Clinical trial NCT06967519: OPTImizing Malaria And HIV Treatment in a Shifting Landscape in Africa
Official title: OPTImizing Malaria And HIV Treatment in a Shifting Landscape in Africa
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Malaria
Hiv
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2025-05-13
Enrollment: 380
Sex: ALL
Minimum age (years): 5
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Only Busia participants (HIV-infected and HIV-uninfected, Cohorts 3 and 4) will be enrolled and then randomized to receive either artemether- lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) for each episode of malaria which occurs over longitudinal follow-up in year one. During year 1, they will continue to receive the same antimalarial each time they are treated for uncomplicated malaria. In year two, those randomized to the AL arm will begin to receive an alternating regimen for each subsequent malaria episode (AS-AQ, then AL, then AS-AQ, etc..). CLHIV, ages 5-17 years, will be identified from respective registers at Baylor-Uganda (in Kampala) and the Masafu HIV clinic (and nearby clinics) in Busia Uganda. HIV-uninfected children, also ages 5-17 years, will be enrolled from catchment areas at these two sites. Recruitment will be balanced by age and sex.
Primary purpose: TREATMENT

Brief summary: A longitudinal study with four parallel cohorts with each participant followed for 2 years: two cohorts in Busia (high malaria transmission site) and two cohorts in Kampala (low malaria transmission). Each site will have a cohort of children living with HIV (CLHIV) and HIV- uninfected children and will be age-matched, enrolled in parallel, and followed for two years. All children will be enrolled without malaria infection, as determined by a negative blood smear at baseline.

Detailed description: CLHIV will be maintained on a dolutegravir (DTG) based regimen for \>2 weeks prior to enrolment to ensure steady state. All children in Busia (HIV-infected and HIV-uninfected) will be enrolled and then randomized to receive either artemether- lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) for each episode of malaria which occurs over longitudinal follow-up in year one. During year 1, they will continue to receive the same antimalarial each time they are treated for uncomplicated malaria. In year two, those children randomized to the AL arm will begin to receive an alternating regimen for each subsequent malaria episode (AS-AQ, then AL, then AS-AQ, etc..). If local/national guidelines in Uganda for malaria change during the course of the study, the treatment arms will be altered as applicable. Aim 1: To what extent does DTG impact, BMI, body composition and metabolic changes? Aims 2 and 3: Are there critical drug-drug interactions between DTG and first line artemisinin-based combination therapies (ACTs)? Do these changes impact HIV and malaria outcomes? What is the status of ACT resistance and its relationship to PK exposure?

MALARIA CASE DEFINITION:

Uncomplicated malaria (all of the following)

* Fever (≥ 37.5ºC axillary) or history of fever in the previous 24 hours
* Positive thick blood smear (any parasitemia)
* Absence of severe malaria Severe malaria
* Evidence of severe malaria as per WHO criteria

Eligibility criteria: Inclusion Criteria:

* Agreement to come to the clinic for all follow-up evaluations
* Provision of informed consent and assent (as appropriate)
* Residency within approximately 30 km of the study clinic
* Negative blood smear for malaria (all sites)
* For Children and adolescents living with HIV

  * Confirmed HIV infection
  * On DTG-based regimen for ≥14 days
* For HIV-uninfected children - documentation of HIV-negative status by at least 1 assay

Exclusion Criteria:

* Significant comorbidities such as malignancy, active TB, chronic/active hepatitis B/C, diabetes, severe acute malnutrition, mitochondrial disorders
* Receipt of known CYP interacting drugs at enrolment (except HAART) - see list of disallowed medications
* Anemia defined by hemocue (Hb \< 7.0) at the time of enrolment
* Signs of uncomplicated or severe malaria at the time of enrollment
* Prior intolerance to AL or AS-AQ (for those in Busia only)
* Pregnancy at enrolment (testing done at enrollment for all those of child-bearing age)
* Concurrent enrolment in another research study

Primary outcomes:
measure: Change in Body Mass Index (BMI)
timeFrame: baseline and 2 years
measure: Drug pharmacokinetic (PK) exposure
timeFrame: baseline up to 2 years
measure: Drug pharmacokinetic exposure
timeFrame: baseline up to 2 years
measure: Recurrence rate of malaria
timeFrame: 28 days and 42 days
Secondary outcomes:
measure: Average change in glucose sensor readings
timeFrame: every 6 months up to 2 years
measure: Change in insulin resistance (HOMA-IR)
timeFrame: baseline and 2 years
measure: Change in Body Mass Index (BMI)
timeFrame: baseline and 2 years
measure: Pharmacokinetic parameters
timeFrame: immediately post drug exposure (Day 1)
measure: Change in HIV viral load
timeFrame: every 6 months up to 2 years
measure: Malaria treatment outcome
timeFrame: 28 days and 42 days
measure: HIV genotypic resistance to DTG
timeFrame: baseline and 2 years
measure: Artemisinin PK concentration-time profile
timeFrame: During treatment of malaria episodes over 2 years
measure: Rate of parasite clearance
timeFrame: During treatment of malaria episodes over 2 years
measure: Rate of parasite clearance and HIV
timeFrame: During treatment of malaria episodes over 2 years
measure: Gametocyte quantity
timeFrame: At the time of presentation with malaria up to 2 years
Other outcomes:
measure: Time to resistance
timeFrame: up to 2 years
measure: K13 mutations
timeFrame: up to 2 years
measure: Prevalence of mutations in malaria transporters
timeFrame: During treatment of malaria episodes over 2 years
Locations:
city: Kampala
country: Uganda
facility: Baylor- Uganda
city: Kampala
country: Uganda
facility: Infectious Disease Research Collaboration (IDRC)
Study officials:
affiliation: Yale School of Public Health
name: Sunil Parikh, M.D., MPH
role: PRINCIPAL_INVESTIGATOR
References: