CystinosisPhase 2NCT00001213
Cysteamine Eye Drops to Treat Corneal Crystals in Cystinosis
A Phase 2 study testing Cysteamine in people with Cystinosis, run by National Eye Institute (NEI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 years and older
- Conditions the study is for
- Cystinosis
- What is being tested?
- Cysteamine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 328 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 1986to Jul 2013
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Patients must have a documented clinical diagnosis of cystinosis.
- Patients should be 2 years old or older.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Trial of Topical Cysteamine in the Treatment of Corneal Cystine Crystal Accumulation in Cystinosis
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.
Read the 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.
- Conditions
- Cystinosis
- Being tested
- Cysteamine
- Keywords
- Cysteamine Eye Drops, Nephropathic Cystinosis, Corneal Crystals, Benzalkonium, Toxicity, Efficacy, Cystinosis
- Medical subject headings
- Cystinosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CysteamineDrug
| Study group | Role | What they receive |
|---|---|---|
| Cysteamine topical solution | Experimental | Cysteamine topical solution administered hourly while awake in both eyes Receives: Drug: Cysteamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Serious and Non-Serious Adverse Events
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.
Measured: Any Time Point up to 27 Years
Number of Eyes With a Corneal Cystine Crystal Score (CCCS) Response
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.
Measured: Any Time Point Up to 19 Years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 1999 (estimated)
- Study startApr 1986
- Primary completionJul 2013
- Study completionJul 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for CystinosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 328 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Eye Institute (NEI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Rachel J Bishop, M.D., Principal investigator, National Eye Institute (NEI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00001213
- Sponsor's protocol ID
- 860062
- Other IDs
- 86-EI-0062
- Status last verified
- Jun 2014
- First submitted
- 3 Nov 1999
- Last updated
- 22 Jul 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
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. doi: 10.1056/NEJM198703263161304.
PubMed 3821824Kaiser-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. doi: 10.1001/archopht.1990.01070070075038.
PubMed 2185723Gahl WA. Cystinosis coming of age. Adv Pediatr. 1986;33:95-126. No abstract available.
PubMed 3541536Gahl 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. doi: 10.1006/mgme.2000.3062.
PubMed 11001803Iwata 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. doi: 10.1006/mgme.1998.2725.
PubMed 9758713
Study at a glance
From the registry record, last updated by the sponsor on 22 Jul 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Trial of Topical Cysteamine in the Treatment of Corneal Cystine Crystal Accumulation in Cystinosis
- ClinicalTrials.gov ID
- NCT00001213
- Acronym / sponsor ID
- 860062
- Conditions
- Cystinosis
- Keywords
- Cysteamine Eye Drops, Nephropathic Cystinosis, Corneal Crystals, Benzalkonium, Toxicity, Efficacy, Cystinosis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 328 participants (actual)
- Lead sponsor
- National Eye Institute (NEI)US National Institutes of Health
- Study start
- Apr 1986
- Primary completion
- Jul 2013 (actual)
- Study completion
- Jul 2013 (actual)
- First posted
- 4 Nov 1999 (estimated)
- Results
- Posted 22 Jul 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Cysteamine topical solution | Experimental | Drug: CysteamineCysteamine topical solution administered hourly while awake in both eyes |
Who may qualify
- Ages
- 2 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (2 listed)
- Patients must have a documented clinical diagnosis of cystinosis.
- Patients should be 2 years old or older.
Key exclusion criteria (2 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cysteamine | Drug | Cysteamine topical solution |
Primary outcome
Number of Participants With Serious and Non-Serious Adverse Events
Time frame: 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
Time frame: 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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jul 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 3821824Kaiser-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. doi: 10.1056/NEJM198703263161304.
- Background: PubMed 2185723Kaiser-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. doi: 10.1001/archopht.1990.01070070075038.
- Background: PubMed 3541536Gahl WA. Cystinosis coming of age. Adv Pediatr. 1986;33:95-126. No abstract available.
- Background: PubMed 11001803Gahl 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. doi: 10.1006/mgme.2000.3062.
- Background: PubMed 9758713Iwata 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. doi: 10.1006/mgme.1998.2725.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rachel J Bishop, M.D. principal investigator
National Eye Institute (NEI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Cysteamine in people with Cystinosis, run by National Eye Institute (NEI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Jul 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Jul 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Serious and Non-Serious Adverse Events (time frame: Any Time Point up to 27 Years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00001213, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jul 2014.