Phase 2 Efficacy Study of Primaquine and Methylene Blue

Study Overview
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Brief Summary
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The purpose of this study is to determine the most efficacious transmission blocking drug regimen for seasonal malaria chemoprophylaxis in Mali. The primary outcome measure will be the proportion of mosquitoes infected pre and post-treatment, assessed through membrane feeding and measured by oocyst prevalence in mosquitoes dissected on day 7 post feed. Primary endpoint will be a within group comparison between the mean of the pretreatment infectivity (Day 0) and infectivity at 7 days post first dose.

Detailed Description
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Protocol will be shared on request.

Official Title
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Efficacy, Safety, and Pharmacokinetics of Sulphadoxine-pyrimethamine-amodiaquine (SP-AQ), SP-AQ Plus Primaquine, Dihydroartemisinin-piperaquine (DP), DP Plus Methylene Blue for Preventing Transmission of P. Falciparum Gametocytes in Mali

Conditions
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Malaria

Intervention / Treatment
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* Drug: Sulphadoxine-pyrimethamine
* Drug: 0.25 mg/kg primaquine
* Drug: Dihydroartemisinin-piperaquine
* Drug: Methylene blue
* Drug: Amodiaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Glucose-6-phosphate dehydrogenase (G6PD) normal defined by CareStart™ G6PD rapid diagnostic test (RDT) or the OSMMR2000 G6PD semi-qualitative test Absence of symptomatic falciparum malaria, defined by fever upon enrollment Presence of P. falciparum gametocytes on thick blood film at a density >30 gametocytes/µL (i.e. ≥2 gametocytes recorded in the thick film against 500 white blood cells) No allergies to study drugs No self-reported use of antimalarial drugs over the past 7 days (as reported by the participant) Hemoglobin ≥ 10 g/dL Individuals weighing <80 kg No evidence of severe or chronic disease Written, informed consent Exclusion Criteria: Age < 5 years or > 50 years Female gender Blood thick film negative for sexual stages of malaria Previous reaction to study drugs/known allergy to study drugs Signs of severe malaria, including hyperparasitemia, defined as asexual parasitemia > 100,000 parasites / µL) Signs of acute or chronic illness, including hepatitis Use of other medications (with the exception of paracetamol and/or aspirin) Consent not given

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

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: SP-AQ only<br>Subjects will receive sulphadoxine-pyrimethamine (SP) as single dose and administered in combination with amodiaquine (AQ), which will be given once daily for 3 days. | Drug: Sulphadoxine-pyrimethamine<br>* Each Fansidar tablet is scored containing 500mg sulphadoxine and 25 mg pyrimethamine. Doses will be administered by weight.<br>* Other names: Fansidar;Drug: Amodiaquine<br>* Amodiaquine will be administered once daily for 3 days, following weight-based dosing of 150 mg tablets.<br>|
| Experimental: SP-AQ plus PQ<br>Participants in this arm will receive SP-AQ in combination with a single low dose of primaquine at the World Health Organization (WHO) recommended dose of 0.25 mg/kg. | Drug: Sulphadoxine-pyrimethamine<br>* Each Fansidar tablet is scored containing 500mg sulphadoxine and 25 mg pyrimethamine. Doses will be administered by weight.<br>* Other names: Fansidar;Drug: 0.25 mg/kg primaquine<br>* Primaquine will be administered in an aqueous solution according to weight-based dosing.<br>Drug: Amodiaquine<br>* Amodiaquine will be administered once daily for 3 days, following weight-based dosing of 150 mg tablets.<br>|
| Active Comparator: DP only<br>Participants in this arm will be treated with dihydroartemisinin-piperaquine (DP), which will be administered once a day for three days. | Drug: Dihydroartemisinin-piperaquine<br>* 160mg/20mg or 320mg/40mg of dihydroartemisinin/piperaquine tablets will be used to administer weight-based doses.<br>* Other names: Eurartesim;|
| Experimental: DP plus MB<br>Study participants in this arm will receive DP as described above combined with once-daily methylene blue (MB) for 3 days, at 15 mg/kg/day (45 mg/kg total over 3 days). | Drug: Methylene blue<br>* Methylene blue will be given as minitablets in prepackaged sachets according to weight groups.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mosquito infectivity assessed through membrane feeding assays | Infectivity will be measured by oocyst prevalence in dissected mosquitoes. Primary endpoint will be a comparison between mean of pretreatment infectivity (day 0) and infectivity at days 2 and 7 post first dose. | 7 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gametocyte prevalence, density, and sex ratio measured microscopically and by molecular methods. | Outcome measured at baseline and days 1, 2, 3, 7, 14, 28, and 42 post first dose. | 42 days | 
| Asexual parasite prevalence and density | Asexual parasitemia will be evaluated by blood smear microscopy and confirmed by more sensitive, molecular methods. Outcome measured at baseline and days 1, 2, 3, 7, 14, 28, and 42 post first dose. | 42 days | 
| Safety measurements including hemoglobin and signs of hemolysis | The major safety endpoint is hemolysis. For this reason, hemoglobin and methemoglobin values will be measured before treatment, at baseline and on days 1, 2, 3, 7, 14, 28, and 42 post first dose. In addition, clinical review (including additional signs of hemolysis) will be assessed based on active and passive follow-up. | 42 days | 
| Peak plasma concentration (Cmax) of primaquine | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Area under the concentration curve (AUC) of primaquine. | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Elimination half life (t1/2) of primaquine | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Peak plasma concentration (Cmax) of methylene blue | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Area under the concentration curve (AUC) of methylene blue | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Elimination half life (t1/2) of methylene blue | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Peak plasma concentration (Cmax) of sulphadoxine-pyrimethamine | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Area under the concentration curve (AUC) of sulphadoxine-pyrimethamine | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Elimination half-life (t1/2) of sulphadoxine-pyrimethamine | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Peak plasma concentration (Cmax) of dihydroartemisinin-piperaquine | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Area under the concentration curve (AUC) of dihydroartemisinin-piperaquine | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Elimination half-life (t1/2) of dihydroartemisinin-piperaquine | Outcome measured at hours 1, 2, 4, 6, 8, and 24 post first dose. | 24 hours | 
| Identification of cytochrome P450 (CYP) 2D6 and G6PD polymorphisms | CYP2D6 and G6PD genotyping will be performed using Thermo Fisher Scientific OpenArray Technology and Copy Number Variation (CNV) assays on the QuantStudio™ 12K Flex Real-Time PCR System. | 1 hour |