The Primaquine Dose Study Group was formed in May 2019. Research groups with relevant data sets were contacted. Data gathering and curation have started. Further data contributions were accepted until June 2019. Statistical analysis will commence in the second half of 2019 and a manuscript is expected to be submitted for publication in 2020.

Vivax malaria is associated with recurrent parasitaemia and anaemia with both attributable morbidity and mortality. Recurrent P. vivax can arise from recrudescence (treatment failure), reinfection (new infections) and relapse (reactivation from dormant liver stages). Whilst it is currently not possible to differentiate reliably between these alternatives, early recurrence is more likely to be due to relapse or recrudescence, whereas later recurrences are more likely to be due to relapse or reinfection. Relapse periodicity varies markedly with geographical location and can occur many months after the initial infection. Other factors influencing the risk, frequency and timing of recurrence include: antimalarial drug resistance, the pharmacokinetic profile of the antimalarial agents administered, host immunity, the use of hypnozoitocidal drugs and transmission intensity.

Recent pooled analyses through WWARN have identified the risk factors associated with early recurrence prior to day 42. However, risk factors associated with recurrence over a longer duration have not been evaluated comprehensively.

Antirelapse efficacy is related to the total mg/kg dose of primaquine administered. Although higher doses of primaquine may provide greater efficacy, daily dosing is limited by tolerability particularly gastrointestinal symptoms and haemolysis.

1. To investigate the effect of total primaquine mg/kg dose and regimen duration on the risk of P. vivax recurrence
2. To identify additional key host, parasite and pharmacological determinants of recurrent P. vivax
3. To investigate the effect of daily primaquine mg/kg dose on drug tolerability

• Prospective clinical efficacy studies of uncomplicated vivax malaria with a minimum 42 days follow up:
  • Treatment with chloroquine or an artemisinin-based combination therapy
  • At least one treatment arm with primaquine
  • 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, gender and weight
• Parasite density at day 0
• Parasite presence during follow-up

• Individual tablet or mg dosing
• Data on dose adherence
• Documentation on the supervision of drug administration
• Follow up through multiple malaria recurrence events
• Follow up for 180 days or longer
• Haemoglobin (hb) or hematocrit (hct) or red blood count (RBC) measured on day 0
• Malnutrition as gauged by weight and age +/– height or MUAC
• Qualitative or quantitative assessment of G6PD status
• CYP2D6 status
• Primaquine/Carboxyprimaquine drug levels during follow up
• History of malaria within the past 28 days
• History of fever
• Data on vomiting post administration
• Genotyping to potentially distinguish recrudescence and reinfection

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 effect of primaquine mg/kg dose and the duration of the primaquine regimen on the risk of recurrence will be explored by multivariable Cox regression analysis and network meta-analysis methods will be used for comparisons of primaquine regimens that have not been directly compared within a single trial (i.e. indirect comparisons). The following covariates will also be examined: age, sex, weight, nutritional status, G6PD status, CYP2D6 status, history of malaria within the past 28 days, history of fever, vomiting primaquine within one hour, baseline parasitaemia, parasite genotyping, baseline haemoglobin, schizontocidal treatment and relapse periodicity.

Subgroup analyses will restrict data to:

i) Patients treated with chloroquine

ii) Studies with a minimum 6 months of follow-up

iii) Presence of symptomatic recurrence. Additional analyses will explore the effect of primaquine mg/kg dose and the duration of the primaquine regimen on incidence rate of recurrence (events per person years) in studies in which patients were followed for 6 months or more.

Multivariable logistic regression analysis will be undertaken to investigate the effect of daily primaquine mg/kg dose on gastrointestinal drug tolerability.

The Primaquine Dose Study Group comprises participating investigators who contribute relevant data sets to the pooled analysis. Data sets will remain the property of the investigator and will not be shared without their consent. Rob Commons and Julie Simpson will oversee the statistical analyses. The Study Group collectively makes decisions with respect to including additional studies and plans for publication. Participating investigators will be recognised in publication as contributors under the banner of the Primaquine Dose Study Group. The Study Group will assign a Writing Committee to coordinate activities including data analysis and drafting of publications and reports for complete group review. The Writing Committee will comprise a group of interested investigators undertaking the data analysis and preparation of the manuscript. Authors will be recognised according to the ICMJE guidelines and the WWARN publication policy.

For further information, please contact Rob Commons rob.commons@wwarn.org.