Single Low Dose Tafenoquine to Reduce P. Falciparum Transmission in Mali (NECTAR2)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the gametocytocidal and transmission reducing activity of dihydroartemisinin-piperaquine (DP) with and without various low doses of tafenoquine (TQ; 1.66mg/kg, 0.83mg/kg, or 0.415mg/kg). Outcome measures will include infectivity to mosquitoes at 2 and 7 days after treatment, gametocyte density throughout follow-up, and safety measures including haemoglobin density.

Detailed Description
-----------------
Full protocol available on request.

Official Title
-----------------
Single Low Dose Tafenoquine to Reduce P. Falciparum Transmission in Mali (NECTAR2)

Conditions
-----------------
Malaria, Falciparum

Intervention / Treatment
-----------------
* Drug: Dihydroartemisinin/Piperaquine
* Drug: Tafenoquine 100mg [Arakoda]


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 12 years and ≤ 50 years Glucose 6 phosphate dehydrogenase (G6PD) normal status defined by Carestart rapid diagnostic test or the G6PD qualitative test (OSMMR2000) 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 No allergies to study drugs No 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 acute severe or chronic disease Written, informed consent Exclusion Criteria: Age < 12 years or > 50 years Women who are pregnant or lactating Blood thick film negative for sexual stages of malaria Detection of a non-P. falciparum species by microscopy 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 The use of other medication (with the exception of paracetamol and/or aspirin) Consent not given G6PD-deficiency by Carestart rapid diagnostic test or the OSMMR2000 G6PD qualitative test Use of antimalarial drugs over the past 7 days (as reported by the participant) The use of other medication (with the exception of paracetamol and/or aspirin) Clinically significant illness (intercurrent illness e.g. pneumonia, pre-existing condition e.g. renal disease, malignancy or conditions that may affect absorption of study medication e.g. severe diarrhea 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 hematology values (laboratory guideline values for exclusion are hemoglobin < 10 g/dL, platelets < 50,000/μl, White Blood Cell count (WBC) < 2000/μl, serum creatinine >2.0mg/dL, or ALT or AST more than 3 times the upper limit of normal for age. Family history of diseases leading to QT prolongation or recent treatment with drugs linked to QT prolongation Blood transfusion in the last 90 days. Consistent with the long half-life of tafenoquine, effective contraception should be continued for 5 half-lives (3 months) after the end of treatment. History of psychiatric disorders

