Gametocytocidal and Transmission-blocking Efficacy of ASAQ and ALAQ With or Without PQ in Mali

Study Overview
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Brief Summary
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The purpose of this study is to compare the gametocytocidal and transmission reducing activity of artesunate-amodiaquine (ASAQ) and artemether-lumefantrine-amodiaquine (ALAQ) with and without a single dose of 0.25mg/kg primaquine (PQ). Outcome measures will include infectivity to mosquitoes at 2, 7 and 14 days after treatment, gametocyte density throughout follow-up, and safety measures including haemoglobin density and the frequency of adverse events.

Detailed Description
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Full protocol available on request

Official Title
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A Five-arm Trial Comparing Artesunate-amodiaquine and Artemether-lumefantrine-amodiaquine With or Without Single-dose Primaquine to Reduce P. Falciparum Transmission in Mali

Conditions
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Malaria,Falciparum

Intervention / Treatment
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* Drug: Artesunate-amodiaquine combination
* Drug: Primaquine Phosphate
* Drug: Artemether-lumefantrine
* Drug: Amodiaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 10 years and ≤ 50 years Absence of symptomatic falciparum malaria, defined by fever on enrolment Presence of P. falciparum gametocytes on thick blood film at a density >16 gametocytes/µL (i.e. ≥ gametocytes recorded in the thick film against 500 white blood cells) Absence of other non-P. falciparum species on blood film Haemoglobin ≥ 10 g/dL Individuals weighing < = 80 kg No evidence of acute severe or chronic disease Written, informed consent Exclusion Criteria: Women who are pregnant or lactating (tested at baseline). Urine and/or serum pregnancy testing (β-hCG) will be used. Detection of a non-P. falciparum species by microscopy Previous reaction to study drugs / known allergy to study drugs, such as sudden high fevers, shaking or severe sore throat or ulcers in the mouth during treatment with Amodiaquine Current eye disease with retinal damage Signs of severe malaria, including hyperparasitaemia (defined as asexual parasitaemia > 100,000 parasites / µL) Signs of acute or chronic illness, including hepatitis The use of other medication (except for paracetamol and/or aspirin), including antacids, other medicines used to treat malaria, abnormal heart rhythm, depression or mental illness or HIV/AIDS, and medicines that have antibiotic/antifungal properties Use of antimalarial drugs over the past 7 days (as reported by the participant) Clinically significant illness (intercurrent illness e.g., pneumonia, pre-existing condition e.g., renal disease or HIV/AIDS, malignancy or conditions that may affect absorption of study medication e.g., severe diarrhoea or any signs of malnutrition as defined clinically) Signs of hepatic injury (such as nausea and/or abdominal pain associated with jaundice) or known severe liver disease (i.e., decompensated cirrhosis, Child Pugh stage B or C) Signs, symptoms or known renal impairment Clinically significant abnormal laboratory values as determined by history, physical examination, or routine blood chemistries and haematology values (laboratory guideline values for exclusion are haemoglobin < 10 g/dL, platelets < 50,000/μl, White Blood Cell count (WBC) < 2000/μl, serum creatinine >2.0mg/dL, or ALT more than 3 times the upper limit of normal for age. Blood transfusion in the last 90 days. Known Electrocardiogram (ECG) corrected QT interval of more than 450 ms Documented or self-reported history of cardiac conduction problems Documented or self-reported history of epileptic seizures

