A randomized, double-blind, active-control trial to evaluate the efficacy and safety of a three day course of tafenoquine monotherapy for the treatment of Plasmodium vivax malaria

Abstract

Background: Tafenoquine is an investigational 8-aminoquinoline for the prevention of Plasmodium vivax relapse. Tafenoquine has a long half-life and the potential for more convenient dosing, compared with the currently recommended 14-day primaquine regimen.

Methods: This randomized, active-control, double-blind trial was conducted in Bangkok, Thailand. Seventy patients with microscopically confirmed P. vivax were randomized (2:1) to tafenoquine 400 mg once daily for 3 days or 2500 mg total dose chloroquine phosphate (1500 mg chloroquine base) given over 3 days plus primaquine 15 mg daily for 14 days. Patients were followed to day 120.

Results: Day 28 adequate clinical response rate in the per-protocol population was 93% (40/43) (90%CI 83-98%) with tafenoquine, and 100% (22/22) (90%CI 87-100%) with chloroquine/primaquine. Day 120 relapse prevention was 100% (35/35) with tafenoquine (90%CI 92-100%), and 95% (19/20) (90%CI 78-100%) with chloroquine/primaquine. Mean (SD) parasite, gametocyte and fever clearance times with tafenoquine were 82.5 h (32.3), 49.1 h (33.0), and 41.1 h (31.4) versus 40.0 h (15.7), 22.7 h (16.4), and 24.7 h (17.7) with chloroquine/primaquine, respectively. Peak methemoglobin was 1.4-25.6% (median 7.4%, mean 9.1%) in the tafenoquine arm, and 0.5-5.9% (median 1.5%, mean 1.9%) in the chloroquine/primaquine arm. There were no clinical symptoms of methemoglobinemia in any patient.

Discussion: Although there was no difference in efficacy in this study, the slow rate of parasite, gametocyte and fever clearance indicates that tafenoquine should not be used as monotherapy for radical cure of P. vivax malaria. Also, monotherapy increases the potential risk of resistance developing to this long-acting agent. Clinical trials of single-dose tafenoquine 300 mg combined with standard 3-day chloroquine or artemisinin-based combination therapy are ongoing.

Trial registration: Clinicaltrials.gov NCT01290601.

Conflict of interest statement

Competing Interests: JAG and KM are employees of GlaxoSmithKline and hold shares in the company. HN has received grants and personal fees from GlaxoSmithKline. This does not alter our adherence to PLOS ONE policies on sharing data and materials. For all other authors there is no potential conflict of interest to report, other than writing support for this manuscript as noted in the acknowledgments.

Figures

Fig 1. Study design, patient disposition and main efficacy outcomes.

*The three patients with early treatment failure (at day 7) in the tafenoquine group cleared parasitemia spontaneously on day 8 without additional treatment, and were relapse free for the duration of their follow-up (until day 28 for one patient, day 60 for the second and day 120 for the third).

Fig 2. Dosing schedule.

The planned enrollment for this study was 70 patients in each of two cohorts in order to yield at least 60 evaluable patients in each cohort. Using a 2:1 randomization ratio and assuming a true success rate on treatment of at least 98%, the sample size of 40 evaluable tafenoquine patients provided 90% power to show that the lower limit of the one-sided 95% confidence interval for the day 28 cure rate was above 85%.

Fig 3. Individual patient tafenoquine plasma concentrations.

*The three patients with early treatment failure (at day 7) in the tafenoquine group and slow parasite clearance had similar tafenoquine plasma concentrations to the population that had parasite clearance at day 7.