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Credit: Penn State

Low-dose Primaquine Efficacy and Safety Study Groups

Pooled analyses of the efficacy and safety of single low-dose primaquine to interrupt P. falciparum malaria transmission.

Update & overview

Data collection has closed and analysis is nearly complete. Both manuscripts are in the process of being drafted.

Rationale

Primaquine is the only commercially available drug that can clear mature P. falciparum gametocytes, the parasite lifecycle stage responsible for the transmission of malaria from the human to the mosquito (White 2013). Primaquine can cause hemolysis in some individuals with an inherited enzyme deficiency, glucose-6-phosphate dehydrogenase (G6PD) deficiency (von Seidlein et al. 2013). The level of hemolysis experienced by an individual depends primarily on the dose of primaquine used and G6PD enzyme level in that individual (Eziefula et al. 2014). Other safety and tolerability issues with primaquine include gastrointestinal upset and methaemoglobinaemia (Ashley et al, 2014; Hill et al. 2006).

In 2012, in areas facing artemisinin resistance or approaching malaria elimination, the WHO recommended the addition of a single low (0.25 mg/kg) dose of primaquine to an artemisinin-based combination treatment (ACT), without G6PD testing (WHO 2012). This recommendation was based on pooled, unstandardized efficacy studies of primaquine and plasmoquin (its more toxic predecessor) and a variety of different blood schizonticide partner drugs and was further supported by a comprehensive analysis of published literature (Ashley et al, 2014). As no formal dose-finding studies have been conducted, this recommendation, did not come with the statement “strong recommendation, high quality evidence” typical of WHO recommendations for antimalarial use (WHO 2012).

Adoption of the WHO recommendation to add a 0.25 mg/kg dose of primaquine to ACT therapy has been slow (Chen & Gosling 2014). To support the WHO recommendation, stakeholders collaborated to identify the critical gaps and barriers that are preventing the widespread implementation of this approach, and to develop a low-dose primaquine roadmap. A key priority identified by the roadmap is establishment of the safe, effective therapeutic range of single-dose primaquine, values that would define the lowest efficacious dose and the highest safe dose in G6PD-normal and deficient individuals. Determination of this safe therapeutic range could avoid hemolysis in G6PD-deficient individuals, and guide the establishment of appropriate dosing recommendations in field settings (Chen et al. 2015).

There will be two study groups focused on the assessment of single low-dose primaquine; one that will address efficacy in the prevention of transmission and a second that will focus on safety. Although studies will generally address both efficacy and safety, these aspects will be analyzed separately. 

Objectives of the efficacy study group

  • To use pooled efficacy data to establish, through individual patient meta-analysis, an efficacy profile to provide evidence to inform clinical and policy decisions on use of low dose primaquine as a transmission-blocking agent
  • To validate measures of infectivity through comparison of dose-response using QT NASBA, qPCR, and/or membrane feeding analyses (currently considered as the gold standard)

Inclusion criteria for data sets analyzed for efficacy

  • Individual patient data from a clinical trial measuring treatment efficacy of uncomplicated P. falciparum infection containing at least one study arm with a combination of an ACT + single low-dose primaquine
  • Patient demographics (including age, gender, weight)
  • Weekly follow-up during 28 days
  • Infectivity assessed by gametocyte carriage and density (microscopy and/or molecular methods) and/or membrane feeding assay
  • Information on dosing (mg/kg) of the ACTs and primaquine

Objective of the safety study group

  • To use pooled safety data to establish, through individual patient meta-analysis, an evidence base and safety profile to inform decision-making as it relates to low dose primaquine as a transmission-blocking agent

Inclusion criteria for data sets analyzed for safety

  • Individual patient data from a clinical trial or prospective cohort study measuring the safety of the treatment of uncomplicated P. falciparum infection containing at least one arm (or exposure group, if prospective cohort study) with a combination of one ACT + single low dose of PQ
    • Safety data to include the collection of haemoglobin or hematocrit levels at day 0 and day 7 and any serious1 adverse events at baseline (day 0) and during follow-up
    • Baseline data on patient demographics (including age, gender and weight)

1 Defined as an event which: results in death; is life threatening; results in hospitalisation or prolongation of existing hospitalisation; results in significant or persistent disability; is a congenital anomaly.

Additional data requested for efficacy and/or safety (but not required for inclusion)

  • Known G6PD status (qualitative and/or quantitative) of patients treated
  • Haemoglobin or haematocrit levels on day 3 and any subsequent follow-up visits to 28 days   
  • Additional hematology measures (including methemoglobin and hemoglobinurea)

Data standardisation and analysis

After upload to the WWARN Data Repository, data sets will be transformed, standardised and pooled according to the WWARN Pharmacology and Clinical Data Management and Statistical Analysis Plans. The statistician appointed to the project is developing a statistical analysis plan specifically for the pooled analysis, in close collaboration with the Global Health Group at the University of California, San Francisco, the Liverpool School of Tropical Medicine, the University of Washington, and with Study Group members.

Study group governance and membership

The Study Group includes investigators who contribute relevant data sets to the pooled analysis. Data sets remain the property of the investigator. The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the WWARN Publication Policy. The Efficacy Study Group is being coordinated by Ingrid Chen, Philippe Guérin, and Kasia Stepniewska. Andy Stergachis and Elizabeth Allen are coordinating the Safety Study Group. 

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

References

Ashley E, Recht J, White N: Primaquine: the risks and the benefits. Malaria Journal 2014, 13(1):418. Avaialable at: http://www.ncbi.nlm.nih.gov/pubmed/25363455.

Chen, I. et al., 2015. An assessment of the supply, programmatic use, and regulatory issues of single low-dose primaquine as a Plasmodium falciparum gametocytocide for sub-Saharan Africa. Malaria Journal, 14(1), p.204. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25971688 [Accessed May 15, 2015].

Chen, I.T. & Gosling, R.D., 2014. Targeting Plasmodium falciparum transmission with primaquine: same efficacy, improved safety with a lower dose? Expert Review of Clinical Pharmacology, 7(6), pp.681–6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25118908 [Accessed May 20, 2015].

Eziefula, A.C. et al., 2014. Glucose-6-phosphate dehydrogenase status and risk of hemolysis in Plasmodium falciparum-infected African children receiving single-dose primaquine. Antimicrobial Agents and Chemotherapy, 58(8), pp.4971–3. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136063 [Accessed May 20, 2015].

Von Seidlein, L. et al., 2013. Review of key knowledge gaps in glucose-6-phosphate dehydrogenase deficiency detection with regard to the safe clinical deployment of 8-aminoquinoline treatment regimens: a workshop report. Malaria Journal, 12, p.112. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616837 [Accessed April 10, 2015].

White, N.J., 2013. Primaquine to prevent transmission of falciparum malaria. The Lancet Infectious Diseases, 13(2), pp.175–181. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23182932.

WHO, 2012. Single dose Primaquine as gametocytocide in Plasmodium falciparum malaria. WHO/Global Malaria Programme. Available at: http://www.who.int/malaria/pq_updated_policy_recommendation_en_102012.pdf.