Clinical trial NCT03453840: Extended Duration Artemether-lumefantrine Treatment for Malaria in Children
Official title: Extended Duration Artemether-lumefantrine Treatment for Malaria in Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Uncomplicated Plasmodium Falciparum Malaria
Keywords: malaria
HIV
Children
Efavirenz
artemether
lumefantrine
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Yale University
name: Infectious Diseases Research Collaboration, Uganda
First posted: 2018-03-05
Enrollment: 305
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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..
Primary purpose: TREATMENT

Brief summary: This project determines 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 were enrolled for intensive PK studies, as well as additional children for population PK studies to enhance association analyses with clinical outcomes.

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 was made for the purposes of this study except for the extension of AL to 5-day dosing. This study enrolled 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 used a design where children were 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 were enrolled for each of the intensive study groups. 16 (9 HIV-infected on 3-day and 7 HIV-infected on 5-day) and 120 (60 HIV-uninfected on 3-day and 60 HIV-uninfected on 5-day) subjects were enrolled for each of the population study groups. Enrollment of HIV-infected subjects for population PK study groups was not halted due to the lack of HIV-infected children in the study area. Comparisons of AL PK exposure were 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 were based on an intensive PK design for AL area under the concentration-time curve (AUC) estimations.

Eligibility 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 18 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 18 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.

Primary outcomes:
measure: AUC0-21d
timeFrame: Study day 0-day21
measure: Recurrent Parasitemia Following Treatment by Day 42 (Recrudescence or New Infection)
timeFrame: up to study day 42
measure: AUC0-8h for Artemether
timeFrame: 0-8hr
measure: AUC0-8h for Dihydroartemisinin
timeFrame: 0-8hr
measure: Cmax for Lumefantrine
timeFrame: 0-21 days
measure: Cmax for Artemether
timeFrame: 0-8hr
measure: Cmax for Dihydroartemisinin
timeFrame: 0-8hr
Secondary outcomes:
measure: Number of Participants With Serious Adverse Events
timeFrame: study day 0-42
Other outcomes:
measure: Relationship Between Drug Resistance and Treatment Failure
timeFrame: study day 0-42
measure: Metabolomic Measurements in HIV Infected vs HIV Uninfected Children
timeFrame: study day 0-42
measure: Height-for-age (HFA) Associations With PK
timeFrame: study day 0
measure: Diagnostic Sensitivity of LAMP, HS-RDT, and Microscopy for the Detection of Recurrent Parasitemia
timeFrame: study day 0-42
measure: Weight-for-height (WFH) Associations With PK
timeFrame: study day 0
measure: Weight-for-age (WFA) Associations With PK
timeFrame: study day 0
measure: Prevalence of Gametocytemia
timeFrame: study day 0-42
Locations:
city: Busia
country: Uganda
facility: MGH campus
city: Tororo
country: Uganda
facility: IDRC- Tororo Research Clinic and Tororo District Hospital
Study officials:
affiliation: University of California, San Francisco
name: Francesca Aweeka, Pharm. D
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University School of Public Health
name: Sunil Parikh, M.D., MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Whalen ME, Kajubi R, Goodwin J, Orukan F, Colt M, Huang L, Richards K, Wang K, Li F, Mwebaza N, Aweeka FT, Parikh S. The Impact of Extended Treatment With Artemether-lumefantrine on Antimalarial Exposure and Reinfection Risks in Ugandan Children With Uncomplicated Malaria: A Randomized Controlled Trial. Clin Infect Dis. 2023 Feb 8;76(3):443-452. doi: 10.1093/cid/ciac783.
citation: Whalen ME, Kajubi R, Goodwin J, Orukan F, Colt M, Huang L, Richards K, Hoffmann TJ, Aweeka FT, Parikh S, Mwebaza N. Extended Treatment Duration of Artemether-Lumefantrine in Ugandan Children with HIV on Efavirenz-Based Antiretroviral Therapy: A Randomized Controlled Pharmacokinetic and Pharmacodynamic Trial. J Clin Pharmacol. 2025 Jan 24. doi: 10.1002/jcph.6193. Online ahead of print.