"Prolonging the Therapeutic Life Span of Artemisinin-based Combination Therapies (ACT) in Bagamoyo District, Tanzania" (ALU-PQ)

Muhimbili University of Health and Allied Sciences (MUHAS)

Status and phase: Completed; Phase 4

Conditions: Malaria,Falciparum

Treatments: Drug: Primaquine Phosphate 0.25 mg/kg; Other: Placebo; Drug: Artemether-Lumefantrine Tab 20-120mg

Study type: Interventional

Funder types: Other

Identifiers

NCT03241901

No. 01.05.2017

Details and patient eligibility

About

This clinical trial evaluates the advantage of prolonging the therapeutic life span of Artemether-lumefantrine from 3 days to 6 days, and addition of single low dose of Primaquine 0.25mg/kg. The study will have two arms, one that will receive standard treatment of uncomplicated malaria with Artemether-lumefantrine, and the other arm will receive the prolonged dose of 6 days together with single low dose primaquine. This approach is expected to provide strategies for malaria control in an era of imminent Plasmodium falciparum resistance.

Full description

Despite documented high cure rates of ACT in Tanzania, and Africa elsewhere, clinical trials conducted in Tanzania with Swedish International Development cooperation Agency (SIDA) and Swedish Research Council support, provide evidence for in vivo selection of lumefantrine tolerant/resistant parasites among recurrent infections. Similarly, molecular epidemiology studies from Bagamoyo District, Tanzania, have shown temporal selection of lumefantrine associated genetic tolerance/resistance markers in the parasite population following wide scale use of Artemether-lumefantrine, but without signs of compromised treatment efficacy.

During the last decade, and despite the documented rapid microscopy determined parasite clearance of artemether-lumefantrine in Bagamoyo District, interest has developed in understanding the observation of high residual polymerase chain reaction (PCR) determined positivity rate on day 3 after supervised artemether-lumefantrine treatment in the magnitude of almost 30% in previous assessments from 2015. Using deep sequencing approaches studies have recently detected PCR determined delayed parasite clearance curves in P. falciparum sub-populations in Bagamoyo District. The clearance times by PCR of these sub-populations were similar to artemisinin resistant parasites in Myanmar as assessed by microscopy, but the former did, importantly, not harbor any of the described mutations in Kelch13 propeller associated with artemisinin resistance. However, these Tanzanian parasite sub-populations need to be further studied and characterized since they may provide important clues to the understanding of artemisinin survival strategies among the East African P. falciparum parasite population.

Taken together, longitudinal clinical and molecular data described above from Tanzania, East Africa, extending from pre-ACT implementation, (before 2006), to a decade of wide scale artemether-lumefantrine use in Bagamoyo district, provide evidence for declining susceptibility to ACT, both to artemether and lumefantrine, among the P. falciparum population. These parasites ("last man standing") that survived 10 years of ACT exposure have indeed shown excellent survival instincts and may thus be particularly resistant prone. However, if P. falciparum resistance to ACT develops in Africa, this will have devastating effects on malaria morbidity and mortality and may swiftly ruin the improvements the global malaria community achieved during the past decade with ACT as a key component for success.

Based on the above the investigators suggest prolonged treatment with ACT and addition of transmission blocking treatment using a single low dose of primaquine administered on the last day of ACT treatment.

Enrollment: 280 patients

Sex: All

Ages: 1 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Age more than 1 year and less than 65 years.
2. Weight 10 kg and above;
3. Body temperature ≥37.5°C or history of fever in the last 24 hours;
4. Microscopy determined asexual P. falciparum mono-infection regardless of parasitemia
5. Normal - corrected QT Interval in Baseline ECG of less than 440ms in male and 460ms in females

Exclusion criteria

1. Symptoms/signs of severe malaria or danger signs;
2. Pregnancy, Breastfeeding or unwilling to practice birth control during participation in the study.
3. Known allergy to study medications;
4. Hb <8 g/dl;
5. Reported antimalarial intake within last 2 weeks;
6. On regular medication, which may interfere with antimalarial pharmacokinetics and
7. Blood transfusion within last 90 days.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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280 participants in 2 patient groups

3 Days Artemether-Lumefantrine + Placebo

Active Comparator group

Description:

Oral tablets of artemether-lumefantrine (20-120mg): 1. tablet for 5-14kg; 2. tablets for 15-24 kg; 3. tables for 25 - 34kg and 4. tablets for above 35 Kg. The full course of treatment is 6-doses for 3 days given twice daily, at 0, 8, 24, 36, 48, 60 with the dose being given as directly observed therapy. Oral placebo after completion of the standard 3 days-six dose regimen. A fatty snack (biscuits) will be administered together with all artemether-lumefantrine doses to optimize absorption.

Treatment:

Drug: Artemether-Lumefantrine Tab 20-120mg

Other: Placebo

6Days Artemether/Lumefantrine+Primaquine

Experimental group

Description:

Artemether-lumefantrine (20-120mg) twice daily for 6 days according to body weight as in the active comparator arm. And in addition to that, , a single 0.25 mg/kg primaquine dose (Primaquine phosphate) will be administered concomitantly with the last (i.e. twelfth) artemether-lumefantrine dose. Primaquine will be prepared and administered in an aqueous solution.

Treatment:

Drug: Artemether-Lumefantrine Tab 20-120mg

Drug: Primaquine Phosphate 0.25 mg/kg