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Paediatric single low-dose primaquine efficacy study group

The paediatric single low-dose (SLD) primaquine efficacy study group aims to assess and compare the efficacy 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.

Rationale

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 assess and compare the efficacy 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 quantitatively compare changes in gametocyte prevalence and density with time following administration of SLD primaquine given in combination with different ACTs in young children versus older children and adults
  • To quantitatively assess and compare the infectivity of gametocytes with time as measured by membrane feeding assay following administration of SLD primaquine given in combination with different ACTs in young children versus older children and adults

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
  • Transmission potential assessed by gametocyte carriage using molecular methods and/or by membrane feeding assay conducted on day 0 and any other visit up to day 14

Desirable data

  • Baseline parasitaemia
  • Haemoglobin/haematocrit on enrolment
  • 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
  • Any data on the performance of assays in the membrane feeding experiment
  • Fever on enrolment (or history of fever within the last 24 hours)
  • Data on vomiting within 1 hour post administration

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 and 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.

Funder

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

For further information, email wwarn [at] wwarn [dot] org

References

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.