Single-Dose Drug Prevents Malaria Relapse, Patient Selection Key

Jennifer Garcia

January 16, 2019

The anti-malarial drug tafenoquine (Krintafel, GlaxoSmithKline) reduces relapse risk in patients with Plasmodium vivax, but declines in hemoglobin were noted in some patients, according to data from two phase 3, double-blind, randomized controlled trials. Both studies were published online today in the New England Journal of Medicine.

Data from the two studies led to FDA approval of the drug last year.

The first study, the Dose and Efficacy Trial Evaluating Chloroquine and Tafenoquine in Vivax Elimination (DETECTIVE), enrolled 522 patients from Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. All patients had confirmed P vivax infection and received a 3-day course of chloroquine (600 mg on days 1 and 2 and 300 mg on day 3) plus study medication.

Marcus V.G. Lacerda, MD, from Fundação de Medicina Tropical Dr Heitor Vieira Dourado in Brazil, and colleagues randomly assigned patients in a 2:1:1 manner to receive a single dose of tafenoquine (300 mg), primaquine (15 mg once a day for 14 days), or placebo. Matched placebos were administered as needed to ensure blinding and patients were followed for 6 months. Due to the risk associated with both tafenoquine and primaquine for drug-induced hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, only those with normal G6PD activity were included in the study.

In the intention-to-treat population, the researchers found that 62.4% of patients in the tafenoquine group (95% confidence interval [CI], 54.9 - 69.0) were recurrence-free at 6 months compared with 69.6% in the primaquine group (95% CI, 60.2 - 77.1), and 27.7% in the placebo group (95% CI, 19.6 - 36.6).

With respect to safety, the researchers found the greatest decline in hemoglobin among patients in the tafenoquine group, with 14 (5.4%) of 260 patients experiencing a decline of >3 g/dL or ≥ 30% of baseline. This was noted in only 2 (1.5%) of 133 patients in the placebo group and 2 (1.6%) of 129 patients in the primaquine group. No symptoms of anemia were reported, and no clinical intervention was required for any patient.

The second study, the Global Assessment of Tafenoquine Hemolytic Risk (GATHER), also compared tafenoquine to primaquine for prevention of P vivax relapse. In this trial, Alejandro Llanos‑Cuentas, MD, from the Universidad Peruana Cayetano Heredia in Peru, and colleagues enrolled 251 patients with confirmed P vivax parasitemia from seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand. An effort was made to recruit female patients with moderate G6PD levels (≥40% to <70% of the site-specific normal value); however, only one person met the inclusion criteria. All other recruited patients had normal G6PD enzyme activity.

Study Details

Patients were randomly assigned 2:1 to receive a single dose of tafenoquine (300 mg) plus a 14-day placebo; or primaquine (15 mg) once a day for 14 days plus a single-dose placebo. All patients received chloroquine for 3 days (600 mg on days 1 and 2 and 300 mg on day 3) and were followed for 6 months.

With respect to the primary outcome of safety, the researchers found a similar decline in hemoglobin and hematocrit (in terms of both level and time course) between the 2 groups: 4 (2.4%) of 166 patients in the tafenoquine group (95% CI, 0.9 - 6.0) and 1 (1.2%) of 85 patients in the primaquine group (95% CI, 0.2 - 6.4). None required intervention.

With respect to treatment efficacy, the researchers found that 100 (74.1%) of 135 patients in the tafenoquine group were recurrence free at 6 months compared with 57 (76%) of 75 patients in the primaquine group.

The GATHER researchers went on the conduct a patient-level meta-analysis to determine noninferiority of tafenoquine to primaquine with respect to prevention of P Vivax relapse. Using GATHER data as well as data from the DETECTIVE trial, the researchers noted recurrence rates of 67% (95% CI, 61.0 - 72.3) in the tafenoquine group and 72.8% (95% CI, 65.6 - 78.8) in the primaquine group. The difference fell outside the prespecified criteria for noninferiority and, therefore, noninferiority of tafenoquine to primaquine was not demonstrated.

Further, the researchers found that patients in the tafenoquine group (19 of 483 [3.9%]) were more likely to experience a decline in hemoglobin level compared with those in the primaquine group (4 of 264 [1.5%]).

Promising Results, but Appropriate Screening Is Critical

In an accompanying editorial, Nicholas J. White, FRS, professor of tropical medicine at Mahidol University, Bangkok, Thailand, writes: "The two current studies showed that with appropriate G6PD testing, tafenoquine can be given safely" and "solves the potentially important problem of poor adherence to daily primaquine by providing a radical cure in a single dose."

However, White continues, "the requirement for accurate quantitative G6PD assessments and the current prescribing restrictions (pregnancy, lactation, or age younger than 16 years) will limit the potential deployment of tafenoquine, at least in the immediate future."

This sentiment is echoed by authors of the DETECTIVE trial. "The qualitative [G6PD] test evaluated here failed to identify 16 patients most at risk for hemolysis. If tafenoquine use is expanded, adoption of reliable quantitative point-of-care G6PD tests will be needed; such tests are not currently available but are in development," they conclude.

Funding for both studies was provided by GlaxoSmithKline and Medicines for Malaria Venture. Several coauthors report funding from or employment with GlaxoSmithKline, and the meta-analysis was funded and conducted by the company. The full disclosures can be found on the journal website.

N Eng J Med. Published online January 16, 2019. Abstract, Editorial

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