Steady State PK in Malnourished HIV Infected Children (P1092)

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified June 2014 by International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
International Maternal Pediatric Adolescent AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01818258
First received: January 14, 2013
Last updated: June 26, 2014
Last verified: June 2014
  Purpose

HIV-infected children from sub-Saharan Africa often present with severe malnutrition as their AIDS defining illness. Severe malnutrition that is not responding to nutritional rehabilitation is an indication to initiate highly active antiretroviral therapy (HAART). 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. The paucity of ARV pharmacokinetic (PK) data in these vulnerable severely malnourished children speaks to the need to determine the PKs of ARVs and the most appropriate time to initiate HAART in this group of children. This 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. The findings of this study will determine the PK of HAART in this population with the overall goal of determining whether the current recommended doses are optimum doses for severely malnourished children and the most appropriate time to initiate HAART in the severely malnourished child.


Condition Intervention Phase
HIV Positive
Malnourished
Drug: ZDV+3TC+LPV/r
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase IV Evaluation Of The Steady State Pharmacokinetics Of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in Severely Malnourished HIV-1-Infected, Antiretroviral-Naïve Children Who Are Initiating HAART

Resource links provided by NLM:


Further study details as provided by International Maternal Pediatric Adolescent AIDS Clinical Trials Group:

Primary Outcome Measures:
  • Safety/ tolerability of ZDV, 3TC and Lopinavir/ritonavir (LPV/r) in severely and normal/mild malnourished children [ Time Frame: 1, 12 and 24 weeks after initiation of HAART ] [ Designated as safety issue: No ]
    numbers (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.

  • PK exposure comparison between severely malnourished children with children with normal/mild malnutrition [ Time Frame: 24 weeks after initiation of HAART ] [ Designated as safety issue: Yes ]
    Steady-state Area under the curve (AUC) and plasma clearance (CL/F) for ZDV, 3TC, and LPV/r


Secondary Outcome Measures:
  • Minimum concentration comparison between severely malnourished children with children with normal/mild malnutrition [ Time Frame: 1, 4, 8, 12, 16, 24, 36 and 48 weeks after initiation of HAART ] [ Designated as safety issue: No ]
    To compare the minimum trough concentration 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 initiation of HAART

  • LPV protein binding comparison between severely malnourished children with children with normal/mild malnutrition [ Time Frame: 1, 12 and 24 weeks after initiation of HAART ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 50
Study Start Date: September 2014
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Severe Malnutrition

Both arms got the ZDV+3TC+LPV/r combination drugs. Zidovudine (ZDV, Retrovir®) will be in a glycerin/sucrose base at a concentration of 10 mg/ml, administered two times daily orally at the WHO weight band dose for 48 weeks.

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), administered two times daily orally at the WHO weight band dose for 48 weeks.

Lopinavir 80 mg/ritonavir 20 mg per milliliter oral solution (Kaletra®, LPV/r) contains 42.4% alcohol by volume, administered two times daily orally at the WHO weight band dose for 48 weeks

Drug: ZDV+3TC+LPV/r
Zidovudine (ZDV, Retrovir®) will be in a glycerin/sucrose base at a concentration of 10 mg/ml, two times daily orally at the WHO weight band dose for 48 weeks 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), two times daily orally at the WHO weight band dose for 48 weeks Lopinavir 80 mg/ritonavir 20 mg per milliliter oral solution (Kaletra®, LPV/r) contains 42.4% alcohol by volume, two times daily orally at the WHO weight band dose for 48 weeks
Active Comparator: Normal Nutrition/Mild Malnutrition

Both arms got the ZDV+3TC+LPV/r combination drugs. Zidovudine (ZDV, Retrovir®) will be in a glycerin/sucrose base at a concentration of 10 mg/ml, administered two times daily orally at the WHO weight band dose for 48 weeks.

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), administered two times daily orally at the WHO weight band dose for 48 weeks.

Lopinavir 80 mg/ritonavir 20 mg per milliliter oral solution (Kaletra®, LPV/r) contains 42.4% alcohol by volume, administered two times daily orally at the WHO weight band dose for 48 weeks.

Drug: ZDV+3TC+LPV/r
Zidovudine (ZDV, Retrovir®) will be in a glycerin/sucrose base at a concentration of 10 mg/ml, two times daily orally at the WHO weight band dose for 48 weeks 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), two times daily orally at the WHO weight band dose for 48 weeks Lopinavir 80 mg/ritonavir 20 mg per milliliter oral solution (Kaletra®, LPV/r) contains 42.4% alcohol by volume, two times daily orally at the WHO weight band dose for 48 weeks

  Eligibility

Ages Eligible for Study:   6 Months to 36 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age >6 to <36 months at entry
  2. Documentation of HIV-1 infection defined as positive results from two samples collected at different time points. The same method may be used at both time points. All samples tested must be whole blood, serum or plasma.

    Acceptable tests when subjects are ≤18 months of age the first test may be any of the following:

    • One HIV DNA Polymerase Chain Reaction (PCR)
    • One HIV RNA (quantitative >5,000 copies/mL or qualitative)
    • One HIV culture (prior to August 2009)
    • One total HIV nucleic acid If the first test(s) is positive, a second sample collected and tested using any of the tests listed above (except for qualitative RNA assays) in a laboratory participating in an appropriate external quality assurance program and NIH approved.

