EXALT: Extended Duration Artemether-lumefantrine Treatment for Malaria in Children
Study Details
Study Description
Brief Summary
This project will determine the pharmacokinetic/pharmacodynamic (PK/PD) of an extended artemether-lumefantrine (AL) dosing regimen in HIV-infected children on efavirenz (EFV)-based antiretroviral therapy (ART) that is designed to improve the PK exposure and treatment efficacy of this artemisinins-based combination therapy (ACT) regimen. Our overarching goal is to inform the best treatment guidelines for young children in Africa. HIV-infected and HIV-uninfected children will be enrolled for intensive PK studies, as well as additional children for population PK studies to enhance association analyses with clinical outcomes.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 4 |
Detailed Description
This is a prospective multi-site study to evaluate the PK/PD of extended duration AL in HIV-infected children on EFV-based ART and HIV-uninfected children not on ART. AL is the first-line treatment for malaria in Uganda. No change in standard of care treatment will be made for the purposes of this study except for the extension of AL to 5-day dosing. This study will enroll a) HIV-infected children, and b) HIV-uninfected children. All participants may be enrolled through Tororo District Hospital (TDH) or Masafu General Hospital (MGH) in Busia, or other referral centers the area. we will use a design where children will be randomized to either 3-day or 5-day AL and then for subsequent episodes of malaria, should they occur. Conservatively, assuming each enrolled child participates for only a single episode of malaria, up to 60 (30 HIV-infected on 3-day and 30 HIV-infected on 5-day) and 100 (50 HIV-uninfected on 3-day and 50 HIV-uninfected on 5-day) subjects will be enrolled for each of the intensive study groups. Up to 100 (50 HIV-infected on 3-day and 50 HIV-infected on 5-day) and 120 (60 HIV-uninfected on 3-day and 60 HIV-uninfected on 5-day) subjects will be enrolled for each of the population study groups. Comparisons of AL PK exposure will be made among and between a) HIV-infected children with malaria receiving EFV-based ART and b) HIV-uninfected children who are not on ART. Comparisons will be based on an intensive PK design for AL area under the concentration-time curve (AUC) estimations. Population PK study will be combined with intensive PK studies to allow for optimal PK-outcomes assessments.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Active Comparator: HIV-infected 3-day AL Standard 3-day twice daily (BID) regimen of artemether-lumefantrine for uncomplicated malaria, given over 4 days (Study Days 0, 1, 2 and 3) so that sampling will begin in the morning of day 3. These participants are HIV-infected and stabilized on EFV-based ART. |
Drug: Artemether-lumefantrine
Children will receive the dispersible formulation of AL which contains 20 mg artemether, 120 mg of lumefantrine (Coartem® Dispersible). Weight-based dosing will be as below: <15kg, 1tablet; 15-25kg, 2 tablets; 25-35kg, 3 tablets; >=35kg, 4 tablets.
Other Names:
|
Experimental: HIV-infected 5-day AL Extended 5-day BID regimen of artemether-lumefantrine, given over 6 days (Study Days 0, 1, 2, 3, 4, and 5) so that sampling will begin in the morning of day 5. These participants are HIV-infected and stabilized on EFV-based ART. |
Drug: Artemether-lumefantrine
Children will receive the dispersible formulation of AL which contains 20 mg artemether, 120 mg of lumefantrine (Coartem® Dispersible). Weight-based dosing will be as below: <15kg, 1tablet; 15-25kg, 2 tablets; 25-35kg, 3 tablets; >=35kg, 4 tablets.
Other Names:
|
Active Comparator: HIV-uninfected 3-day AL Standard 3-day BID regimen of artemether-lumefantrine for uncomplicated malaria, given over 4 days (Study Days 0, 1, 2 and 3) so that sampling will begin in the morning of day 3. These participants are HIV-uninfected. |
Drug: Artemether-lumefantrine
Children will receive the dispersible formulation of AL which contains 20 mg artemether, 120 mg of lumefantrine (Coartem® Dispersible). Weight-based dosing will be as below: <15kg, 1tablet; 15-25kg, 2 tablets; 25-35kg, 3 tablets; >=35kg, 4 tablets.
Other Names:
|
Experimental: HIV-uninfected 5-day AL Extended 5-day BID regimen of artemether-lumefantrine, given over 6 days (Study Days 0, 1, 2, 3, 4, and 5) so that sampling will begin in the morning of day 5. These participants are HIV-uninfected. |
Drug: Artemether-lumefantrine
Children will receive the dispersible formulation of AL which contains 20 mg artemether, 120 mg of lumefantrine (Coartem® Dispersible). Weight-based dosing will be as below: <15kg, 1tablet; 15-25kg, 2 tablets; 25-35kg, 3 tablets; >=35kg, 4 tablets.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Area under the plasma concentration versus time curve (AUC) for all drug analytes [Study day 0-day21]
AUC 8hr for artemether and dihydroartemisinin, AUC inf for lumefantrine.
