Evaluation of the Gametocytocidal Efficacy and Safety of Primaquine in Uncomplicated Falciparum Malaria in Uganda - Full Text View

Purpose

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	Intervention	Phase
Falciparum Malaria	Drug: Primaquine	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Outcomes Assessor) Primary Purpose: Prevention
Official Title:	Evaluation of the Efficacy and Safety of Primaquine for Clearance of Gametocytes in Uncomplicated Falciparum Malaria in Uganda

Resource links provided by NLM:

MedlinePlus related topics: Malaria

Drug Information available for: Primaquine phosphate Primaquine

U.S. FDA Resources

Further study details as provided by London School of Hygiene and Tropical Medicine:

Primary Outcome Measures:

Mean number of days to gametocyte clearance (gametocyte clearance time, GCT) [ Time Frame: 14 days ] [ Designated as safety issue: No ]
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 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
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 [ Time Frame: 14 days ] [ Designated as safety issue: No ]
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 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Percentage of children receiving blood transfusion per treatment arm during days 0-28
Follow-up day of Hb nadir [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
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 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Percentage (number) per treatment arm during days 0-28
Incidence of gastrointestinal symptoms after taking study drug [ Time Frame: 6 days ] [ Designated as safety issue: Yes ]
Percentage (number) of children with gastrointestinal symptoms per treatment arm during days 2-7

Estimated Enrollment:	500
Study Start Date:	December 2011
Estimated Study Completion Date:	September 2012
Estimated Primary Completion Date:	August 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: primaquine phosphate
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 Name: primaquine phosphate
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 Name: primaquine phosphate
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 Name: primaquine phosphate

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.

Eligibility

Ages Eligible for Study:	1 Year to 10 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01365598

Contacts

Contact: Alice C Eziefula, MBBS MRCP MRCPath	+256784448758	chi.eziefula@gmail.com
Contact: Sarah G Staedke, MD, PhD		sarah.staedke@lshtm.ac.uk

Locations

Uganda
Walukuba Health Centre IV	Recruiting
Jinja, Eastern Region, Uganda
Contact: Alice C Eziefula, MBBS MRCP MRCPath +256784448758 chi.eziefula@gmail.com
Contact: Humphrey Wanzira, MD wanzirah@yahoo.com

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

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.

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.

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 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. 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. Epub 2010 Sep 9.

Responsible Party:	London School of Hygiene and Tropical Medicine
ClinicalTrials.gov Identifier:	NCT01365598 History of Changes
Other Study ID Numbers:	PQPF912
Study First Received:	June 1, 2011
Last Updated:	January 19, 2012
Health Authority:	Uganda: National Drug Authority

Keywords provided by London School of Hygiene and Tropical Medicine:

malaria
uncomplicated malaria
gametocytocidal drug
gametocytocidal
gametocyte
primaquine

transmission blocking
malaria transmission
sexual parasite
sexual stage
Uganda
Africa

Additional relevant MeSH terms:

Malaria
Malaria, Falciparum
Protozoan Infections
Parasitic Diseases
Primaquine
Antimalarials

Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 21, 2013