Trial of Topical Cysteamine in the Treatment of Corneal Cystine Crystal Accumulation in Cystinosis

Protocol 86-EI-0062 began as a randomized, double-masked, placebo controlled study to evaluate the efficacy and safety of 0.5% topical cysteamine but was subsequently amended as a natural history protocol. Additional protocols conducted at the National Eye Institute (NEI) at the National Institutes of Health (NIH) began after this protocol and tested various formulations of cysteamine topical solution for efficacy and safety in patients with cystinosis. Subjects from these NIH protocols testing various formulations were ultimately transferred to this natural history protocol for open-label treatment once it was established that the formulation within this study was the most effective. All subjects enrolled in this protocol received the most effective cysteamine topical solution formulation in both eyes. The control was defined as the natural course of corneal crystal accumulation in patients with cystinosis. The efficacy data were obtained from all of the studies conducted at NIH evaluating various cysteamine ophthalmic solution formulations from 1986 until 2005. The safety data were collected from 1986 until the termination of this protocol in July 2013. OBJECTIVE: The free thiol cysteamine depletes cystinotic leukocytes and other cells of cystine, whose accumulation is considered the cause of organ damage in cystinosis. This organ damage involves most tissues of the body. Cysteamine therapy improved growth and stabilized renal function in pre-renal transplant cystinosis, without substantial toxicity but there was no noticeable effect on cystine crystal accumulation in the cornea, most likely because of inadequate local cysteamine concentration in the cornea. Previous studies have shown the safety of cysteamine 0.5% topical solution in benzalkonium chloride and its efficacy in resolving the cystine corneal crystals. The main purpose of this protocol is to maintain topical cysteamine treatment in patients with nephropathic cystinosis until the drops are approved by the FDA. When the NDA for the Sigma-Tau standard formulation is granted, the present protocol (86-EI-0062) will be terminated. STUDY POPULATION: Up to 350 adults and children over two years old, who have a confirmed diagnosis of cystinosis will be enrolled. STUDY DESIGN: This is an open label treatment protocol. Eligible subjects will receive drops of cysteamine 0.5% topical solution in benzalkonium chloride hourly while awake in both eyes. They will undergo an eye examination at their baseline visit. They will take cysteamine eye drops in both eyes every hour during waking hours. They will return to the NIH Clinical Center for a follow-up safety eye examination one year after the baseline visit, and then every two years thereafter until the drug is available commercially. OUTCOME MEASURES: The initial pre-specified primary outcome measure was the reduction of cystine corneal crystals. The post-hoc primary outcome measure (after the protocol was modified) was the collection of safety data.