Clinical trial NCT05764746: Triple Artemisinin-based Combination Therapy for Delaying Drug Resistance Development - a Randomized Clinical Trial
Official title: Can Triple Artemisinin-based Combination Therapy for Treatment of Uncomplicated Plasmodium Falciparum Malaria, Delay Drug Resistance Development of Plasmodium Falciparum in Tanzania: a Randomized Three Arm Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Uncomplicated Plasmodium Falciparum Malaria
Keywords: Artemisinin-based Combination Therapy
Plasmodium falciparum
Uncomplicated malaria
Lead sponsor: Muhimbili University of Health and Allied Sciences
Sponsor class: OTHER
Collaborators: name: The Swedish Research Council
name: Uppsala University
First posted: 2023-03-13
Enrollment: 384
Sex: ALL
Minimum age (years): 6
Maximum age (years): 120
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A health facility-based, three-arm partially blinded randomized clinical trial will be conducted to assess efficacy and safety of a sequential administration of artemether-lumefantrine followed immediately by artesunate-amodiaquine (AL+ASAQ) or artemether-lumefantrine with by amodiaquine (AL+AQ) compared to artemether-lumefantrine plus placebo (AL+PBO).
Primary purpose: TREATMENT

Brief summary: Background: Artemisinin resistance has emerged in parts of Southeast Asia, and there are reports in Africa of reduced susceptibility of Plasmodium falciparum parasites against artemisinin-based combination therapy (ACT). No new drugs are available in the pipeline to replace ACTs in case they fail.

This study aims to assess whether a sequential administration of triple ACTs with different partner-drugs can improve the efficacy of ACT for treatment of uncomplicated malaria.

Methods: A health facility-based, three-arm partially blinded randomized clinical trial will be conducted to assess efficacy and safety of a sequential administration of artemether-lumefantrine followed immediately by artesunate-amodiaquine (AL+ASAQ) or artemether-lumefantrine with by amodiaquine (AL+AQ) compared to artemether-lumefantrine plus placebo (AL+PBO). Eligible children aged 6 - 120 months and with microscopy confirmed uncomplicated P. falciparum malaria will be enrolled, administered with trial medicines and followed-up at 0 (just prior to first drug intake) and 8 hours on day 0, 12 hourly on days 1, 2, 3, 4, 5, followed by once daily on days 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42 and 56 for clinical and laboratory evaluations. Clinical evaluation will involve assessment of signs and symptoms related to the disease and or trial medicine during follow-up. Laboratory evaluation will include microscopic determination of presence of malaria parasites and species, hemoglobin level, molecular analysis for markers of drug resistance and to differentiate recrudescence from new infection. The primary outcome will be Polymerase Chain Reaction (PCR)-adjusted adequate clinical and parasitological cure rate on days 28 and 42.

Expected outcomes: The findings will give an insight on whether 3 ACTs are more efficacious than the use of first-line regimen alone, and are tolerable for treatment of uncomplicated falciparum malaria.


Eligibility criteria: Patients presenting at the health facility with suspected acute uncomplicated malaria will be screened for eligibility.

Inclusion Criteria:

* Age from 6 - 120 months
* Weight ≥ 5 kg
* Body temperature ≥37.5°C or history of fever in the last 24 hours
* Microscopy confirmed P. falciparum mono-infection
* Parasitemia level of 1000-200000/μL
* Ability to swallow oral medication
* Ability and willingness to abide by the study protocol and the stipulated follow-up visits
* A written proxy informed consent from a parent/guardian

Exclusion Criteria:

* Children aged below 6 months will not be included in the study because ACTs are contraindicated in this group.
* Evidence of severe malaria or danger signs
* Known allergy to trial medicines
* Reported antimalarial intake ≤2 weeks
* Haemoglobin \<5 g/dL
* Blood transfusion within last 90 days
* Febrile condition other than malaria
* Known underlying chronic or severe disease (including severe malnutrition).

Primary outcomes:
measure: Crude recurrent parasitemia by day 56 in the respective arms
timeFrame: 56th day since enrolment
Secondary outcomes:
measure: PCR adjusted cure rates by day 28, 42 and 56.
timeFrame: Through study completion, an average of 1 year
Other outcomes:
measure: Median time to recurrent parasitemia by microscopy
timeFrame: 56 days since enrolment
measure: PCR determined parasite clearance times
timeFrame: Baseline to day 3
measure: Maximum plasma concentrations (Cmax) of the intervention drugs.
timeFrame: Baseline and Day 7
measure: Change in hemoglobin level (g/dl)
timeFrame: Baseline and day 7
measure: Proportion of Microscopy determined gametocyte carriage
timeFrame: Baseline and day 3
measure: Prevalence of genetic markers of drug resistance.
timeFrame: Through study completion, an average of 1 year
Locations:
city: Bagamoyo
country: Tanzania
facility: Kibindu
state: Dar esSalaam
city: Bagamoyo
country: Tanzania
facility: Yombo Dispensary
state: Yombo
Study officials:
affiliation: Muhimbili University of Health and Allied Sciences
name: Billy E Ngasala, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Muhimbili University of Health and Allied Sciences
name: Andreas Mårtensson, PhD
role: PRINCIPAL_INVESTIGATOR
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citation: Mwaiswelo R, Ngasala B, Gil JP, Malmberg M, Jovel I, Xu W, Premji Z, Mmbando BP, Bjorkman A, Martensson A. Sustained High Cure Rate of Artemether-Lumefantrine against Uncomplicated Plasmodium falciparum Malaria after 8 Years of Its Wide-Scale Use in Bagamoyo District, Tanzania. Am J Trop Med Hyg. 2017 Aug;97(2):526-532. doi: 10.4269/ajtmh.16-0780.
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