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

Falciparum Malaria Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01365598
• Other study ID #: PQPF912
• Status: Completed
• Phase: Phase 3
• First received: June 1, 2011
• Last updated: June 11, 2013
• Start date: December 2011
• Est. completion date: May 2013

Study information

• Verified date: June 2013
• Source: London School of Hygiene and Tropical Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: Uganda: National Drug Authority
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 468
• Est. completion date: May 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 10 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Falciparum Malaria
• Malaria
• Malaria, Falciparum

Intervention

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).

Locations

Country	Name	City	State
Uganda	Walukuba Health Centre IV	Jinja	Eastern Region

Sponsors (2)

Lead Sponsor	Collaborator
London School of Hygiene and Tropical Medicine	Wellcome Trust

Country where clinical trial is conducted

Uganda, 

References & Publications (5)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	Yes
Secondary	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	No
Secondary	Requirement for blood transfusion	Percentage of children receiving blood transfusion per treatment arm during days 0-28	28 days	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	Incidence of gastrointestinal symptoms after taking study drug	Percentage (number) of children with gastrointestinal symptoms per treatment arm during days 2-7	6 days	Yes