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IMPAACT P1092: Steady State PK in Malnourished HIV Infected Children

Primary Purpose

HIV Positive, Malnourished

Status

Completed

Phase

Phase 4

Locations

International

Study Type

Interventional

Intervention

ZDV+3TC+LPV/r

About this trial

This is an interventional treatment trial for HIV Positive focused on measuring HIV, Children, HAART, Malnourished

Eligibility Criteria

6 Months - 36 Months (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Blantyre CRS (30301)
Malawi CRS (12001)
Kilimanjaro Christian Medical Centre (5118)
Makerere University-Johns Hopkins University (MUJHU) Research Collaboration (30293)
Harare Family Care (31890)

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Severe Malnutrition

Normal Nutrition/Mild Malnutrition

Arm Description

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

Outcomes

Primary Outcome Measures

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.

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

Steady-state Lopinavir Area Under the Curve

Steady-state area under the curve (AUC) for Lopinavir (LPV)

Plasma Clearance of Lopinavir

Steady-state plasma clearance (CL/F) of LPV

Steady-state Ritonavir Area Under the Curve

Steady-state area under the curve (AUC) for Ritonavir (RTV)

Plasma Clearance of Ritonavir

Steady-state plasma clearance (CL/F) of RTV

Steady-state Lamivudine Area Under the Curve

Steady-state area under the curve (AUC) of Lamivudine (3TC)

Plasma Clearance of Lamivudine

Steady-state plasma clearance (CL/F) of Lamivudine (3TC)

Steady-state Zidovudine Area Under the Curve

Steady-state area under the curve (AUC) of zidovudine (ZDV)

Plasma Clearance of Zidovudine

Steady-state plasma clearance (CL/F) of Zidovudine (ZDV)

Secondary Outcome Measures

Minimum Trough Concentration (Ctrough) of Lopinavir

Count (%) of participants with minimum trough concentration (Ctrough) of steady-state Lopinavir >= 1 ug/mL

Free Fraction of LPV at Hour 2 Post Dose

Free fraction of steady-state lopinavir at 2 hours post dose

Change in HIV Viral Load From Baseline

Change from baseline in plasma HIV RNA viral load

HIV Viral Load <400 Copies/mL

Count (%) of participants with plasma HIV RNA viral load <400 copies/mL

Change in CD4 Percent

Change in CD4 percent from baseline

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.

Change in Mid-upper Arm Circumference

Change in mid-upper arm circumference (MUAC) from entry

Full Information

NCT ID

NCT01818258

First Posted

January 14, 2013

Last Updated

July 19, 2021

Sponsor

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Mental Health (NIMH)

1. Study Identification

Unique Protocol Identification Number

NCT01818258

Brief Title

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

2. Study Status

Record Verification Date

July 2021

Overall Recruitment Status

Completed

Study Start Date

October 26, 2015 (Actual)

Primary Completion Date

April 11, 2017 (Actual)

Study Completion Date

September 29, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Mental Health (NIMH)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV Positive, Malnourished

Keywords

HIV, Children, HAART, Malnourished

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

52 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Severe Malnutrition

Arm Type

Active Comparator

Arm Description

Arm Title

Normal Nutrition/Mild Malnutrition

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

ZDV+3TC+LPV/r

Other Intervention Name(s)

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

Primary Outcome Measure Information:

Title

Grade 3 or Higher Adverse Events Through 24 Weeks

Description

Number (percent) of participants with at least one grade 3 or higher adverse event (AE) regardless of the relationship to study drugs.

Time Frame

From week 0 to week 24

Title

Grade 3 or Higher Adverse Events Related to Study Drugs Through Week 24

Description

Number (percent) of participants with at least one Grade 3 or higher adverse event related to study drugs

Time Frame

From week 0 to week 24

Title

Steady-state Lopinavir Area Under the Curve

Description

Steady-state area under the curve (AUC) for Lopinavir (LPV)

Time Frame