Assessing the safety of low dose primaquine in Plasmodium falciparum infected African children with glucose 6 phosphate dehydrogenase deficiency

Malaria remains a major problem in tropical countries, especially in Africa. Insecticide treated bednets and new powerful antimalarial drugs have led to a reduction in the number of malaria deaths. However malaria control remains poor in many areas, and if we are to eliminate and eventually eradicate the disease from the world we will require the use of all the tools at our disposal.

One potentially very valuable tool, currently underused, is the antimalarial drug primaquine, which is uniquely able to kill the mature male and female sexual forms of the malaria parasite. Research has shown that primaquine greatly reduces the malaria offspring in the mosquito and thus effectively reduces transmission of the disease. So, primaquine looks to be a good ‘transmission blocker’ and, if used widely in patients, may reduce malaria transmission and contribute to the elimination of malaria in a community.

Unfortunately primaquine has one major disadvantage. It can damage the red blood cells and cause anaemia in individuals who carry a very common genetic abnormality deficiency of an enzyme called glucose-6-phosphate dehydrogenase, G6PD for short. This deficiency is much more common in men because of the way it is inherited. This is called haemolysis. This is a real downside of primaquine, though this problem has mainly been seen when primaquine is given in high doses for many days. However, for its ‘transmission blocking’ effects on the malaria parasite only a single, low dose of primaquine is thought to be required. This is considered by most experts to be too little primaquine to cause a major problem with haemolysis.

Despite this many malaria control programmes are unwilling to use primaquine because they consider it too dangerous. You can test for G6PD deficiency but this requires test kits and staff to administer them. Many countries cannot afford to test millions of malaria patients before giving primaquine. In 2012 the World Health Organization (WHO) concluded on the basis of the available evidence and expert opinion that single low dose primaquine was safe to use even in malaria patients with G6PD deficiency. However the WHO also called for more research.

Four years later virtually no one is using low dose primaquine because that research has not been done. If the researchers can show beyond doubt that low dose primaquine is safe in G6PD deficient children with malaria, malaria programmes would feel much happier giving it and they could then go to the drug companies and ask them to make primaquine that is suitable for children.

To see if single low dose primaquine is as safe as experts think, the team plans to study over 1,500 children with malaria attending outpatients in two hospitals in Uganda and one in the Democratic Republic of the Congo. Using a simple test for G6PD deficiency they will find 750 children with malaria who have G6PD deficiency, and 750 who have normal G6PD levels. Within these two groups they will, on a random basis, give half of the patients normal antimalarial treatment and the other half normal antimalarial treatment PLUS single low dose primaquine. They will then watch the children very carefully to see whether giving primaquine causes more anaemia than not giving primaquine, and whether this occurs particularly in the G6PD deficient group. They need to have comparison groups of children who do not receive primaquine and some children who do not have G6PD deficiency as malaria itself causes haemolysis, as can G6PD deficiency in some circumstances even without primaquine treatment. The aim is to unpick the effects of G6PD deficiency, malaria, and primaquine administration to really be sure whether in all circumstances giving low dose primaquine is safe.

If this research shows that giving single low dose primaquine is safe, this will enable WHO and national governments to recommend safe treatment regimens that will both cure the patient and also prevent transmission of malaria to other children.

Study Type: Interventional (Clinical Trial)

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose: Treatment

Intervention Model Description: This is a randomized, double-blind, parallel-group trial evaluating the safety of adding single low-dose primaquine (SLDPQ, 0.25 mg/kg) to standard artemether-lumefantrine (AL) treatment in children aged 6 months to 12 years with acute uncomplicated Plasmodium falciparum malaria, both in G6PD-deficient and G6PD-normal participants. A total of 1,572 children from the Democratic Republic of the Congo (Kinshasa) and Uganda (Soroti and Mbale) will be enrolled, with 393 participants per arm. Participants will be assigned to:

1. AL + SLDPQ
2. AL alone

Children will be followed for 42 days, with primary endpoints focused on the incidence of profound anaemia (Hb <4 g/dL) or severe anaemia (Hb <5 g/dL with severe malaria features). Secondary outcomes include gametocyte clearance, pharmacokinetics, and haemoglobin recovery.

Funding details

Drug-based Strategies
Impact of Interventions
Operational Research
Vulnerable Populations

Aug 2016 — Jul 2020

$2.67M

Dem. Rep. of Congo
Uganda
United Kingdom