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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Aiming at Prolonging the Therapeutic Life Span of Artemisinin-based Combination Therapies (ACT) in an Era of Imminent Plasmodium Falciparum Resistance in Bagamoyo District, Tanzania - New Strategies With Old Tools

Conditions
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Malaria,Falciparum

Intervention / Treatment
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* Drug: Artemether-Lumefantrine Tab 20-120mg
* Drug: Primaquine Phosphate 0.25 mg/kg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age more than 1 year and less than 65 years. Weight 10 kg and above; Body temperature ≥37.5°C or history of fever in the last 24 hours; Microscopy determined asexual P. falciparum mono-infection regardless of parasitemia Normal - corrected QT Interval in Baseline ECG of less than 440ms in male and 460ms in females Exclusion Criteria: Symptoms/signs of severe malaria or danger signs; Pregnancy, Breastfeeding or unwilling to practice birth control during participation in the study. Known allergy to study medications; Hb <8 g/dl; Reported antimalarial intake within last 2 weeks; On regular medication, which may interfere with antimalarial pharmacokinetics and Blood transfusion within last 90 days.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 3 Days Artemether-Lumefantrine + Placebo<br>Oral tablets of artemether-lumefantrine (20-120mg): tablet for 5-14kg; tablets for 15-24 kg; tables for 25 - 34kg and 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. | Drug: Artemether-Lumefantrine Tab 20-120mg<br>* Artemether-Lumefantrine Tablet 20-120mg<br>* Other names: ALU;Other: Placebo<br>* Aqueous solution prepared to mimic the taste of the intervention drug.<br>* Other names: Placebo for Artemether Lumefantrine + Primaquine Phosphate;|
| Experimental: 6Days Artemether/Lumefantrine+Primaquine<br>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. | Drug: Artemether-Lumefantrine Tab 20-120mg<br>* Artemether-Lumefantrine Tablet 20-120mg<br>* Other names: ALU;Drug: Primaquine Phosphate 0.25 mg/kg<br>* Primaquine Phosphate 0.25 mg/kg<br>* Other names: PQ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parasite Clearance Times | Proportion of PCR detectable parasitemia on Day 5 | 5 Days | 
| Parasite Clearance Times | Proportion of PCR detectable parasitemia on Day 7 | 7 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gametocyte Clearance | PCR determined gametocyte carriage/clearance times | 42 Days | 
| Cure Rate | Crude and PCR corrected cure rates by day 28 | 28 Days | 
| Genetic Markers of Drug Resistance | Selection of genetic drug resistance markers during the early treatment phase | 6 Days | 
| Pharmacokinetics | Area under the plasma concentration versus time curve (AUC) of Artemether-lumefantrine | 7 Days | 
| Peak Plasma Concentration (Cmax) | Peak Plasma Concentration (Cmax) of Lumefantrine measured for 28 days | At hours, -1, 0 ,2 ,4 ,12, 24, 36, 40, 48, 52, 60, 72, 84, 88, 96, 100, 108,120, 132, 134, 136 ,144, 168, 192, 240, 336, 504 and 672 | 
| Day 7 plasma lumefantrine | Day 7 plasma lumefantrine concentrations in the respective arms | 7 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Artemether-Lumefantrine, Primaquine