Cysteamine Eye Drops to Treat Corneal Crystals in Cystinosis
Study Details
Study Description
Brief Summary
Cystinosis is an inherited disease that results in poor growth and kidney disease, among other things. The damage to the kidneys and other organs is thought to be due to accumulation of cystine inside the cells of various body tissues. This chemical also accumulates in the cornea-the covering of the eye over the pupil and iris. After 10 to 20 years, the corneas of some patients become so packed with crystals that the surfaces may become irregular, occasionally causing small, painful breaks.
Patients enrolled in a NIH study on cystinosis are receiving the drug cysteamine. Taken by mouth, this drug reduces cystine in some tissues, but not in the cornea. This study began in 1986 to test whether cysteamine eye drops could prevent or reduce corneal cystine crystals in these patients. The drops have been very effective in removing crystals and reducing pain in patients who take the medication as directed. Patients who do not take the medication as prescribed do not benefit.
After the effectiveness of the drops was proven, the main purpose was modified to continue to evaluate the long-term safety and effectiveness of cysteamine eye drops for treating cystine crystals in the corneas of patients with cystinosis until the drops are approved by the Food and Drug Administration (FDA). When the New Drug Application (NDA) for the Sigma-Tau standard formulation is granted, this protocol will be terminated.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cysteamine topical solution Cysteamine topical solution administered hourly while awake in both eyes |
Drug: Cysteamine
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Serious and Non-Serious Adverse Events [Any Time Point up to 27 Years]
Since efficacy of ophthalmic cysteamine was established and a New Drug Application (NDA) filed, the post-hoc primary outcome measure is the evaluation of safety information. There was no specified time frame for this outcome measure, as safety data was being collected until the drug became available for commercial purchase in May 2013.
- Number of Eyes With a Corneal Cystine Crystal Score (CCCS) Response [Any Time Point Up to 19 Years]
Response is defined as a decrease from baseline of at least 1 in Corneal Cystine Crystal Score (CCCS) at any time on study when baseline CCCS is greater than or equal to 1, or CCCS does not increase at least 1 at any time on study when baseline CCCS is less than 1. The CCCS is based on a library of slit-lamp photographs of corneas with increasing crystal densities (0-3). Slit-lamp photos were to be taken to assess the extent of the corneal crystal accumulation. To minimize bias when assessing the extent of corneal crystal accumulation, photos were centrally graded at the National Eye Institute (NEI) where each photo was graded independently by masked graders. If more than one CCCS was recorded in a given study year, the highest (worst) CCCS value was used for that year. The results were obtained from a combined analyses of the NIH cysteamine studies evaluating various cysteamine ophthalmic solution formulations from 1986 through 2005.
Eligibility Criteria
Criteria
INCLUSION CRITERIA:
-
Patients must have a documented clinical diagnosis of cystinosis.
-
Patients should be 2 years old or older.
EXCLUSION CRITERIA:
-
Inability to travel to NIH for a baseline examination, after 1 year, and every two years thereafter for follow-up
-
Inability to cooperate for slit-lamp examination
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Eye Institute (NEI)
Investigators
- Principal Investigator: Rachel J Bishop, M.D., National Eye Institute (NEI)
Study Documents (Full-Text)
None provided.More Information
Publications
- Gahl WA, Kuehl EM, Iwata F, Lindblad A, Kaiser-Kupfer MI. Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eyedrops. Mol Genet Metab. 2000 Sep-Oct;71(1-2):100-20. Review.
- Gahl WA. Cystinosis coming of age. Adv Pediatr. 1986;33:95-126. Review.
- Iwata F, Kuehl EM, Reed GF, McCain LM, Gahl WA, Kaiser-Kupfer MI. A randomized clinical trial of topical cysteamine disulfide (cystamine) versus free thiol (cysteamine) in the treatment of corneal cystine crystals in cystinosis. Mol Genet Metab. 1998 Aug;64(4):237-42.
- Kaiser-Kupfer MI, Fujikawa L, Kuwabara T, Jain S, Gahl WA. Removal of corneal crystals by topical cysteamine in nephropathic cystinosis. N Engl J Med. 1987 Mar 26;316(13):775-9.
