatitis, your child may have one or more of the following: stomach 
pain, nausea, and vomiting.  
 Abnormal pancreatic and liver function blood tests 
 
 
 


 
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Protease Inhibitors 
 
The use of protease inhibitors may be associated with the following: 
  
 Increases in the amount of triglycerides and/or cholesterol in the blood  
 Development of diabetes or the worsening of high blood sugar 
 
There have been reports of increased bleeding in HIV-infected persons with hemophilia 
who were treated with protease inhibitors.  It is not known if protease inhibitors were the 
cause of these bleeding episodes. 
 
Lopinavir/Ritonavir (LPV/r, KALETRATM) 
Abbott Laboratories 
 
The following serious side effects are associated with the use of lopinavir/ritonavir: 
 
 Abnormal heart rhythm and electrocardiogram (EKG) changes. These changes can 
lead to serious heart problems. Your child’s risk for these problems may be higher if 
your child : 
o Already has a history of abnormal heart rhythm or other types of heart disease 
o Takes other medicines that can affect your child’s heart rhythm while your child 
takes lopinavir/ritonavir 
 
If your child develops abnormal heart rhythm your child may experience lightheadedness, 
fainting spells or an abnormal heart beat.  
 
Pancreatitis (inflammation of the pancreas), which may cause death. If your child 
develops pancreatitis, your child may have one or more of the following: 
 
 Stomach pain, nausea, vomiting or abnormal pancreatic function blood tests  
 Large increases in triglycerides and cholesterol in the blood  
 
Liver problems and worsening liver disease, which may result in death. People with these 
conditions may have abnormal liver function blood tests. If your child is developing liver 
problems, your child may have one or more of the following: yellowing of the skin or 
whites of the eyes, dark urine, pain on the right side of your stomach, loss of appetite, 
upset stomach or vomiting, pale colored stools, itchy skin.  Additional side effects may 
include: 
 
 Abnormal bowel movements (stools), including loose or watery stools, upset stomach 
and stomach pain  
 Feeling weak and tired 
 Headache 
 Rash which could blister and may be severe or life-threatening. Contact your health 
care provider if your child develops a rash. 


 
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Risks When Drawing Blood  
 
Drawing blood from a vein or heel stick can cause pain, bruising or bleeding at the place 
where the needle goes into the skin. There is also a small risk of inflammation or 
infection of the vein.  
 
Risks of Resistance  
 
All anti-HIV medicines can cause resistance. When resistance occurs, a medicine no 
longer works against HIV, which can limit the choices of medicines a person can take 
against HIV in the future. To avoid resistance, it is important to take anti- HIV medicines 
as instructed and not to miss doses. 
 
Other Risks 
 
If your child joins this study, some hospital staff and all study staff will know that your 
child has HIV.  These workers are very serious about your privacy.  Study staff will make 
every possible effort to be sure that others do not learn your child’s HIV status.  
However, sometimes if your child receives special treatment or attends a special clinic, it 
may make others wonder if your child has HIV. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If your child takes part in this study, there is no guarantee of direct benefit to your child 
since the levels of drug in your child’s body will not be done immediately after your child 
takes it.  The information learned from this study may help other children who have HIV.  
Your child’s participation would benefit others by allowing access to anti-HIV 
medications that are not currently available as first line treatment for children starting 
anti-HIV medications. 
 
WHAT OTHER CHOICES DOES MY CHILD HAVE BESIDES THIS STUDY? 
 
Instead of being in this study your child has the choice of: 
 
treatment with prescription drugs available to your child in care programs 
 
treatment with experimental drugs, if your child qualifies  
 
no treatment 
 
Please talk to your doctor about these and other choices available to your child. Your 
doctor will explain the risks and benefits of these choices. 
 


 
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WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your child’s personal information confidential.  We cannot 
guarantee absolute confidentiality.  Your child’s personal information may be disclosed if 
required by law.  Any publication of this study will not use your child’s name or identify 
your child personally. 
 
Your child’s records may be reviewed by the [insert name of site] IRB/EC, National 
Institutes of Health (NIH), Office for Human Research Protections (OHRP), study staff, 
study monitors, and drug companies supporting this study. 
 
WHAT ARE THE COSTS TO ME? 
 
There is no cost to you for the study visits, examinations, blood tests or the anti-HIV 
study drugs, zidovudine , lamivudine or lopinavir/ritonavir your child is required to take.  
If your doctor needs to switch your child to another anti-HIV medication, such as 
abacavir, there may be a cost to you as this drug is not provided by the study.  [Note to 
sites: This statement can be modified as needed for your site.] 
 
Taking part in this study may lead to added costs to you and your insurance company. In 
some cases it is possible that your insurance company will not pay for these costs because 
your child is taking part in a research study. [Note to sites: Language related to insurance 
can be deleted if it is not relevant to your site.] 
 
WHAT HAPPENS IF MY CHILD IS INJURED? 
 
If your child is injured as a result of being in this study, your child will be given 
immediate treatment for his/her injuries.  The cost for this treatment will be charged to 
you or your insurance company.  There is no program for compensation either through 
this institution or the National Institutes of Health (NIH).  You will not be giving up any 
of your legal rights by signing this consent form. 
 
WHAT ARE MY CHILD’S RIGHTS AS A RESEARCH SUBJECT? 
 
Taking part in this study is completely voluntary.  You may choose not to allow your 
child to take part in this study or take your child out of the study at any time.  Your child 
will be treated the same no matter what you decide. Your decision will not have any 
impact on your child’s participation in other studies conducted by NIH and will not result 
in any penalty or loss of benefits to which your child is otherwise entitled.   
 
We will tell you about new information from this or other studies that may affect your 
child’s health, welfare or your willingness to allow your child to stay in this study.  If you 
want the results of the study, let the study staff know. 
 


 
IMPAACT P1092 
FINAL Version 2.0   
11 February 2015 
 
84 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
[name of the investigator or other study staff] 
 
[telephone number of above]  
 
For questions about your child’s rights as a research subject, contact: 
 
[name or title of person on the Institutional Review Board (IRB) or other 
organization appropriate for the site] 
 
[telephone number of above]   
 
 
SIGNATURE PAGE   
 
If you have read this consent form (or had it explained to you), all your questions have 
been answered and you agree to allow your child to take part in this study, please sign 
your name below. 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent or Legal Guardian Name  
Parent or Legal Guardian  
 
Date 
(print)  
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name  
 
 
Witness Signature 
 
 
Date 

SAP_001.pdf: 
 
 
 
 
IMPAACT P1092 
 
IMPAACT P1092: PHASE IV EVALUATION OF THE STEADY STATE PHARMACOKINETICS OF 
ZIDOVUDINE, LAMIVUDINE, AND LOPINAVIR/RITONAVIR 
IN SEVERELY MALNOURISHED HIV-1-INFECTED CHILDREN 
 
 
Statistical Analysis Plan 
 
Version 3.0 
 
August 20, 2018 
 
ClinicalTrials.gov ID: NCT01818258 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is IMPAACT P1092 SAP Version 3.0 with names of authors, names of publication writing team 
members and analysis timeline redacted. 
 
 


 P1092 Statistical Analysis Plan  
 
August 20, 2018 
 
Page 2 of 14 
 
 
Table of Contents: 
 
1. 
Introduction .................................................................................................................................... 3 
2. 
Study Overview ............................................................................................................................... 3 
2.1 
Study Design ............................................................................................................................. 3 
2.2 
Hypotheses .............................................................................................................................. 4 
2.3 
Study Objectives ...................................................................................................................... 4 
2.3.1 
Primary Objectives and Outcome Measures ................................................................... 4 
2.3.2 
Secondary Objectives and Outcome Measures ............................................................... 4 
2.4 
Study Sample Size .................................................................................................................... 5 
2.5 
Protocol Visit and Evaluation Schedule ................................................................................... 5 
2.5.1 
Stage 1 .............................................................................................................................. 5 
2.5.2 
Stage 2 .............................................................................................................................. 5 
2.6 
Major Changes in Protocol History .......................................................................................... 6 
2.7 
Monitoring ............................................................................................................................... 6 
2.7.1 
SMC Review History ......................................................................................................... 6 
2.8 
General Statistical Considerations ........................................................................................... 7 
3. 
Key Elements of the Statistical Report ............................................................................................ 8 
3.1 
Screening .................................................................................................................................. 8 
3.2 
Accrual...................................................................................................................................... 8 
3.3 
Eligibility Violations .................................................................................................................. 8 
3.4 
Selected Characteristics at Screening and Baseline ................................................................. 8 
3.5 
Study Follow-up Status ............................................................................................................ 9 
3.6 
ARV Initiation and Modification ............................................................................................... 9 
3.7 
Descriptive Summaries ............................................................................................................ 9 
3.7.1 
Pharmacokinetics ............................................................................................................. 9 
3.7.2 
Safety ............................................................................................................................... 9 
3.7.3 
HIV Plasma Viral Load ....................................................................................................10 
3.7.4 
Growth ...........................................................................................................................10 
4. 
Primary Analysis ............................................................................................................................10 
5. 
Secondary Analyses .......................................................................................................................11 
6. 
Appendix .......................................................................................................................................13 
 
 
  
 
 


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1. Introduction 
 
This document describes the proposed content for the primary statistical analysis of study P1092, focusing on 
analyses that address the primary objectives and secondary objectives that will contribute to the planned 
primary manuscript.  This version 2.0 of the plan focuses on the final analysis and updates version 1.0 which 
described the analyses in reports for the Study Monitoring Committee (SMC) while the study was ongoing. This 
plan forms the core of any presentation or publication used to disseminate the primary conclusions of the 
study.  
2. Study Overview 
2.1 Study Design 
 
P1092 (version 2.0) is a Phase IV open label study to evaluate the pharmacokinetics (PK), safety, and tolerability 
of antiretroviral drugs zidovudine (ZDV), lamivudine (3TC), and ritonavir boosted lopinavir (LPV/r) in  
children infected with HIV and children aged ≥6 months (≥180 days) to <36 months who were grouped by their 
nutritional status.  The overall goals for P1092 are to characterize the PK and safety of ARVs in severely 
malnourished children (SAM) following the initiation of nutritional rehabilitation to compare results to normal-
mildly malnourished children in order to determine if current recommended doses are optimum in severely 
malnourished children.  
 
Two cohorts of children were targeted: cohort 1: children living with HIV who were severely malnourished and 
eligible for HAART as defined by WHO 2013 pediatric guidelines (described in protocol section 4.14 and below) 
and cohort 2: a control group of children living with HIV and mild malnutrition-normal nutrition who were also 
eligible for HAART.  Children with severe malnutrition underwent an approximate two week nutrition 
rehabilitation program before entering the study.    
 
