IMPAACT P1092: Steady State PK in Malnourished HIV Infected Children

NCT ID: NCT01818258

Last Updated: 2021-08-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-26
• Study Completion Date: 2017-09-29

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.

Conditions

HIV Positive; Malnourished

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Severe Malnutrition

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

Group Type: ACTIVE_COMPARATOR

ZDV+3TC+LPV/r

Intervention Type: DRUG

Normal Nutrition/Mild Malnutrition

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

Group Type: ACTIVE_COMPARATOR

ZDV+3TC+LPV/r

Intervention Type: DRUG

Interventions

ZDV+3TC+LPV/r

Intervention Type: DRUG

Other Intervention Names

Zidovudine; Retrovir; Lamivudine; Epivir; Lopinavir/ritonavir; Kaletra

Eligibility Criteria

Inclusion Criteria

• Documentation of HIV-1 infection defined as positive results from two samples collected at different time points, using protocol-specified tests
• Meets WHO classification for severe malnutrition, normal nutrition status, or mild malnutrition
• Eligible for HAART defined by WHO 2013 pediatric guidelines
• 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
• Qualifying hematology and chemistry laboratory values obtained from specimens collected within the study-specific screening period
• 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:
• 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)

Exclusion Criteria

• Edematous malnutrition at the time of study entry
• ≥ Grade 3 respiratory distress or presence of cardio respiratory compromise within 3 days prior to entry
• Chemotherapy for malignancy
• Acute infection for which the child has received appropriate antimicrobial treatment for <5 days
• Tuberculosis disease
• Clinic hepatitis as evidenced by jaundice and hepatomegaly
• Taking any disallowed medications
• 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.

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 36 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Maxensia O Owor, MBChB, MMED, MPH

Role: STUDY_CHAIR

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Locations

Blantyre CRS (30301)

Blantyre, , Malawi

Malawi CRS (12001)

Lilongwe, , Malawi

Kilimanjaro Christian Medical Centre (5118)

Moshi, , Tanzania

Makerere University-Johns Hopkins University (MUJHU) Research Collaboration (30293)

Kampala, , Uganda

Harare Family Care (31890)

Harare, , Zimbabwe

Countries

Malawi; Tanzania; Uganda; Zimbabwe

References

Owor M, Tierney C, Ziemba L, Browning R, Moye J, Graham B, Reding C, Costello D, Norman J, Wiesner L, Hughes E, Whalen ME, Purdue L, Mmbaga BT, Kamthunzi P, Kawalazira R, Nathoo K, Bradford S, Coletti A, Aweeka F, Musoke P. Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092. Pediatr Infect Dis J. 2021 May 1;40(5):446-452. doi: 10.1097/INF.0000000000003055.

Reference Type: RESULT

PMID: 33464021 (View on PubMed)

Bwakura-Dangarembizi M, Ziemba L, Tierney C, Reding C, Bone F, Bradford S, Costello D, Browning R, Moye J, Vhembo T, Ngocho JS, Mallewa M, Chinula L, Musoke P, Owor M. Micronutrients and nutritional status among children living with HIV with and without severe acute malnutrition: IMPAACT P1092. BMC Nutr. 2023 Nov 2;9(1):121. doi: 10.1186/s40795-023-00774-1.

Reference Type: DERIVED

PMID: 37919816 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Informed Consent Form

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables

Signs/symptoms, laboratory events, and diagnoses were graded using the Division of AIDS (DAIDS) Table for Grading Severity of Adult and Pediatric Adverse Events, Corrected Version 2.0, November 2014.

http://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-adverse-events-daids

Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

Other Identifiers

U01AI068632

Identifier Type: NIH

Identifier Source: secondary_id

View Link

11689

Identifier Type: OTHER

Identifier Source: secondary_id

IMPAACT P1092

Identifier Type: -

Identifier Source: org_study_id