- Kaiser-Kupfer MI, Gazzo MA, Datiles MB, Caruso RC, Kuehl EM, Gahl WA. A randomized placebo-controlled trial of cysteamine eye drops in nephropathic cystinosis. Arch Ophthalmol. 1990 May;108(5):689-93.
- 860062
- 86-EI-0062
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Cysteamine Topical Solution |
|---|---|
| Arm/Group Description | Cysteamine topical solution administered hourly while awake in both eyes Cysteamine |
| Period Title: Overall Study | |
| STARTED | 328 |
| COMPLETED | 310 |
| NOT COMPLETED | 18 |
Baseline Characteristics
| Arm/Group Title | Cysteamine Topical Solution |
|---|---|
| Arm/Group Description | Cysteamine topical solution administered hourly while awake in both eyes Cysteamine |
| Overall Participants | 328 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
13.1
(10.04)
|
| Gender (participants) [Number] | |
| Female |
153
46.6%
|
| Male |
173
52.7%
|
Outcome Measures
| Title | Number of Participants With Serious and Non-Serious Adverse Events |
|---|---|
| Description | Since efficacy of ophthalmic cysteamine was established and a New Drug Application (NDA) filed, the post-hoc primary outcome measure is the evaluation of safety information. There was no specified time frame for this outcome measure, as safety data was being collected until the drug became available for commercial purchase in May 2013. |
| Time Frame | Any Time Point up to 27 Years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Cysteamine Topical Solution |
|---|---|
| Arm/Group Description | Cysteamine topical solution administered hourly while awake in both eyes Cysteamine |
| Measure Participants | 328 |
| Number [participants] |
257
78.4%
|
| Title | Number of Eyes With a Corneal Cystine Crystal Score (CCCS) Response |
|---|---|
| Description | Response is defined as a decrease from baseline of at least 1 in Corneal Cystine Crystal Score (CCCS) at any time on study when baseline CCCS is greater than or equal to 1, or CCCS does not increase at least 1 at any time on study when baseline CCCS is less than 1. The CCCS is based on a library of slit-lamp photographs of corneas with increasing crystal densities (0-3). Slit-lamp photos were to be taken to assess the extent of the corneal crystal accumulation. To minimize bias when assessing the extent of corneal crystal accumulation, photos were centrally graded at the National Eye Institute (NEI) where each photo was graded independently by masked graders. If more than one CCCS was recorded in a given study year, the highest (worst) CCCS value was used for that year. The results were obtained from a combined analyses of the NIH cysteamine studies evaluating various cysteamine ophthalmic solution formulations from 1986 through 2005. |
| Time Frame | Any Time Point Up to 19 Years |
Outcome Measure Data
| Analysis Population Description |
|---|
| One hundred sixty-one (161) participants were analyzed in the pre-specified intent-to-treat population [defined as patients who received study medication (between 1986 and 2005), and had a baseline and a post-baseline CCCS value]. After 2005, all participants enrolled received open-label treatment and only safety data was obtained. |
| Arm/Group Title | Cysteamine Topical Solution |
|---|---|
| Arm/Group Description | Cysteamine topical solution administered hourly while awake in both eyes Cysteamine |
| Measure Participants | 161 |
| Measure eyes | 321 |
| Number [eyes] |
98
|
Adverse Events
| Time Frame | Adverse events (AEs) were collected throughout the study. No specified time period is noted, as participants were followed until the drug became available commercially. | |