The 2013 WHO pediatric guidelines for severe acute malnutrition (non-edematous), mild nutrition, and normal 
nutrition were used to classify the two cohorts (protocol section 4.14). The classification was as follows: 
 
Severe non-edematous malnutrition: weight for height z-score (WHZ) < - 3 or mid-upper arm 
circumference (MUAC) < 115 mm (Cohort 1) 
 
Mild nutrition: -2 < weight for height z-score (WHZ) ≤ -1 (Cohort 2) 
 
Normal nutrition: weight for height z-score (WHZ) > -1    (Cohort 2) 
 
The study involved two stages.  Stage 1 was the pre-entry/screening stage for both cohorts.   Children with 
severe malnutrition underwent a 10 to 18 day nutrition rehabilitation program in Stage 1 before entering the 
study. The WHO (World Health Organization) approach to the management of SAM was used, which involves a 
stabilization and rehabilitation phase. Stage 2 began with the study participant’s registration to the study and 
initiation of the study antiretroviral (ARV) regimen.  All participants were to receive ZDV+3TC+LPV/r upon study 
entry/registration (Stage 2).   For children with severe malnutrition, pre-entry/screening and enrollment 
occurred during an inpatient stay in the nutritional rehabilitation unit, with the entry/registration visit 
conducted 10-18 days after the day of admission to the nutritional rehabilitation unit.  Children with mild 
malnutrition-normal nutrition were enrolled from HIV treatment centers and were scheduled to have the 
entry/registration visit within 14 days after pre-entry/screening.  Children in both cohorts were judged by their 
clinician to be stable before study entry/registration. Participants needed to clinically improve on nutrition 
rehabilitation in order to be registered/enrolled to the study after Stage 1 (see protocol section 4.17 for the 
definition of nutrition rehabilitation).  The study regimen was ideally initiated on the day of enrollment but was 
permitted to be initiated up to 3 days after the day of enrollment. ARVs were dosed based on WHO weight 
band dosing (see protocol section 5.1). Participants were allowed to have a receipt of ARVs prior to study entry, 
including during the rehabilitation period.  
 


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Each enrolled participant was to be followed for 48 weeks, with scheduled visits at weeks 1, 2, 4, 8, 12, 16, 20, 
24, 36, and 48 of follow-up. At weeks 1, 12, and 24, intensive PK sampling was to be carried out following a 
morning dose of ARVs; for children weighing at least 5 kg, an additional sample generating 1 mL of plasma was 
collected at the 2 hour time point to measure free fraction of lopinavir at the time of peak concentration at 
weeks 1, 12, and 24.  At weeks 4, 8, 16, 36, and 48 a trough PK sample was collected just prior to the morning 
dose of ARVs.  PK trough samples were collected also just prior to dosing as part of intensive sampling at weeks 
1, 12, and 24. Steady state was expected to be reached by week 1.  
 
It was expected that 25 children needed to be enrolled in each cohort to achieve 17 evaluable in each cohort, 
with evaluable defined as having results available for the week 1 intensive PK evaluations and either the week 
12 or the week 24 intensive PK evaluations.  Fifty-two participants were enrolled: 25 in cohort 1 and 27 in 
cohort 2. The study accrued for a total of 13 months with cohort 2 closing to accrual in March 2016 and cohort 
1 closing to accrual in November 2016. Each nutrition cohort was stratified by two age groups of <18 months 
and 18 months. Because it was desired to achieve balanced age distribution within and between cohorts, an 
initial upper bound of 13 participants was established for each cohort age group.  Eleven and 13 participants 
under 18 months were enrolled in cohort 1 and cohort 2, respectively. Fourteen participants aged 18 months 
or older were enrolled in cohort 1, and 14 were enrolled in cohort 2.  
2.2 Hypotheses 
 
It is hypothesized that children with severe acute malnutrition will have reduced absorption of antiretroviral 
drugs compared to those with mild malnutrition-normal nutrition (protocol section 1.12). 
A secondary hypothesis is the change from baseline for CD4 percent at 12 and 24 weeks will be smaller for the 
cohort with severe malnutrition at baseline (protocol section 1.23).  
2.3 Study Objectives  
 
Objectives and outcomes are per protocol version 2.0, sections 2 and 8, except where indicated with text in 
italics. 
2.3.1 
Primary Objectives and Outcome Measures 
 
1. Objective: To compare the PK exposure (as estimated by the area under the plasma concentration 
versus time curve, AUC) and clearance of ZDV, 3TC, and LPV/r under steady-state conditions between 
severely malnourished children and children with mild malnutrition-normal nutrition at weeks 1, 12, 
and 24 following study entry.  
Outcome Measure: Steady-state AUC and plasma clearance (CL/F) for ZDV, 3TC, and LPV/r 
 
2. Objective: To evaluate the safety and tolerability of ZDV, 3TC, and LPV/r in severely malnourished 
children and children with mild malnutrition-normal nutrition at 24 weeks following study entry. 
Outcome Measure: Safety and tolerability measures, which include the number and percent of 
participants with at least Grade 3 adverse events related to study drugs and at least Grade 3 adverse 
events regardless of the relationship to study drugs through week 24. 
2.3.2 
Secondary Objectives and Outcome Measures 
 
1. Objective: To compare the minimum concentration (Ctrough) of LPV/r between severely malnourished 
children and children with mild malnutrition-normal nutrition at 1, 4, 8, 12,16, 24, 36, and 48 weeks 
following study entry. 
Outcome Measure: The minimum concentration (“trough”) of LPV/r in the two cohorts at weeks 1, 4, 
8, 12, 16, 36, and 48 


 P1092 Statistical Analysis Plan  
 
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2. Objective: To investigate the impact of malnutrition on LPV protein binding by comparing the free 
fraction of LPV in severely malnourished children and children with mild malnutrition-normal nutrition 
at 1, 12, and 24 weeks following study entry. 
Outcome Measure: The measures of LPV protein binding (free fraction) in the two cohorts at weeks 1, 
12, and 24 
 
3. Objective: To compare the viral loads between severely malnourished children and children with mild 
malnutrition-normal nutrition at baseline, 12, 24, 36, and 48 weeks following study entry. 
Outcome Measure: The plasma HIV-RNA load in the two cohorts at study entry and Weeks 12, 24, 36, 
and 48 
 
4. Objective: To compare CD4 cell percent between severely malnourished children and children with 
mild malnutrition-normal nutrition at baseline, 12, 24, 36, and 48 weeks following study entry.    
Outcome Measure: The CD4 percent in the two cohorts at study entry and Weeks 12, 24, 36, and 48 
 
5. Objective: To describe the recovery of lean body mass and linear growth in severe acute malnutrition 
at 24 and 48 weeks following study entry. 
Outcome Measures:  
 
Description of the recovery of the lean body mass by assessment of weight to height z-score 
(WHZ) and mid-upper arm circumference (MUAC) in children in severe acute malnutrition at 
weeks 24 and 48  
 
Assessment of height and change in height over time in severe acute malnutrition.    
 
Analyses of all primary and secondary outcome measures, except secondary outcome measure 2 investigating 
LPV protein binding, will contribute to the planned primary manuscript. The LPV protein binding analysis and 
additional exploratory analyses, including the investigation of micronutrient data, will be evaluated in future 
analyses.  
2.4 Study Sample Size  
 
From protocol version 2.0 section 8.4: “The primary objective is to compare severely malnourished and 
normal–mildly malnourished children on HAART with respect to pharmacokinetic exposures quantified as 
concentration AUCs. The coefficient of variation of AUC for LPV was estimated to be approximately 0.40 in 
similarly aged children (50). The protocol team considers a 40% difference between groups with respect to LPV 
AUC to be clinically important. A parallel-arm study with two groups would require N=17 patients per group to 
detect a 40% difference between groups in the LPV AUC with 80% power and a two-sided Type I error of 5% for 
a CV of 0.4. In addition, a 10% LTFU and 20% mortality rate (current mortality rate in the malnutrition unit) is 
considered for the estimate. This yields a necessary sample size of 17 children + 30% for a total of 23 children 
required per treatment group. Because of uncertainties in the estimation of AUC CV and possible 
heterogeneity in variance associated with differential malnutrition status, we suggest a further 10% inflation to 
25 children per nutrition status stratified by age.” 
2.5 Protocol Visit and Evaluation Schedule 
2.5.1 
Stage 1 
The Stage 1 visits begin after consent and include screening/pre-entry visit data. Stage 1 visits must have been 
performed within 18 days prior to entry/registration for cohort 1 and within 14 days prior to entry/registration 
for cohort 2.   
2.5.2 
Stage 2 


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Clinic study visits for Stage 2 were scheduled at Stage 2 registration (entry/registration visit), week 1 (+3 days), 
week 2 (+/- 2 days), week 4 (+/- 7 days), then every 4 weeks (± 7 days) until week 24, then every 12 weeks (+/- 
14 days) until week 48 (+/- 14 days).  
2.6 Major Changes in Protocol History 
 
Protocol version 1.0 was finalized on February 24, 2012.   Letter of Amendment (LoA) #1 was issued on 
September 13, 2012 and included a number of protocol modifications. While waiting for the site institutional 
review board (IRB) approval, IMPAACT leadership paused the protocol.  After IMPAACT leadership gave 
approval for further development of the protocol in 2014, protocol version 2.0 was finalized on February 11, 
2015.  No participants were enrolled under version 1.0 or LoA #1 of the protocol.  All participants were enrolled 
under protocol version 2.0.  
 
LoA #1 for protocol version 2.0 was issued on April 12, 2016. Initially, the SMC was notified when hematologic 
grade 3 or 4 events occurred and accrual was temporarily suspended. Instead of stopping accrual for every 
hematologic grade 3 or 4 event, the LoA #1 allowed the DAIDS/NICHD Medical Officers to review grade 3 and 4 
hematologic events to determine if accrual needed to be temporarily suspend and if an SMC review was 
required.  
2.7 Monitoring 
 
The P1092 Core Team (the protocol chair, vice chair, DAIDS and NICHD medical officers, clinical trials 
specialists, data and laboratory data managers, statisticians, pharmacologists, immunologist, nutritionist, 
laboratory technologist) was responsible for ongoing safety monitoring.  The Core Team focused on the clinical 
management of individual participants.  Conference calls were scheduled monthly to review protocol 
activation, accrual, barriers to any issues arising with study conduct, and new adverse events as well as 
assessment of relationship to study treatment by the Chairs and Medical Officers recorded in the database by 
the data manager.  In addition, serious adverse events (SAEs) were reported to the DAIDS Safety Office during 
the protocol-defined expedited adverse event (EAE) reporting period which was the entire study duration for 
an individual participant (from study enrollment until study completion or discontinuation).  
At any time the P1092 Core Team could have requested an external review by the SMC to review any study 
treatment-related events that may have compromised participant safety.   
2.7.1 
SMC Review History 
 
The SMC reviewed study conduct, including accrual, retention, and safety.  A full review was to occur every 12 
months or on a schedule specified by the SMC. An ad-hoc SMC review was required if: 
 
 
Any participant had a life-threatening adverse event that was judged to be probably or definitely 
attributable to study drug or any Grade 4 event that may not be judged to be life-threatening but was 
judged to be probably or definitely attributable to the study drug.  
 
