A Randomized, Controlled, Double-masked, Clinical Trial of Autologous Serum Eye Drops for Severe Ocular Chronic Graft-versus-host Disease (GVHD) in Hematopoietic Stem Cell Transplant (HSCT) Patients

Graft vs Host Disease Clinical Trial

Official title:

A Randomized, Controlled, Double-Masked, Clinical Trial of Autologous Serum Eye Drops for Severe Ocular Chronic Graft-versus-Host Disease (GVHD) in Hematopoietic Stem Cell Transplant (HSCT) Patients

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT01972438
• Other study ID #: 130206
• Secondary ID: 13-EI-0206
• Status: Suspended
• Phase: Phase 1/Phase 2
• First received: October 23, 2013
• Last updated: January 12, 2016
• Start date: September 2013
• Est. completion date: December 2016

Study information

• Verified date: May 2015
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

Objective:

A common, serious and debilitating long term complication of hematopoietic stem cell transplant (HCST) is chronic graft-versus-host disease (GVHD). Ocular GVHD develops in up to 85% of patients with chronic GVHD. It is characterized by progressive keratitis sicca and cicatrizing ocular inflammatory surface disease with T cell mediated damage to conjunctival and corneal epithelium and lacrimal tissue. Various medical and surgical treatments have been used, such as various lubricating agents, steroid drops and ointments, cyclosporin drops, punctal plugs or cautery and partial tarsorrhaphy. However, in severe cases, none offer acceptable, long-lasting relief from pain, irritation, dryness and diminished vision associated with ocular GVHD. An alternative treatment that has previously been safely investigated is autologous serum eye drops (ASEDs). The objective of this study is to determine whether ASEDs are more effective than control (normal saline) in the treatment of severe chronic ocular GVHD in HSCT patients unresponsive to standard medical treatment.

Study Population:

Eighteen post-HSCT patients with severe ocular GVHD unresponsive to standard medical treatment are enrolled. Initially, 34 post-HSCT patients with severe ocular GVHD unresponsive to standard medical treatment were to be enrolled. However, only 18 are enrolled, as the IP will no longer be provided to participants.

Design: This is a Phase 2, randomized, double-masked, controlled, crossover, single-center study to investigate ASEDs in participants with severe chronic ocular GVHD. During the initial crossover phase of the study, participants participated in a two-period, six-month, crossover study in which participants were randomized to one of two treatment sequence groups. The two groups were: 1) daily administration of ASEDs for the first three months and then crossover to control (normal saline) eye drops beginning at Month 3 through Month 6, or 2) daily administration of control (normal saline) eye drops for the first three months and then crossover to ASEDs beginning at Month 3 through Month 6. Participants in both groups applied the assigned drops four times per day for six months, as well as maintain their current standard ocular GVHD therapy. Following the initial crossover phase, beginning at the Month 6 visit, participants were provided ASEDs as open-label treatment on an as-needed basis until study completion. The participants were informed to discontinue use of the IP and send it back the NIH Pharmacy. During the first year, required clinic visits occurred at Baseline, Months 3, 6 and 12 with required telephone follow-up visits at Months 7 and 9. Following the Month 12 visit, participants were evaluated every six months, alternating telephone follow-up visits with clinic visits, until the last enrolled participant reaches his/her Month 12 visit. All study participants will now be scheduled for a final safety visit. At the discretion of the Investigator, participants who have not completed the Month 12 visit may have the most recent study visit constitute as the final safety visit, otherwise the participant will be scheduled for a final safety visit within 4 1/2 months. Participants who have already surpassed the Month 12 visit will be scheduled for a final safety visit within 4 1/2 months.

Outcome Measures:

The primary outcome is the proportion of participants experiencing a

greater than or equal to 50% reduction in the combined score of the modified Oxford punctate keratopathy grading and the NIH/NEI visual analogue scale in the study eye from baseline to Month 3. A greater than or equal to 50% reduction in the combined score will be considered a treatment success. While the design is a crossover study, the primary outcome is assessed after the first period at Month 3. Secondary outcomes include changes in the combined score of the modified Oxford punctate keratopathy grading and the NIH/NEI visual analogue scale in both eyes from baseline to the end of each period, changes in the chronic ocular GVHD Composite Assessment Scale (CAS) score, objective testing, subjective testing and global chronic GVHD assessments in both eyes. Safety outcomes will be the number and severity of systemic and ocular toxicities and adverse events. The number of participants withdrawn from the study treatment due to vision loss, adverse events or treatment failure will also contribute to the assessment of safety.

Description:

Objective:

A common, serious and debilitating long term complication of hematopoietic stem cell transplant (HCST) is chronic graft-versus-host disease (GVHD). Ocular GVHD develops in up to 85% of patients with chronic GVHD. It is characterized by progressive keratitis sicca and cicatrizing ocular inflammatory surface disease with T cell mediated damage to conjunctival and corneal epithelium and lacrimal tissue. Various medical and surgical treatments have been used, such as various lubricating agents, steroid drops and ointments, cyclosporin drops, punctal plugs or cautery and partial tarsorrhaphy. However, in severe cases, none offer acceptable, long-lasting relief from pain, irritation, dryness and diminished vision associated with ocular GVHD. An alternative treatment that has previously been safely investigated is autologous serum eye drops (ASEDs). The objective of this study is to determine whether ASEDs are more effective than control (normal saline) in the treatment of severe chronic ocular GVHD in HSCT patients unresponsive to standard medical treatment.

