A multicentre randomised double masked clinical trial of a new formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis

Abstract

Aim: To evaluate the safety and efficacy of a new topical cysteamine formulation, stable at room temperature, for the treatment of corneal cystine crystals in cystinosis. Methods: 20 study subjects were enrolled in the safety study and 16 in the efficacy study. Both studies were randomised and double blind. The primary outcome for the safety study was the occurrence of predefined serious adverse reactions over 6 months and for the efficacy study the reduction of corneal cystine crystal score (CCCS) by 1.00 or more units on photographs graded by a reading centre using a standardised protocol. Results: No study subject developed any serious adverse reactions. In the efficacy study, 47% of eyes receiving the standard formulation experienced a reduction in the CCCS of >1.00 after 1 year, while 7% of eyes on the new formulation experienced such a decrease (p=0.04). Conclusion: Although no serious adverse reactions were observed with either formulation, the new formulation was not as effective as the standard formulation. N ephropathic cystinosis is an autosomal recessive lysosomal storage disorder caused by deficiency of the normal carrier mediated system that transports cystine out of lysosomes.1-4 Cystine crystals accumulate in the lysosomes of most cells and tissues. In the eye corneal cystine crystals result in severe photophobia, blepharospasm, and recurrent corneal erosions. 6The mainstay of treatment for cystinosis, oral cysteamine, if begun early and provided diligently, stabilises glomerular function, improves growth velocity, and obviates the requirement for thyroid hormone replacement.7-10 However, it does not dissolve corneal crystals, 11 most probably because of inadequate local cysteamine concentrations.In single centre trials, topical cysteamine treatment has been proved to efficiently dissolve corneal crystals and significantly alleviate the symptoms of photophobia, blepharospasm and eye pain that compromise the quality of life of cystinosis study subjects.12-14 The drops may be used at room temperature for up to 1 week. However, at room temperature, cysteamine oxidises to its disulfide form, cystamine. A randomised, controlled, double masked trial has eliminated cystamine as an alternative to cysteamine. 15The objective of this study was to evaluate the safety and efficacy of a new formulation, which retains cysteamine as a free thiol in stable form for 7 months at room temperature and up to 24 months under refrigeration. METHODS Study designThe study was designed as two prospective, double masked, randomised trials. The safety study was conducted at the National Eye Institute. The efficacy study was concurrently conducted at the National Eye Institute, University of Michigan School of Medicine and University of California, San Diego, School of Medicine. The protocol was approved by all participating centres' institutional review boards. Study subjectsPatients with cystinosis over 1 year of age, already receiving the standard topical cysteamine formulation, were eligible for the safety study. Exclusi...

Essential Role of Transglutaminase 2 in Vascular Endothelial Growth Factor–Induced Vascular Leakage in the Retina of Diabetic Mice

“…Several low-molecular-weight inhibitors have been reported to prevent TGase2 transamidating activity, and the most widely used TGase inhibitor in vivo is cystamine (23). Cystamine is used for the treatment of corneal crystals in nephropathic cystinosis (34,35). Cystamine was also used in clinical trials of Huntington disease and cystic fibrosis (34,35).…”

“…Cystamine is used for the treatment of corneal crystals in nephropathic cystinosis (34,35). Cystamine was also used in clinical trials of Huntington disease and cystic fibrosis (34,35). Cysteamine, the reduced form of cystamine, was recently reported to restore cystic fibrosis transmembrane conductance regulator function in patients with cystic fibrosis (36).…”

Hematological Manifestations of Nephropathic Cystinosis

“…The proximal tubular impairment (Fanconi syndrome) of cystinosis does not appear to respond to long-term cysteamine therapy [1, 24]. Cystine crystals deposited in the cornea are not dissolved by orally administered cysteamine, though topical cysteamine eyedrops are effective in ameliorating photophobia and decreasing the risk of blepharospasm [23, 25]. The drops can dissolve corneal cystine crystals almost completely within 1–2 years [26].…”

Ophthalmic Manifestations and Histopathology of Infantile Nephropathic Cystinosis: Report of a Case and Review of the Literature

“…17 In several single-center and one multicenter trial, topical cysteamine treatment has proven safe and efficient in dissolving corneal crystals in both young and old cystinosis patients; it also significantly alleviates the symptoms of photophobia, blepharospasm and eye pain. 8,10,48,49,51,53,54,59,60,73,93 The recommended regimen is a 0.55% (50 mM) cysteamine hydrochloride solution with benzalkonium chloride 0.01% as a preservative, used 10-12 times per day. 60 It is important to note that, at room temperature, the active free thiol, cysteamine, oxidizes to the disulfide form, cystamine, requiring shipping and storage of the topical solution in the frozen state.…”