Or if more than 6 out of the first 20 participants or at least 30% of participants thereafter have Grade 
3 or greater toxicity that was judged to be definitely related to study drug. 
 
The Core Team monitored participant events and assessed relationship with study treatment within 48 hours 
of notification. If events were assessed as probably or definitely related to study drug by the Core Team, 
accrual was required to immediately pause and the SMC to be urgently convened to review the events and 
determine whether the study should be suspended or modified.  Immediately following review by the SMC, the 
Core Team provided the study sites with documentation of the events that occurred, the team and SMC review 
of the events, and the recommendations of the SMC, for submission to their ethical and drug regulatory review 
bodies.  


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August 20, 2018 
 
Page 7 of 14 
 
The IMPAACT SMC conducted 4 interim reviews to monitor accrual, safety, participant growth and viral load, 
PK sample evaluability, and study implementation quality approximately every six months. After the second 
interim review, the SMC suggested to no longer require pausing accrual for grade 3 or 4 hematologic events.  
 
2.8 General Statistical Considerations 
 
Sample 
a. Participants’ data through their study follow-up discontinuation (off study) date will be summarized. 
b. PK evaluability: the goal of the study was to have all participants have intensive PK parameters 
available for weeks 1, 12, and 24 following initiation. One criterion for evaluability was the participant 
must have had results for the week 1 intense PK evaluations and either week 12 or 24 intense PK 
results. Additional exclusions for PK evaluability will be summarized along with reasons for the 
exclusion.  
c. 
Participants will be excluded from the week AUC calculation if 3 or more concentration samples are 
missing from the intensive PK evaluation. 
d. Drug concentration levels: the lower limit of detection (LLD) of the assays was the following for the 
study ARVs: 24 ng/mL for ZDV, 24 ng/mL for 3TC, 0.02 ng/mL for LPV, and 0.005 ng/mL for RTV.  Drug 
concentrations below the limit of quantification (BLQ, the equivalent to LLD) will be handled using 
standard pharmacokinetic methods to assure all data are handled in a consistent manner. Pre-dose 
concentrations BLQ will be assigned a concentration of 0. The first concentration value post-dose BLQ 
will be assigned 50% BLQ then a concentration of 0 thereafter.   
e. Participants eligible for safety and tolerability analyses received at least one dose of ZDV, 3TC, and 
LPV/r. 
Definitions 
f. 
Participant level PK parameters will be calculated by the study pharmacologists and data will be 
submitted to the study database (see protocol section 9). 
1. Per protocol, for PK AUCs a non-compartmental analysis will be performed for individual PK 
estimates via the linear up-log down trapezoidal rule in conjunction with an oral input model 
using WinNonlin 5.0.1 (Pharsight Corporation, Mountain View, USA) from intensive PK sampling 
visits. PK AUC is based on a 0-12 hour dosing cycle.  
2. Per protocol, plasma PK data from intensive sampling visit will be analyzed using non-
compartmental analysis to determine the following PK measures for ZDV, 3TC, LPV and RTV. 
Ctrough, Cmax, and Tmax will be determined by inspection of the results.  
g. Per protocol section 9.3, Ctrough is the pre-dose sample concentration, Cmax is the peak plasma 
concentration, and Tmax is the time to reach Cmax after drug ingestion.  Ctrough samples will be included 
in analyses if drawn within 2 hours before dosing (post-protocol definition). If there is more than one 
sample within 2 hours before dosing, the minimum concentration value will be used as the Ctrough 
measurement. Safety outcome measures related events were graded according to The Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0. 
h. Weight-for-height z-scores were calculated from the SAS macro for Z-score calculations based on 
WHO standards for children aged 0-≤ 5 years (< 61 months), assuming length was measured. More 
information on the SAS macro is located at www.who.int/childgrowth/software/en.                                                                         
For each clinical visit, weight and height were collected and weight-for-height z-scores will be 
calculated from these measurements with the SAS macro.   
i. 
Early ARV treatment discontinuation is permanently discontinuing all components the study drugs of 
ZDV, 3TC, and LPV/r before completing 48 weeks of study follow-up as defined by the protocol for any 
reason (participant must have a study discontinuation date within or after the window for the week 
48 visit date). Switches to abacavir (ABC) due to ZDV toxicity will be summarized with early treatment 
discontinuation reasons, if applicable. 
Statistical Analyses 
j. 
Unless otherwise stated, summaries will be shown by cohort group. 