- Recurrent malaria following treatment by day 42 (recrudescence or new infection) [up to study day 42]
Recurrent malaria determined by microscopy (thick blood smears),loop mediated isothermal amplification (LAMP), or rapid diagnostic test (RDT).
Secondary Outcome Measures
- Safety of 5-day vs 3-day AL regimens evaluated via graded toxicity [study day 0-42]
We will record participants tolerance of AL using the NIH Division of AIDS Adult and Pediatric Toxicity Tables.
- Prevalence of gametocytemia following treatment in 3-day vs 5-day AL regimens determined by thick blood smears [study day 0-42]
At varied time points, blood smears for the determination of parasitemia will be obtained.
- Weight-for-age (WFA) associations with PK [study day 0]
weight-for-age is an indicator of nutrition status and decreased weight-for-age reflects the combination of chronic and acute protein-calorie malnutrition.
- Height-for-age (HFA) associations with PK [study day 0]
chronic protein-calorie malnutrition resulting in slow linear growth (decreased height-for-age: HFA; stunting).
- Weight-for-height (WFH) associations with PK [study day 0]
acute protein-calorie malnutrition resulting in weight loss or slow weight gain (decreased weight-for-height: WFH; wasting).
- Diagnostic sensitivity of LAMP, HS-RDT, and microscopy for the detection of recurrent parasitemia [study day 0-42]
Using Loop-mediated isothermal amplification (LAMP), highly sensitive Rapid Diagnostic Test (HS-RDT), and microscope to diagnose recurrent parasitemia.
- Metabolomic measurements in HIV infected vs HIV uninfected children [study day 0-42]
Small-molecule metabolites, including metabolic intermediates, hormones and other signaling molecules, and secondary metabolites will be measured in plasma and reported as fold-change (e.g. infected vs uninfected). This is an exploratory study. The multiple measurements could be aggregated to fold-change.
- Relationship between drug resistance and treatment failure [study day 0-42]
drug resistance will be accessed by molecular markers. Polymorphic markers will be typed using capillary electrophoresis.
Eligibility Criteria
Criteria
Inclusion Criteria:
1, All participants:
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Residency within 60 km of the study clinics either at TDH or at MGH
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Agreement to come to clinic for all follow-up clinical and PK evaluations
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Provision of informed consent
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Weight ≥6 kg
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Presentation with uncomplicated falciparum malaria as indicated by positive smear for malaria parasites along with clinical evidence of infection (fever or history of fever in the past 24 hours)
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Willingness to undergo intensive PK sampling and/or population PK sampling during episode(s) of malaria.
2 HIV-infected participants:
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Confirmed HIV infection (positive rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment)
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On stable EFV-based ART for at least 10 days prior to enrollment
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Age 3 years to 10 years
3 HIV-uninfected participants:
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Confirmed HIV negative test (negative rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment)
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Age 6 months to 10 years
Exclusion Criteria:
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History of significant comorbidities such as malignancy, active tuberculosis or other World Health Organization (WHO) stage 4 disease
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Current infection with non-P. falciparum species
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Receipt of any medications known to affect CYP450 metabolism (except ART) within 14 days of study enrollment (see 4.2.2)
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Hemoglobin < 7.0 g/dL
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For the population PK study, prior treatment for malaria within 14 days of enrollment
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For the intensive PK study, prior treatment for malaria within 28 days of enrollment
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Signs or evidence of complicated malaria, defined as unarousable coma or any two of the following symptoms: Recent febrile convulsions, altered consciousness, lethargy, unable to drink, unable to stand/sit due to weakness, severe anemia (Hb < 5.0 gm/dL), respiratory distress, jaundice (see Appendix D)
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History of toxicity to AL
The following medications are disallowed within 3 weeks prior to receiving study drug:
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Carbamazepine
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Clarithromycin
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Erythromycin (oral)
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Ketoconazole
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Phenobarbital
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Phenytoin
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Rifabutin
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Rifampin
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Halofantrine
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Any other medication known to significantly affect CYP450 metabolism.
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Grapefruit juice should be avoided during the study due to its potential effects on CYP3A4.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | MGH campus | Busia | Uganda | ||
2 | IDRC- Tororo Research Clinic and Tororo District Hospital | Tororo | Uganda |
Sponsors and Collaborators
- University of California, San Francisco
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Yale University
- Infectious Diseases Research Collaboration, Uganda
Investigators
- Principal Investigator: Francesca Aweeka, Pharm. D, University of California, San Francisco
- Principal Investigator: Sunil Parikh, M.D., MPH, Yale University School of Public Health
Study Documents (Full-Text)
More Information
Publications
None provided.- 17-22578
- 2R01HD068174-06A1