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 the disease is to be eliminated and eventually eradicated from the world, the use of all available tools will be required.

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. Therefore, primaquine appears 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 red blood cells and cause anaemia in individuals who carry a very common genetic abnormality — a deficiency of an enzyme called glucose-6-phosphate dehydrogenase (G6PD). This deficiency is much more common in men because of the way it is inherited. This condition, known as haemolysis, is a significant downside of primaquine, although it 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. Most experts consider this dose too small to cause a major problem with haemolysis.

Despite this, many malaria control programmes are unwilling to use primaquine because it is considered too dangerous. Testing for G6PD deficiency is possible, but 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, WHO also called for more research.

Four years later, virtually no one is using low-dose primaquine because that research has not been completed. If research can show beyond doubt that low-dose primaquine is safe in G6PD-deficient children with malaria, malaria programmes would likely be more confident in giving it, and drug companies could then be approached to produce primaquine suitable for children.

To determine whether single low-dose primaquine is as safe as experts believe, the planned study will enrol over 1,500 children with malaria attending outpatient clinics in two hospitals in Uganda and one in the Democratic Republic of the Congo. Using a simple test for G6PD deficiency, 750 children with malaria who have G6PD deficiency and 750 who have normal G6PD levels will be identified. Within these two groups, half of the patients will receive standard antimalarial treatment, and the other half will receive standard antimalarial treatment plus single low-dose primaquine, assigned at random. The children will then be monitored closely to assess whether primaquine causes more anaemia than standard treatment alone, and whether this effect occurs particularly in the G6PD-deficient group.

Comparison groups of children who do not receive primaquine and children who do not have G6PD deficiency are necessary, as malaria itself causes haemolysis, and G6PD deficiency can also cause haemolysis in some circumstances even without primaquine treatment. The aim is to distinguish the effects of G6PD deficiency, malaria, and primaquine administration to ensure that, under all circumstances, giving low-dose primaquine is safe.

If the research confirms the safety of single low-dose primaquine, WHO and national governments would be able to recommend safe treatment regimens that both cure the patient and prevent transmission of malaria to others.

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: The study will enroll over 1,500 children with Plasmodium falciparum malaria attending outpatient clinics in two hospitals in Uganda and one in the Democratic Republic of the Congo. Using a point-of-care test for G6PD deficiency, approximately 750 G6PD-deficient and 750 G6PD-normal children will be identified. Within each G6PD status group, participants will be randomized to receive either:

1. Standard antimalarial treatment (artemether-lumefantrine)
2. Standard antimalarial treatment + single low-dose primaquine (0.25 mg/kg)

The trial will compare the incidence of haemolysis and anaemia between intervention and control arms in both G6PD-deficient and G6PD-normal children, to determine whether single low-dose primaquine is safe for use without prior G6PD testing in malaria control programs.

Drug-based Strategies
Impact of Interventions
Operational Research
Vulnerable Populations

Sep 2016 — Jul 2020

$473,212

United Kingdom