 P1092 Statistical Analysis Plan  
 
August 20, 2018 
 
Page 8 of 14 
 
k. 
Unless otherwise stated, tests will be two-sided; continuous outcome measures will be compared 
between cohorts with a t-test with unequal variance; categorical outcome measures will be compared 
by Fisher’s exact test.  
l. 
Repeated measure analyses will use a linear mixed effects model to evaluate intensive PK parameters 
and of growth over time within and between cohorts. The average difference and difference in 
trajectories of PK and growth parameters will be evaluated.  
m. Summaries for PK parameters will provide the following: mean, standard deviation, and quartiles on 
the original scale, geometric mean and geometric mean ratio. All comparisons will be performed on 
the (natural) logarithmic scale.   
n. Per protocol section 8, pre-specified null hypotheses will be tested individually at the 0.05 level of 
significance. Ad hoc analysis of data within subgroups will be presented with caveats. 
o. This is a phase IV study and not subject to NIH requirements that primary analyses of treatment 
comparisons be summarized by sex and race. 
p. Statistical software SAS 9.4 will be used to generate analysis summaries. 
3. Key Elements of the Statistical Report 
3.1 Screening 
 
Summary of inclusion and exclusion screening failures  
3.2 Accrual 
 
a. Summary of participants enrolled over time by country, site, cohort, and age group.  
b. Summary of the time between screening and entry/registration  
 
3.3 Eligibility Violations 
 
Summary of the types of reported eligibility violations by cohort and age group 
3.4 Selected Characteristics at Screening and Baseline 
 
Baseline values are the values measured on the Stage 2 study entry/registration visit (≤ 0 days from 
entry/registration). 
Screening/pre-entry values are the values measured on the Stage 1 screening visit (date of consent). If 
screening/pre-entry measurements were taken at multiple times before entry/registration, the measurement 
closest to the entry/registration date will be used if within 18 days of the entry/registration date for cohort 1 or 
14 days for cohort 2 (maximum days between screening/pre-entry and entry/registration visits are defined in 
protocol version 2.0).  
No statistical comparison will be done comparing cohorts. 
 
The following characteristics will be summarized at either baseline or screening, as specified: 
 
Age at enrollment (months) and categorized age groups(<18, ≥18 months) 
 
Gender  
 
Race/ethnicity 
 
Country 
 
Nutrition category (normal, mild malnutrition, and severe malnutrition) 
 
Baseline HIV-1 RNA (copies/mL) (< 400, 2,000-< 10,000, 10,000-<20,000, ≥ 20,000) 
 
WHO clinical stage 


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August 20, 2018 
 
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 
Categorized screening/pre-entry absolute CD4+ counts (cells/mm3) (< 400, 400-<1,100, 1,000-< 
1,500, 1,500-<2,000, 2,000-<2,500, 2,500-<3,000, ≥ 3,000) 
 
Categorized screening/pre-entry CD4% (< 15, 15-<25, 25-<50, ≥ 50) 
 
Screening/pre-entry absolute CD4+ counts (cells/mm3), CD4%  
 
Baseline log10 HIV-1 plasma RNA (copies/mL) 
 
Baseline weight (kg) 
 
Baseline height (cm) 
 
Baseline head circumference (cm) 
 
Baseline middle upper arm circumference (cm) 
 
Baseline weight-for-height WHO Z-score 
 
ARV regimens previously taken by participants 
 
Most common diagnoses before or ongoing at study entry/registration 
 
Baseline electrolyte abnormalities and lipid profiles 
 
3.5 Study Follow-up Status  
 
a. CONSORT diagram statistics summarizing the number of participants screened, enrolled, started 
treatment, completed treatment, completed study, and reasons for the early discontinuation of 
treatment or the study  
b. Total summary of participant off study week with reason for discontinuing 
c. 
Summary of participant off study week with reason for discontinuing by cohort and age group  
d. Summary of types of reported protocol deviations 
3.6 ARV Initiation and Modification 
 
a. Summary of days from entry/registration to study ARV initiation 
b. Summary of early permanent study ARV treatment discontinuations with reasons 
c. Summary of switches from ZDV to Abacavir (ABC)  
3.7 Descriptive Summaries  
3.7.1 
Pharmacokinetics  
 
Summary PK measures will be provided for study drugs ZDV, 3TC, LPV, and RTV. Intensive PK measurements 
were scheduled for sampling at pre-dose and hours 1, 2, 4, 8, and 12 post-dose. 
 
a. Summary of exclusions from PK analyses and reasons for exclusions 
b. Summary of imputations for concentration values below the lower limit 
c. 
Concentration-time plots for each participant at weeks 1, 12, and 24 by study drug  
d. Summary of Cmax, Tmax, Ctrough, and AUC of study drugs at weeks 1, 12, and 24  
e. Summary of time between past dose, Ctrough sample measurement, and next dosing 
3.7.2 
Safety  
 
a. Descriptions and narratives of study deaths  
b. Summary of grade 3 or higher adverse events regardless of relationship to study treatment 
 
Notes for safety outcome measure definitions: 
 


 P1092 Statistical Analysis Plan  
 
August 20, 2018 
 
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1. The protocol required grading of events according to The Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Version 2.0, Nov 2014, which is available on the RCC website: 
http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/DAIDS_AE_Grading_Table_v2_NOV2014_Highlighted_Ch
anges.pdf 
 
2. The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, was used for study event 
reporting. In addition, other events that sites were required to report in an expedited fashion included all 
malignancies, seizures, and grade 3 and 4 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 could not be ruled 
out.   
 
3. The drugs that were assessed for relatedness included ZDV, 3TC, and LPV/r. If participants switched from 
ZDV to ABC, this was noted and relatedness to ABC was also assessed.  
 
4. The following are examples of details which clarify the events to be included or excluded: 
 
Events with date of onset or specimen date prior to or on the first study treatment dose will be 
excluded  
 
All events afterwards (on or off study treatment) will be included 
 
Signs and symptoms with an onset date the same as the date of the first study treatment dose will be 
considered a sign and symptom at baseline and will be excluded.  
 
Laboratory abnormalities with a specimen date the same as the date of the first study treatment dose 
will be excluded on the assumption that the specimen was drawn before study treatment was 
administered.   
 
Deaths will be included with grade assigned 5 and will be included in analyses 
 
5. During the study, the Core Team assigned their assessment of treatment relationship to the following 
targeted study events: 
 
Grade ≥ 3 signs/symptoms, laboratory values  
 
All diagnoses at entry/registration and thereafter 
 
For Triglycerides/Total Cholesterol, if fasting, we will report all grade ≥ 3 events. Since we do not have 
DAIDS grading criteria for non-fasting Triglycerides/Total Cholesterol, we will use the grade 2 cut off 
values for non-fasting participants for Triglycerides/Total Cholesterol.  It is specified as follows: 
Triglycerides is > 300mg/dL or Triglycerides > 3.42mmol/L, Total Cholesterol ≥ 200mg/dL or Total 
Cholesterol ≥ 5.15mmol/L  
3.7.3 
HIV Plasma Viral Load  
 
Longitudinal summary of the log10 HIV-1 plasma RNA copies/mL for each participant  
3.7.4 
Growth 
 
a. Longitudinal summary of the by-participant weight-for-height WHO Z-score  
b. Longitudinal summary of the by-participant growth data including: height, weight, head circumference, 
skin fold thickness, and MUAC  
4. Primary Analysis 
 
1. Objective: To compare the PK exposure (as estimated by the area under the plasma concentration versus 
time curve, AUC) and clearance of ZDV, 3TC, and LPV/r under steady-state conditions between severely 


 P1092 Statistical Analysis Plan  
 
August 20, 2018 
 
Page 11 of 14 
 
malnourished children and children with mild malnutrition-normal nutrition at 1, 12, and 24 weeks 
following study entry/registration.  
 
Outcome Measure: Steady-state AUC0-12 and plasma clearance (CL/F) for ZDV, 3TC, and LPV/r 
 
Analysis:  Two-sided t-tests with 95% CIs will be applied at weeks 1, 12, and 24 to compare the geometric 
mean of AUC and clearance using the log (ln) transformed values between the two cohorts.  
 
A sensitivity analysis linear regression adjusting for the age stratification factor will be conducted to 
compare the cohort differences of AUC and clearance.  
 
A supplementary repeated measures analysis using a mixed effects model will be applied to evaluate AUC 
and plasma clearance over time with indicator (class) week variables.  The average AUC (clearance) over 
time will be estimated within and compared between cohorts. Pairwise differences between weeks in PK 
parameters will be assessed within and between cohorts. 
 
2. Objective: To evaluate the safety and tolerability of ZDV, 3TC, and LPV/r in severely malnourished children 
and children with mild malnutrition-normal nutrition at 24 weeks following study entry/registration. 
 
Outcome Measure: Grade 3 or higher adverse events at least related to the study treatment and grade 3 
or higher adverse events regardless of the relationship to the study treatment through week 24 in stage 2 
follow-up. 
 
Two-sided Fisher exact tests (presenting both 90% and 95% confidence intervals, as specified in the sample 
size calculation in protocol section 8) will be applied to compare the frequencies of the grade 3 or higher 
adverse events through week 24 between cohorts. One test will be restricted to adverse events assessed 
by the Core Team as related to the study treatment. Summaries of other toxicity measures such as 
proportion of participants experiencing vomiting and diarrhea, and frequency of serious of adverse events 
through week 24 will also be provided.  
 
A subset analysis will be completed to compare the proportion of adverse events experienced among 
participants evaluable for the intensive PK analysis.  
 
5. Secondary Analyses 
 
1. 
Objective: To compare the minimum concentration (Ctrough) of LPV/r between severely malnourished 
children and children with mild malnutrition-normal nutrition at 1, 4, 8, 12, 16, 24, 36, and 48 weeks 
following study entry. 
 
Analysis: Summaries of the Ctrough of LPV and RTV will be provided at weeks 1, 4, 8, 12, 16, 24, 36, and 48 
between the two cohorts.  
 
Target PK—The trough measurements collected in children will be compared to published measurements 
for lopinavir trough of >1 ng/mL. The proportion (with 95% CI) of children with >1 ng/mL of LPV trough will 
be summarized for each week by cohort. The proportion of children with Ctrough of LPV above 1 ng/mL 
across all weeks will also be summarized by cohort. A repeated measures analysis will be applied to 
evaluate Ctrough of LPV over time.  
 
A sensitivity analysis adjusting for age stratification factors will be conducted to compare the cohort 
differences of the Ctrough of LPV and RTV.  