Study Population:

Eighteen post-HSCT patients with severe ocular GVHD unresponsive to standard medical treatment are enrolled. Initially, 34 post-HSCT patients with severe ocular GVHD unresponsive to standard medical treatment were to be enrolled. However, only 18 are enrolled, as the IP will no longer be provided to participants.

Design:

This is a Phase 2, randomized, double-masked, controlled, crossover, single-center study to investigate ASEDs in participants with severe chronic ocular GVHD. During the initial crossover phase of the study, participants participated in a two-period, six-month, crossover study in which participants were randomized to one of two treatment sequence groups. The two groups were: 1) daily administration of ASEDs for the first three months and then crossover to control (normal saline) eye drops beginning at Month 3 through Month 6, or 2) daily administration of control (normal saline) eye drops for the first three months and then crossover to ASEDs beginning at Month 3 through Month 6. Participants in both groups applied the assigned drops four times per day for six months, as well as maintain their current standard ocular GVHD therapy. Following the initial crossover phase, beginning at the Month 6 visit, participants were provided ASEDs as open-label treatment on an as-needed basis until study completion. The participants were informed to discontinue use of the IP and send it back the NIH Pharmacy. During the first year, required clinic visits occurred at Baseline, Months 3, 6 and 12 with required telephone follow-up visits at Months 7 and 9. Following the Month 12 visit, participants were evaluated every six months, alternating telephone follow-up visits with clinic visits, until the last enrolled participant reaches his/her Month 12 visit. All study participants will now be scheduled for a final safety visit. At the discretion of the Investigator, participants who have not completed the Month 12 visit may have the most recent study visit constitute as the final safety visit, otherwise the participant will be scheduled for a final safety visit within 4 1/2 months. Participants who have already surpassed the Month 12 visit will be scheduled for a final safety visit within 4 1/2 months.

Outcome Measures:

The primary outcome is the proportion of participants experiencing a

greater than or equal to 50% reduction in the combined score of the modified Oxford punctate keratopathy grading and the NIH/NEI visual analogue scale in the study eye from baseline to Month 3. A greater than or equal to 50% reduction in the combined score will be considered a treatment success. While the design is a crossover study, the primary outcome is assessed after the first period at Month 3. Secondary outcomes include changes in the combined score of the modified Oxford punctate keratopathy grading and the NIH/NEI visual analogue scale in both eyes from baseline to the end of each period, changes in the chronic ocular GVHD Composite Assessment Scale (CAS) score, objective testing, subjective testing and global chronic GVHD assessments in both eyes. Safety outcomes will be the number and severity of systemic and ocular toxicities and adverse events. The number of participants withdrawn from the study treatment due to vision loss, adverse events or treatment failure will also contribute to the assessment of safety.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 18
• Est. completion date: December 2016
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

• INCLUSION CRITERIA:

1. Participant must be 18 years of age or older.

2. Participant must understand and sign the protocol s informed consent document.

3. Participant must have severe ocular GVHD in one (unilateral) or both (bilateral) eyes with the following characteristics in the study eye:

1. Combined score of modified Oxford punctate keratopathy grading and NIH/NEI visual analogue scale of greater than or equal to 4, and

2. Composite assessment scale score of greater than or equal 3, and

3. Schirmer s tear test without anesthesia of less than or equal to 5 mm, and

4. Not responsive to standard medical treatment for at least three months prior to randomization. Standard medical treatment includes cyclosporine (Restasis[R]) ophthalmic emulsion (if tolerated), steroid drops (unless contraindicated), lubricating drops and ointments.

4. Participant is enrolled in an NIH study at the NCI or NHLBI.

5. Participant is willing and able to supply an adequate amount of blood to create the ASEDs.

EXCLUSION CRITERIA:

1. Participant is unable to comply with study procedures or follow-up visits.

2. Participant is seropositive with positive nucleic acid confirmatory tests for HIV-12, HTLV-I/II, HCV, and/or HBV without confirmed history of vaccination.

3. Participant has GVHD proliferative keratopathy, uveitis or GVHD retinopathy in either eye.

4. Participant has an active ocular infection in either eye.

5. Participant has an allergy to dilating or anesthetic eye drops.

6. Participant has used Boston Scleral Lens (or similar lenses) in either eye or has used ASEDs in either eye within the past two months. Participants who have used the Boston Scleral Lens (or similar lenses) or ASEDs in either eye who did not respond to treatment and have stopped using them for at least two months are eligible.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Graft vs Host Disease

Intervention

Drug:
• Autologous Serum Eye Drops

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Eye Institute (NEI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea. 2003 Oct;22(7):640-50. Review. — View Citation

Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. — View Citation

Yamada C, King KE, Ness PM. Autologous serum eyedrops: literature review and implications for transfusion medicine specialists. Transfusion. 2008 Jun;48(6):1245-55. doi: 10.1111/j.1537-2995.2008.01665.x. Epub 2008 Apr 10. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary outcome is the proportion of participants experiencing a & gt; = 50% reduction in the combined score of the modified Oxford punctate keratopathy grading and the NIH/NEI visual analogue scale in the study eye from baseline to Mont...		0, 3 months	No
Secondary	Safety: number and severity of systemic and ocular toxicities and adverse events. The number of participants withdrawn from the study treatment due to vision loss, adverse events or treatment failure will also contribute to the assessment of ...		Ongoing	Yes
Secondary	Changes in the combined score of the modified Oxford punctate keratopathy grading and the NIH visual analogue scale in the studyeye, changes in the chronic ocular GVHD CAS score, objective and subjective testing and chronic GVHD assessments.		0, 3, 6 months	No

External Links

•   NIH Clinical Center Detailed Web Page