Extended Duration Artemether-lumefantrine Treatment for Malaria in Children

Phase 4

Completed

• Conditions: Uncomplicated Plasmodium Falciparum Malaria
• Interventions: Drug: Artemether-lumefantrine

• Registration Number: NCT03453840
• Lead Sponsor: University of California, San Francisco

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.

Study Timeline

• Study First Submitted: 2017-12-22
• Study Start: 2018-02-21
• Study First Submitted QC: 2018-03-02
• Study First Posted: 2018-03-05
• Primary Completion: 2021-08-31
• Study Completion: 2021-08-31
• Results First Submitted: 2024-05-30
• Status Verified: 2024-12
• Results First Submitted QC: 2024-12-20
• Last Update Submitted: 2024-12-20
• Results First Posted: 2025-01-03
• Last Update Posted: 2025-01-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 305

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
HIV-infected 3-day AL	Artemether-lumefantrine	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.
HIV-infected 5-day AL	Artemether-lumefantrine	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.
HIV-uninfected 5-day AL	Artemether-lumefantrine	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.
HIV-uninfected 3-day AL	Artemether-lumefantrine	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.

Primary Outcome Measures

Name	Time	Method
AUC0-21d	Study day 0-day21	Area under the plasma concentration versus time curve (AUC) from time 0 to day 21 for lumefantrine
Recurrent Parasitemia 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).
AUC0-8h for Artemether	0-8hr	Area under the plasma concentration versus time curve (AUC) from 0 to 8hr post last dose for artemether (ARM)
AUC0-8h for Dihydroartemisinin	0-8hr	Area under the plasma concentration versus time curve (AUC) from time 0 to 8hr post last dose for Dihydroartemisinin (DHA)
Cmax for Lumefantrine	0-21 days	Maximal concentration post last dose for lumefantrine
Cmax for Artemether	0-8hr	Maximal concentration post last dose for artemether
Cmax for Dihydroartemisinin	0-8hr	Maximal concentration post last dose for dihydroartimisinin (DHA)

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Serious Adverse Events	study day 0-42	We recorded participants tolerance of AL using the NIH Division of AIDS Adult and Pediatric Toxicity Tables.

Trial Locations

Locations (2)

IDRC- Tororo Research Clinic and Tororo District Hospital; 🇺🇬 Tororo, Uganda

MGH campus; 🇺🇬 Busia, Uganda