Browsing by Author "Siôn W. Jones"

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    Single-dose tafenoquine to prevent relapse of plasmodium vivax malaria
    (2019-01-17) Marcus V.G. Lacerda; Alejandro Llanos-Cuentas; Srivicha Krudsood; Chanthap Lon; David L. Saunders; Rezika Mohammed; Daniel Yilma; Dhelio Batista Pereira; Fe E.J. Espino; Reginaldo Z. Mia; Raul Chuquiyauri; Fernando Val; Martín Casapía; Wuelton M. Monteiro; Marcelo A.M. Brito; Mônica R.F. Costa; Nillawan Buathong; Harald Noedl; Ermias Diro; Sisay Getie; Kalehiwot M. Wubie; Alemseged Abdissa; Ahmed Zeynudin; Cherinet Abebe; Mauro S. Tada; Françoise Brand; Hans Peter Beck; Brian Angus; Stephan Duparc; Jörg Peter Kleim; Lynda M. Kellam; Victoria M. Rousell; Siôn W. Jones; Elizabeth Hardaker; Khadeeja Mohamed; Donna D. Clover; Kim Fletcher; John J. Breton; Cletus O. Ugwuegbulam; Justin A. Green; Gavin C.K.W. Koh; GlaxoSmithKline, USA; University of Gondar; Gokila; Universidad Peruana Cayetano Heredia; Jimma University; University of Oxford; Fundacao Oswaldo Cruz; Universitat Basel; Mahidol University; Medizinische Universitat Wien; Medicines for Malaria Venture; Rio Tuba Nickel Foundation Hospital; Centro de Pesquisas em Medicina Tropical
    Copyright © 2019 Massachusetts Medical Society. 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 (P0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P0.001). 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.
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    Tafenoquine versus primaquine to prevent relapse of plasmodium vivax malaria
    (2019-01-17) Alejandro Llanos-Cuentas; Marcus V.G. Lacerda; Tran T. Hien; Iván D. Vélez; Chayadol Namaik-Larp; Cindy S. Chu; Maria F. Villegas; Fernando Val; Wuelton M. Monteiro; Marcelo A.M. Brito; Mônica R.F. Costa; Raul Chuquiyauri; Martín Casapía; Chau H. Nguyen; Sandra Aruachan; Ratchadaporn Papwijitsil; François H. Nosten; Germana Bancone; Brian Angus; Stephan Duparc; Graham Craig; Victoria M. Rousell; Siôn W. Jones; Elizabeth Hardaker; Donna D. Clover; Lindsay Kendall; Khadeeja Mohamed; Gavin C.K.W. Koh; Viviana M. Wilches; John J. Breton; Justin A. Green; GlaxoSmithKline, USA; Universidad Peruana Cayetano Heredia; Universidad de Antioquia; University of Oxford; Fundacao Oswaldo Cruz; GlaxoSmithKline plc.; Mahidol University; Medicines for Malaria Venture; IMAT Onco-medica; Centro de Investigaciones Clínicas; Oxford University Clinical Research Unit
    Copyright © 2019 Massachusetts Medical Society. 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.