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: artesunate-amodiaquine (ASAQ)<br>Subjects will receive artesunate-amodiaquine (ASAQ) daily for 3 days. | Drug: Artesunate-amodiaquine combination<br>* Tablets containing 50mg/135 mg or 100mg/270 mg of artesunate/amodiaquine will be administered according to weight as per manufacturer guidelines<br>* Other names: Camoquin;|
| Experimental: ASAQ with 0.25mg/kg primaquine (PQ)<br>Subjects will receive artesunate-amodiaquine (ASAQ) daily for 3 days and a single dose of 0.25mg/kg primaquine (PQ) on the first day of ASAQ treatment. | Drug: Artesunate-amodiaquine combination<br>* Tablets containing 50mg/135 mg or 100mg/270 mg of artesunate/amodiaquine will be administered according to weight as per manufacturer guidelines<br>* Other names: Camoquin;Drug: Primaquine Phosphate<br>* The single dose of 0.25mg/kg PQ will be administered in an aqueous solution, according to a standard operating procedure (SOP) provided by the manufacturer.<br>* Other names: Primaquine;|
| Active Comparator: Artemether-Lumefantrine (AL)<br>Subjects will receive artemether-lumefantrine (AL) twice daily for 3 days. | Drug: Artemether-lumefantrine<br>* Tablets containing 20 mg artemether and 120 mg lumefantrine will be administered according to weight as per manufacturer guidelines<br>* Other names: Coartem;|
| Experimental: Artemether-Lumefantrine-Amodiaquine (ALAQ)<br>Subjects will receive artemether-lumefantrine (AL) and amodiaquine (AQ) twice daily for 3 days. | Drug: Artemether-lumefantrine<br>* Tablets containing 20 mg artemether and 120 mg lumefantrine will be administered according to weight as per manufacturer guidelines<br>* Other names: Coartem;Drug: Amodiaquine<br>* Tablets containing 153 mg of amodiaquine will be administered according to weight, aiming for a dosage of approximately 10 mg (7.7-15.3mg)/kg/day, given once or twice daily (together with artemether-lumefantrine) for three days.<br>|
| Experimental: Artemether-Lumefantrine-Amodiaquine (ALAQ) with 0.25 mg/kg primaquine (PQ)<br>Subjects will receive artemether-lumefantrine (AL) and amodiaquine (AQ) twice daily for 3 days and a single dose of 0.25mg/kg primaquine (PQ) on the first day of ALAQ treatment. | Drug: Primaquine Phosphate<br>* The single dose of 0.25mg/kg PQ will be administered in an aqueous solution, according to a standard operating procedure (SOP) provided by the manufacturer.<br>* Other names: Primaquine;Drug: Artemether-lumefantrine<br>* Tablets containing 20 mg artemether and 120 mg lumefantrine will be administered according to weight as per manufacturer guidelines<br>* Other names: Coartem;Drug: Amodiaquine<br>* Tablets containing 153 mg of amodiaquine will be administered according to weight, aiming for a dosage of approximately 10 mg (7.7-15.3mg)/kg/day, given once or twice daily (together with artemether-lumefantrine) for three days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mosquito infection rate assessed through membrane feeding assays | Within person percent change (presented as percent reduction) in mosquito infection rate in infectious individuals from baseline (day 0, pre-treatment) to day 2 post treatment in the ASAQ, ASAQ-PQ, AL, ALAQ and ALAQ-PQ arms. | 2 days (days 0 and 2): 3 day span | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mosquito infection rate assessed through membrane feeding assays (all timepoints) | Within person percent change (presented as percent reduction) in mosquito infection rate from baseline to all feeding time-points, with comparison within and between arms. | 6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Mosquito infection rate assessed through membrane feeding assays | Mosquito infection rate at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms. | 6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Human infectivity to locally reared mosquitoes assessed through membrane feeding assays | Infectivity to mosquitoes at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms. | 6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Mosquito infection density assessed through membrane feeding assays | Oocyst intensity (in all/all infected mosquitoes) at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms. | 6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Gametocyte infectivity | Infectiousness to mosquitoes for a given gametocyte density (measured as mosquito infection rate/gametocyte) at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms. | 6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Asexual/sexual stage parasite prevalence | Male and female gametocyte prevalence at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms. Asexual and total parasite prevalence at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms. | 6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Asexual/sexual stage parasite density | Male and female gametocyte density at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms. Asexual and total parasite density at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms. | 6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Sexual stage parasite sex ratio | Male and female gametocyte sex ratio (proportion male) at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms. | 6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Sexual stage parasite circulation time | Gametocyte circulation time (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms. | 6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Sexual stage parasite area under the curve (AUC) | Gametocyte area under the curve (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms. | 6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Haemoglobin density | Haemoglobin density (g/dL) at all time-points, with comparison within treatment arms compared to baseline, and between arms. | 7 days (day 0, day 1, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Change in haemoglobin density | Within person percent change (presented as percent reduction) in haemoglobin density (g/dL) from baseline to all time-points, with comparison within and between arms. | 7 days (day 0, day 1, day 2, day 7, day 14, day 21, day 28): 28 day span | 
| Incidence of adverse events | The frequency and prevalence of adverse events (all AE's, treatment related AE's, and haematological AE's) observed up to and including day 2, 7, and 14 post-treatment, and at all timepoints. | 7 days (day 0, day 1, day 2, day 7, day 14, day 21, day 28): 28 day span |