 P1092 Statistical Analysis Plan  
 
August 20, 2018 
 
Page 12 of 14 
 
 
 
2. 
Objective: To investigate the impact of malnutrition on LPV protein binding by comparing the free fraction 
of LPV in severely malnourished children and children with mild malnutrition-normal nutrition at 1, 12, and 
24 weeks following study entry. [This objective will not be included in the primary manuscript] 
 
Analysis:  Summaries of the free fraction of LPV will be provided for weeks 1, 12, and 24 following study 
entry/registration between the two cohorts. The average and 95% CI for each week by cohort will be 
calculated. T-tests with 95% CIs will be applied at weeks 1, 12, and 24 to compare the free fraction of LPV 
between the two cohorts. A repeated measures analysis will be applied to evaluate the free fraction of LPV 
over time. 
 
A sensitivity analysis adjusting for age stratification factors will be conducted to compare the cohort 
differences of the free fraction of LPV.  
 
 
3. 
Objective: To compare the viral loads between severely malnourished children and children with mild 
malnutrition-normal nutrition at baseline, 12, 24, 36, and 48 weeks following study entry. 
 
Analysis: 
 
a. T-test on the mean change of log10 HIV plasma viral load from study entry/registration at weeks 
12, 24, 36, and 48 between cohorts 
b. Number of participants (%) with a HIV viral load ≤ 400 copies/mL at study entry/registration, 
weeks 24 and 48 by cohort. Two-sided Fisher exact tests will be applied to compare frequencies 
between cohorts. A sensitivity analysis including all participants on study, counting those who do 
not have data as not suppressed, will also be conducted.  
 
 
4. 
Objective: To compare CD4 cell percent between severely malnourished children and children with mild 
malnutrition-normal nutrition at baseline, 12, 24, 36, and 48 weeks following study entry.    
 
Analysis:  T-test between cohorts on the mean change of CD4% from baseline to weeks 12, 24, 36, and 48. 
 
Note: CD4 was observed at the screening visit. The CD4% measurement closest to the entry/registration 
visit will be used for this analysis.  
 
 
5. 
Objective: To describe the recovery of lean body mass and linear growth in severe acute malnutrition at 24 
and 48 weeks following study entry. 
 
Analysis: The following analyses will be carried within the cohort 1 (severely malnourished) and will 
employ a two sided one-sample t-test at a 5% type I error level for the change in WHO weight-for-height Z-
score from baseline at weeks 24 and 48. A repeated measures analysis will be applied to evaluate the 
growth of participants over time with mixed effects model, with week as a continuous covariate.  
   
The recovery of the lean body mass will be assessed by WHO weight-for-height z-score (WHZ) and mid-
upper arm circumference (MUAC) in children in severe acute malnutrition (protocol section 8.2). Linear 
growth will be assessed by height and change in height over time in severe acute malnutrition (protocol 
section 8.2). 
 
Summaries of WHZ, MUAC, height, and MUAC Z-Score will provided for cohort 1 at study 
entry/registration, weeks 24 and 48.  


 P1092 Statistical Analysis Plan  
 
August 20, 2018 
 
Page 13 of 14 
 
6. Appendix 
 
Schedule of Evaluations 
 
Screening 
Entry 
Week 1  
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 36 
Week 48 
Physical Exam1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nutritional 
Assessment2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology3 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
Chemistries4 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
Total Protein/ 
Albumin 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
Glucose 
 
 
 
 
X 
 
 
 
 
 
 
X 
Lipid Profile5 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Micronutrients6 
 
X 
 
 
 
 
 
 
 
 
 
X 
HIV-1 RNA7 
X 
X 
 
 
 
 
X 
 
 
X 
X 
X 
Lymphocyte 
Subsets8 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
Trough PK  
 
 
 
 
X 
X 
 
X 
 
 
X 
X 
Intensive PK 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
1. 
Physical exam includes length, weight, head circumference, and vital signs (temperature, heart rate, and 
respiratory rate). Skin fold thickness (triceps) will be at entry, weeks 24 and 48  
2. 
Nutritional assessment includes mid upper arm circumference  
3. 
Hematology include CBC with differential and platelet count 
4. 
Chemistries include AST, ALT, creatinine, sodium, potassium, chloride, and bicarbonate 
5. 
Lipid profile includes triglycerides and total cholesterol 
6. 
Micronutrients include zinc and selenium to be processed and stored until shipping to the central laboratory for 
testing 
7. 
Must be performed at DAIDS VQA-certified laboratory 
8. 
Lymphocyte subsets include absolute counts and percentages of CD4 and CD8 
 
 
 
 


 P1092 Statistical Analysis Plan  
 
August 20, 2018 
 
Page 14 of 14 
 
 
 
SAP Version History 
 Version 
Changes Made 
Date 
1.0 
First Version 
February 22, 2016 
2.0 
 Expanded on SMC Review History 
 Clarification added to Sections 1 and 2 
 Letters a-k added to General Statistical Considerations Section 
 Summaries (including tables and figures) used only for monitoring reports were 
omitted 
 Sections 3.4-3.7 were added or updated for final report summaries 
 Planned statistical analyses were updated for clarification or summaries were added 
to both primary outcomes and all secondary outcomes 
 Core manuscript writing team roster updated 
 Schedule of evaluations added per protocol 
 Timeline for data analysis and manuscript preparation updated 
February 1, 2018 
 
 
 
 
 
 
 
 
3.0 
 Clarified what ARVs could be taken prior to study entry  
 Provided updates in section 2.8 for clarification  
 Provided further clarification on longitudinal analysis in section 2.8 and in section 4 
for analysis of primary outcomes  
 Table summary (c) in 3.7.2 was deleted 
 Both confidence intervals (90% and 95%) will be presented for the safety primary 
analysis  
August 20, 2018