Clinical Trials

MainTitle

HIV Protease Inhibitors for the Prevention of Malaria in Ugandan Children (PROMOTE-PEDS)

This study has been completed
Sponsor
University of California, San Francisco

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

Information provided by (Responsible Party)
University of California, San Francisco
ClinicalTrials.gov Identifier
NCT00978068

First received: September 14, 2009
Last updated: December 5, 2018
Last Verified: December 2018
History of Changes
Purpose

Purpose

HIV and malaria are major causes of morbidity and mortality in Sub-Saharan Africa and children bear the greatest brunt of both diseases. No single existing intervention is likely to control malaria in Africa. Rather, improvements in malaria prevention are likely to come from strategies that employ multiple proven interventions targeting different populations. HIV-infected children represent one of the most vulnerable subpopulations in these countries. It is possible that the use of protease inhibitor (PI) - based antiretroviral therapy (ART) in HIV-infected children living in areas of high malaria transmission could prevent malaria in this vulnerable population. An effective remedy that offers the possibility to further reduce malaria risk, such as PIs, is highly desirable. This study will determine whether a PI based ART regimen will reduce malaria among children living in a malaria endemic area of Uganda and receiving insecticide-treated bed nets (ITN) and TS. This study will compare two different ART regimens. Children enrolled in the study will start or continue to receive either standard Ugandan first line treatment ART regimen (NNRTI+2 NRTIs) or an ART regimen containing the HIV protease inhibitor (lopinavir/ritonavir +2 NRTIs) and followed for a period of 24 months.

Condition Intervention Phase
Malaria
HIV Infections

Drug : Lopinavir/Ritonavir (LPV/r)
Drug : Nevirapine (NVP)
Drug : Efavirenz (EFV)
Drug : 2 nucleoside reverse transcriptase inhibitor (NRTI)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Randomized Open Label Trial of HIV Protease Inhibitors for the Prevention of Malaria in HIV-Infected Children

Further study details as provided by University of California, San Francisco:

Primary Outcome Measures

  • Incidence-density of Malaria Defined as the Number of Incident Episodes of Malaria Per Time at Risk. [ Time Frame: Time from randomization to at least 24 months of follow up or until end of the study ]
Secondary Outcome Measures:
  • Percentage of Uncomplicated Malaria Episodes With Accompanying Adverse Events That Occurred in the 28 Days Following Antimalarial Therapy [ Time Frame: 28 days after antimalarial therapy ]
    The rates of adverse events, defined as severity grade 2 or higher that are possibly, probably or definitely related to study drugs over the course of the 28-day period after antimalarial therapy with artemether-lumefantrine (AL).
  • Incidence-density of Malaria Defined as the Number of Incident Episodes of Complicated Malaria Per Time at Risk. [ Time Frame: Time from randomization to at least 24 months of follow up or until end of the study ]
  • Estimates of the 6-month Risk of a First Episode of Malaria [ Time Frame: Enrollment to 6 months follow up ]
    To assess the effect of ART independently of potential interactions with antimalarial therapy after treatment for malaria, we compared the two groups with respect to the time to the first episode of malaria. Cumulative risk was estimated using the Kaplan-Meier product-limit formula.
  • 28-day Risk of Recurrent Parasitemia [ Time Frame: 28 days after antimalarial therapy ]
    To assess the effect of potential interactions between ART and artemether-lumefantrine, the risks of recurrent parasitemia at 28 days were compared between the two groups.
  • 63-day Risk of Recurrent Malaria [ Time Frame: 28 days after antimalarial therapy ]
    To assess the effect of potential interactions between ART and artemether-lumefantrine, the risks of recurrent malaria at 63 days were compared between the two groups.

Enrollment: 176
Study Start Date: September 2009
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Active Comparator: Lopinavir/ritonavir (LPV/r) +2 NRTI
Lopinavir/ritonavir (LPV/r) +2 nucleoside reverse transcriptase inhibitor (NRTI)
Drug: Lopinavir/Ritonavir (LPV/r)
Other Name: Aluvia
Drug: 2 nucleoside reverse transcriptase inhibitor (NRTI)

The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.

Active Comparator: Nevirapine (NVP) or Efavirenz (EFV) +2 NRTI
Nevirapine (NVP) or Efavirenz (EFV) +2 nucleoside reverse transcriptase inhibitor (NRTI)
Drug: Nevirapine (NVP)

NVP will be used for children < 3 years of age

Drug: Efavirenz (EFV)

EFV for children ≥3 years of age

Drug: 2 nucleoside reverse transcriptase inhibitor (NRTI)

The same NRTI choice strategy will be used for both arms. Lamivudine will be used with all children. The second NRTI will be zidovudine unless the participant has a hemoglobin < 8 gm/dL, in which case it will be Abacavir. Stavudine will be used in the event that a participant is unable to take Abacavir for safety or other reasons.

