Extended Duration Artemether-lumefantrine Treatment for Malaria in Children

NCT ID: NCT03453840

Last Updated: 2025-04-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 305 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-02-21
• Study Completion Date: 2021-08-31

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.

Conditions

Uncomplicated Plasmodium Falciparum Malaria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Artemether-lumefantrine

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Artemether-lumefantrine

Intervention Type: DRUG

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.

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.

Group Type: ACTIVE_COMPARATOR

Artemether-lumefantrine

Intervention Type: DRUG

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.

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.

Group Type: EXPERIMENTAL

Artemether-lumefantrine

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Coartem, AL

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.

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

Yale University

OTHER

Sponsor Role: collaborator

Infectious Diseases Research Collaboration, Uganda

OTHER

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Francesca Aweeka, Pharm. D

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Sunil Parikh, M.D., MPH

Role: PRINCIPAL_INVESTIGATOR

Yale University School of Public Health

Locations

MGH campus

Busia, , Uganda

IDRC- Tororo Research Clinic and Tororo District Hospital

Tororo, , Uganda

Countries

Uganda

References

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.

Reference Type: RESULT

PMID: 36130191 (View on PubMed)

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 Jul;65(7):909-922. doi: 10.1002/jcph.6193. Epub 2025 Jan 24.

Reference Type: RESULT

PMID: 39853752 (View on PubMed)

Goodwin J, Kajubi R, Wang K, Li F, Wade M, Orukan F, Huang L, Whalen M, Aweeka FT, Mwebaza N, Parikh S. Persistent and multiclonal malaria parasite dynamics despite extended artemether-lumefantrine treatment in children. Nat Commun. 2024 May 7;15(1):3817. doi: 10.1038/s41467-024-48210-7.

Reference Type: DERIVED

PMID: 38714692 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form: Informed Consent Forms

View Document

Document Type: Informed Consent Form: Assent and consent for future use of specimen

View Document

Other Identifiers

2R01HD068174-06A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

17-22578

Identifier Type: -

Identifier Source: org_study_id