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Vivax and Ovale Paediatric Primaquine Haematological Safety Study Group

Analysis of how age impacts the effect of primaquine dose on haematological safety in patients with Plasmodium vivax and Plasmodium ovale malaria

Update and overview

The Vivax and Ovale Paediatric Primaquine Haematological Safety Study Group was created as an extension of the Vivax Primaquine Efficacy, Safety and Tolerability Study Group formed in August 2019. Research groups with relevant data sets will be contacted.

Rationale

Primaquine, an 8-aminoquinoline (8-AQ), is the only widely available antimalarial that kills dormant liver stages (hypnozoites) of Plasmodium vivax and Plasmodium ovale. Plasmodium vivax remains widespread and is becoming the predominant cause of malaria outside of Africa and is expected to be a greater obstacle to malaria elimination than Plasmodium falciparum.

The main burden of malaria is in young children and yet there is no suitable paediatric formulation available. Reliance on the adult tablet formulation may result in inaccurate paediatric dosing, and thus have a higher risk of adverse events and lower efficacy in preventing P. vivax recurrence.

Whilst primaquine is highly efficacious against hypnozoites and gametocytes, it can cause severe drug-induced haemolysis in individuals with G6PD deficiency. The risk of haemolysis depends on the duration and dose of primaquine administration, which is almost 20-fold higher for P. vivax radical cure than the single low dose administered for P. falciparum gametocytocidal activity. At high doses, primaquine induces gastro-intestinal symptoms that often reduce patient adherence.

Since its introduction into clinical practice more than 60 years ago there is a wealth of data from clinical trials documenting the safety and efficacy of primaquine in patients with P. vivax malaria, but relatively limited data in P. ovale malaria. Individual patient data (IPD) meta-analyses ensure the best use of available data from which to generate evidence that will inform improved dosing regimens with a new, clinically relevant, age-appropriate formulation. A paediatric formulation will result in improved safety, tolerability, efficacy, and adherence. 

Aims

  1. To describe and compare reductions (absolute) in haemoglobin in children (<15 years) and how this relates to daily dose of primaquine.
  2. To assess if the relationship between daily dose of primaquine and reductions (absolute and relative) in haemoglobin differs for young children, older children and adults
  3. To describe cases of haemolysis / haemoglobinuria, methemoglobinemia and leucopoenia and compare the frequency and severity of these cases in young children (<5 years) to that in older children and adults, data permitting.

Essential inclusion criteria

  • Prospective clinical efficacy studies of uncomplicated vivax or ovale malaria with a minimum 28 days follow up:
    • Treatment with chloroquine or one of four common artemisinin-based combination therapies (artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, dihydroartemisinin-piperaquine)
    • At least one treatment arm with primaquine given over multiple days and commencing within seven days of blood schizontocidal treatment
    • Study includes at least one patient aged under 15 years
    • Information on dose of schizontocidal treatment
    • Information on use, timing and dose of primaquine
  • Study meta-data as described in the Clinical Data Management and Statistical Analysis Plan
  • Baseline data on patient age and sex
  • Haemoglobin or haematocrit measured at least on day 0 and one or more follow up measurements

Desirable criteria

  • ³42 days follow up
  • Baseline weight
  • Individual primaquine dosing data (mg/kg dose; actual dose times; treatment supervision)
  • Individual schizontocidal dosing data (mg/kg dose; actual dose times; treatment supervision)
  • Nutritional status according to weight/ height/ middle upper arm circumference
  • Qualitative or quantitative assessment of G6PD status
  • CYP2D6 genotype/phenotype
  • Outcome of malaria treatment according to standardized WHO/CDISC criteria
  • Additional haematology measures (including methaemoglobin, transfusion needed, leucopaenia and haemoglobinuria)
  • Adverse event description, time, grade, causality assessment
  • Any concomitant medication documented

Data standardisation and statistical analysis

After upload to the WWARN Data Repository, WWARN will standardise data sets according to the WWARN Clinical Data Management and Statistical Analysis Plan and pool all primary data sets into a single database of quality-assured individual patient data. The interaction between age and the daily and total primaquine mg/kg dose on haematological safety will be explored through multivariable logistic regression analysis.

 

Study group governance

The Vivax and Ovale Paediatric Primaquine Haematological Safety Study Group comprises participating investigators who contribute relevant data sets to the pooled analysis. The Study Group comprises participating investigators who contribute relevant IPD sets to the IPD meta-analysis. The Study Group collectively makes decisions with respect to data analysis and plans for publication. Participating investigators will be recognised in publication as contributors under the banner of the Study Group. A Writing Committee will coordinate activities, undertaking the data analysis and preparation of the reports and publications for review by the study group. Authors will be recognised according to the ICMJE guidelines and the WWARN publication policy.

For further information, please contact Rob Commons on email: rob [dot] commons [at] wwarn [dot] org