Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria

Abstract

Background: Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed "radical cure."

Methods: We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin.

Results: A protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, -4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96).

Conclusions: Among patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123 .).

Figure 1

Enrollment, Randomization, and Trial Populations in the GATHER Trial. The safety population included all patients who underwent randomization and received at least one dose of a trial medication in a blinded manner. The intention-to-treat population was a subgroup of patients from the safety population who had microscopically confirmed Plasmodium vivax parasitemia. The per-protocol population was a subgroup of patients from the intention-to-treat population who had no major protocol violations. Patients may have had more than one reason for exclusion from the analysis populations. GATHER denotes Global Assessment of Tafenoquine Hemolytic Risk.

Figure 2

Changes in Key Hematologic Measures among Individual Patients Who Met the Primary Safety Outcome of a Protocol-Defined Decrease in the Hemoglobin Level in the GATHER Trial (Safety Population). A protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter) occurred in 4 of 166 patients in the tafenoquine group and in 1 of 85 patients in the primaquine group. To convert bilirubin to milligrams per deciliter, divide by 17.1.

Figure 3

Patient-Level Meta-Analysis of the Primary Efficacy Outcome of Freedom from Recurrence of P. vivax Parasitemia at 6 Months (Per-Protocol Population). Panel A shows the Kaplan–Meier analysis of freedom from recurrence of P. vivax parasitemia at 6 months in the tafenoquine group, as compared with the primaquine group, across the phase 3 Dose and Efficacy Trial Evaluating Chloroquine and Tafenoquine in Vivax Elimination (DETECTIVE) trial and the GATHER trial. Censored data are indicated by X’s in the primaquine group and by open circles in the tafenoquine group. Panel B shows the estimated odds ratios according to trial and region (top; the size of the solid circles indicates the study size) and the results from the meta-analysis of treatment difference in freedom from recurrence at 6 months across the phase 3 DETECTIVE trial and the GATHER trial (bottom). The dashed vertical line represents the prespecified noninferiority margin of an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine), which was derived from the phase 2b DETECTIVE trial.