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 (GVHD ASED)

Some eye diseases can be helped by eye drops made from a person's own blood. These eye drops are called autologous serum eye drops, or ASEDs. ASEDs have been studied in only a few people with graft vs. host disease (GVHD) affecting the eye and were found to be helpful with few side effects.

The purpose of this study was to determine whether ASEDs are safe and more effective than control (normal saline) and can help with eye symptoms in people with severe chronic eye GVHD.

Each participant in this study was to have blood drawn to prepare ASEDs specifically for the participant. Each participant was scheduled to receive ASEDs for 3 months and placebo eye drops (salt water) for 3 months. Participants did not know when they were receiving the ASEDs and when they were receiving placebo eye drops.

Study Overview

• Status: Terminated
• Conditions: Graft vs Host Disease
• Intervention / Treatment: Drug: ASEDs; Drug: Saline

Detailed 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 was 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 were enrolled. Initially, 34 post-HSCT patients with severe ocular GVHD unresponsive to standard medical treatment were to be enrolled. However, only 18 enrolled, as the investigational product (IP) was no longer provided to participants as of June 2015 due to manufacturing issues.

Design:

This was 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 maintained 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. As of June 2015, 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 reached his/her Month 12 visit. At the discretion of the Investigator, participants who did not complete the Month 12 visit had the most recent study visit constitute as the final safety visit, otherwise the participant was scheduled for a final safety visit within 4 1/2 months. Participants who already surpassed the Month 12 visit were scheduled for a final safety visit within 4 1/2 months.

Outcome Measures:

