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CompletedNCT03453840EXALTUpdated Apr 15, 2025Results posted

Extended Duration Artemether-lumefantrine Treatment for Malaria in Children

A Phase 4 interventional study of Artemether-lumefantrine in Uncomplicated Plasmodium Falciparum Malaria, sponsored by University of California, San Francisco. Completed at 2 sites in Uganda. Open to participants aged 6 Months to 18 Years. Per ClinicalTrials.gov, last updated 2025-04-15.

Sponsored by University of California, San Francisco · Phase 4, Interventional, and Treatment

Phase
Phase 4
Study type
Interventional
Enrollment
305
Allocation
Randomized
Ages
6 Months to 18 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Uncomplicated Plasmodium Falciparum Malaria

Keywords

  • malaria
  • HIV
  • Children
  • Efavirenz
  • artemether
  • lumefantrine
03

Who can participate

Ages eligible
6 Months to 18 Years
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
04

Study design

Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
305 participants (actual)

Study arms

  • 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

  • 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

  • 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

  • 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

Interventions

  • DrugArtemether-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.

    Also known as: Coartem, AL

05

What researchers measure

Primary outcomes

  1. AUC0-21d

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

    Time frame: Study day 0-day21

  2. 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).

    Time frame: up to study day 42

  3. AUC0-8h for Artemether

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

    Time frame: 0-8hr

  4. AUC0-8h for Dihydroartemisinin

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

    Time frame: 0-8hr

  5. Cmax for Lumefantrine

    Maximal concentration post last dose for lumefantrine

    Time frame: 0-21 days

  6. Cmax for Artemether

    Maximal concentration post last dose for artemether

    Time frame: 0-8hr

  7. Cmax for Dihydroartemisinin

    Maximal concentration post last dose for dihydroartimisinin (DHA)

    Time frame: 0-8hr

Secondary outcomes

  1. Number of Participants With Serious Adverse Events

    We recorded participants tolerance of AL using the NIH Division of AIDS Adult and Pediatric Toxicity Tables.

    Time frame: study day 0-42

Other outcomes

  1. Relationship Between Drug Resistance and Treatment Failure

    drug resistance will be accessed by molecular markers. Polymorphic markers will be typed using capillary electrophoresis.

    Time frame: study day 0-42

  2. 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.

    Time frame: study day 0-42

  3. Height-for-age (HFA) Associations With PK

    chronic protein-calorie malnutrition resulting in slow linear growth (decreased height-for-age: HFA; stunting).

    Time frame: study day 0

  4. 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

    Time frame: study day 0-42

  5. 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).

    Time frame: study day 0

  6. 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.

    Time frame: study day 0

  7. 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.

    Time frame: study day 0-42

06

Results

Posted Jan 3, 2025

Participant flow

The recruitment started on 2/21/2018 and ended on 07/23/2019 and last follow up date was 09/03/2019. Study location was at Masafu General Hospital. Intensive PK recruitments were completed for all 4 arms: HIV negative 3-day and 5-day arm (n=50 each), HIV positive 3-day and 5-day arm (n=30). Population PK recruitments reached the target for HIV negative arms (n=60 each), but not for HIV-positive arms, because of the lack of HIV positive patients in the study sites.

Participant flow — Overall Study
MilestoneHIV-infected 3-day ALHIV-infected 5-day ALHIV-uninfected 3-day ALHIV-uninfected 5-day AL
Started3937115114
Completed3536110110
Not completed4154

Outcome measures

PrimaryAUC0-21d

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

Time frame:
Study day 0-day21
Reported as:
Geometric mean · hr*ug/mL
AUC0-21d
hr*ug/mLHIV-infected 3-day AL Intensive PKHIV-infected 5-day AL Intensive PKHIV-uninfected 3-day AL Intensive PKHIV-uninfected 5-day AL Intensive PK
AUC0-21d144 (114 to 182)205 (151 to 279)259 (222 to 302)318 (274 to 370)
PrimaryRecurrent 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).

