Antimalarial Pharmacology in Children and Pregnant Women in Uganda
The burden of malaria is greatest in children and pregnant women in sub-Saharan Africa. Malaria is one of the most important infectious diseases in the world. Uganda reports among the highest transmission intensities in the world. Children and pregnant women are the most vulnerable populations. HIV is also reported at high rates for these populations. If malaria and HIV require treatment at the same time, there is a high risk for drug-drug interactions. This study will:
- Determine if the use of anti-HIV medications including lopinavir/ritonavir (LPV/r), nevirapine (NVP) and efavirenz (EFV) will affect the pharmacokinetic (PK) exposure of antimalarial medications (specifically artemether-lumefantrine, AL) during the treatment for uncomplicated malaria in HIV-infected children and pregnant women, and
- Evaluate the impact of age and pregnancy on the PK exposure of AL.
|Study Design:||Observational Model: Cohort
Time Perspective: Prospective
|Official Title:||Antimalarial Pharmacology in HIV Infected and Uninfected Children and Pregnant Women in Uganda|
- Primary outcome measurement is the area under the plasma concentration versus time curve for all drug analytes. [ Time Frame: At time of the last dose of a 6 dose regimen and up to 42 days of F/U ] [ Designated as safety issue: No ]Pharmacokinetic exposure for the antimalarial medication is estimated through sparse or intensive blood sampling around the last dose and for several days following the last dose.
- Malaria reinfection (recrudescence or new infection) [ Time Frame: From Day 0 to 42 days of F/U when using artemether-lumefantrine for uncomplicated malaria ] [ Designated as safety issue: No ]The association between PK exposure and malaria reinfection is the main secondary outcome.
- Parasite clearance rate [ Time Frame: Days 0 to 42 of follow-up ] [ Designated as safety issue: No ]To assess the relationship between artemisinin exposure and parasite clearance
- AL and ART toxicity [ Time Frame: Days 0 to 42 of follow-up ] [ Designated as safety issue: Yes ]To assess the relationship between artemether, lumefantrine and antiretroviral exposure and toxicity, particularly neutropenia
Biospecimen Retention: Samples With DNA
Samples are for drug level measurements,parasite density. RNA samples are for host transcriptional and molecular markers of resistance. Samples are also retained for future use including possible genetic testing for drug metabolism variants
|Study Start Date:||August 2012|
|Estimated Study Completion Date:||December 2015|
|Estimated Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
HIV+children on LPV/r
HIV+ children who are stabilized on a LPV/r based ART regimen
HIV+ children on nevirapine
HIV+ children who are stabilized on an nevirapine based ART regimen
HIV+ children on efavirenz
HIV+ children who are stabilized on an efavirenz based ART regimen
HIV+ pregnant women on LPV/r
HIV+ pregnant women who are stabilized on an LPV/r based ART regimen
HIV+ pregnant women on NVP
HIV+ pregnant women who are stabilized on an nevirapine based ART regimen
HIV+ pregnant women on EFV
HIV+ pregnant women stabilized on an efavirenz based ART regimen
HIV negative children
HIV negative children that will serve as a control for HIV positive children on either a LPV/r, NVP or EFV based ART regimen and will be compared to HIV negative non-pregnant adults
HIV negative adults
HIV negative adults that will serve as a control for comparing results to HIV negative children and HIV negative pregnant women
HIV negative pregnant women
HIV negative pregnant women who will serve as a control for HIV positive pregnant women on either a LPV/r, NVP or EFV based ART regimen and will be compared to HIV negative non-pregnant adults
This study is designed to directly address antimalarial PK and pharmacodynamics (PD) objectives in children and pregnant women, the populations most vulnerable to malaria. This study will focus on the pharmacology of artemether-lumefantrine (AL), the most commonly prescribed anti-malarial drug in sub-Saharan Africa and inform specific dosing guidelines for AL treatment of uncomplicated malaria for these populations. Traditionally, studies have focused on non-pregnant adults, largely ignoring the effects of childhood maturation and pregnancy on drug disposition. This gap in research is specified as a top priority by the WorldWide Antimalarial Resistance Network (WWARN), who emphasize the importance of proper PK and PD study in relevant populations to reduce the threat of ACT drug resistance and treatment failure. This study will allow optimization of ACT regimens, especially in the setting of HIV co-infection and inform use of ART, specifically for the nucleoside analogues, in the setting of malaria and ACT, with the goal of reducing toxicity.
This study complements ongoing PROMOTE trials and provides valuable PK and PD data leveraged to the existing trials, greatly decreasing research costs. This study involves co-enrollment of HIV-infected children and pregnant women already enrolled in PROMOTE which is investigating PI- vs NNRTI-based ART treatment strategies for reducing malaria-related morbidity in HIV and malaria co-infected children and pregnant women. PROMOTE trials were designed in collaboration with Ugandan health care experts and officials and results are expected to rapidly impact Ugandan health policy. This study builds on knowledge gained through PROMOTE. The study also permits enrollment of HIV infected children and pregnant women not in PROMOTE but managed through TDH or other referral site in the Tororo area. Lastly this study will enroll HIV uninfected children, pregnant women and non-pregnant adults.
This study utilizes state-of-the-art PK designs and drug assay methods relying on a combination of intensive and population models to optimize PK/PD analysis. Intensive studies using serial sampling in a relatively small number of subjects will address focused questions on PK exposure while population studies using less frequent sampling in large numbers of subjects will study relationships between PK exposure, clinical response (treatment failure, new infection, and placental malaria), and toxicity (neutropenia) while considering multiple potential covariates. This study includes development and utilization of small volume assay methods for ACT and ART to optimize PK/PD study in children and pregnant women and will be a useful tool for future research trials in resource limited settings.
Rationale for this study is summarized below:
- Dosing guidelines for children and pregnant women have relied on studies carried out in non-pregnant adults
- Children and pregnant women exhibit distinct physiological characteristics that impact how drugs are handled by the body and thus are likely treated improperly
- This gap in research has been deemed an area of high priority by WWARN • Improper dosing may compromise care of acute infection but more importantly contribute to develop of resistance
- ACT therapies must be protected from factors contributing to resistance
- Drug-drug interactions between anti-malarial treatment and ART must be evaluated to assure optimized dosing.
- Drug toxicity, in particular neutropenia, in the setting of HIV-malaria co-infection may be due to important drug-drug interactions
- Intensive PK design resulting in determination of a precise area under the concentration versus time curve (AUC) will permit robust comparisons so that results will inform treatment guidelines and policy for HIV-infected children and pregnant women.
- Once optimized dosing is determined, the PK of this new dosing will be confirmed through follow-up (F/U) studies
- We need state of the art analytical tools to quantitate key drugs in small volume samples collected from vulnerable populations including young children
Please refer to this study by its ClinicalTrials.gov identifier: NCT01717885
|Contact: Norah Mwebaza, MBchB, MScfirstname.lastname@example.org|
|Contact: Jane Achan, MBChB, MPedemail@example.com|
|IDRC- Tororo Research Clinic and Tororo District Hospital||Recruiting|
|Contact: Richard Kajubi +256776211591 firstname.lastname@example.org|
|Contact: Norah Mwebaza, MBChB, MSc +256782589889 email@example.com|
|Principal Investigator: Norah Mwebaza, MBChB|
|Study Director:||Francesca T Aweeka, Pharm.D.||University of California, San Francisco|
|Principal Investigator:||Sunil Parikh, MD MPH||Yale University|
|Principal Investigator:||Norah Mwebaza, MBChB, MSc||Makerere University|
|Principal Investigator:||Myaing Nyunt, MD PhD||Johns Hopkins University|