Summary of anti-malarial prophylactic efficacy of tafenoquine from three placebo-controlled studies of residents of malaria-endemic countries

Geoffrey S Dow, Jun Liu, Gina Lin, Brian Hetzell, Sarah Thieling, William F McCarthy, Douglas Tang, Bryan Smith, Geoffrey S Dow, Jun Liu, Gina Lin, Brian Hetzell, Sarah Thieling, William F McCarthy, Douglas Tang, Bryan Smith

Abstract

Background: Tafenoquine is a long half-life primaquine analog being developed for malaria prophylaxis. The US Army recently performed a unified analysis of efficacy in preparation for a regulatory submission, utilizing legacy data from three placebo-controlled studies conducted in the late 1990s and early 2000s. The subjects were residents of Africa who were naturally exposed to Plasmodium falciparum for 12-26 weeks.

Methods: The prophylactic efficacy of tafenoquine and mefloquine (included in some studies as a comparator) was calculated using incidence density among subjects who had completed the three-day loading doses of study drug, had at least one maintenance dose and had at least one blood smear assessed during the prophylactic period. The three placebo-controlled studies were analysed separately and then in two pooled analyses: one for tafenoquine versus placebo (three studies) and one for tafenoquine and mefloquine versus placebo (two studies).

Results: The pooled protective efficacy (PE) of a tafenoquine regimen with three daily loading doses plus weekly maintenance at 200-mg for 10 weeks or longer (referred to as 200-mg weekly hereafter) relative to placebo in three placebo-controlled studies was 93.1 % [95 % confidence interval (CI) 89.1-95.6 %; total N = 492]. The pooled PEs of regimens of tafenoquine 200-mg weekly and mefloquine 250-mg weekly relative to placebo in two placebo-controlled studies (total N = 519) were 93.5 % (95 % CI 88.6-96.2 %) and 94.5 % (95 % CI 88.7-97.3 %), respectively. Three daily loading plus weekly maintenance doses of 50- and 100-mg, but not 25-mg, exhibited similar PEs. The PEs of tafenoquine regimens of a three-day loading dose at 400-mg with and without follow-up weekly maintenance doses at 400-mg were 93.7 % (95 % CI 85.4-97.3 %) and 81.0 % (95 % CI 66.8-89.1 %), respectively.

Conclusions: Tafenoquine provided the same level of prophylactic efficacy as mefloquine in residents of Africa. These data support the prophylactic efficacy of tafenoquine and mefloquine that has already been demonstrated in the intended malaria naive population.

Figures

Fig. 1
Fig. 1
Study schematic for Study 030
Fig. 2
Fig. 2
Study schematic for Study 043
Fig. 3
Fig. 3
Study schematic for Study 045
Fig. 4
Fig. 4
Plot of estimated protective efficacies and 95 % confidence intervals

References

    1. US Army Unpublished Clinical Study Report. A randomized, double blind, placebo controlled evaluation of weekly tafenoquine (WR 238605/SB252263) compared to mefloquine for chemosuppression of Plasmodium falciparum in Western Kenya (SB Document Number: SB-252263/RSD-101KZH/1), 2003.
    1. Hale BR, Owusu-Agyei S, Fryauff DJ, Koram KA, Adjuik M, Oduro AR, et al. A randomized, double-blind, placebo-controlled, dose-ranging trial of tafenoquine for weekly prophylaxis against Plasmodium falciparum. Clin Infect Dis. 2003;36:541–549. doi: 10.1086/367542.
    1. Shanks GD, Oloo AJ, Aleman GM, Ohrt C, Klotz FW, Braitman D, et al. A new primaquine analogue, tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria. Clin Infect Dis. 2001;33:1968–1974. doi: 10.1086/324081.
    1. Walsh DS, Eamsila C, Sasiprapha T, Sangkharomya S, Khaewsathien P, Supakalin P, et al. Efficacy of monthly tafenoquine for prophylaxis of Plamodium vivax and multidrug-resistant P. falciparum malaria. J Infect Dis. 2004;190:1456–1463. doi: 10.1086/424468.
    1. Nasveld PE, Edstein MD, Reid M, Brennan L, Harris IE, Kitchener SJ, et al. Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects. Antimicrob Agents Chemother. 2010;54:792–798. doi: 10.1128/AAC.00354-09.
    1. Dow GS, McCarthy WF, Reid M, Smith B, Tang D, Shanks GD. A retrospective analysis of the protective efficacy of tafenoquine and mefloquine as prophylactic antimalarials in non-immune individuals. Malar J. 2014;13:49. doi: 10.1186/1475-2875-13-49.
    1. Zhou G, Afrane YA, Dixit A, Atieli HE, Lee MC, Wanjala CL, et al. Modest additive effects of integrated vector control measures on malaria prevalence and transmission in western Kenya. Malar J. 2013;12:256. doi: 10.1186/1475-2875-12-256.
    1. Aborah S, Akweongo P, Adjuik M, Atinga RA, Welanga P, Adongo P. The use of non-prescribed anti-malarial drugs for the treatment of malaria in the Bolgatanga municipality, northern Ghana. Malar J. 2013;12:266. doi: 10.1186/1475-2875-12-266.
    1. FDA. Guidance for industry malaria: developing drug and nonvaccine biological products for treatment and prophylaxis. 2007.
    1. Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10:101–129. doi: 10.2307/3001666.
    1. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–1558. doi: 10.1002/sim.1186.
    1. Hardy RJ, Thompson SG. Detecting and describing heterogeneity in meta-analysis. Stat Med. 1998;17:841–856. doi: 10.1002/(SICI)1097-0258(19980430)17:8<841::AID-SIM781>;2-D.
    1. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. doi: 10.1016/0197-2456(86)90046-2.
    1. Mantel N, Haenszel MW. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Institute. 1959;22:719–748.
    1. Steffen R, Fuchs E, Schildknecht J, Naef U, Funk M, Schlagenhauf P, et al. Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting east Africa. Lancet. 1993;341:1299–1303. doi: 10.1016/0140-6736(93)90814-W.
    1. Lobel HO, Miani M, Eng T, Bernard KW, Hightower AW, Campbell CC. Long-term malaria prophylaxis with weekly mefloquine. Lancet. 1993;341:848–851. doi: 10.1016/0140-6736(93)93058-9.
    1. Department of Defense. Guidance on medications for prophylaxis of malaria. 2013.
    1. Dow GS, Magill AJ, Ohrt C. Clinical development of new prophylactic antimalarial drugs after the 5th Amendment to the Declaration of Helsinki. Ther Clin Risk Manag. 2008;4:803–819.
    1. Hogh B, Clarke PD, Camus D, Nothdurft HD, Overbosch D, Gunther M, et al. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travelers: a randomised, double-blind study. Malarone International Study Team. Lancet. 2000;356:1888–1894. doi: 10.1016/S0140-6736(00)03260-8.
    1. Edstein MD, Kocisko DA, Walsh DS, Eamsila C, Charles BG, Rieckmann KH. Plasma concentrations of tafenoquine, a new long-acting antimalarial agent, in Thai soldiers receiving monthly prophylaxis. Clin Infect Dis. 2003;37:1654–1658. doi: 10.1086/379718.
    1. Leary KJ, Riel MA, Roy MJ, Cantilena LR, Bi D, Brater DC, 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;81:356–362.
    1. Elmes NJ, Nasveld PE, Kitchener SJ, Kocisko DA, Edstein MD. The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific. Trans R Soc Trop Med Hyg. 2008;102:1095–1101. doi: 10.1016/j.trstmh.2008.04.024.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren