A Randomized Clinical Trial of Ex Vivo Corneal Cross-Linking of Donor Keratoplasty Tissue for Keratoconus Used for Keratoplasty in Keratoconus Patients

Study Overview
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Brief Summary
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This randomized clinical trial will assess corneal astigmatism and visual outcomes in participants who have undergone corneal transplantation for keratoconus with ex vivo cross-linked donor corneal tissue versus participants who have undergone corneal transplantation for keratoconus with non-cross-linked donor corneas. Crosslinking is a procedure that stabilizes the biomechanical properties of the cornea; as a result, the cornea stiffens. It has been shown that this procedure stabilizes the cornea of patients with keratoconus or corneal ectasias. The FDA currently approves crosslinking for patients with progressive keratoconus and corneal ectasia following refractive surgery. Ex vivo crosslinking of donor corneal tissue for patients with keratoconus undergoing PK or DALK could stabilize the cornea and reduce the risk of high astigmatism and improve vision in patient with keratoconus.

Detailed Description
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The 15 clinical sites are expected to recruit cumulatively 216 cases over 18 months. Eligibility is assessed during a routine examination by an investigator. Informed consent will be obtained prior to collecting any information that is not part of usual care. Patients who meet all inclusion criteria and none of the exclusion criteria will be given the opportunity to participate in the study. Participants will be randomly assigned to the treatment group (cross-linked corneal tissue) or control group (non-cross-linked corneal tissue that has been exposed to riboflavin, but no ultraviolet light). The investigator will request a cadaveric cornea from the study's central eye bank CorneaGen, which will prepare the cadaveric cornea. Participants will receive the cross-linked donor tissue or control donor tissue during surgery. Clinical sites, including surgeons, and participants will be masked to treatment assignment. Participants will be followed up post-operatively by the site investigators as per the standard of care. This will include visits at 1 Day, 1 Week, 1 Month, 6 Months, 1 Year, 1.5 Years, 2 Years, and 2.5 Years post-surgery. Some participants may need to be seen more regularly for routine care. The investigators will monitor for systemic and ocular adverse events at all follow-up visits.

Official Title
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A Randomized Clinical Trial of Ex Vivo Corneal Cross-Linking of Donor Keratoplasty Tissue for Keratoconus

Conditions
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Keratoconus

Intervention / Treatment
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* Drug: Riboflavin 5'-phosphate in 20% dextran ophthalmic solution) 0.146% with UV light
* Drug: Riboflavin 5'-phosphate in 20% dextran ophthalmic solution) 0.146% without UV light


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent. Willing and able to comply with study assessments for the full duration of the study. Age ≥18 years but ≤50 years History of keratoconus (without a previous transplant) requiring keratoplasty Willing to commit to not having further cross-linking, corneal relaxing incisions, intacs, or corneal laser vision correction during the course of the study Exclusion Criteria: Age < 18 years >50 Inability to provide written informed consent and comply with study assessments for the full duration of the study Participation in another simultaneous interventional medical investigation or trial Systemic History of Stevens-Johnson syndrome or ocular pemphigoid Signs of current infection, including fever and current treatment with antibiotics Pregnancy (positive pregnancy test) or lactating Pre-menopausal sexually active women not using adequate contraception (Reliable intrauterine devices, hormonal contraception or a spermicide in combination with a barrier method) Recipient Eye Corneal or ocular surface infection within 30 days prior to study entry History of previous cross-linking History of previous corneal transplant Non-healing epithelial defect of at least 0.5x0.5 mm in host corneal bed lasting ≥6 weeks preoperatively Ocular or periocular malignancy Lid abnormalities that in the opinion of the investigator could confound the study results and these include clinically significant ectropion, lagophthalmos, cicatrization, entropion, and rosacea Neurotrophic cornea Monocular Uncontrolled glaucoma Glaucoma filtering devices or trabeculectomies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is a multicenter, double-masked, parallel, and randomized study with a subsequent follow-up period of 30 months. 216 subjects (of any race or gender) who have keratoconus (between the ages of 18 and 50) will sign the consent for their first PK or DALK surgery in the study eye. Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion criteria and none of the exclusion criteria will be given the opportunity to participate in the study. Subjects will either randomized to the treatment group (crosslinked corneal tissue) or control group (non-crosslinked corneal tissue that has been exposed to riboflavin, but no ultraviolet light).
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ex vivo cross linking of donor corneal tissue<br>Treatment Arm: The donor corneal tissue used in the PK or DALK procedures will previously undergo ex vivo crosslinking. | Drug: Riboflavin 5'-phosphate in 20% dextran ophthalmic solution) 0.146% with UV light<br>* A wavelength of 365 nm ultraviolet A light will be used to direct 5.4 J/cm2 using a beam diameter of 9.5mm to treat the de-epithelialized corneal surface of a donor cornea for 30 minutes. Every 2 minutes, the UV light will be used while another drop of riboflavin is applied on top of the donor cornea.<br>* Other names: PHOTREXA VISCOUS;|
| Sham Comparator: Non-cross-linked donor corneal tissue for keratoplasty<br>Control Arm: The donor corneal tissue used in the PK or DALK procedures will not previously undergo ex vivo crosslinking. | Drug: Riboflavin 5'-phosphate in 20% dextran ophthalmic solution) 0.146% without UV light<br>* The corneal tissue for the control arm will be treated the same as the crosslinked tissue except that it will not be exposed to ultraviolet light. The donor cornea will be placed on an artificial anterior chamber maintainer and the epithelium will be removed mechanically. Riboflavin solution (0.1% riboflavin and 20% dextran supplied in a sterile, single-dose container) will be applied to the cornea every 2 minutes for 30 minutes.<br>* Other names: PHOTREXA VISCOUS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Keratometric astigmatism with Pentacam Schiempflug imaging at 130 weeks post-surgery. | • Keratometric astigmatism with Pentacam Schiempflug imaging at 130 weeks post-surgery | 130 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Best spectacle corrected visual acuity (BSCVA) with ETDRS methodology at 2.5 years (130 weeks) post-surgery | • Best spectacle corrected visual acuity (BSCVA) with ETDRS methodology at 2.5 years (130 weeks) post-surgery | 130 weeks | 
| Manifest cylinder astigmatism at 130 weeks post-surgery | Manifest cylinder astigmatism at 130 weeks post-surgerykeratometry, anterior mean keratometry, posterior mean keratometry | 130 weeks | 
| Uncorrected visual acuity (UCVA) 130 weeks post-surgery | Uncorrected visual acuity (UCVA) 130 weeks post-surgery | 130 weeks | 
| Low-contrast BSCVA with ETDRS methodology at 130 weeks post-surgery | Low-contrast BSCVA with ETDRS methodology at 130 weeks post-surgerypermeable contact lens. | 130 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Corneal Crosslinking, Penetrating Keratoplasty, Deep Anterior Lamellar Keratoplasty