Extended Duration Artemether-lumefantrine Treatment for Malaria in Children

• Status: Completed
• Trial end date: 2020-01-09
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of California, San Francisco
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Infectious Diseases Research Collaboration, Uganda; Yale University
• Treatments: Artemether; Artemether-lumefantrine combination; Artemether, Lumefantrine Drug Combination; Artemisinins; Lumefantrine

Criteria

Inclusion Criteria:

1, All participants:

1. Residency within 60 km of the study clinics either at TDH or at MGH

2. Agreement to come to clinic for all follow-up clinical and PK evaluations

3. Provision of informed consent

4. Weight ≥6 kg

5. 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)

6. Willingness to undergo intensive PK sampling and/or population PK sampling during episode(s) of malaria.

2 HIV-infected participants:

1. Confirmed HIV infection (positive rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment)

2. On stable EFV-based ART for at least 10 days prior to enrollment

3. Age 3 years to 10 years

3 HIV-uninfected participants:

1. Confirmed HIV negative test (negative rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment)

2. Age 6 months to 10 years

Exclusion Criteria:

1. History of significant comorbidities such as malignancy, active tuberculosis or other World Health Organization (WHO) stage 4 disease

2. Current infection with non-P. falciparum species

3. Receipt of any medications known to affect CYP450 metabolism (except ART) within 14 days of study enrollment (see 4.2.2)

4. Hemoglobin < 7.0 g/dL

5. For the population PK study, prior treatment for malaria within 14 days of enrollment

6. For the intensive PK study, prior treatment for malaria within 28 days of enrollment

7. 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)

8. 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.