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

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ClinicalTrials.gov Identifier: NCT03453840
Recruitment Status : Recruiting
First Posted : March 5, 2018
Last Update Posted : August 20, 2018
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Yale University
Infectious Diseases Research Collaboration, Uganda
Information provided by (Responsible Party):
Fran Aweeka, University of California, San Francisco

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.

Condition or disease Intervention/treatment Phase
Uncomplicated Plasmodium Falciparum Malaria Drug: Artemether-lumefantrine Phase 4

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 380 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: Extended Duration Artemether-lumefantrine Treatment for Malaria in Children
Actual Study Start Date : February 19, 2018
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : August 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS Malaria

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 Name: 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 Name: 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 Name: 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 Name: Coartem, AL




Primary Outcome Measures :
  1. Area under the plasma concentration versus time curve (AUC) for all drug analytes [ Time Frame: Study day 0-day21 ]
    AUC8hr for artemether and dihydroartemisinin, AUCinf for lumefantrine.

  2. Recurrent malaria following treatment by day 42 (recrudescence or new infection) [ Time Frame: up to study day 42 ]

Secondary Outcome Measures :
  1. Safety of 5-day vs 3-day AL regimens evaluated via graded toxicity [ Time Frame: study day 0-42 ]
    We will record participants tolerance of AL using the NIH Division of AIDS Adult and Pediatric Toxicity Tables.

  2. Prevalence of gametocytemia following treatment in 3-day vs 5-day AL regimens determined by thick blood smears [ Time Frame: study day 0-42 ]
    At varied time points, blood smears for the determination of parasitemia will be obtained.

  3. Weight-for-age (WFA) associations with PK [ Time Frame: study day 0 ]
    weight-for-age is an indicator of nutrition status and decreased weight-for-age reflects the combination of chronic and acute protein-calorie malnutrition.

  4. Height-for-age (HFA) associations with PK [ Time Frame: study day 0 ]
    chronic protein-calorie malnutrition resulting in slow linear growth (decreased height-for-age: HFA; stunting).

  5. Weight-for-height (WFH) associations with PK [ Time Frame: study day 0 ]
    acute protein-calorie malnutrition resulting in weight loss or slow weight gain (decreased weight-for-height: WFH; wasting).

  6. Diagnostic sensitivity of LAMP, HS-RDT, and microscopy for the detection of recurrent parasitemia [ Time Frame: study day 0-42 ]
    Using Loop-mediated isothermal amplification (LAMP), highly sensitive Rapid Diagnostic Test (HS-RDT), and microscope to diagnose recurrent parasitemia.

  7. Metabolomic measurements in HIV infected vs HIV uninfected children [ Time Frame: study day 0-42 ]
    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.

  8. Relationship between drug resistance and treatment failure [ Time Frame: study day 0-42 ]
    drug resistance will be accessed by molecular markers. Polymorphic markers will be typed using capillary electrophoresis.



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Ages Eligible for Study:   6 Months to 10 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 10 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 10 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. Prior treatment for malaria within 28 days of enrollment
  6. 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)
  7. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03453840


Contacts
Contact: Norah Mwebaza, MBChB 256782589889 mwebno@yahoo.com
Contact: Richard Kajubi, MBChB 256776211591 rkajubi@gmail.com

Locations
Uganda
MGH campus Recruiting
Busia, Uganda
Contact: Arthur Mpimbaza, MBChB       ampimbaza@idrc-uganda.org   
IDRC- Tororo Research Clinic and Tororo District Hospital Not yet recruiting
Tororo, Uganda
Contact: Richard Kajubi    +256776211591    richardkajubi@yahoo.com   
Contact: Norah Mwebaza, MBChB, MSc    +256782589889    mwebno@yahoo.com   
Principal Investigator: Norah Mwebaza, MBChB         
Sponsors and Collaborators
University of California, San Francisco
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
  Study Documents (Full-Text)

Documents provided by Fran Aweeka, University of California, San Francisco:

Responsible Party: Fran Aweeka, Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03453840     History of Changes
Other Study ID Numbers: 17-22578
2R01HD068174-06A1 ( U.S. NIH Grant/Contract )
First Posted: March 5, 2018    Key Record Dates
Last Update Posted: August 20, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Keywords provided by Fran Aweeka, University of California, San Francisco:
malaria
HIV
Children
Efavirenz
artemether
lumefantrine

Additional relevant MeSH terms:
Parasitic Diseases
Malaria
Malaria, Falciparum
Protozoan Infections
Lumefantrine
Artemether
Artemisinins
Artemether-lumefantrine combination
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antifungal Agents
Coccidiostats
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics