Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria

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, 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

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 .).

Figures

Figure 1
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
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

Figure 3

Patient-Level Meta-Analysis of the Primary…

Figure 3

Patient-Level Meta-Analysis of the Primary Efficacy Outcome of Freedom from Recurrence of P.…
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.
Figure 3
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.

References

    1. Howes RE, Battle KE, Mendis KN, et al. . Global epidemiology of Plasmodium vivax. Am J Trop Med Hyg 2016; 95: Suppl: 15-34.
    1. Control and elimination of Plasmodium vivax malaria — a technical brief. Geneva: World Health Organization, 2015. ().
    1. Guidelines for the treatment of malaria. 3rd ed Geneva: World Health Organization, 2015. ().
    1. Llanos-Cuentas A, Lacerda MV, Rueangweerayut R, et al. . Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study. Lancet 2014; 383: 1049-58.
    1. Lacerda MVG, Llanos-Cuentas A, Krudsood S, et al. . Single-dose tafenoquine to prevent relapse of Plasmodium vivax malaria. N Engl J Med 2019; 380:215-28.
    1. Rochford R, Ohrt C, Baresel PC, et al. . Humanized mouse model of glucose 6-phosphate dehydrogenase deficiency for in vivo assessment of hemolytic toxicity. Proc Natl Acad Sci U S A 2013; 110: 17486-91.
    1. Dern RJ, Beutler E, Alving AS. The hemolytic effect of primaquine V: primaquine sensitivity as a manifestation of a multiple drug sensitivity. J Lab Clin Med 1981; 97: 750-9.
    1. Rueangweerayut R, Bancone G, Harrell EJ, et al. . Hemolytic potential of tafenoquine in female volunteers heterozygous for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PD Mahidol variant) versus G6PD-normal volunteers. Am J Trop Med Hyg 2017; 97: 702-11.
    1. Howes RE, Piel FB, Patil AP, et al. . G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical model-based map. PLoS Med 2012; 9(11): e1001339.
    1. Pamba A, Richardson ND, Carter N, et al. . Clinical spectrum and severity of hemolytic anemia in glucose 6-phosphate dehydrogenase-deficient children receiving dapsone. Blood 2012; 120: 4123-33.
    1. Chu CS, Bancone G, Moore KA, et al. . Haemolysis in G6PD heterozygous females treated with primaquine for Plasmodium vivax malaria: a nested cohort in a trial of radical curative regimens. PLoS Med 2017; 14(2): e1002224.
    1. Galappaththy GN, Tharyan P, Kirubakaran R. Primaquine for preventing relapse in people with Plasmodium vivax malaria treated with chloroquine. Cochrane Database Syst Rev 2013; 10: CD004389.
    1. Kim JR, Nandy A, Maji AK, et al. . Genotyping of Plasmodium vivax reveals both short and long latency relapse patterns in Kolkata. PLoS One 2012; 7(7): e39645.
    1. Malaria microscopy standard operating procedures. Geneva: World Health Organization, 2016. ().
    1. Beck HP, Wampfler R, Carter N, et al. . Estimation of the antirelapse efficacy of tafenoquine, using Plasmodium vivax genotyping. J Infect Dis 2016; 213: 794-9.
    1. Koepfli C, Mueller I, Marfurt J, et al. . Evaluation of Plasmodium vivax genotyping markers for molecular monitoring in clinical trials. J Infect Dis 2009; 199: 1074-80.
    1. Bennett JW, Pybus BS, Yadava A, et al. . Primaquine failure and cytochrome P-450 2D6 in Plasmodium vivax malaria. N Engl J Med 2013; 369: 1381-2.
    1. St Jean PL, Xue Z, Carter N, et al. . Tafenoquine treatment of Plasmodium vivax malaria: suggestive evidence that CYP2D6 reduced metabolism is not associated with relapse in the phase 2b DETECTIVE trial. Malar J 2016; 15: 97.
    1. Noori-Daloii MR, Hajebrahimi Z, Najafi L, et al. . A comprehensive study on the major mutations in glucose-6-phosphate dehydrogenase-deficient polymorphic variants identified in the coastal provinces of Caspian Sea in the north of Iran. Clin Biochem 2007; 40: 699-704.
    1. Laosombat V, Sattayasevana B, Janejindamai W, et al. . Molecular heterogeneity of glucose-6-phosphate dehydrogenase (G6PD) variants in the south of Thailand and identification of a novel variant (G6PD Songklanagarind). Blood Cells Mol Dis 2005; 34: 191-6.
    1. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 2008; 83: 234-42.
    1. Leary KJ, Riel MA, Roy MJ, et al. . A randomized, double-blind, safety and tolerability study to assess the ophthalmic and renal effects of tafenoquine 200 mg weekly versus placebo for 6 months in healthy volunteers. Am J Trop Med Hyg 2009; 81: 356-62.
    1. Woodruff AW, Ansdell VE, Pettitt LE. Cause of anaemia in malaria. Lancet 1979; 1: 1055-7.
    1. Mauri L, D’Agostino RB Sr.. Challenges in the design and interpretation of noninferiority trials. N Engl J Med 2017; 377: 1357-67.
    1. Lon C, Manning JE, Vanachayangkul P, et al. . Efficacy of two versus three-day regimens of dihydroartemisinin-piperaquine for uncomplicated malaria in military personnel in northern Cambodia: an open-label randomized trial. PLoS One 2014; 9(3): e93138.
    1. Thriemer K, Ley B, Bobogare A, et al. . Challenges for achieving safe and effective radical cure of Plasmodium vivax: a round table discussion of the APMEN Vivax Working Group. Malar J 2017; 16: 141.
    1. Khantikul N, Butraporn P, Kim HS, Leemingsawat S, Tempongko MA, Suwonkerd W. Adherence to antimalarial drug therapy among vivax malaria patients in northern Thailand. J Health Popul Nutr 2009; 27: 4-13.
    1. Maneeboonyang W, Lawpoolsri S, Puangsa-Art S, et al. . Directly observed therapy with primaquine to reduce the recurrence rate of Plasmodium vivax infection along the Thai-Myanmar border. Southeast Asian J Trop Med Public Health 2011; 42: 9-18.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe