Optimizing Malaria Treatment for HIV-Malaria Co-infected Individuals

Optimizing Malaria Treatment for HIV-Malaria Co-Infected Individuals by Addressing Drug Interactions Between Artemether-Lumefantrine and Efavirenz; a Randomized Controlled Trial

Sponsoren

Hauptsponsor: Makerere University

Quelle Makerere University
Kurze Zusammenfassung

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.

detaillierte Beschreibung

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.

Gesamtstatus Not yet recruiting
Anfangsdatum April 2021
Fertigstellungstermin March 2024
Primäres Abschlussdatum January 2024
Phase Phase 4
Studientyp Interventional
Primärer Ausgang
Messen Zeitfenster
Measure of malaria treatment outcome adjusted by genotyping and classified as reinfection or recrudescence. Day 42
Sekundäres Ergebnis
Messen Zeitfenster
Change Maximum concentration [Cmax] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine over 120hours
Measuring level of Hemoglobin Hemoglobin will be measured from on follow-up days; 7, 14, 21 and 28.
Change in Area under the time-concentration curve [AUC] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine over 120hours
Change in Time to maximum concentration [Tmax] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine) over 120hours
Change in Clearance [Cl/F] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine) over 120hours
Change in Trough concentration [Ctrough]) of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine) over 120hours
Prolongation of the QT interval Over 35days
Change in the level on the liver enzymes ALT and ALP Over 35days
Change in creatinine and urea levels Over 35days
Einschreibung 888
Bedingung
Intervention

Interventionsart: Drug

Interventionsname: Artemether-lumefantrine

Beschreibung: A three-arm single blind Randomized Clinical Trial in which HIV-malaria co-infected individuals with uncomplicated malaria receiving efavirenz-based ART will be randomized to one of three arms; a standard dose of artemether-lumefantrine, or a double dose of artemether-lumefantrine, or a 5-day course of artemether-lumefantrine for treatment of uncomplicated malaria. Participants will be followed up for 42 days to determine safety, drug pharmacokinetics and malaria treatment outcomes. The 4th objective focuses on the interaction between Dolutegravir and Artemether Lumefantrine hence this will be a single blind pharmacokinetic trial among HIV-malaria co-infected individuals receiving Dolutegravir based ART and standard dose of artemether-lumefantrine for treatment of uncomplicated malaria.

Teilnahmeberechtigung

Kriterien:

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

Geschlecht: All

Mindestalter: 18 Years

Maximales Alter: N/A

Gesunde Freiwillige: No

Insgesamt offiziell
Nachname Rolle Zugehörigkeit
Pauline Byakika-Kibwika, PHD Principal Investigator IDI
Gesamtkontakt

Nachname: Pauline Byakika-Kibwika, PHD

Telefon: 077262688

Email: [email protected]

Ort
Einrichtung: Kontakt: Ermittler: Tororo District Hospital Pauline Byakika-Kibwika, PHD 077262688 [email protected] Pauline Byakika-Kibwika, PHD Principal Investigator
Standort Länder

Uganda

Überprüfungsdatum

November 2020

Verantwortliche Partei

Art: Sponsor

Hat den Zugriff erweitert No
Bedingung Durchsuchen
Anzahl der Waffen 3
Armgruppe

Etikette: Standard dose of Artemether lumefantrine

Art: Experimental

Beschreibung: Dose comparison-concurrent control In this arm, Participants receiving Efavirenz400mg based ART will be randomized to standard dose Artemether Lumefantrine when treating uncomplicated malaria in HIV-malaria co-infected participants

Etikette: Double dose Artemether lumefantrine

Art: Experimental

Beschreibung: Dose comparison concurrent control In this arm, Participants receiving Efavirenz based ART will be randomized to double dose Artemether Lumefantrine when treating uncomplicated malaria in HIV-malaria co-infected participants

Etikette: 5 day course of Artemether lumefantrine

Art: Experimental

Beschreibung: Dose comparison concurrent control In this arm, Participants receiving Efavirenz based ART will be randomized to 5 day course of Artemether Lumefantrine as opposed to the standard 3day course when treating uncomplicated malaria in HIV-malaria co-infected participants

Akronym OPTIMAL
Patientendaten Yes
Studiendesign Info

Zuweisung: Randomized

Interventionsmodell: Parallel Assignment

Beschreibung des Interventionsmodells: 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

Hauptzweck: Treatment

Maskierung: Single (Investigator)

Maskierungsbeschreibung: study physicians and laboratory technicians will be blinded to treatment group assignments.

Quelle: ClinicalTrials.gov