Clinical trial NCT01818258: IMPAACT P1092: Steady State PK in Malnourished HIV Infected Children
Official title: IMPAACT 1092: Phase IV Evaluation Of The Steady State Pharmacokinetics Of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in Severely Malnourished HIV-1-Infected Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Positive
Malnourished
Keywords: HIV
Children
HAART
Malnourished
Lead sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Institute of Mental Health (NIMH)
First posted: 2013-03-26
Enrollment: 52
Sex: ALL
Minimum age (years): 6
Maximum age (years): 36
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Grade 3 or Higher Adverse Events Through 24 Weeks
timeFrame: From week 0 to week 24
measure: Grade 3 or Higher Adverse Events Related to Study Drugs Through Week 24
timeFrame: From week 0 to week 24
measure: Steady-state Lopinavir Area Under the Curve
timeFrame: 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry
measure: Plasma Clearance of Lopinavir
timeFrame: 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry
measure: Steady-state Ritonavir Area Under the Curve
timeFrame: 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry
measure: Plasma Clearance of Ritonavir
timeFrame: 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry
measure: Steady-state Lamivudine Area Under the Curve
timeFrame: 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry
measure: Plasma Clearance of Lamivudine
timeFrame: 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry
measure: Steady-state Zidovudine Area Under the Curve
timeFrame: 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry
measure: Plasma Clearance of Zidovudine
timeFrame: 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry
Secondary outcomes:
measure: Minimum Trough Concentration (Ctrough) of Lopinavir
timeFrame: Measured 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 4, 8, 12, 16, 24, 36 and 48 weeks following study entry
measure: Free Fraction of LPV at Hour 2 Post Dose
timeFrame: Weeks 1, 12 and 24
measure: Change in HIV Viral Load From Baseline
timeFrame: Weeks 0, 12, 24, 36 and 48
measure: HIV Viral Load <400 Copies/mL
timeFrame: Baseline and weeks 12, 24, and 48
measure: Change in CD4 Percent
timeFrame: Weeks 0, 12, 24, 36 and 48
measure: Change in WHO Weight-for-height Z-score
timeFrame: Weeks 0, 24, and 48
measure: Change in Mid-upper Arm Circumference
timeFrame: Weeks 0, 24, and 48
Other outcomes:
Locations:
city: Blantyre
country: Malawi
facility: Blantyre CRS (30301)
city: Lilongwe
country: Malawi
facility: Malawi CRS (12001)
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical Centre (5118)
city: Kampala
country: Uganda
facility: Makerere University-Johns Hopkins University (MUJHU) Research Collaboration (30293)
city: Harare
country: Zimbabwe
facility: Harare Family Care (31890)
Study officials:
affiliation: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
name: Maxensia O Owor, MBChB, MMED, MPH
role: STUDY_CHAIR
References:
citation: 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.