Extended Duration Artemether-lumefantrine Treatment for Malaria in Children

NCT03453840 | Completed Phase 4 Results

• 2 other identifiers: 17-225782R01HD068174-06A1
• Study Type: interventional
• Target: 305
• Locations: 1 country
• Sites: 2

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.

Conditions

Uncomplicated Plasmodium Falciparum Malaria

Keywords

malaria; HIV; Children; Efavirenz; artemether; lumefantrine

Outcome Measures

Primary Outcomes (7)

• AUC0-21d

  Area under the plasma concentration versus time curve (AUC) from time 0 to day 21 for lumefantrine

  Study day 0-day21

• Recurrent Parasitemia 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

• AUC0-8h for Artemether

  Area under the plasma concentration versus time curve (AUC) from 0 to 8hr post last dose for artemether (ARM)

  0-8hr

• AUC0-8h for Dihydroartemisinin

  Area under the plasma concentration versus time curve (AUC) from time 0 to 8hr post last dose for Dihydroartemisinin (DHA)

  0-8hr

• Cmax for Lumefantrine

  Maximal concentration post last dose for lumefantrine

  0-21 days

• Cmax for Artemether

  Maximal concentration post last dose for artemether

  0-8hr

• Cmax for Dihydroartemisinin

  Maximal concentration post last dose for dihydroartimisinin (DHA)

  0-8hr

Secondary Outcomes (1)

• Number of Participants With Serious Adverse Events

  study day 0-42

Other Outcomes (7)

• Relationship Between Drug Resistance and Treatment Failure

  study day 0-42

• Metabolomic Measurements in HIV Infected vs HIV Uninfected Children

  study day 0-42

• Height-for-age (HFA) Associations With PK

  study day 0

Study Arms (4)

HIV-infected 3-day AL

ACTIVE COMPARATOR

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

HIV-infected 5-day AL

EXPERIMENTAL

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

HIV-uninfected 3-day AL

ACTIVE COMPARATOR

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

HIV-uninfected 5-day AL

EXPERIMENTAL

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

Interventions

Artemether-lumefantrine 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.

Also known as: Coartem, AL

HIV-infected 3-day AL; HIV-infected 5-day AL; HIV-uninfected 3-day AL; HIV-uninfected 5-day AL

Eligibility Criteria

• Age: 6 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• , 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.
• 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 18 years
• 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 18 years

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Francisco: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• Yale University: collaborator
• Infectious Diseases Research Collaboration, Uganda: collaborator

Study Sites (2)

MGH campus

Busia, Uganda

Location

IDRC- Tororo Research Clinic and Tororo District Hospital

Tororo, Uganda

Location

Related Publications (3)

• 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.

  PMID: 36130191 RESULT

• 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.

  PMID: 39853752 RESULT

• 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.

  PMID: 38714692 DERIVED

MeSH Terms

Conditions

Malaria

Interventions

Artemether, Lumefantrine Drug Combination

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Liusheng Huang (Co-Investigator and Drug Research Unit Co-Director)
• Organization: University of California San Francisco

liusheng.huang@ucsf.edu

415-502-2594

Study Officials

• Francesca Aweeka, Pharm. D

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Sunil Parikh, M.D., MPH

  Yale University School of Public Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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..

Study Record Dates

• First Submitted: December 22, 2017
• First Posted: March 5, 2018
• Study Start: February 21, 2018
• Primary Completion: August 31, 2021
• Study Completion: August 31, 2021
• Last Updated: April 15, 2025
• Results First Posted: January 3, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

UG (2)