|---|---|---|
| Adverse Event Reporting Description | Cystinosis patients typically have multiple medical problems, including kidney failure. The AEs reported do not reflect these systemic problems, focusing instead on ocular AEs (e.g., renal failure is noted in only 2 of 328 patients, though the majority have been managed for kidney disease and/or failure and have received a kidney transplant). | |
| Arm/Group Title | Cysteamine Topical Solution | |
| Arm/Group Description | Cysteamine topical solution administered hourly while awake in both eyes Cysteamine | |
All Cause Mortality |
||
| Cysteamine Topical Solution | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Cysteamine Topical Solution | ||
| Affected / at Risk (%) | # Events | |
| Total | 11/328 (3.4%) | |
| Eye disorders | ||
| Optic disc disorder | 1/328 (0.3%) | 1 |
| Blindness | 1/328 (0.3%) | 1 |
| Gastrointestinal disorders | ||
| Intestinal obstruction | 1/328 (0.3%) | 1 |
| Infections and infestations | ||
| Gastrointestinal infection | 1/328 (0.3%) | 1 |
| Nervous system disorders | ||
| Benign intracranial hypertension | 8/328 (2.4%) | 8 |
| Renal and urinary disorders | ||
| Renal failure | 2/328 (0.6%) | 2 |
Other (Not Including Serious) Adverse Events |
||
| Cysteamine Topical Solution | ||
| Affected / at Risk (%) | # Events | |
| Total | 257/328 (78.4%) | |
| Eye disorders | ||
| Photophobia | 239/328 (72.9%) | 239 |
| Conjunctival hyperaemia | 69/328 (21%) | 69 |
| Eye pain | 66/328 (20.1%) | 66 |
| Ocular hyperaemia | 52/328 (15.9%) | 52 |
| Eye irritation | 49/328 (14.9%) | 49 |
| Lacrimation increased | 23/328 (7%) | 23 |
| Optic disc disorder | 19/328 (5.8%) | 19 |
| Vision blurred | 20/328 (6.1%) | 20 |
| Keratitis | 19/328 (5.8%) | 19 |
| Dry eye | 14/328 (4.3%) | 14 |
| Eye pruritis | 13/328 (4%) | 13 |
| Conjunctivitis | 12/328 (3.7%) | 12 |
| Eyelid oedema | 12/328 (3.7%) | 12 |
| Retinal disorder | 11/328 (3.4%) | 11 |
| Blindness | 9/328 (2.7%) | 9 |
| Corneal epithelium disorder | 6/328 (1.8%) | 6 |
| Blepharitis | 5/328 (1.5%) | 5 |
| Erythema of eyelid | 5/328 (1.5%) | 5 |
| Eye swelling | 3/328 (0.9%) | 3 |
| Conjunctival oedema | 2/328 (0.6%) | 2 |
| Eye oedema | 1/328 (0.3%) | 1 |
| Eyelid cyst | 1/328 (0.3%) | 1 |
| Eyelid irritation | 1/328 (0.3%) | 1 |
| Ulcerative keratitis | 1/328 (0.3%) | 1 |
| Drug ineffective | 1/328 (0.3%) | 1 |
| Gastrointestinal disorders | ||
| Vomiting | 8/328 (2.4%) | 8 |
| Abdominal pain | 1/328 (0.3%) | 1 |
| General disorders | ||
| Instillation site irritation | 33/328 (10.1%) | 33 |
| Instillation site pain | 22/328 (6.7%) | 22 |
| Adverse drug reaction | 7/328 (2.1%) | 7 |
| Instillation site erythema | 5/328 (1.5%) | 5 |
| Swelling | 2/328 (0.6%) | 2 |
| Instillation site lacrimation | 1/328 (0.3%) | 1 |
| Instillation site reaction | 1/328 (0.3%) | 1 |
| Immune system disorders | ||
| Drug hypersensitivity | 2/328 (0.6%) | 2 |
| Infections and infestations | ||
| Eye infection | 6/328 (1.8%) | 6 |
| Conjunctivitis ineffective | 3/328 (0.9%) | 3 |
| Hordeolum | 3/328 (0.9%) | 3 |
| Investigations | ||
| Visual evoked potentials abnormal | 1/328 (0.3%) | 1 |
| Nervous system disorders | ||
| Headache | 94/328 (28.7%) | 94 |
| Visual field defect | 35/328 (10.7%) | 35 |
| Benign intracranial hypertension | 4/328 (1.2%) | 4 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Rachel J. Bishop, MD, Principal Investigator, National Eye Institute |
|---|---|
| Organization | National Institutes of Health |
| Phone | 301-402-3771 |
| bishopra@nei.nih.gov |
- 860062
- 86-EI-0062