Extended Duration Artemether-lumefantrine Treatment for Malaria in Children

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Extended Duration Artemether-lumefantrine Treatment for Malaria in Children

Conditions
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Uncomplicated Plasmodium Falciparum Malaria

Intervention / Treatment
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* Drug: Artemether-lumefantrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1, All participants: Residency within 60 km of the study clinics either at TDH or at MGH Agreement to come to clinic for all follow-up clinical and PK evaluations Provision of informed consent Weight ≥6 kg 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) Willingness to undergo intensive PK sampling and/or population PK sampling during episode(s) of malaria. 2 HIV-infected participants: Confirmed HIV infection (positive rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment) On stable EFV-based ART for at least 10 days prior to enrollment Age 3 years to 10 years 3 HIV-uninfected participants: Confirmed HIV negative test (negative rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment) Age 6 months to 10 years Exclusion Criteria: History of significant comorbidities such as malignancy, active tuberculosis or other World Health Organization (WHO) stage 4 disease Current infection with non-P. falciparum species Receipt of any medications known to affect CYP450 metabolism (except ART) within 14 days of study enrollment (see 4.2.2) Hemoglobin < 7.0 g/dL For the population PK study, prior treatment for malaria within 14 days of enrollment For the intensive PK study, prior treatment for malaria within 28 days of enrollment 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) History of toxicity to AL The following medications are disallowed within 3 weeks prior to receiving study drug: Carbamazepine Clarithromycin Erythromycin (oral) Ketoconazole Phenobarbital Phenytoin Rifabutin Rifampin Halofantrine Any other medication known to significantly affect CYP450 metabolism. Grapefruit juice should be avoided during the study due to its potential effects on CYP3A4.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a prospective multi-site study accomplished through a randomized design where children will be randomized to either 3-day or 5-day AL regimen and then for subsequent episodes of malaria, should they occur..
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: HIV-infected 3-day AL<br>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<br>* 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.<br>* Other names: Coartem, AL;|
| Experimental: HIV-infected 5-day AL<br>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<br>* 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.<br>* Other names: Coartem, AL;|
| Active Comparator: HIV-uninfected 3-day AL<br>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<br>* 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.<br>* Other names: Coartem, AL;|
| Experimental: HIV-uninfected 5-day AL<br>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<br>* 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.<br>* Other names: Coartem, AL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) for all drug analytes | AUC 8hr for artemether and dihydroartemisinin, AUC inf for lumefantrine. | Study day 0-day21 | 
| Recurrent malaria following treatment by day 42 (recrudescence or new infection) | Recurrent malaria determined by microscopy (thick blood smears),loop mediated isothermal amplification (LAMP), or rapid diagnostic test (RDT). | up to study day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of 5-day vs 3-day AL regimens evaluated via graded toxicity | We will record participants tolerance of AL using the NIH Division of AIDS Adult and Pediatric Toxicity Tables. | study day 0-42 | 
| Prevalence of gametocytemia following treatment in 3-day vs 5-day AL regimens determined by thick blood smears | At varied time points, blood smears for the determination of parasitemia will be obtained. | study day 0-42 | 
| Weight-for-age (WFA) associations with PK | weight-for-age is an indicator of nutrition status and decreased weight-for-age reflects the combination of chronic and acute protein-calorie malnutrition. | study day 0 | 
| Height-for-age (HFA) associations with PK | chronic protein-calorie malnutrition resulting in slow linear growth (decreased height-for-age: HFA; stunting). | study day 0 | 
| Weight-for-height (WFH) associations with PK | acute protein-calorie malnutrition resulting in weight loss or slow weight gain (decreased weight-for-height: WFH; wasting). | study day 0 | 
| Diagnostic sensitivity of LAMP, HS-RDT, and microscopy for the detection of recurrent parasitemia | Using Loop-mediated isothermal amplification (LAMP), highly sensitive Rapid Diagnostic Test (HS-RDT), and microscope to diagnose recurrent parasitemia. | study day 0-42 | 
| Metabolomic measurements in HIV infected vs HIV uninfected children | 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. | study day 0-42 | 
| Relationship between drug resistance and treatment failure | drug resistance will be accessed by molecular markers. Polymorphic markers will be typed using capillary electrophoresis. | study day 0-42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malaria, HIV, Children, Efavirenz, artemether, lumefantrine