IMPAACT P1092: Steady State PK in Malnourished HIV Infected Children

Study Overview
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Brief Summary
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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
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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.

Official Title
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IMPAACT 1092: Phase IV Evaluation Of The Steady State Pharmacokinetics Of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in Severely Malnourished HIV-1-Infected Children

Conditions
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HIV Positive, Malnourished

Intervention / Treatment
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* Drug: ZDV+3TC+LPV/r


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 36 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Severe Malnutrition<br>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 | Drug: ZDV+3TC+LPV/r<br> <br> * Other names: Kaletra;|
| Active Comparator: Normal Nutrition/Mild Malnutrition<br>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 | Drug: ZDV+3TC+LPV/r<br> <br> * Other names: Kaletra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3 or Higher Adverse Events Through 24 Weeks | Number (percent) of participants with at least one grade 3 or higher adverse event (AE) regardless of the relationship to study drugs. | From week 0 to week 24 | 
| Grade 3 or Higher Adverse Events Related to Study Drugs Through Week 24 | Number (percent) of participants with at least one Grade 3 or higher adverse event related to study drugs | From week 0 to week 24 | 
| Steady-state Lopinavir Area Under the Curve | Steady-state area under the curve (AUC) for Lopinavir (LPV) | 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry | 
| Plasma Clearance of Lopinavir | Steady-state plasma clearance (CL/F) of LPV | 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry | 
| Steady-state Ritonavir Area Under the Curve | Steady-state area under the curve (AUC) for Ritonavir (RTV) | 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry | 
| Plasma Clearance of Ritonavir | Steady-state plasma clearance (CL/F) of RTV | 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry | 
| Steady-state Lamivudine Area Under the Curve | Steady-state area under the curve (AUC) of Lamivudine (3TC) | 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry | 
| Plasma Clearance of Lamivudine | Steady-state plasma clearance (CL/F) of Lamivudine (3TC) | 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry | 
| Steady-state Zidovudine Area Under the Curve | Steady-state area under the curve (AUC) of zidovudine (ZDV) | 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry | 
| Plasma Clearance of Zidovudine | Steady-state plasma clearance (CL/F) of Zidovudine (ZDV) | 0, 1, 2, 4, 8, and 12 hours post-dose on 1, 12, and 24 weeks following study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum Trough Concentration (Ctrough) of Lopinavir | Count (%) of participants with minimum trough concentration (Ctrough) of steady-state Lopinavir >= 1 ug/mL | 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 | 
| Free Fraction of LPV at Hour 2 Post Dose | Free fraction of steady-state lopinavir at 2 hours post dose | Weeks 1, 12 and 24 | 
| Change in HIV Viral Load From Baseline | Change from baseline in plasma HIV RNA viral load | Weeks 0, 12, 24, 36 and 48 | 
| HIV Viral Load <400 Copies/mL | Count (%) of participants with plasma HIV RNA viral load <400 copies/mL | Baseline and weeks 12, 24, and 48 | 
| Change in CD4 Percent | Change in CD4 percent from baseline | Weeks 0, 12, 24, 36 and 48 | 
| Change in WHO Weight-for-height Z-score | Change in WHO weight-for-height Z-score from entry. A Z-score indicates the number of standard deviations the measurement is away from the mean. A Z-score of 0 is equal to the mean of the reference population. Negative numbers indicate values lower than the reference population and positive numbers indicate values higher than the reference population. The reference population was determined by the World Health Organization for children from 0 up to 5 years. | Weeks 0, 24, and 48 | 
| Change in Mid-upper Arm Circumference | Change in mid-upper arm circumference (MUAC) from entry | Weeks 0, 24, and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Children, HAART, Malnourished