Cysteamine hydrochloride eye drop solution for the treatment of corneal cystine crystal deposits in patients with cystinosis: an evidence-based review

Figures & data

Table 1 Summary of efficacy studies of cysteamine hydrochloride eye drop solutions

Study		Year of publication	Location			Duration of investigations	Type of study	Number of patients	Mean age	Inclusion criteria	End point	Drug under investigation	Results
Kaiser- Kupfer et al^Citation57		1990	Bethesda, Maryland, USA			November 1985 to September 1989	Double- blind randomized placebo- controlled	25	7.2±8.3 years	Typical clinical presentation Leukocyte cysteine concentration of >3 nmol half- cystine/mg protein (normal <0.2) All patients under age 4 on oral cysteamine	Blinded observers Difference in the density of corneal crystals in the two eyes and a decrease in the corneal cystine crystal density in the “better” eye from previous visit Library of standard transparency slides with a corneal cystine crystal score using arbitrary scale from 0 to 3.00 (0.125 increments)	0.1%–0.5% cysteamine hydrochloride drops (in 0.9% NaCl) in one eye Versus 0.9% NaCl in the second eye 1-hourly during waking hours National Institutes of Health Clinical Center’s Pharmaceutical Development Service	10 reached end point (8/16 from the group under age of 4 years and 2/9 from the group between ages 4–31 years) (p<0.002)
Jones et al^Citation58		1991	Manchester, UK			NA	Case report	1	2 years	Typical clinical presentation	Nonblinded observer Clinical and photographic change of corneal cystine crystal density	0.5% cysteamine eye drops in one eye (nil other details) 1-hourly during waking hours	Complete clearance of visual axis and significant but incomplete clearance of peripheral cornea
Bradbury et al^Citation59		1991	Leeds, UK		December 1989 to May 1990		Double- blind randomized placebo- controlled	5	11.2±3.3 years	Typical clinical presentation >3 nmol half- cystine/mg protein or fibroblast culture 4/5 patients on oral cysteamine	Blinded observers Corneal cysteine crystal score using arbitrary scale from 0 to 4.00 (0.5 increments)	0.2% cysteamine hydrochloride +0.9% NaCl + disodium edetate 0.02% in one eye Versus 0.9% NaCl in the second eye Six times per day Pharmacy Department, St James’ Hospital, Leeds, UK	All patients had at least a 0.5 unit improvement in crystal density score
Iwata et al^Citation60		1998	Bethesda, Maryland, USA		NA		Double- blind randomized	14	15.2±9.5 years	Typical clinical presentation >3 nmol half- cystine/mg protein All patients had oral cysteamine	Blinded observers Corneal cysteine crystal score using arbitrary scale from 0 to 3.00 (0.25 increments)	0.5% cysteamine with BAC 0.01% in one eye versus 0.5% cystamine with BAC 0.01% in the second eye 1-hourly during waking hours National Institutes of Health Pharmaceutical Development Service under Investigational New Drug No 45321	Mean reduction in corneal density score of 1.02 units in the cysteamine eyes compared to 0.07 unit reduction in cystamine eyes (p=0.015)
Tsilou et al^Citation61		2003	Bethesda, Maryland, USA		September 1998 to July 1999		Double- blind randomized	15	6 years (2–11 years)	Typical clinical presentation >2 nmol half- cystine/mg protein	Blinded observers Corneal cystine crystal score using arbitrary units 0–3.00 (0.25 increments)	Cysteamine hydrochloride 0.55% with BAC 0.01% in one eye National Institutes of Health Pharmaceutical Development Service under Investigational New Drug No 40593 Versus cysteamine hydrochloride 0.55% with monosodium phosphate 1.85%, disodium EDTA 0.1%, BAC 0.01% in the second eye Sigma-Tau Pharmaceuticals (amendment to INDNo 40593) 1-hourly during waking hours	Median reduction in corneal cysteine crystal score of 0.75 with the standard formulation and no change with the new formulation (p=0.0005)
Al- Hemidan et al^Citation62		2017	King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia		2004–2012		Prospective study	32	8 years (8 months to 19 years)	Typical clinical presentation >2 nmol half- cystine/mg protein	Clinical assessment of corneal cysteine crystal score 0= no crystals 1=1–10 crystals/mm^2 2=11–50 crystals/mm^2 3=>50 crystals/mm^2	Cysteamine 0.55% to both eyes 2-hourly during waking hours King Faisal Specialist Hospital & Research Center pharmacy	21 patients had a stable score and 11 patients had worsening of the score (p=0.037)
Labbé et al^Citation63	2014			Quinze-Vingts National Eye Center, Paris, France	January 2008 to March 2012		Phase I/IIa Open-label Dose– response, pilot study (The Cystadrops OCT-1 Study)	8	12.1±4.6 years	Typical clinical presentation >1.5 nmol half- cystine/mg protein All patients received oral cysteamine	In vivo confocal microscopy total score of corneal cysteine crystal density on both epithelium and stroma independently using a 400×400 µm image area 0= no crystals 1=<25% area 2=25%–50% area 3=50%–75% area 4=>75% area	Cysteamine hydrochloride 0.1% in both eyes for 1 month Pharmacie Centrale des Hopitaux de Paris (AGEPS), Paris, France Versus Cystadrop^® gel – Cysteamine hydrochloride 0.55%, carmellose sodium, BAC, disodium edetate, citric acid monohydrate, sodium hydroxide, 0.1 M hydrochloric acid, purified water on dark bottles in both eyes till 4 years Orphan Europe, France Initial dosage 4.0±0.5 drops per day and titrated after3 months and remained between 1 and 4 drops per day per eye	IVCM score was stable with 0.1% cysteamine hydrochloride treatment at 11.38±2.94, from a baseline score of 11.38±3.30 IVCM score significantly reduced with Cystadrop gel from baseline to 8.13±4.15 by 29.9%±26.29% (p=0.001)
Liang et al^Citation64	2017			Quinze-Vingts National Eye Center, Paris, France	January 2013 to June 2013		Open-label randomized phase III trial	31	17.1±13.0 years	Typical clinical presentation >1.5 nmol half- cystine/mg protein	In vivo confcal microscopy total score of corneal cysteine crystal density on both epithelium and stroma independently using a 400×400 µm image area 0= no crystals 1=<25% area 2=25%–50% area 3=50%–75% area 4=>75% area Corneal cystine crystal score using arbitrary units from 0 to 3.00 (0.25 increments)	Cysteaine hydrochloride 0.55%, carmellose sodium (similar to Cystadrop gel) in both eyes Versus cysteamine hydrochloride 0.1% in both eyes Four times per day AP-HP Hospital pharmacies (AGEPS), Paris, France	IVCM score reduced to 6.0±2.1 by 40.4%±16.0% from baseline score of 10.6±4.2 in the cysteamine 0.55% gel group and to 9.8±3.8 by 0.7%±33.0% from baseline score of 0.8±3.5 in the cysteamine 0.1% group (p<0.0001) CCCS reduced by 0.59±0.52 from 2.26±0.56 in the cysteamine 0.55% gel group and increased by 0.11±0.24 from 1.98±0.50 (p=0.0015)

Abbreviations: AGEPS, Pharmacie Centrale des Hôpitaux de Paris; BAC, benzalkonium chloride; CCCS, Corneal Cystine Crystal Scoring; EDTA, edetate; IND, Investigational New Drug; IVCM, in vivo confocal microscopy; NaCl, sodium chloride.

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