Clinical trial NCT03241901: "Prolonging the Therapeutic Life Span of Artemisinin-based Combination Therapies (ACT) in Bagamoyo District, Tanzania"
Official title: "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"
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Malaria,Falciparum
Keywords: Artemether-Lumefantrine, Primaquine
Lead sponsor: Muhimbili University of Health and Allied Sciences
Sponsor class: OTHER
Collaborators: name: Uppsala University
name: Karolinska Institutet
name: The University of Western Australia
First posted: 2017-08-08
Enrollment: 280
Sex: ALL
Minimum age (years): 1
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Parasite Clearance Times
timeFrame: 5 Days
measure: Parasite Clearance Times
timeFrame: 7 Days
Secondary outcomes:
measure: Gametocyte Clearance
timeFrame: 42 Days
measure: Cure Rate
timeFrame: 28 Days
measure: Genetic Markers of Drug Resistance
timeFrame: 6 Days
measure: Pharmacokinetics
timeFrame: 7 Days
measure: Peak Plasma Concentration (Cmax)
timeFrame: 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
measure: Day 7 plasma lumefantrine
timeFrame: 7 Days
Other outcomes:
measure: Fever Clearance Time
timeFrame: 7 Days
measure: Incidence of Treatment-Emergent Adverse Events (Safety and tolerability)
timeFrame: Baseline and day 7
measure: Incidence of Severe anemia
timeFrame: baseline to day 7, 14, 28, 42
measure: Incidence of Biochemistry parameters derangements
timeFrame: Baseline and day 7
Locations:
city: Bagamoyo
country: Tanzania
facility: Fukayosi Dispensary
state: Pwani
city: Bagamoyo
country: Tanzania
facility: Yombo Dispensary
state: Yombo
Study officials:
affiliation: Muhimbili University of Health and Allied Sciences
name: Lwidiko E Mhamilawa, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Uppsala University
name: Andreas Martensson, PhD
role: STUDY_CHAIR
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