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dihydroartemisinin-Piperaquine (DP)<br>Subjects will receive Dihydroartemisinin-Piperaquine (DP) once daily for 3 days, and a low dose of 1.66mg/kg, 0.83mg/kg, or 0.415mg/kg. Tafenoquine (TQ) on the first date of DP treatment. | Drug: Dihydroartemisinin/Piperaquine<br>* Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine (Eurartesim, Sigma Tau), administered according to weight as per the manufacturer instructions.<br>* Other names: Euartesim;|
| Experimental: DP with 0.415mg/kg Tafenoquine (TQ)<br>Subjects will receive Dihydroartemisinin-Piperaquine (DP) once daily for 3 days, and a single dose of 0.415mg/kg Tafenoquine (TQ) on the first date of DP treatment. | Drug: Dihydroartemisinin/Piperaquine<br>* Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine (Eurartesim, Sigma Tau), administered according to weight as per the manufacturer instructions.<br>* Other names: Euartesim;Drug: Tafenoquine 100mg [Arakoda]<br>* Extemporaneous preparation of 1mg/mL Tafenoquine solution, from tablets containing 100mg primaquine (Arakoda, 60degrees pharmaceuticals, DC) dissolved in 100mL water with a non-interacting fruit-flavoured syrup. Solution will be given according to weight as indicated per treatment arm in 5kg bands.<br>* Other names: Arakoda;|
| Experimental: DP with 0.83 mg/kg TQ<br>Subjects will receive Dihydroartemisinin-Piperaquine (DP) once daily for 3 days, and a single dose of 0.83mg/kg Tafenoquine (TQ) on the first date of DP treatment. | Drug: Dihydroartemisinin/Piperaquine<br>* Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine (Eurartesim, Sigma Tau), administered according to weight as per the manufacturer instructions.<br>* Other names: Euartesim;Drug: Tafenoquine 100mg [Arakoda]<br>* Extemporaneous preparation of 1mg/mL Tafenoquine solution, from tablets containing 100mg primaquine (Arakoda, 60degrees pharmaceuticals, DC) dissolved in 100mL water with a non-interacting fruit-flavoured syrup. Solution will be given according to weight as indicated per treatment arm in 5kg bands.<br>* Other names: Arakoda;|
| Experimental: DP with 1.66mg/kg TQ<br>Subjects will receive Dihydroartemisinin-Piperaquine (DP) once daily for 3 days, and single dose of 1.66mg/kg Tafenoquine (TQ) on the first date of DP treatment. | Drug: Dihydroartemisinin/Piperaquine<br>* Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine (Eurartesim, Sigma Tau), administered according to weight as per the manufacturer instructions.<br>* Other names: Euartesim;Drug: Tafenoquine 100mg [Arakoda]<br>* Extemporaneous preparation of 1mg/mL Tafenoquine solution, from tablets containing 100mg primaquine (Arakoda, 60degrees pharmaceuticals, DC) dissolved in 100mL water with a non-interacting fruit-flavoured syrup. Solution will be given according to weight as indicated per treatment arm in 5kg bands.<br>* Other names: Arakoda;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mosquito infectivity assessed through membrane feeding assays (day 7) | The proportion of mosquitoes infected, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 7 post feed, compared to baseline | 2 days (Days 0 & 7): 7 day span | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mosquito infectivity assessed through membrane feeding assays (days 2 and 14) | The proportion of mosquitoes infected, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 2 and 14 post feed, compared to baseline | 3 days (Days 0, 2, & 14): 14 day span | 
| Mosquito infection density assessed through membrane feeding assays | Mosquito infection density, assessed through membrane feeding and measured as oocyst density in mosquitoes dissected on day 2, 7 and 14 post feed, compared within and between study arms | 4 days (Days 0, 2, 7 & 14): 14 day span | 
| Mosquito infection prevalence assessed through membrane feeding assays | Mosquito infection prevalence and density, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 2, 7 and 14 post feed, compared within and between study arms | 4 days (Days 0, 2, 7 & 14): 14 day span | 
| Human infectivity assessed through membrane feeding assays | The proportion of individuals that infect any number of mosquitoes, assessed through membrane feeding and measured as oocyst prevalence/density in mosquitoes dissected on day 2, 7 and 14 post feed, compared within and between study arms | 4 days (Days 0, 2, 7 & 14): 14 day span | 
| Haemoglobin density | Haemolysis will be monitored by measuring haemoglobin levels (g/dL) on days 0, 1, 2, 7, 14, 21, and 28 post treatment as part of the clinical assessment. | 7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span | 
| Methmoglobin density | Methmoglobin density (g/dL) will be monitored on days 0, 1, 2, 7, 14, 21, and 28 post treatment as part of the clinical assessment. | 7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span | 
| Aspartate transaminase (AST)/alanine transaminase (ALT) ratio | Aspartate transaminase (AST)/alanine transaminase (ALT) ratio will be recorded on days 0, 1, 2, 7, 14, 21, and 28 post treatment as part of the clinical assessment. | 7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span | 
| Blood creatinine level | Blood creatine level will be recorded on days 0, 1, 2, 7, 14, 21, and 28 post treatment as part of the clinical assessment. | 7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span | 
| Asexual/sexual stage parasite density | Asexual/sexual stage parasite density (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 14, 21, and 28 post treatment. | 7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span | 
| Asexual/sexual stage parasite prevalence | Asexual/sexual stage parasite prevalence will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 14, 21, and 28 post treatment. | 7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span | 
| Asexual/sexual stage parasite circulation time | Asexual/sexual stage parasite circulation time (days) will be determined from measures of density. | 28 days | 
| Asexual/sexual stage parasite area under the curve (AUC) | Asexual/sexual stage parasite area under the curve (AUC: Gametocytes per microlitre per day) will be determined from measures of density. | 28 days | 
| Sexual stage parasite sex ratio | Gametocyte density will be determined by molecular methods for males and females separately, allowing analysis of sex ratio (proportion of total that is male) on days 0, 1, 2, 7, 14, 21 and 28 post treatment. | 7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span | 
| Incidence of adverse events | Incidence of adverse events will be monitored at each active (day 0,1,2,7,14,21,28) follow up visit. AE's will also be recorded and acted upon if present at any other time during follow up. | 7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span |