Detailed Description:

This is an open label, single site, randomized clinical trial comparing PI-based ART to NNRTI-based ART for the prevention of malaria in HIV-infected children. The two ART drug regimens that will be used include: Treatment arm 1. LPV/r + 2 NRTIs and Treatment arm 2. NVP or EFV + 2 NRTIs. The study is designed to test the hypothesis that children receiving a PI-based ART regimen will have lower the incidence of malaria compared to children receiving an NNRTI- based ART regimen. The primary study endpoint of the study is malaria incidence.
The study site will be the Tororo District Hospital campus situated in Eastern Uganda, an area of high malaria transmission. Using convenience sampling, 300 HIV-infected children identified from the Tororo community aged 2 months to <11 years either eligible for ART-initiation or already receiving a first line ART regimen with HIV RNA<400 copies/ml will be evaluated for enrollment.
Eligible children will be randomized at enrollment to receive either a PI- based or an NNRTI-based ART regimen. At enrollment, all study participants will receive a long lasting ITN as part of a basic care package including a safe water vessel and multivitamins and given TS chemoprophylaxis, as per current standard of care for HIV-infected children in Uganda. On the day of ART initiation, patients will be counseled about the importance of adherence to ART and possible ART related toxicities. After 2 weeks, patients will be seen to assess adherence and toxicity to study medications by interview and clinical examination. Apart from this visit at week 2, patients will be seen at 4 week intervals timed from ART-initiation. Assessment of adherence will also be done for TS prophylaxis, ITN use and ART. Assessment of adherence to ART will be done by self report of missed doses and pill counts.
Participants will receive all routine and acute medical care at a designated study clinic open 7 days a week from 8 a.m. to 5 p.m. Parents/guardians will be asked to bring their child to the study clinic for all medical care. If after hours, they will be instructed to bring them to Tororo District Hospital premises (where the study clinic is located) and request that the study physician on-call be contacted. They will be followed for at least 24 months and up to 3 years. They will be seen monthly for routine assessments with laboratory evaluations done at every 3 months. At these visits, the study protocol will be reinforced with discussion regarding the need to come to the study clinic promptly upon the onset of any illness and to avoid use of outside medications. Study participants will also be followed closely for adverse events potentially due to study drugs and for malaria and HIV treatment outcomes. During the follow-up period, all patients presenting to the clinic with a new episode of fever will undergo standard evaluation (history, physical examination) and Giemsa-stained blood smear for the diagnosis of malaria.

Eligibility

Eligibility

Ages Eligible for Study: 2 Months to 10 Years  
Sexes Eligible for Study: All  
Accepts Healthy Volunteers: Yes  

Criteria

Inclusion criteria:

  1. Age 2 months to < 11 years
  2. Confirmed HIV diagnosis. i. Children > 18 months: Documentation of HIV status must come from two assays. Assays include DNA PCR, HIV RNA, Western blot, or rapid HIV antibody test ii. Children < 18 months: Documentation will be DNA PCR confirmation only along with documentation of testing from the referral entity
  3. ART-naïve patients eligible for ART initiation per WHO/Uganda guidelines (see Table 1) or Patients receiving first line ART regimen with NNRTI +2 NRTI with at least one HIV RNA <400 copies/ml within the past 6 months
  4. Agreement to come to the study clinic for any febrile episode or other illness
  5. Agreement to avoid medications administered outside study protocol
  6. Provision of informed consent by parent/guardian and agreement to have child's care at the clinical site
  7. Lives within 50 km of study site

  • Exclusion Criteria:
  • ART-naïve children: children or their mothers that have received any dose of Nevirapine in the past 24 months
  • Active medical problem requiring in-patient evaluation at the time of screening or enrollment
  • History of cardiac conduction disorder or known significant cardiac structural defect
  • Children receiving any disallowed medications (see section 4.3)
  • Moderate, Severe or Life-threatening (Grade 2, 3, or 4) AST or ALT found within 4 weeks prior to enrollment:
    • AST: >113U/L (>2.5xULN)
    • ALT: >113U/L (>2.5xULN)
  • Life-threatening (Grade 4) screening laboratory value found within 4 weeks prior to enrollment for the following:
    • Absolute neutrophil count: <500 mm3
    • Hemoglobin: <6.5 g/dL
    • Creatinine: >3.5xULN
    • Platelets: <25,000/mm3

    contacts and locations

    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: NCT00978068

    Locations

    Uganda
    IDRC - Tororo Research Clinic
    Tororo, Uganda

    Sponsors and Collaborators

    University of California, San Francisco
    Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

    Investigators

    Study Director: Diane V Havlir, MD University of California, San Francisco
    Principal Investigator: Moses R Kamya MBChB, MMed, MPH Makerere University
    Principal Investigator: Grant Dorsey, MD, PhD University of California, San Francisco
    Principal Investigator: Ted Ruel, MD University of California, San Francisco
    Principal Investigator: Jane Achan, MBChB, MPed Makerere University
    More Information

    More Information


    Responsible Party: University of California, San Francisco  
    ClinicalTrials.gov Identifier: NCT00978068   History of Changes  
    Other Study ID Numbers: H5747-34097  
      NIH PO1 HD059454  
      2009-114  
      HS-620  
      551/ESR/NDA/DID-08/09  
      H5741-34097 and 10-00991  
    Study First Received: September 14, 2009  
    Last Updated: December 5, 2018  

    Keywords provided by University of California, San Francisco:

    Pediatric HIV
    Malaria
    Uganda
    Nevirapine
    Zidovudine
    Lamivudine
    Lopinavir/ritonavir
    Stavudine
    Efavirenz
    HIV

    Additional relevant MeSH terms:
    Malaria
    Ritonavir
    Lopinavir
    Nevirapine
    Efavirenz
    Reverse Transcriptase Inhibitors

    ClinicalTrials.gov processed this data on August 13, 2020
    This information is provided by ClinicalTrials.gov.