Clinical trial NCT04708496: Optimizing Malaria Treatment for HIV-Malaria Co-infected Individuals
Official title: Optimizing Malaria Treatment for HIV-Malaria Co-Infected Individuals by Addressing Drug Interactions Between Artemether-Lumefantrine and Efavirenz; a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: HIV Coinfection
Malaria
Lead sponsor: Makerere University
Sponsor class: OTHER
First posted: 2021-01-14
Enrollment: 888
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A three arm single blind randomized trial. Study participants will be randomized to one of the 3 arms. Standard dose, double dose or 5 day course of Artemether-lumefantrine
Primary purpose: TREATMENT

Brief summary: Optimal is a Randomized clinical trial to optimize treatment of malaria in HIV -malaria co infected patients. It has been demonstrated that, when the antimalarial drug Artemether Lumefantrine is co administered with Efavirenz based ART in HIV-malaria co-infected individuals, sub therapeutic levels of the drug are achieved hence resulting in poor malaria treatment outcomes.

The study then hypothesizes that, : HIV-malaria co-infected individuals receiving efavirenz-based ART plus a double-dose or 5-day course of artemether-lumefantrine will achieve higher and adequate artemether-lumefantrine serum concentrations with adequate 42-day treatment outcomes compared to individuals with HIV-malaria co-infection receiving efavirenz-based ART plus a standard-dose of artemether-lumefantrine.

Detailed description: Malaria and HIV have significant interactions at various levels. The geographical and epidemiological overlap increases risk for co-infection and co-treatment. The immune suppression due to HIV increases malaria incidence, severity and risk for poor treatment outcomes including mortality and adverse pregnancy outcomes such as anemia and low birth weight. Malaria infection increases HIV viral replication. Both malaria and HIV are treated with combination therapy to enhance treatment outcomes and reduce risk for development of resistance, consequently creating potential for drug-drug interactions (DDIs) when the two diseases are treated concomitantly. Previous studies demonstrated significant reduction in systemic exposure to Artemether, its metabolite dihydroartemisinin, and the long acting partner drug lumefantrine when the ACT artemether-lumefantrine was co-administered with efavirenz-based ART to HIV-malaria co-infected individuals.

Exposure to sub therapeutic antimalarial drug concentrations poses a risk for poor malaria treatment outcomes such as prolonged morbidity, anemia, death and poor birth outcomes for pregnant women plus increased economic costs and risk for drug resistance. There are currently limited drug options available for both malaria and HIV treatment especially in sub-Saharan Africa, thus the need to protect drug effectiveness. There are very scanty data on effects of drug interactions on malaria clinical outcomes, and such studies would be unethical currently. Despite these gaps, co-administration of antimalarial and antiretroviral drugs occurs with no guidance on therapeutic interventions to overcome these deleterious effects. Data are therefore urgently needed to optimize treatment of malaria for HIV-malaria co-infected individuals.

General Objective: To utilize innovative interventions to overcome drug interactions between artemether-lumefantrine and efavirenz to guide malaria treatment for individuals co-infected with HIV and malaria.

Specific objectives:

Objectives

1. To determine the safety and Pharmacokinetics of the double dose artemether-lumefantrine when administered to healthy volunteers (malaria negative and HIV negative individuals).
2. To determine the safety and Pharmacokinetics of the 5-day course of artemether-lumefantrine when administered to healthy volunteers (malaria negative and HIV negative individuals).
3. To determine the safety, pharmacokinetics and malaria treatment outcome of a standard dose of artemether-lumefantrine compared to double of the standard dose for weight and a 5-day course of artemether-lumefantrine for treatment of uncomplicated malaria among HIV-Malaria co-infected individuals receiving efavirenz (400mg) based ART.
4. To determine the safety and Pharmacokinetics of artemether-lumefantrine when administered with Dolutegravir based ART among HIV-malaria co-infected individuals.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent
2. Willing and able to comply with study treatment and procedures
3. Age above 18 years
4. Confirmed HIV positive and receiving efavirenz or dolutegravir based ART for objectives 3 and 4
5. Confirmed Malaria blood film positive without evidence for severe malaria for objectives 3 and 4
6. Confirmed Malaria blood film negative for objectives 1 and 2

Exclusion Criteria:

1. Serum alanine transaminase levels above 3x upper limit of normal
2. Serum creatinine levels above 2x upper limit of normal
3. Use of known inducers/inhibitors of CYP or glucuronyl transferase UGT1A1 within past 2 months (e.g. anticonvulsants, TB medications, HIV agents for prophylaxis, azole antifungals)
4. Pregnant women or female subjects who are unwilling to use a suitable contraceptive method for the duration of the study (condom, diaphragm, IUD or contraceptive implant)
5. Likely to be poorly adherent based on clinician's medical judgement
6. Known to be current injection drug user
7. Administration of any additional antimalarial drugs that are not study drugs within 24 hours before study enrollment and during the course of the study.
8. Presence of any non-malarial febrile illness which may interfere with the classification of malaria treatment outcome
9. Movement away from the study area interfering with follow-up assessment
10. Patients with contraindications to taking the study drugs
11. Evidence of QT prolongation on ECG (rate adjusted QT interval\>45ms (men (or \>470ms for women

Primary outcomes:
measure: Measure of malaria treatment outcome adjusted by genotyping and classified as reinfection or recrudescence.
timeFrame: Day 42
Secondary outcomes:
measure: Change Maximum concentration [Cmax] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine
timeFrame: over 120hours
measure: Measuring level of Hemoglobin
timeFrame: Hemoglobin will be measured from on follow-up days; 7, 14, 21 and 28.
measure: Change in Area under the time-concentration curve [AUC] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine
timeFrame: over 120hours
measure: Change in Time to maximum concentration [Tmax] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine)
timeFrame: over 120hours
measure: Change in Clearance [Cl/F] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine)
timeFrame: over 120hours
measure: Change in Trough concentration [Ctrough]) of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine)
timeFrame: over 120hours
measure: Prolongation of the QT interval
timeFrame: Over 35days
measure: Change in the level on the liver enzymes ALT and ALP
timeFrame: Over 35days
measure: Change in creatinine and urea levels
timeFrame: Over 35days
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Infectious Diseases Institute
city: Tororo
country: Uganda
facility: Tororo District Hospital
Study officials:
affiliation: IDI
name: Pauline Byakika-Kibwika, PHD
role: PRINCIPAL_INVESTIGATOR
References: