Compared to primaquine, tafenoquine had a similar safety profile and acceptable efficacy for the radical cure of malaria, but non-inferiority for preventing relapse could not be shown, a phase III trial found.
Both drugs had similar safety profiles, each with small declines in hemoglobin level among patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme levels, and the majority of patients in both groups were free of the Plasmodium vivax malaria parasite at 6 months, reported Alejandro Llanos‑Cuentas, MD, of Universidad Peruana Cayetano Heredia, Lima, Peru, and colleagues in the New England Journal of Medicine.
However, non-inferiority of tafenoquine compared to primaquine was not met in the primary efficacy outcome of recurrence, which came from a patient-level meta-analysis that included participants in the so-called GATHER and DETECTIVE trials (OR for recurrence 1.81, 95% CI 0.82-3.96; the prespecified maximum OR for non-inferiority was 1.45).
Tafenoquine was approved by the FDA for the radical cure of P. vivax malaria in July. G6PD-deficiency was raised as an issue by the FDA in briefing documents prior to the approval of the drug, when they said that the drug should not be prescribed to patients with G6PD enzymatic activity <70% of normal, that safety data are "negligible" in patients with G6PD enzymatic activity 40%-60%, and that monitoring of hematologic parameters would be recommended for anemic patients.
“The hemolytic risk with tafenoquine relative to that with primaquine has been characterized among healthy volunteers with normal G6PD enzyme activity and volunteers who were heterozygous for G6PD deficiency,” the authors wrote. “A possible interaction between drug effects and malaria-induced hemolysis requires a formal evaluation of hemolytic risk among patients with P. vivax malaria.”
They added that “a direct comparison between tafenoquine and primaquine (administered under supervision) in terms of efficacy is critical for decision making by physicians.”
GATHER, the Global Assessment of Tafenoquine Hemolytic Risk trial, was a phase III prospective, double-blind study conducted in seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand. Patients were ages ≥16 with microscopically confirmed P. vivax malaria infection. For this trial, the authors noted that women patients were required to have a G6PD enzyme level at least 40% of the site-specific normal value, and men, a G6PD enzyme level at least 70% of the site-specific normal value. Most patients were required to have a hemoglobin level of at least 7 g per deciliter.
Patients were randomized 2:1 to receive either a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days, and all patients received a 3-day course of chloroquine and were followed for 180 days, the authors said.
A protocol-defined decrease in hemoglobin level was the primary safety outcome, while freedom from recurrence of P. vivax parasitemia at 6 months via a planned patient-level meta-analysis of this trial plus another phase III trial of tafenoquine and primaquine. Non-inferiority was defined via an odds ratio for recurrence of 1.45 (tafenoquine vs primaquine).
Overall, 251 patients were recruited — 166 in the tafenoquine group and 85 in the primaquine group. This was also the safety population, with 135 and 75, respectively, included in the per-protocol population.
Examining hematologic safety, a protocol-defined decrease in the hemoglobin level occurred in 2.4% (95% CI 0.9-6.0) of patients in the tafenoquine group versus 1.2% (95% CI 0.2-6.4) in the primaquine group — albeit with a wide confidence interval. Between-group difference was 1.2 percentage points (95% CI -4.2 to 5.0).
Data from the patient-level meta-analysis that included DETECTIVE participants found 67.0% (95% CI 61.0-72.3) in the tafenoquine group and 72.8% in the primaquine group (95% CI 65.6-78.8) were free from recurrence at 6 months, the authors said.
DETECTIVE was a phase IIb/phase III trial comparing tafenoquine to placebo and primaquine to placebo. Its results were also written up in NEJM by Marcus V.G. Lacerda, MD, of Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus in Brazil, and colleagues. In this study, patients with confirmed P. vivax infection and normal G6PD activity were randomized to tafenoquine, primaquine, or placebo, along with chloroquine.
An intent-to-treat analysis found 62.4% of patients in the tafenoquine group (95% CI 54.9-69.0), 27.7% of patients in the placebo group (95% CI 19.6-36.6), and 69.6% of patients in the primaquine group (95% CI 60.2-77.1) were free from recurrence at 6 months.
An accompanying editorial on both studies by Nicholas J. White, FRS, of Mahidol University in Bangkok, Thailand, said that both confirmed that with appropriate G6PD testing, tafenoquine can be given safely, but “follow-up needs to be sufficient to capture the majority of relapses, which may occur up to a year after the primary illness” and may vary based on “geography, the degree of previous exposure and immunity.”
White added that the current prescribing restrictions on tafenoquine (pregnancy, lactation, age <16) may limit its widespread use.
“The developers of tafenoquine deserve credit for persevering with this potentially valuable antimalarial drug, despite the difficulties, but it is too early to say whether tafenoquine can be used safely on a large scale in routine practice,” he wrote.
The studies were supported by GlaxoSmithKline (GSK) and Medicines for Malaria Venture. The meta-analysis was funded and conducted by GSK.
Llanos-Cuertas disclosed support from GSK.
Lacerda disclosed no conflicts of interest.
Other co-authors disclosed support from GSK, Medicines for Malaria Venture, the Gambia, and LSTMH.
White disclosed no conflicts of interest.