Cyclosporine Implant for Ocular Graft-Versus-Host Disease

Graft Vs Host Disease Clinical Trial

Official title: A Phase I Clinical Trial to Study the Safety of a Sustained-Release Subconjunctival Cyclosporine Implant for Ocular Graft-vs-Host Disease (GVHD1)

Status Completed

Clinical Trial Summary

Graft-vs.-Host Disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (SCT) commonly affecting the skin, liver, gastrointestinal tract, and eye. The most common clinical manifestations of ocular GVHD generally result from

involvement of the lacrimal gland and the conjunctiva. Lacrimal gland involvement can lead to aqueous tear deficiency resulting in severe keratoconjunctivitis sicca (KCS) which can significantly increase the morbidity of patients with chronic GVHD.

Systemic immunosuppressants such as cyclosporine (CsA) can be effective for treating ocular GVHD including lacrimal gland dysfunction. However, systemic immunosuppression is not generally prescribed for patients whose sole manifestation of GVHD is ocular complications as it may negate the overall graft-vs.-tumor effect and decrease patient survival. Topical CsA and corticosteroids are generally not effective for treating aqueous tear deficiency possible due to epithelial barriers preventing penetration of the drugs to the lacrimal gland. A sustained-release subconjunctival CsA implant was developed to bypass these epithelial barriers and significantly increase the CsA concentrations in the lacrimal gland to treat aqueous tear deficiency related to GVHD.

The objective of this randomized pilot study is to investigate the safety and potential efficacy of a CsA implant in patients with lacrimal gland involvement and aqueous tear deficiency related to GVHD. Safety will be evaluated in terms of adverse events related to the implant. Efficacy will be evaluated by changes in Schirmer tear test (with anesthesia). Secondary efficacy evaluation will include changes in corneal and conjunctival staining grades, best-corrected visual acuity (BCVA), the Ocular Surface Disease Index (OSDI), changes in conjunctival GVHD grades, tear break-up time and meibomian gland dysfunction.

Patients with active systemic GVHD with aqueous tear deficiency associated with lacrimal gland dysfunction following allogeneic hematopoietic SCT who are nine years of age or older are eligible for inclusion in this pilot study. The study will involve surgical placement of the CsA implant into the subconjunctival space adjacent to the lacrimal gland of one eye in each participant. Participants older than 12 years of age will be randomized to receive one of two implant release rates. All participants under the age of 12 will receive the smaller, lower dose implant. However, all participants under age 12 will not be randomized and will only be eligible to receive the smaller, lower dose implant.

The implant will remain in place for up to two years and then be removed. IF the participant has clinical success, they will be given the option of allowing the implant to remain in place for an additional year. Clinical success is achieved if the participant meets any of the following measures in either eye assessed at the 1-year visit:

Interval change from baseline characteristics

Decrease in corneal staining by greater than or equal to 2

Decrease in temporal or nasal conjunctival staining grades by greater than or equal to 2

Decrease in total staining grade by greater than or equal to 2

Decrease in OSDI calculated score by greater than or equal to 20%

Increase in Schirmer tear test measurement by greater than or equal to 3 mm

Meets mild-moderate KCS characteristics at 1 year

Corneal staining grade less than or equal to 3

Nasal or temporal conjunctival staining grades less than or equal to 3

OSDI calculated score less than or equal to 15

Schirmer tear test measurement greater than or equal to 5 mm

For participants with implant duration of one year, safety evaluations will be conducted at baseline (pre-implantation) and monthly post-implantation for 13 months. Additional safety assessments will be done at 1 day, and at 1 and 2 weeks post-operatively for implant placement and removal procedures. Safety and efficacy evaluations will be conducted at baseline, at 1, 3, 6, 9, and 12 months post-implantation, and at 3 months following implant removal (15 months post-implantation). For participants with clinical success and who choose the implant to remain for another year, visits will be held as described above then conducted at 2-month intervals starting at month 14. Safety evaluations will be conducted every 2 months until the end of the second year. Additional safety assessments will be done at 1 day, and at 1 and 2 weeks post-operatively for implant removal procedures. Safety and efficacy evaluations will be conducted at 16, 20, and 24 months post-implantation, and at 3 months following implant removal (27 months post-implantation).

Clinical Trial Description

The objective of this randomized pilot study is to investigate the safety and potential efficacy of a CsA implant in participants with lacrimal gland involvement and aqueous tear deficiency related to GVHD. Safety will be evaluated in terms of adverse events related to the implant. Efficacy will be evaluated by changes in Schirmer tear test (with anesthesia). Secondary efficacy evaluation will include changes in corneal and conjunctival staining grades, best-corrected visual acuity (BCVA), the Ocular Surface Diseases Index (OSDI), changes in conjunctival GVHD grades, tear break-up time and meibomian gland dysfunction.

Participants with active systemic GVHD with aqueous tear deficiency associated with lacrimal gland dysfunction following allogeneic hematopoietic SCT who are nine years of age or older are eligible for inclusion in this pilot study. The study will involve surgical placement of the CsA implant into the subconjunctival space adjacent to the lacrimal gland of one eye in each participant. Participants older than 12 years of age will be randomized to receive one of two implant release rates. However, all participants under age 12 will not be randomized and will only be eligible to receive the smaller, lower dose implant. On each anniversary study visit a participant will be given the opportunity to retain the implant on an annual basis. This will be based upon the determination of clinical success (defined in the Study Design section below) combined with a participant's report of symptom improvement. The Implant will be removed if the Investigator believes the implant is harmful or if the participant requests the implant to be removed. ;

Related Conditions & MeSH terms

• Graft Vs Host Disease

• NCT number: NCT00102583
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: October 14, 2004
• Completion date: March 15, 2011