PAC

Primaquine in African Children Study

Study acronym

PAC

Background

Primaquine can reduce the transmission of Plasmodium falciparum malaria by killing mature gametocytes—the parasite stage transmitted from infected people to mosquitoes.

The World Health Organization recommends adding a single low dose of primaquine to artemisinin-based combination therapy in settings where reducing malaria transmission is a priority. However, implementation in sub-Saharan Africa has been limited by concerns that primaquine may cause red-blood-cell breakdown and severe anaemia, particularly among people with glucose-6-phosphate dehydrogenase deficiency.

PAC was conducted to provide robust safety evidence among African children, including those most vulnerable to primaquine-related haemolysis.

Study purpose

The study evaluated whether an age-based single low dose of primaquine was safe and well tolerated when added to standard treatment for children with acute uncomplicated falciparum malaria.

The primary focus was children with glucose-6-phosphate dehydrogenase deficiency. The study also examined children with normal G6PD status and heterozygous girls.

Study design

PAC was a multicentre, randomised, double-blind, placebo-controlled, non-inferiority trial.

Participants received one of four treatment combinations:

• Artemether–lumefantrine plus single low-dose primaquine;
• Artemether–lumefantrine plus placebo;
• Dihydroartemisinin–piperaquine plus single low-dose primaquine; or
• Dihydroartemisinin–piperaquine plus placebo.

Randomisation was stratified according to participants’ age and G6PD status. The primaquine dose was administered using age-based dosing bands.

Study population

The trial enrolled 1,137 children aged 6 months to 11 years with acute uncomplicated Plasmodium falciparum malaria and an initial haemoglobin concentration of at least 6 g/dL.

The median age of participants was five years. Among those enrolled, 284 children had genetically confirmed G6PD deficiency and 119 were heterozygous girls. PAC primary publication

Study sites

The study was conducted at:

• Mbale Regional Referral Hospital, Uganda; and
• Kinshasa Mahidol Oxford Research Unit, Democratic Republic of the Congo.

Recruitment took place in Kinshasa from July 2017 to October 2019 and in Mbale from December 2017 to October 2019.

Study leadership

Professor Nicholas J. P. Day and Dr Walter R. J. Taylor conceived the study and obtained its funding.

Professor Peter Olupot-Olupot served as the Site Principal Investigator at Mbale Regional Referral Hospital. Professor Marie A. Onyamboko was the Site Principal Investigator at the Kinshasa Mahidol Oxford Research Unit.

The Mbale study team included researchers and clinical staff from Mbale Clinical Research Institute and Mbale Regional Referral Hospital.

Sponsor

The trial was sponsored by the Chancellor, Masters and Scholars of the University of Oxford.

Funders

PAC was funded through the Joint Global Health Trials Scheme by:

• UK Government Department for International Development;
• UK Medical Research Council;
• UK National Institute for Health Research; and
• Wellcome Trust.

The grant reference was MR/P006973/1. PAC primary publication

Primary outcome

The primary outcome was the development, within 21 days of treatment, of either:

• Profound anaemia, defined as haemoglobin below 4 g/dL; or
• Severe anaemia, defined as haemoglobin below 5 g/dL together with clinical severity features.

Principal findings

No participant developed profound anaemia. Only three of the 1,137 enrolled children developed severe anaemia.

Among children with G6PD deficiency, severe anaemia occurred in one child who received primaquine and none who received placebo. Among children without G6PD deficiency, severe anaemia occurred in one participant in each treatment group.

Overall, age-dosed single low-dose primaquine was well tolerated. Its safety profile was comparable to placebo, including among children with G6PD deficiency. These findings support wider use of single low-dose primaquine in African malaria-control programmes. The Lancet Infectious Diseases study

Additional findings

Further analyses found that post-treatment haemoglobin changes were not adversely affected by single low-dose primaquine. Blood-transfusion requirements were also similar between the primaquine and placebo groups.

Pharmacokinetic analyses showed that primaquine exposure varied according to factors including age, bodyweight, starting haemoglobin concentration and CYP2D6 metabolic status. These findings provide useful information for refining paediatric dosing.

A subsequent analysis concluded that the haemoglobin findings were reassuring and supported primaquine deployment without routine G6PD screening in African settings. BMC Medicine analysis

Importance of the study

PAC provided important evidence addressing a major barrier to using primaquine for malaria control in Africa.

The findings support age-based dosing, which is easier to implement than weight-based dosing in settings where weighing equipment may not always be available. Wider use of single low-dose primaquine could help reduce the transmission of falciparum malaria and support efforts to contain emerging artemisinin-resistant parasites.

Trial registration

The study was registered as ISRCTN11594437.

Ethics and regulatory approvals

The study received approvals from:

• Oxford Tropical Research Ethics Committee: 53-16
• Mbale Regional Referral Hospital Research Ethics Committee: MRRH-REC OUT-COM 006/2017
• Uganda National Drug Authority: CTA0028
• Uganda National Council for Science and Technology: HS2205
• University of Kinshasa Public Health School Ethics Committee
• Relevant health authorities in Kinshasa, Democratic Republic of the Congo

Study publications

The primary safety findings were published in The Lancet Infectious Diseases in 2023.

Additional publications have reported:

• Primaquine pharmacokinetics in Ugandan and Congolese children;
• Haemoglobin changes following malaria treatment;
• The influence of G6PD status and inherited blood conditions; and
• Plasma folate patterns following antimalarial treatment.

Study status

PAC is a completed study. Recruitment ended in October 2019, and the primary and secondary findings have been published.