NCT01814683

Improving the Radical Cure of Vivax Malaria: A Multicentre Randomised Comparison of Short and Long Course Primaquine Regimens

Completed NA Last updated 16 September 2019

What this trial tests

NA trial testing Primaquine in Uncomplicated Vivax Malaria in 2,388 participants. Completed in 28 February 2018.

Timeline

1 July 2014

Primary endpoint
28 February 2018

28 February 2018

Quick facts

Lead sponsor	University of Oxford
Phase	NA
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	treatment
Enrollment	2,388
Start date	1 July 2014
Primary completion	28 February 2018
Estimated completion	28 February 2018
Sites	8 locations across Afghanistan, Ethiopia, Indonesia, Vietnam

Drugs / interventions tested

• Primaquine — full drug profile →
• Primaquine — full drug profile →
• Placebo

Conditions studied

• Uncomplicated Vivax Malaria — all drugs for Uncomplicated Vivax Malaria →

Sponsor

University of Oxford

Who can join

6 Months and older, any sex, with Uncomplicated Vivax Malaria. Patients with the condition only — healthy volunteers not accepted.

What's being measured

Primary outcomes are the specific endpoints the trial is designed to prove or disprove.

• Incidence rate (per person-year) of symptomatic recurrent P. vivax
  Time frame: 12 months
  The incidence rate (i.e. per person-year) of symptomatic recurrent P. vivax parasitaemia (detected by microscopy) over 12 months of follow-up in the 7 versus 14-day primaquine groups for all sites combined and stratified by site.

Sponsor's own description

The main determinant of primaquine efficacy is the total dose of primaquine administered, rather than the dosing schedule. Previous trials have demonstrated that the standard low dose regimen of primaquine (3.5 mg/kg total) fails to prevent relapses in many different endemic locations. For this reason the 2010 WHO antimalarial guidelines now recommend a high dose regimen of 7 mg/kg (equivalent to an adult dose of 30mg per day), although many countries still recommend lower doses for fear of causing more serious harm to unscreened G6PDd patients.

Shorter courses of higher daily doses of primaquine have the potential to improve adherence and thus effectiveness without compromising efficacy. Primaquine also has relatively weak but clinically relevant asexual stage activity against P. vivax so larger daily doses may substantially augment chloroquine's blood stage activity at low levels of resistance. In Thailand directly observed primaquine (1mg/kg/day) administered over 7 days was well tolerated and reduced relapses by day 28 to 4%. This is encouraging but not definitive since many relapses present after one month. Longer follow-up is needed to distinguish whether relapse was prevented or deferred. If the efficacy, tolerability and safety of short-course, high-dose primaquine regimens can be assured across the range of endemic settings, along with reliable point-of-care G6PDd diagnostics, then this new primaquine regimen would be a major advance in malaria treatment improving adherence to and thus the effectiveness of anti-relapse therapy.

Due to the long duration of standard primaquine treatment regimens, courses are difficult to supervise, are poorly adhered to and lack effectiveness. This proposed multicentre randomised clinical trial will provide evidence across a variety of endemic settings on the safety and efficacy of high dose-short course primaquine in G6PD normal patients. In a parallel single arm study the investigators will also gather safety data on the use of weekly primaquine in patients with G6PDd. This study aims to generate evidence that will directly inform global public health policy for the radical cure of P. vivax. A better understanding of the risks and benefits of primaquine is crucial in persuading policy makers and clinicians of the importance of the radical cure of vivax malaria that will reduce the parasite reservoir and decrease transmission.

The funder is Medical Research Council, UK. Grant number: MRC Reference: MR/K007424/1

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial.
   Taylor WRJ, Thriemer K, von Seidlein L, Yuentrakul P, et al · · 2019 · cited 147× · PMID 31327563 · DOI 10.1016/s0140-6736(19)31285-1
2. Primaquine for preventing relapse in people with Plasmodium vivax malaria treated with chloroquine.
   Galappaththy GN, Tharyan P, Kirubakaran R. · · 2013 · cited 61× · PMID 24163057 · DOI 10.1002/14651858.cd004389.pub3
3. Variation in Glucose-6-Phosphate Dehydrogenase activity following acute malaria.
   Ley B, Alam MS, Satyagraha AW, Phru CS, et al · · 2022 · cited 17× · PMID 35544453 · DOI 10.1371/journal.pntd.0010406
4. Improving the radical cure of vivax malaria (IMPROV): a study protocol for a multicentre randomised, placebo-controlled comparison of short and long course primaquine regimens.
   IMPROV Study Group. · · 2015 · cited 16× · PMID 26643116 · DOI 10.1186/s12879-015-1276-2
5. Primaquine at alternative dosing schedules for preventing relapse in people with Plasmodium vivax malaria.
   Milligan R, Daher A, Graves PM. · · 2019 · cited 12× · PMID 31274189 · DOI 10.1002/14651858.cd012656.pub2
6. Weekly primaquine for radical cure of patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase deficiency.
   Taylor WRJ, Meagher N, Ley B, Thriemer K, et al · · 2023 · cited 8× · PMID 37672548 · DOI 10.1371/journal.pntd.0011522
7. Case Series of Primaquine-Induced Haemolytic Events in Controlled Trials with G6PD Screening.
   Kosasih A, James R, Chau NH, Karman MM, et al · · 2023 · cited 5× · PMID 37764985 · DOI 10.3390/pathogens12091176
8. The heterogeneity of symptom reporting across study sites: a secondary analysis of a randomised placebo-controlled multicentre antimalarial trial.
   Thriemer K, Commons RJ, Rajasekhar M, Degaga TS, et al · · 2023 · cited 2× · PMID 37667204 · DOI 10.1186/s12874-023-02022-3