Evaluation of the Gametocytocidal Efficacy and Safety of Primaquine in Uncomplicated Falciparum Malaria in Uganda
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Placebo Non-active drug |
Drug: Primaquine
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).
Other Names:
|
| Experimental: Low dose primaquine (PQ1) Lowest experimental dose of primaquine base: 0.1mg/kg |
Drug: Primaquine
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).
Other Names:
|
| Experimental: Intermediate dose primaquine (PQ2) Intermediate experimental dose of primaquine base: 0.4mg/kg |
Drug: Primaquine
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).
Other Names:
|
| Active Comparator: Reference dose primaquine (PQ-R) WHO-recommended dose of primaquine base: 0.75mg/kg |
Drug: Primaquine
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).
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Mean number of days to gametocyte clearance (gametocyte clearance time, GCT) [14 days]
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.
- Mean (+/- SD) maximal fall in Hb (g/dL) from enrollment to day 28 of follow-up [28 days]
Mean maximal greatest negative difference in Hb (measured by Hemocue®) from enrollment value per treatment arm over 28 days follow up
Secondary Outcome Measures
- Mean (+/- SD) area under the curve of gametocyte density per day during 14 days of follow-up [14 days]
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
- Requirement for blood transfusion [28 days]
Percentage of children receiving blood transfusion per treatment arm during days 0-28
- Follow-up day of Hb nadir [28 days]
Mean day of follow up (day 0-28) per treatment arm of lowest Hb measurement (by Hemocue®)
- Incidence of serious adverse events by sign, symptom, laboratory parameter and relationship to taking study drug [28 days]
Percentage (number) per treatment arm during days 0-28
- Incidence of gastrointestinal symptoms after taking study drug [6 days]
Percentage (number) of children with gastrointestinal symptoms per treatment arm during days 2-7
Eligibility Criteria
Criteria
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
-
- 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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Walukuba Health Centre IV | Jinja | Eastern Region | Uganda |
Sponsors and Collaborators
- London School of Hygiene and Tropical Medicine
- Wellcome Trust
Investigators
- Principal Investigator: Alice C Eziefula, MBBS MCRP MRCPath, London School of Hygiene and Tropical Medicine
Study Documents (Full-Text)
None provided.More Information
Publications
- Bousema T, Okell L, Shekalaghe S, Griffin JT, Omar S, Sawa P, Sutherland C, Sauerwein R, Ghani AC, Drakeley C. Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs. Malar J. 2010 May 24;9:136. doi: 10.1186/1475-2875-9-136.
- Schneider P, Bousema JT, Gouagna LC, Otieno S, van de Vegte-Bolmer M, Omar SA, Sauerwein RW. Submicroscopic Plasmodium falciparum gametocyte densities frequently result in mosquito infection. Am J Trop Med Hyg. 2007 Mar;76(3):470-4.
- Shekalaghe S, Drakeley C, Gosling R, Ndaro A, van Meegeren M, Enevold A, Alifrangis M, Mosha F, Sauerwein R, Bousema T. Primaquine clears submicroscopic Plasmodium falciparum gametocytes that persist after treatment with sulphadoxine-pyrimethamine and artesunate. PLoS One. 2007 Oct 10;2(10):e1023.
- Shekalaghe SA, ter Braak R, Daou M, Kavishe R, van den Bijllaardt W, van den Bosch S, Koenderink JB, Luty AJ, Whitty CJ, Drakeley C, Sauerwein RW, Bousema T. In Tanzania, hemolysis after a single dose of primaquine coadministered with an artemisinin is not restricted to glucose-6-phosphate dehydrogenase-deficient (G6PD A-) individuals. Antimicrob Agents Chemother. 2010 May;54(5):1762-8. doi: 10.1128/AAC.01135-09. Epub 2010 Mar 1.
- Smithuis F, Kyaw MK, Phe O, Win T, Aung PP, Oo AP, Naing AL, Nyo MY, Myint NZ, Imwong M, Ashley E, Lee SJ, White NJ. Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. Lancet Infect Dis. 2010 Oct;10(10):673-81. doi: 10.1016/S1473-3099(10)70187-0. Epub 2010 Sep 9.
- PQPF912