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 we 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 we 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 we plan 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 we will find 750 children with malaria who have G6PD deficiency, and 750 who have normal G6PD levels. Within these two groups we 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. We 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. We 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 treat. Our 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.

Adding a single, low dose of primaquine (SLDPQ), 0.25 mg/kg, to the standard treatment of falciparum malaria is recommended by WHO for blocking malaria transmission. However countries are reluctant to use SLDPQ because of concerns that in glucose-6-phosphate deficient (G6PDd) individuals it may cause acute haemolytic anaemia, a well-known side effect of primaquine when given in higher, multiple, doses for vivax radical cure.

Our study examines SDLPQ safety in children with acute uncomplicated falciparum malaria in a randomised, double blind, parallel group treatment trial of artemether-lumefantrine (AL)+SLDPQ vs. AL alone in G6PDd and in normal patients. We hypothesise that, compared to AL alone, SLDPQ+AL will not result in more profound anaemia (haemoglobin (Hb) <4 g/dL) or severe anaemia (Hb <5 g/dL) with features of severe malaria. The sample size is 1,572, 393/arm (80% power, one sided alpha 0.025), assuming a 1.5% event rate in G6PDd AL recipients and a 2.5% non-inferiority margin.

Children from the Democratic Republic of Congo (Kinshasa) and Uganda (Soroti and Mbale) aged 6m-12y with Hb concentrations >= 6 g/dL will be recruited. Treated initially in hospital, they will be followed up daily for the first 5 days, day 7, then weekly to Day 42. Investigations include G6PD genotype & enzyme activity, malaria films (asexual and gametocyte counts), Hbs, molecular quantification of gametocytes, and primaquine and lumefantrine pharmacokinetics. Data analysis includes comparing rates of profound and severe anaemia, gametocyte clearance times, assessing risk factors for profound/severe anaemia, and modelling clinical, parasitological and pharmacokinetic factors for Hb recovery and gametocyte clearance.

The results will provide high quality evidence on the safety of SLDPQ, informing drug policy for malaria elimination. They will also enable us to develop an optimised, age-based, SLDPQ regimen and so increase access to this valuable tool.

Single low dose primaquine (SLDPQ) is a promising and potentially valuable tool for malaria elimination, and is recommended by WHO to be given routinely to patients with falciparum malaria to prevent further transmission of the infection. It also has potential to be used widely in the pre-elimination setting as part of mass drug administration programmes. The results of this study will hopefully resolve a number of key issues currently inhibiting widespread deployment of SLDPQ.

First and foremast is the question of the safety of giving SLDPQ to malaria patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd) - a red cell disorder that affects some 400 million people, mostly living in the malaria endemic world. Will the low dose of primaquine recommended by WHO which expert opinion considers safe be so in G6PDd malaria patients when used under real life conditions? A related key question is whether pretesting for G6PDd should be conducted before giving SLDPQ.

Secondly, what are the pharmacokinetic characteristics of low dose primaquine in young children with falciparum malaria and what is the relationship between primaquine PK and the haemolytic pharmacodynamic (PD) effect of primaquine? Will primaquine be absorbed less well in younger children, as is the case with other antimalarial drugs?

Thirdly, how best can primaquine be dosed in a user friendly fashion, and how can we resolve the challenge of there being no paediatric formulation? Currently, drug companies are waiting for further evidence on safety and PK/PD in children before engaging in formulation and tablet strength work and clinical studies required for drug registration.

These are all critical issues that our study will address. Once we have the study results, we will be able to say with confidence if SLDPQ, as recommended, is safe in the key group at risk - those with G6PDd. We will define the PK-PD relationship and identify those at risk of developing profound or severe anaemia.

All of these data will feed into national and international guidelines (e.g. WHO Malaria Treatment Guidelines) on the treatment of malaria and strategies to reduce the risk of SLDPQ toxicity. Thus, our study has the potential to influence drug policy and allow malaria elimination and ultimately eradication efforts to move forward - a move that would benefit untold numbers of individuals.

There is also very likely to be a positive effect on primaquine formulation work that the Medicines for Malaria Venture (MMV) are currently engaged in with drug companies.