Time frame:
up to study day 42
Reported as:
Count of participants · Participants
Recurrent Parasitemia Following Treatment by Day 42 (Recrudescence or New Infection)
ParticipantsHIV-infected 3-day ALHIV-infected 5-day ALHIV-uninfected 3-day ALHIV-uninfected 5-day AL
Recurrent Parasitemia Following Treatment by Day 42 (Recrudescence or New Infection)19188066
PrimaryAUC0-8h for Artemether

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

Time frame:
0-8hr
Reported as:
Geometric mean · hr*ng/mL
AUC0-8h for Artemether
hr*ng/mLHIV-infected 3-day AL Intensive PKHIV-infected 5-day AL Intensive PKHIV-uninfected 3-day AL Intensive PKHIV-uninfected 5-day AL Intensive PK
AUC0-8h for Artemether64.0 (45.5 to 90)71.7 (54.8 to 93.8)95.8 (77.5 to 118)78.6 (61.3 to 101)
PrimaryAUC0-8h for Dihydroartemisinin

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

Time frame:
0-8hr
Reported as:
Geometric mean · hr.ng/mL
AUC0-8h for Dihydroartemisinin
hr.ng/mLHIV-infected 3-day AL Intensive PKHIV-infected 5-day AL Intensive PKHIV-uninfected 3-day AL Intensive PKHIV-uninfected 5-day AL Intensive PK
AUC0-8h for Dihydroartemisinin109 (83.9 to 142)95.8 (69.7 to 132)241 (216 to 269)229 (202 to 261)
PrimaryCmax for Lumefantrine

Maximal concentration post last dose for lumefantrine

Time frame:
0-21 days
Reported as:
Geometric mean · ng/mL
Cmax for Lumefantrine
ng/mLHIV-infected 3-day AL Intensive PKHIV-infected 5-day AL Intensive PKHIV-uninfected 3-day AL Intensive PKHIV-uninfected 5-day AL Intensive PK
Cmax for Lumefantrine5065 (3894 to 6589)6027 (4253 to 8543)7236 (6023 to 8692)8450 (7085 to 10079)
PrimaryCmax for Artemether

Maximal concentration post last dose for artemether

Time frame:
0-8hr
Reported as:
Geometric mean · ng/mL
Cmax for Artemether
ng/mLHIV-infected 3-day AL Intensive PKHIV-infected 5-day AL Intensive PKHIV-uninfected 3-day AL Intensive PKHIV-uninfected 5-day AL Intensive PK
Cmax for Artemether22.4 (15.3 to 32.8)23.0 (16.4 to 32.3)32.5 (25.4 to 41.5)27.3 (20.5 to 36.3)
PrimaryCmax for Dihydroartemisinin

Maximal concentration post last dose for dihydroartimisinin (DHA)

Time frame:
0-8hr
Reported as:
Geometric mean · ng/mL
Cmax for Dihydroartemisinin
ng/mLHIV-infected 3-day AL Intensive PKHIV-infected 5-day AL Intensive PKHIV-uninfected 3-day AL Intensive PKHIV-uninfected 5-day AL Intensive PK
Cmax for Dihydroartemisinin43.8 (33.5 to 57.2)34.9 (24.6 to 49.4)89.0 (77.4 to 102)87.9 (75.8 to 102)
SecondaryNumber of Participants With Serious Adverse Events

We recorded participants tolerance of AL using the NIH Division of AIDS Adult and Pediatric Toxicity Tables.

Time frame:
study day 0-42
Reported as:
Count of participants · Participants
Number of Participants With Serious Adverse Events
ParticipantsHIV-infected 3-day ALHIV-infected 5-day ALHIV-uninfected 3-day ALHIV-uninfected 5-day AL
Number of Participants With Serious Adverse Events0020
Other pre-specifiedRelationship Between Drug Resistance and Treatment Failure

drug resistance will be accessed by molecular markers. Polymorphic markers will be typed using capillary electrophoresis.

Time frame:
study day 0-42

Results for this outcome have not been posted.

Other pre-specifiedMetabolomic 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.

Time frame:
study day 0-42

Results for this outcome have not been posted.

Other pre-specifiedHeight-for-age (HFA) Associations With PK

chronic protein-calorie malnutrition resulting in slow linear growth (decreased height-for-age: HFA; stunting).

Time frame:
study day 0

Results for this outcome have not been posted.

