Paediatric single low-dose primaquine safety study group

Paediatric single low-dose primaquine safety study group

The paediatric single low-dose (SLD) primaquine safety study group aims to describe and compare the safety of SLD primaquine for transmission blocking of Plasmodium falciparum in young children (under 5 years of age) with that in older children and adults.

Update and overview

The systematic review is near completion. Invitations to authors of eligible studies will be sent imminently. Data collation will close by Q4 2020. The statistical analysis plan will be circulated among all study group participants for feedback prior to analysis.


Primaquine clears mature Plasmodium falciparum gametocytes, the parasite lifecycle stage responsible for the transmission of malaria from the human to the mosquito (White 2013). The World Health Organization recommends a single low dose (SLD) of 0.25mg/kg primaquine be given with an artemisinin-based combination therapy (ACT) in low transmission areas or areas threatened by artemisinin resistance (WHO 2015). Recent WWARN individual patient data (IPD) meta-analyses support implementation of this WHO recommendation, demonstrating 0.25mg/kg primaquine to be the lowest efficacious dose and generally safe (Stepniewska 2020, Low-dose Primaquine Efficacy and Safety Study Groups). However, sustained vigilance is required in those with risk factors for an increased drop in haemoglobin concentration and haemoglobinuria, including G6PD deficiency, high baseline parasitaemia and importantly young age.

A major challenge to achieving the SLD primaquine coverage required to impact on transmission is that dosing 0.25 mg/kg primaquine in children requires tablets to be dissolved in water and measured out exactly for each child by weight (Chen 2015), as no paediatric formulation is currently available and the only tablet strengths are 7.5 and 15mg. Moreover, primaquine tablets are coated in a hard and shiny surface to hide their bitter taste and are not designed to be dissolved. Clinics must therefore use a sub-optimal formulation, make weight-based dose calculations, and administer primaquine to children using measuring cups/oral syringes. These practicalities compromise implementation of primaquine as per the WHO recommendations. Meanwhile in most such countries primaquine is either not licensed or used “off label” where primaquine is only licensed for radical cure of P. vivax and P. ovale.

Rather than launching expensive clinical trials on primaquine efficacy and safety in young children, WWARN has been asked to compare available IPD (including those completed since the previous WWARN IPD-meta-analyses) on primaquine’s efficacy and safety in young children with that in older children and adults to support dossiers to be submitted for licensing new paediatric formulations of primaquine.

Aim and objectives

The overall aim is to describe and compare the safety of SLD primaquine for transmission blocking of Plasmodium falciparum in young children (under 5 years of age) with that in older children and adults. To achieve this, we will conduct meta-analyses using IPD (where available) to inform the following objectives:

  • To describe and compare haematological changes and their association with SLD primaquine administration (of ≤ 0.75 mg/kg) between baseline and day 7 in young children to that in older children and adults
  • To characterise and compare adverse events (AEs) and/or symptom reports in young children to those in older children and adults and their association with primaquine administration (data permitting)
Inclusion criteria for studies

Studies are eligible for inclusion if they have available IPD from a trial or prospective cohort of children (or children and adults) with at least one arm with a combination of an ACT and SLD (target dose <= 0.75 mg/kg) primaquine for Plasmodium falciparum transmission blocking. We will not include mass drug administration studies or malaria program data, healthy volunteer studies or adult only studies.

Minimum required data
  •  Baseline data on participant characteristics: age, sex, weight (unless primaquine target dose available)
  • Day and dose (actual/target) of <0.75 mg/kg primaquine (mg/kg) provided in combination with ACT
  • Haemoglobin (Hb) or haematocrit levels at enrolment and at least one data on follow up date until day 14 and/or any AE or symptom data on follow up
Desirable data
  • Baseline parasitaemia
  • Known G6PD status (qualitative and/or quantitative)
  • CYP 2D6 metabolism phenotype
  • Documentation on the supervision of drug administration
  • Nutritional status as gauged by weight and age +/- height or middle upper arm circumference (MUAC)
  • Primaquine/carboxyprimaquine drug levels during follow up
  • Haemoglobin or haematocrit levels at visits after day 14
  • Methaemoglobin measured at baseline and during follow up 
  • Haemoglobinuria (including reports of dark urine by any method) assessed at baseline and during follow up               
  • ECG results
  • Data on vomiting within 1 hour post administration (with re-dose if relevant)
  • Method used for eliciting participant reported adverse events
  • Data on any gastro-intestinal disturbance detected within 28 days of dose (if not included as part of above)
  • Data on blood transfusions (if not included as part of above)
Data standardisation and analysis

After upload to the WWARN Data Repository, data sets will be transformed, standardised and pooled according to the WWARN Clinical Data Management and Statistical Analysis Plans and a statistical analysis plan designed specifically for these analyses.

Study group governance and membership

The Study Group is led by Prof Karen Barnes coordinated by Caitlin Richmond, Programme Manager at WWARN. It includes WWARN staff, and investigators who contribute relevant data sets which remain their property. The group collectively makes decisions with respect to including studies, data analysis and plans for publication in line with the WWARN Publication Policy.


This work was funded by the Bill and Melinda Gates Foundation as part of a grant to Oxford University.

For further information, email


Chen I, Piorot E, Newman M, Kandula D, Shah R, Hwang J, et al. An assessment of the supply, programmatic use, and regulatory issues of the single low-dose primaquine as a Plasmodium falciparum gametocytocide for sub-Saharan Africa. Malar J. 2015;14:204.

Stepniewska K, Humphreys GS, Gonçalves BP, Craig E, Gosling R, Guerin PJ, Price RN, Barnes KI, Raman J, Smit MR, D’Alessandro U, Stone WJR, Bjorkman A, Samuels AM, Arroyo-Arroyo MI, Bastiaens GJH, Brown JM, Dicko A, El-Sayed BB, Elzaki SG, Eziefula AC, Kariuki S, Kwambai TK, Maestre AE, Martensson A, Mosha D, Mwaiswelo RO, Ngasala BE, Okebe J, Roh ME, Sawa P, Tiono AB, Chen I, Drakeley CJ, Bousema T. Efficacy of single dose primaquine with artemisinin combination therapy on P. falciparum gametocytes and transmission: A WWARN individual patient meta-analysis. J Infect Dis. 2020 Aug 11:jiaa498.

White NJ. Primaquine to prevent transmission of falciparum malaria. Lancet Infect Dis. 2013 Feb;13(2):175-81.

World Health Organization. Policy brief on single-dose primaquine as a gametocytocide in Plasmodium falciparum malaria. Geneva: World Health Organization, 2015.