Evaluation of the Gametocytocidal Efficacy and Safety of Primaquine in Uncomplicated Falciparum Malaria in Uganda

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of lower doses of primaquine compared to the dose recommended by the WHO for reducing P. falciparum gametocytes in the infected human host to prevent transmission of falciparum malaria to the anopheles mosquito vector.

Detailed Description
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A single dose of 0.75mg/kg primaquine base is recommended by the WHO to block transmission of falciparum malaria from infected humans to mosquitoes by clearing gametocytes. However, the optimal dose for safety and efficacy has not been evaluated. Dose-finding data is important because primaquine has a dose-dependent risk of causing haemolysis (destruction of blood cells) in pre-disposed individuals, such as those with G6PD deficiency. G6PD deficiency is most prevalent in malaria-endemic areas. Therefore, it is essential that data on primaquine's safety is available in such areas. The investigators hypothesise that lower doses of primaquine have a lower risk of adverse effects compared to the WHO-recommended dose, but retain the transmission-blocking efficacy. The investigators propose to test this hypothesis in a four-arm clinical trial with a non-inferiority design to evaluate the efficacy and a superiority design to evaluate the safety of the WHO dose (0.75mg/kg) and lower doses of primaquine for clearance of P. falciparum gametocytes in children in Uganda. The study will include a pharmacokinetic analysis.

Official Title
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Evaluation of the Efficacy and Safety of Primaquine for Clearance of Gametocytes in Uncomplicated Falciparum Malaria in Uganda

Conditions
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Falciparum Malaria

Intervention / Treatment
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* Drug: Primaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >/= 1 year and </= 10 years Weight over 10kg Fever >38 degrees C (tympanic) or history of fever in the last 24 hours P. falciparum parasitaemia <500 000/µl Normal G6PD enzyme function Exclusion Criteria: Enrolled in another study Evidence of severe illness/ danger signs Known allergy to study medications Haemoglobin < 8g/dL) Started menstruation Pregnancy or breastfeeding Primaquine taken within the last 4 weeks Blood transfusion within the last 90 days Non-falciparum malaria co-infection

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 10 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Non-active drug | Drug: Primaquine<br>* Single dose of oral primaquine phosphate. Comparator dose is 0.75mg/kg primaquine base. Each experimental arm is a different (reduced) dose of primaquine phosphate. Placebo contains no primaquine phosphate (non-active ingredients only).<br>* Other names: primaquine phosphate;|
| Experimental: Low dose primaquine (PQ1)<br>Lowest experimental dose of primaquine base: 0.1mg/kg | Drug: Primaquine<br>* Single dose of oral primaquine phosphate. Comparator dose is 0.75mg/kg primaquine base. Each experimental arm is a different (reduced) dose of primaquine phosphate. Placebo contains no primaquine phosphate (non-active ingredients only).<br>* Other names: primaquine phosphate;|
| Experimental: Intermediate dose primaquine (PQ2)<br>Intermediate experimental dose of primaquine base: 0.4mg/kg | Drug: Primaquine<br>* Single dose of oral primaquine phosphate. Comparator dose is 0.75mg/kg primaquine base. Each experimental arm is a different (reduced) dose of primaquine phosphate. Placebo contains no primaquine phosphate (non-active ingredients only).<br>* Other names: primaquine phosphate;|
| Active Comparator: Reference dose primaquine (PQ-R)<br>WHO-recommended dose of primaquine base: 0.75mg/kg | Drug: Primaquine<br>* Single dose of oral primaquine phosphate. Comparator dose is 0.75mg/kg primaquine base. Each experimental arm is a different (reduced) dose of primaquine phosphate. Placebo contains no primaquine phosphate (non-active ingredients only).<br>* Other names: primaquine phosphate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean number of days to gametocyte clearance (gametocyte clearance time, GCT) | Mean number of days per treatment arm for gametocytes to become undetectable using sub-microscopic molecular testing methods (real-time nucleic acid sequence-based amplification, QT-NASBA)and interpolated from measured data points. | 14 days | 
| Mean (+/- SD) maximal fall in Hb (g/dL) from enrollment to day 28 of follow-up | Mean maximal greatest negative difference in Hb (measured by Hemocue®) from enrollment value per treatment arm over 28 days follow up | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean (+/- SD) area under the curve of gametocyte density per day during 14 days of follow-up | An estimate of the area under the curve of gametocytes (measured by QT-NASBA) seen over time, averaged per day of follow up (days 0-14) and interpolated from measured data points | 14 days | 
| Requirement for blood transfusion | Percentage of children receiving blood transfusion per treatment arm during days 0-28 | 28 days | 
| Follow-up day of Hb nadir | Mean day of follow up (day 0-28) per treatment arm of lowest Hb measurement (by Hemocue®) | 28 days | 
| Incidence of serious adverse events by sign, symptom, laboratory parameter and relationship to taking study drug | Percentage (number) per treatment arm during days 0-28 | 28 days | 
| Incidence of gastrointestinal symptoms after taking study drug | Percentage (number) of children with gastrointestinal symptoms per treatment arm during days 2-7 | 6 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malaria, uncomplicated malaria, gametocytocidal drug, gametocytocidal, gametocyte, primaquine, transmission blocking, malaria transmission, sexual parasite, sexual stage, Uganda, Africa