Single-Dose Tafenoquine to Prevent Relapse of Plasmodium vivax Malaria

Abstract

Background: Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed "radical cure"). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax.

Methods: This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to <100,000 parasites per microliter) and normal glucose-6-phosphate dehydrogenase (G6PD) activity (with normal activity defined as ≥70% of the median value determined at each trial site among 36 healthy male volunteers who were otherwise not involved in the trial). All patients received a 3-day course of chloroquine (total dose of 1500 mg). In addition, patients were assigned to receive a single 300-mg dose of tafenoquine on day 1 or 2 (260 patients), placebo (133 patients), or a 15-mg dose of primaquine once daily for 14 days (129 patients). The primary outcome was the Kaplan-Meier estimated percentage of patients who were free from recurrence at 6 months, defined as P. vivax clearance without recurrent parasitemia.

Results: In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P<0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P<0.001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, which resolved without intervention.

Conclusions: Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167 .).

Figure 1

Screening, Randomization, and Trial Populations. The intention-to-treat population included all patients who underwent randomization and had microscopically confirmed Plasmodium vivax parasitemia at baseline. The per-protocol population was a subgroup of patients from the intention-to-treat population who had no major protocol violations. The safety population included all patients who underwent randomization and received at least one dose of the assigned treatment. Patients in the intention-to-treat and safety populations may have had more than one reason for exclusion. G6PD denotes glucose-6-phosphate dehydrogenase, and QTcF the QT interval corrected for heart rate according to Fridericia’s formula.

Figure 2

Kaplan–Meier Analysis of the Recurrence of Parasitemia in Patients with P. vivax. Patients were assigned to receive tafenoquine (in a single 300-mg dose), placebo, or primaquine (15 mg, administered once daily for 14 days) in addition to a 3-day course of chloroquine (total dose of 1500 mg). Panel A shows the Kaplan–Meier analysis of the probability of freedom from recurrence of P. vivax parasitemia over 6 months among patients in the intention-to-treat population. The symbols indicate censored data, and the shaded areas indicate confidence intervals. Data were censored at the last parasite assessment if the patients were lost to follow-up, received a drug with antimalarial activity, or completed the trial before recurrence. Data for patients who had a recurrence before day 33 were censored at the time of recurrence. However, any patient with recurrence was considered to have had recurrence irrespective of censoring before the event. Panel B shows the hazard ratios for the risk of recurrence of parasitemia with tafenoquine as compared with placebo, and Panel C the risk of recurrence with primaquine as compared with placebo, according to region.

Figure 3

Mean Hemoglobin Levels in Patients with Normal G6PD Genotype and P. vivax Parasitemia. The y axis has been shifted upward in Panel B to allow data to be compared more easily. The number at risk indicates the number of patients who could be evaluated at each time point. I bars indicate standard errors.