Extended Duration Artemether-lumefantrine Treatment for Malaria in Children (EXALT)

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.

Study Overview

• Status: Completed
• Conditions: Uncomplicated Plasmodium Falciparum Malaria
• Intervention / Treatment: Drug: Artemether-lumefantrine

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 Type: Interventional
• Enrollment (Actual): 305
• Phase: Phase 4

Contacts and Locations

Study Locations

• Uganda
  • Busia, Uganda
    • MGH campus
  • Tororo, Uganda
    • IDRC- Tororo Research Clinic and Tororo District Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 10 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: 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.; Other Names: Coartem, AL
Experimental: 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.	Drug: 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.; Other Names: Coartem, AL
Active Comparator: 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.	Drug: 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.; Other Names: Coartem, AL
Experimental: 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.	Drug: 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.; Other Names: Coartem, AL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relationship Between Drug Resistance and Treatment Failure	drug resistance will be accessed by molecular markers. Polymorphic markers will be typed using capillary electrophoresis.	study day 0-42
Metabolomic Measurements in HIV Infected vs HIV Uninfected Children	Small-molecule metabolites, including metabolic intermediates, hormones and other signaling molecules, and secondary metabolites will be measured in plasma and reported as fold-change (e.g. infected vs uninfected). This is an exploratory study. The multiple measurements could be aggregated to fold-change.	study day 0-42
Height-for-age (HFA) Associations With PK	chronic protein-calorie malnutrition resulting in slow linear growth (decreased height-for-age: HFA; stunting).	study day 0
Diagnostic Sensitivity of LAMP, HS-RDT, and Microscopy for the Detection of Recurrent Parasitemia	Using Loop-mediated isothermal amplification (LAMP), highly sensitive Rapid Diagnostic Test (HS-RDT), and microscope to diagnose recurrent parasitemia. study day 0-42	study day 0-42
Weight-for-height (WFH) Associations With PK	acute protein-calorie malnutrition resulting in weight loss or slow weight gain (decreased weight-for-height: WFH; wasting).	study day 0
Weight-for-age (WFA) Associations With PK	weight-for-age is an indicator of nutrition status and decreased weight-for-age reflects the combination of chronic and acute protein-calorie malnutrition.	study day 0
Prevalence of Gametocytemia	At varied time points, blood smears for the determination of parasitemia will be obtained following treatment in 3-day vs 5-day AL regimens.	study day 0-42

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Yale University; Infectious Diseases Research Collaboration, Uganda
• Investigators: Principal Investigator: Francesca Aweeka, Pharm. D, University of California, San Francisco; Principal Investigator: Sunil Parikh, M.D., MPH, Yale University School of Public Health

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2018
• Primary Completion (Actual): August 31, 2021
• Study Completion (Actual): August 31, 2021

Study Registration Dates

• First Submitted: December 22, 2017
• First Submitted That Met QC Criteria: March 2, 2018
• First Posted (Actual): March 5, 2018

Study Record Updates

• Last Update Posted (Actual): April 15, 2025
• Last Update Submitted That Met QC Criteria: April 4, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: HIV; Children; Efavirenz; malaria; artemether; lumefantrine
• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Infections; Protozoan Infections; Parasitic Diseases; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination
• Other Study ID Numbers: 17-22578; 2R01HD068174-06A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No