IMPROV (Improving the Radical Cure of Vivax Malaria)

Summary

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

Conditions

• Uncomplicated Vivax Malaria

Interventions

DRUG

Primaquine

14 days of supervised primaquine (7mg/kg total dose) administered once per day (0.5 mg/kg).

DRUG

Primaquine

7 days of supervised primaquine (7mg/kg total dose) administered once per day (1.0 mg/kg OD) followed by 7 days of placebo.

DRUG

Placebo

14 days placebo.

Sponsors & Collaborators

• Menzies School of Health Research

  collaborator OTHER

• University of Oxford

  lead OTHER

Principal Investigators

• Ric Price, FRCP · University of Oxford

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

6 Months

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2014-07-31

Primary Completion

2018-02-28

Completion

2018-02-28

Countries

• Afghanistan
• Ethiopia
• Indonesia
• Vietnam

Study Locations