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

NCT ID: NCT01365598

Last Updated: 2013-06-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 468 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-12-31
• Study Completion Date: 2013-05-31

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.

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.

Conditions

Falciparum Malaria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Placebo

Non-active drug

Group Type: PLACEBO_COMPARATOR

Primaquine

Intervention Type: DRUG

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).

Low dose primaquine (PQ1)

Lowest experimental dose of primaquine base: 0.1mg/kg

Group Type: EXPERIMENTAL

Primaquine

Intervention Type: DRUG

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).

Intermediate dose primaquine (PQ2)

Intermediate experimental dose of primaquine base: 0.4mg/kg

Group Type: EXPERIMENTAL

Primaquine

Intervention Type: DRUG

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).

Reference dose primaquine (PQ-R)

WHO-recommended dose of primaquine base: 0.75mg/kg

Group Type: ACTIVE_COMPARATOR

Primaquine

Intervention Type: DRUG

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).

Interventions

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).

Intervention Type: DRUG

Other Intervention Names

primaquine phosphate

Eligibility 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
• 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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 10 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Wellcome Trust

OTHER

Sponsor Role: collaborator

London School of Hygiene and Tropical Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alice C Eziefula, MBBS MCRP MRCPath

Role: PRINCIPAL_INVESTIGATOR

London School of Hygiene and Tropical Medicine

Locations

Walukuba Health Centre IV

Jinja, Eastern Region, Uganda

Countries

Uganda

References

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.

Reference Type: BACKGROUND

PMID: 20497536 (View on PubMed)

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. doi: 10.1371/journal.pone.0001023.

Reference Type: BACKGROUND

PMID: 17925871 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17360869 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20194698 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20832366 (View on PubMed)

Chang HH, Meibalan E, Zelin J, Daniels R, Eziefula AC, Meyer EC, Tadesse F, Grignard L, Joice RC, Drakeley C, Wirth DF, Volkman SK, Buckee C, Bousema T, Marti M. Persistence of Plasmodium falciparum parasitemia after artemisinin combination therapy: evidence from a randomized trial in Uganda. Sci Rep. 2016 May 20;6:26330. doi: 10.1038/srep26330.

Reference Type: DERIVED

PMID: 27197604 (View on PubMed)

Eziefula AC, Bousema T, Yeung S, Kamya M, Owaraganise A, Gabagaya G, Bradley J, Grignard L, Lanke KH, Wanzira H, Mpimbaza A, Nsobya S, White NJ, Webb EL, Staedke SG, Drakeley C. Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised, controlled, double-blind, dose-ranging trial. Lancet Infect Dis. 2014 Feb;14(2):130-9. doi: 10.1016/S1473-3099(13)70268-8. Epub 2013 Nov 13.

Reference Type: DERIVED

PMID: 24239324 (View on PubMed)

Other Identifiers

PQPF912

Identifier Type: -

Identifier Source: org_study_id