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

Primary Purpose

Uncomplicated Plasmodium Falciparum Malaria

Status

Completed

Phase

Phase 4

Locations

Uganda

Study Type

Interventional

Intervention

Artemether-lumefantrine

About this trial

This is an interventional treatment trial for Uncomplicated Plasmodium Falciparum Malaria focused on measuring malaria, HIV, Children, Efavirenz, artemether, lumefantrine

Eligibility Criteria

6 Months - 10 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

1, 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.

2 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 10 years

3 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 10 years

Exclusion Criteria:

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
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.

Sites / Locations

MGH campus
IDRC- Tororo Research Clinic and Tororo District Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Experimental

Active Comparator

Experimental

Arm Label

HIV-infected 3-day AL

HIV-infected 5-day AL

HIV-uninfected 3-day AL

HIV-uninfected 5-day AL

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Area under the plasma concentration versus time curve (AUC) for all drug analytes

AUC 8hr for artemether and dihydroartemisinin, AUC inf for lumefantrine.

Recurrent malaria 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).

Secondary Outcome Measures

Safety of 5-day vs 3-day AL regimens evaluated via graded toxicity

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

Prevalence of gametocytemia following treatment in 3-day vs 5-day AL regimens determined by thick blood smears

At varied time points, blood smears for the determination of parasitemia will be obtained.

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.

Height-for-age (HFA) associations with PK

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

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).

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.

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.

Relationship between drug resistance and treatment failure

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

Full Information

NCT ID

NCT03453840

First Posted

December 22, 2017

Last Updated

October 20, 2022

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

1. Study Identification

Unique Protocol Identification Number

NCT03453840

Brief Title

Extended Duration Artemether-lumefantrine Treatment for Malaria in Children

Acronym

EXALT

Official Title

Extended Duration Artemether-lumefantrine Treatment for Malaria in Children

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Completed

Study Start Date

February 19, 2018 (Actual)

Primary Completion Date

August 31, 2021 (Actual)

Study Completion Date

August 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the 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

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

This project will determine 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 will be 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 will be made for the purposes of this study except for the extension of AL to 5-day dosing. This study will enroll 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 will use a design where children will be 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 will be enrolled for each of the intensive study groups. Up to 100 (50 HIV-infected on 3-day and 50 HIV-infected on 5-day) and 120 (60 HIV-uninfected on 3-day and 60 HIV-uninfected on 5-day) subjects will be enrolled for each of the population study groups. Comparisons of AL PK exposure will be 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 will be based on an intensive PK design for AL area under the concentration-time curve (AUC) estimations. Population PK study will be combined with intensive PK studies to allow for optimal PK-outcomes assessments.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Uncomplicated Plasmodium Falciparum Malaria

Keywords

malaria, HIV, Children, Efavirenz, artemether, lumefantrine

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

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..

Masking

None (Open Label)

Allocation

Randomized

Enrollment

305 (Actual)

8. Arms, Groups, and Interventions

Arm Title

HIV-infected 3-day AL

Arm Type

Active Comparator

Arm Description

Arm Title

HIV-infected 5-day AL

Arm Type

Experimental

Arm Description

Arm Title

HIV-uninfected 3-day AL

Arm Type

Active Comparator

Arm Description

Arm Title

HIV-uninfected 5-day AL

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Artemether-lumefantrine

Other Intervention Name(s)

Coartem, AL

Intervention Description

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.

Primary Outcome Measure Information:

Title

Area under the plasma concentration versus time curve (AUC) for all drug analytes

Description

AUC 8hr for artemether and dihydroartemisinin, AUC inf for lumefantrine.

Time Frame

Study day 0-day21

Title

Recurrent malaria following treatment by day 42 (recrudescence or new infection)

Description

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

Secondary Outcome Measure Information:

Title

Safety of 5-day vs 3-day AL regimens evaluated via graded toxicity

Description

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

Time Frame

study day 0-42

Title

Prevalence of gametocytemia following treatment in 3-day vs 5-day AL regimens determined by thick blood smears

Description

At varied time points, blood smears for the determination of parasitemia will be obtained.

Time Frame

study day 0-42

Title

Weight-for-age (WFA) associations with PK

Description

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

Title

Height-for-age (HFA) associations with PK

Description

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

Time Frame

study day 0

Title

Weight-for-height (WFH) associations with PK

Description

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

Time Frame

study day 0

Title

Diagnostic sensitivity of LAMP, HS-RDT, and microscopy for the detection of recurrent parasitemia

Description

Using Loop-mediated isothermal amplification (LAMP), highly sensitive Rapid Diagnostic Test (HS-RDT), and microscope to diagnose recurrent parasitemia.

Time Frame

study day 0-42

Title

Metabolomic measurements in HIV infected vs HIV uninfected children

Description

Time Frame

study day 0-42

Title

Relationship between drug resistance and treatment failure

Description

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

Time Frame

study day 0-42

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Months

Maximum Age & Unit of Time

10 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 1, 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. 2 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 10 years 3 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 10 years Exclusion Criteria: 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 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Francesca Aweeka, Pharm. D

Organizational Affiliation

University of California, San Francisco

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Sunil Parikh, M.D., MPH

Organizational Affiliation

Yale University School of Public Health

Official's Role

Principal Investigator

Facility Information:

Facility Name

MGH campus

City

Busia

Country

Uganda

Facility Name

IDRC- Tororo Research Clinic and Tororo District Hospital

City

Tororo

Country

Uganda

12. IPD Sharing Statement

Plan to Share IPD

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