Am. J. Trop. Med. Hyg., 81(2), 2009, pp. 356–362 Copyright © 2009 by The American Society of Tropical Medicine and Hygiene 356 INTRODUCTION Malaria remains the most significant parasitic disease in the world, with estimates of over 500 million Plasmodium falciparum and 70–80 million Plasmodium vivax infections annually in malaria-endemic regions, representing a leading cause of morbidity and mortality in the developing world. 1,2 Plasmodium falciparum causes the most virulent form of the disease, and is responsible for the 1–3 million deaths each year. Plasmodium vivax malaria is endemic in Central and South America, South East Asia, Oceania, and parts of Africa. It rep- resents a substantial economic burden and is considered to be a neglected disease. 1–3 Antimalarial drugs remain at the forefront of malaria pre- vention and treatment, and with increasing resistance to exist- ing drugs there is an urgent need for new effective and safe medications. 3,4 Tafenoquine, an 8-aminoquinoline analogue of primaquine, is a promising candidate for causal prophylaxis for non-immune travelers, for the radical cure of P. vivax, and for transmission reduction through gametocytocidal action. 5 The 8-aminoquinolines are the only approved class of drugs with activity against P. vivax hypnozoites and stage 5 P. falciparum gametocytes. The World Health Organization (WHO) recom- mends primaquine in combination with chloroquine for the radical cure of P. vivax malaria, although limited compliance with the 14-day dosing regimen is known to impact effective- ness. 6 Given the long half-life of approximately 14 days, tafeno- quine has the potential to address problems with compliance, as Phase II studies show that 1–3 days of treatment is effective to prevent P. vivax relapse when used alone or in combina- tion with other antimalarials. 7,8 Consequently, tafenoquine is being developed for the radical cure of P. vivax malaria. In addition to effectiveness against hypnozoites, tafenoquine’s antigametocyte activity and long-acting blood stage activity against multidrug resistant strains make it a potentially impor- tant agent for P. falciparum eradication under the new initia- tive by the Bill and Melinda Gates Foundation. 9 Detailed ophthalmic assessments in a sub-group of persons in a large Phase III prophylaxis study in East Timor showed that, although tafenoquine 200 mg weekly for 6 months was well tolerated, 69/74 persons in the tafenoquine group developed vortex keratopathy (phospholipid deposits in the cornea). 10 No keratopathy was seen in the mefloquine-treated persons. The corneal deposits were benign and reversible with resolution in more than 90% of persons at 6 months and com- plete resolution in all persons by 1 year post-prophylaxis. An expert ophthalmology advisory panel concluded that vision had not been affected in any persons, but that the relevance of minor retinal findings, in the absence of baseline assess- ments, could not be ascertained. Therefore, it was considered that potential ophthalmic effects of tafenoquine required fur- ther study. In clinical studies of tafenoquine, small and transient increases in serum creatinine concentration were identi- fied in tafenoquine persons compared with those receiving placebo or comparator drugs. 10 Although these increases were rarely outside the normal range, were asymptomatic, and did not have any long-term consequences, we believed the poten- tial changes in renal function also warranted further study. To address the long-term safety of tafenoquine, the objectives of this study were to assess the ophthalmic and renal effects of tafenoquine after a 600 mg loading dose and 200 mg weekly dosing for 6 months. METHODS Subjects. Healthy male and female volunteers between 18 and 55 years of age were recruited at one center each in the United States (Bethesda, MD) and the United Kingdom (Slough, Berkshire). Women of child-bearing potential could not be pregnant or breast-feeding, and had to agree to the use of double-barrier contraception or to abstain from sexual intercourse during and 12 weeks after dosing. The protocol was approved by study center ethics committees and the U.S. * Address correspondence to Kevin Leary, United States Army Medical Materiel Development Activity, 1430 Veteran’s Drive, Fort Detrick, MD 21702-5009. E-mail: kevin.leary1@us.army.mil 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 Kevin J. Leary,* Michael A. Riel, Michael J. Roy, Louis R. Cantilena, Daoqin Bi, D. Craig Brater, Corina van de Pol, Khadeeja Pruett, Caron Kerr, James M. Veazey Jr, Ronnie Beboso, and Colin Ohrt United States Army Medical Materiel Development Activity, Fort Detrick, Maryland; Uniformed Services University of the Health Sciences, Bethesda, Maryland; Indiana University School of Medicine, Indianapolis, Indiana; Acufocus, Inc., Irvine, California; GlaxoSmithKline Research and Development, Greenford, Middlesex, United Kingdom; Chiltern International Ltd., Early Phase Unit, Slough, Berkshire, United Kingdom; Walter Reed Army Institute of Research, Silver Spring, Maryland Abstract. A randomized, double-blind, placebo-controlled study was conducted to assess the effect of tafenoquine, 200 mg weekly for 6 months on ophthalmic and renal safety. This trial was carried out after observations in previous clini- cal trials that tafenoquine may be associated with the development of corneal deposits and elevations in serum creatinine. In 120 healthy volunteers who received tafenoquine or placebo in a 2:1 randomization, there was no effect on night vision or other ophthalmic indices measured. Persons taking tafenoquine also showed no difference in mean change in glomeru- lar filtration rate (GFR, mL/s/1.73 m 2 ) after 6 months of dosing, with a treatment difference of -0.061 (95% confidence interval, -0.168, 0.045), and non-inferiority margin of -0.247 mL/s/1.73 m 2 . Tafenoquine was well tolerated over the course of the study. The results of this study showed no clinically significant effects of tafenoquine on ophthalmic or renal func- tion, and support its continued development as an antimalarial drug.