    Acceptable tests when subjects are > 18 months of age

    The first test may be any of the following:

    • Two rapid antibody tests from different manufacturers or based on different principles and epitopes
    • One rapid antibody test AND one [enzyme immunoassay (EIA) OR Western blot (WB) OR immunofluorescence OR chemiluminescence]
    • One EIA AND one [WB OR immunofluorescence OR chemiluminescence]
    • One HIV DNA PCR
    • One HIV RNA (quantitative >5,000 copies/mL or qualitative)
    • One HIV culture (prior to August 2009)
    • One total HIV nucleic acid

    If the first test(s) is positive, a second sample collected and tested using any of the tests listed above (except for qualitative RNA assays) a laboratory participating in an appropriate external quality assurance program and either College of American Pathologists (CAP)/Clinical Laboratory Improvement Amendments (CLIA) approved (for US laboratories) or NIH-approved (for international laboratories).

  3. WHO classification for severe malnutrition (non-edematous) and normal nutrition status and mild malnutrition as described below:

    • Severe malnutrition defined as weight for height z (WHZ) score ≤-3 Standard Deviations.
    • Normal nutrition status defined as weight for height z (WHZ) score >-1 Standard Deviations.
    • Mild malnutrition defined as weight for height z (WHZ) score >-2 Standard Deviations ≤-1 Standard Deviations.
  4. Antiretroviral naïve except for ARVs used for prevention of mother-to-child transmission of HIV.
  5. Children with acute serious infection must have been stabilized by at least five days on antimicrobials.
  6. Eligible for HAART as defined by WHO pediatric guidelines described below for infants and children:

    • Initiate ART for all HIV-infected children below 24 months of age irrespective of cluster of differentiation 4 (CD4)count or WHO clinical stage.
    • Initiate ART for all HIV-infected children between 24 and 59 months of age with CD4 count ≤750 cells/mm3 or % CD4 ≤ 25%, whichever is lower, irrespective of WHO clinical stage.
    • Initiate ART for all HIV-infected children with WHO HIV clinical stages 3 and 4, irrespective of CD4 count.
  7. 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
  8. For severely malnourished children: 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:

    • Weight gain of about 3-5gm/kg body weight/day for 1-2 days
    • Normalized electrolytes (sodium and potassium)
    • No evidence of cardiac failure
    • Loss of apathy and starting to play
    • Temperature stable - no hypothermia or pyrexia

    For children with normal - mild malnutrition, clinical stability will be indicated by:

    • Good appetite
    • Normalized electrolytes (sodium and potassium)
    • Temperature stable - no hypothermia (<35°C) or pyrexia (>37.8° C)
  9. An inpatient in the nutrition rehabilitation unit

Exclusion Criteria:

  1. Children with edematous malnutrition at the time of study entry
  2. The following laboratory values within 30 days prior to entry:

    • Any ≥ Grade 2 toxicity (except hemoglobin)
    • Hemoglobin <7.5g/dL
  3. ≥ Grade 3 respiratory distress or presence of cardio respiratory compromise
  4. Chemotherapy for active malignancy
  5. Children with an acute Opportunistic Infection (OI) and on appropriate treatment for <5 days
  6. Active tuberculosis disease
  7. Evidence of hepatitis demonstrated by either positive hepatitis B surface antigen or clinical hepatitis as evidenced by jaundice and hepatomegaly
  8. Taking any disallowed medications
  9. 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01818258

Contacts
Contact: Anne Coletti, MPH 919-544-7040 ext 11238 acoletti@fhi360.org

Locations
Tanzania
Kilimanjaro Christian Medical CRS (12901) Not yet recruiting
IDC Research Offices, Moshi, Tanzania
Contact: Cynthia Asiyo    255-68-6113653    casiyo@gmail.com   
Principal Investigator: Ann Buchanan, M.D., M.P.H., DTM&H         
Uganda
Makerere University - JHU Research Collaboration (30293) Not yet recruiting
Kampala, Uganda
Contact: Irene Lubega, MBChB, DTM&H, MMed    256 712 222290    ilubega@mujhu.org   
Principal Investigator: Mary G. Fowler, MD         
Zimbabwe
UZ-Parirenyatwa CRS (30313) Not yet recruiting
Harare, Zimbabwe
Contact: Jimijika Batani, BA    263-7-72272818    jbatani@uz-ucsf.co.zw   
Principal Investigator: James Hakim, MBChB., MMed. MMedSc         
Sponsors and Collaborators
International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Investigators
Study Chair: Maxensia O Owor, MBChB, MMED International Maternal Pediatric Adolescent AIDS Clinical Trials Group
  More Information

No publications provided

Responsible Party: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT01818258     History of Changes
Other Study ID Numbers: IMPAACT P1092, U01AI068632
Study First Received: January 14, 2013
Last Updated: June 26, 2014
Health Authority: United States: Food and Drug Administration
Uganda: National Council for Science and Technology

Keywords provided by International Maternal Pediatric Adolescent AIDS Clinical Trials Group:
HIV
Children
Positive
Malnourished

Additional relevant MeSH terms:
HIV Seropositivity
Nutrition Disorders
Malnutrition
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Ritonavir
Lopinavir
Lamivudine
Zidovudine
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Antimetabolites

ClinicalTrials.gov processed this record on October 16, 2014