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

Official title

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

Overview

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

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.

Interventions

• Drug Riboflavin 5'-phosphate in 20% dextran ophthalmic solution) 0.146% with UV light
  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.
• Drug Riboflavin 5'-phosphate in 20% dextran ophthalmic solution) 0.146% without UV light
  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.

Primary outcome measures

• • Keratometric astigmatism with Pentacam Schiempflug imaging at 130 weeks post-surgery. [Time frame: 130 weeks]

Secondary outcome measures (4)

• • Best spectacle corrected visual acuity (BSCVA) with ETDRS methodology at 2.5 years (130 weeks) post-surgery [Time frame: 130 weeks]
• Manifest cylinder astigmatism at 130 weeks post-surgery [Time frame: 130 weeks]
• Uncorrected visual acuity (UCVA) 130 weeks post-surgery [Time frame: 130 weeks]
• Low-contrast BSCVA with ETDRS methodology at 130 weeks post-surgery [Time frame: 130 weeks]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Massachusetts Eye and Ear Infirmary — Boston

Publications

• Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol. 1984 Jan-Feb;28(4):293-322. doi: 10.1016/0039-6257(84)90094-8. PMID 6230745
• Tan DT, Por YM. Current treatment options for corneal ectasia. Curr Opin Ophthalmol. 2007 Jul;18(4):284-9. doi: 10.1097/ICU.0b013e3281a7ecaa. PMID 17568202
• Yoshida J, Murata H, Miyai T, Shirakawa R, Toyono T, Yamagami S, Usui T. Characteristics and risk factors of recurrent keratoconus over the long term after penetrating keratoplasty. Graefes Arch Clin Exp Ophthalmol. 2018 Dec;256(12):2377-2383. doi: 10.1007/s00417-018-4131-5. Epub 2018 Sep 8. PMID 30196480
• Bechrakis N, Blom ML, Stark WJ, Green WR. Recurrent keratoconus. Cornea. 1994 Jan;13(1):73-7. doi: 10.1097/00003226-199401000-00012. PMID 8131410
• Abelson MB, Collin HB, Gillette TE, Dohlman CH. Recurrent keratoconus after keratoplasty. Am J Ophthalmol. 1980 Nov;90(5):672-6. doi: 10.1016/s0002-9394(14)75135-9. PMID 7004192
• Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008 May;34(5):796-801. doi: 10.1016/j.jcrs.2007.12.039. PMID 18471635
• Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003 May;135(5):620-7. doi: 10.1016/s0002-9394(02)02220-1. PMID 12719068
• Kelly TL, Williams KA, Coster DJ; Australian Corneal Graft Registry. Corneal transplantation for keratoconus: a registry study. Arch Ophthalmol. 2011 Jun;129(6):691-7. doi: 10.1001/archophthalmol.2011.7. Epub 2011 Feb 14. PMID 21320951

Identifiers

NCT: NCT04584125 · 2020P002132

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