Other pre-specifiedDiagnostic 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

Time frame:
study day 0-42

Results for this outcome have not been posted.

Other pre-specifiedWeight-for-height (WFH) Associations With PK

acute protein-calorie malnutrition resulting in weight loss or slow weight gain (decreased weight-for-height: WFH; wasting).

Time frame:
study day 0

Results for this outcome have not been posted.

Other pre-specifiedWeight-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.

Time frame:
study day 0

Results for this outcome have not been posted.

Other pre-specifiedPrevalence 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.

Time frame:
study day 0-42

Results for this outcome have not been posted.

Adverse events

Collected over days 0 to 42. Non-serious events are listed at a 4% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
HIV-infected 3-day AL0/35 (0%)0/35 (0%)0/35 (0%)
HIV-infected 5-day AL0/36 (0%)0/36 (0%)0/36 (0%)
HIV-uninfected 3-day AL0/114 (0%)2/114 (1.8%)0/114 (0%)
HIV-uninfected 5-day AL0/113 (0%)0/113 (0%)0/113 (0%)
Most frequent serious events
Most frequent serious events
EventHIV-infected 3-day ALHIV-infected 5-day ALHIV-uninfected 3-day ALHIV-uninfected 5-day AL
hypoglycemiaBlood and lymphatic system disorders——1/114—
anemiaBlood and lymphatic system disorders——1/114—

Baseline characteristics

Eligible HIV negative participant age range is 6 months to 18 years and HIV positive participant age range 3-18 years.

Age, Continuous
Age, Continuous(years)HIV-infected 3-day AL Intensive PKHIV-infected 5-day AL Intensive PKHIV-uninfected 3-day ALHIV-uninfected 5-day ALTotal
Median11.5 (7.71 to 14.25)10.4 (7.13 to 13.4)5.3 (4.1 to 7.9)5.9 (4.1 to 8.0)6.2 (4.3 to 9.6)
Sex: Female, Male
Sex: Female, Male(Participants)HIV-infected 3-day AL Intensive PKHIV-infected 5-day AL Intensive PKHIV-uninfected 3-day ALHIV-uninfected 5-day ALTotal
Female21156460160
Male14215053138
Race (NIH/OMB)
Race (NIH/OMB)(Participants)HIV-infected 3-day AL Intensive PKHIV-infected 5-day AL Intensive PKHIV-uninfected 3-day ALHIV-uninfected 5-day ALTotal
American Indian or Alaska Native00000
Asian00000
Native Hawaiian or Other Pacific Islander00000
Black or African American3536114113298
White00000
More than one race00000
Unknown or Not Reported00000
Region of Enrollment
Region of Enrollment(participants)HIV-infected 3-day AL Intensive PKHIV-infected 5-day AL Intensive PKHIV-uninfected 3-day ALHIV-uninfected 5-day ALTotal
Uganda3536114113298
Weight
Weight(kg)HIV-infected 3-day AL Intensive PKHIV-infected 5-day AL Intensive PKHIV-uninfected 3-day ALHIV-uninfected 5-day ALTotal
Median28.4 (22.0 to 35.5)25.8 (21.2 to 30.1)17.3 (15.1 to 23.0)19.1 (15.4 to 22.6)20.2 (15.8 to 26.5)
07

Study locations

2 sites
  • MGH campus
    Busia, Uganda
  • IDRC- Tororo Research Clinic and Tororo District Hospital
    Tororo, Uganda
08

References and documents

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. PubMed 36130191 ↗
  • 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. PubMed 39853752 ↗

Study documents

  • Protocol and statistical analysis plan · Jul 19, 2018
  • Informed consent form · Sep 18, 2019
  • Informed consent form · Sep 18, 2019

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT03453840
Lead 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
Responsible party
Sponsor
First posted
Mar 5, 2018
Start date
Feb 21, 2018
Primary completion
Aug 31, 2021
Completion
Aug 31, 2021
Results posted
Jan 3, 2025
Last update
Apr 15, 2025

Study contacts

Francesca Aweeka, Pharm. D
principal investigator · University of California, San Francisco
Sunil Parikh, M.D., MPH
principal investigator · Yale University School of Public Health

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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