The primary outcome was the proportion of participants experiencing a ≥ 50% reduction in the combined score of the modified Oxford punctate keratopathy grading and the National Institutes of Health (NIH)/National Eye Institute (NEI) visual analogue scale in the study eye from baseline to Month 3. A ≥ 50% reduction in the combined score is considered a treatment success. While the design is a crossover study, the primary outcome was assessed after the first period at Month 3. Secondary outcomes included 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 were 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 also contributed to the assessment of safety.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Graft-versus-host Disease (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 National Institutes of Health (NIH)/National Eye Institute (NEI) visual analogue scale of ≥ 4, and
   2. Composite assessment scale (CAS) score of ≥ 3, and
   3. Schirmer's tear test without anesthesia of ≤ 5 mm, and
   4. Not responsive to standard medical treatment for at least three months prior to randomization. Standard medical treatment includes cyclosporine (Restasis®) ophthalmic emulsion (if tolerated), steroid drops (unless contraindicated), lubricating drops and ointments.
4. Participant is enrolled in an NIH study at the National Cancer Institute (NCI) or National Heart, Lung and Blood Institute (NHLBI).
5. Participant is willing and able to supply an adequate amount of blood to create the autologous serum eye drops (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 human immunodeficiency virus-1/2 (HIV-1/2), human T lymphotropic virus-I/II (HTLV-I/II), hepatitis C virus (HCV), and/or hepatitis B virus (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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ASEDs - Saline; Participants administer autologous serum eye drops (ASEDs) daily for the first three months, then crossover to administer control (normal saline) eye drops daily beginning at Month 3 through Month 6.	Drug: ASEDs; Experimental Intervention; Drug: Saline; Control Intervention
Placebo Comparator: Saline - ASEDs; Participants administer control (normal saline) eye drops daily for the first three months, then crossover to administer autologous serum eye drops (ASEDs) daily beginning at Month 3 through Month 6.	Drug: ASEDs; Experimental Intervention; Drug: Saline; Control Intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants Who Experienced a ≥ 50% Reduction in the Combined Score of the Modified Oxford Punctate Keratopathy Grading and the NIH/National Eye Institute (NEI) Visual Analogue Scale in the Study Eye From Baseline to Month 3.	A ≥ 50% reduction in the combined score was considered a treatment success. While the design is a crossover study, the primary outcome was assessed after the first period at Month 3. Oxford punctate keratopathy is an objective measure from 0-5 (cornea only) and the NIH/NEI visual analogue scale is a subjective grading performed by the participant regarding his/her ocular dryness, redness and irritation (scored 0-3 for each symptom with 0 = none, 1 = mild, 2 = moderate and 3 = severe for a total score between 0-9). The combined score was a number between 0-14 with the higher number representing a worse outcome.	Baseline and 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Systemic and Ocular Toxicities and Adverse Events		Study Duration, up to 24 months
Number of Participants Withdrawn From the Study Treatment Due to Vision Loss, Adverse Events or Treatment Failure		Study Duration, up to 24 months
Mean Change in the Combined Score of the Modified Oxford Punctate Keratopathy Grading and the NIH Visual Analogue Scale in the Study Eye at 3 Months Compared to Baseline	Oxford punctate keratopathy is an objective measure from 0-5 (cornea only) and the NIH/NEI visual analogue scale is a subjective grading performed by the participant regarding his/her ocular dryness, redness and irritation (scored 0-3 for each symptom with 0 = none, 1 = mild, 2 = moderate and 3 = severe for a total score between 0-9). The combined score was a number between 0-14 with the higher number representing a worse outcome.	Baseline and 3 Months
Mean Change in the Combined Score of the Modified Oxford Punctate Keratopathy Grading and the NIH Visual Analogue Scale in the Fellow Eye at 3 Months Compared to Baseline	The fellow eye is the untreated eye. Oxford punctate keratopathy is an objective measure from 0-5 (cornea only) and the NIH/NEI visual analogue scale is a subjective grading performed by the participant regarding his/her ocular dryness, redness and irritation (scored 0-3 for each symptom with 0 = none, 1 = mild, 2 = moderate and 3 = severe for a total score between 0-9). The combined score was a number between 0-14 with the higher number representing a worse outcome.	Baseline and 3 Months
Mean Change in the Combined Score of the Modified Oxford Punctate Keratopathy Grading and the NIH Visual Analogue Scale in the Study Eye at 6 Months Compared to Baseline	Oxford punctate keratopathy is an objective measure from 0-5 (cornea only) and the NIH/NEI visual analogue scale is a subjective grading performed by the participant regarding his/her ocular dryness, redness and irritation (scored 0-3 for each symptom with 0 = none, 1 = mild, 2 = moderate and 3 = severe for a total score between 0-9). The combined score was a number between 0-14 with the higher number representing a worse outcome.	Baseline and 6 Months
Mean Change in the Combined Score of the Modified Oxford Punctate Keratopathy Grading and the NIH Visual Analogue Scale in the Fellow Eye at 6 Months Compared to Baseline	The fellow eye is the untreated eye. Oxford punctate keratopathy is an objective measure from 0-5 (cornea only) and the NIH/NEI visual analogue scale is a subjective grading performed by the participant regarding his/her ocular dryness, redness and irritation (scored 0-3 for each symptom with 0 = none, 1 = mild, 2 = moderate and 3 = severe for a total score between 0-9). The combined score was a number between 0-14 with the higher number representing a worse outcome.	Baseline and 6 Months
Mean Change in the Chronic Ocular GVHD Composite Assessment Scale (CAS) Score in the Study Eye at 3 Months Compared to Baseline	The CAS score is the sum of the scores on three separate assessments: Schirmer's tear test without anesthesia, punctate keratopathy and conjunctival inflammation and scarring (scored according to Robinson et. al*). Each assessment was scored 0-3 with 0 = none, 1 = mild, 2 = moderate and 3 = severe. The higher values represent a worse outcome. The CAS score was a number between 0-9 with the higher number representing a worse outcome. *Robinson MR, Lee SS, Rubin BI, Wayne AS, Pavletic SZ, Bishop MR, Childs R, Barrett AJ, Csaky KG. Topical Corticosteroid Therapy for Cicatricial Conjunctivitis Associated with Chronic Graft Versus Host Disease. Bone Marrow Transplant. 2004; 18:567-9.	Baseline and 3 Months
Mean Change in the Chronic Ocular GVHD Composite Assessment Scale (CAS) Score in the Fellow Eye at 3 Months Compared to Baseline	The fellow eye is the untreated eye. The CAS score is the sum of the scores on three separate assessments: Schirmer's tear test without anesthesia, punctate keratopathy and conjunctival inflammation and scarring (scored according to Robinson et. al*). Each assessment was scored 0-3 with 0 = none, 1 = mild, 2 = moderate and 3 = severe. The higher values represent a worse outcome. The CAS score was a number between 0-9 with the higher number representing a worse outcome. *Robinson MR, Lee SS, Rubin BI, Wayne AS, Pavletic SZ, Bishop MR, Childs R, Barrett AJ, Csaky KG. Topical Corticosteroid Therapy for Cicatricial Conjunctivitis Associated with Chronic Graft Versus Host Disease. Bone Marrow Transplant. 2004; 18:567-9.	Baseline and 3 Months
Mean Change in the Chronic Ocular GVHD Composite Assessment Scale (CAS) Score in the Study Eye at 6 Months Compared to Baseline	The CAS score is the sum of the scores on three separate assessments: Schirmer's tear test without anesthesia, punctate keratopathy and conjunctival inflammation and scarring (scored according to Robinson et. al*). Each assessment was scored 0-3 with 0 = none, 1 = mild, 2 = moderate and 3 = severe. The higher values represent a worse outcome. The CAS score was a number between 0-9 with the higher number representing a worse outcome. *Robinson MR, Lee SS, Rubin BI, Wayne AS, Pavletic SZ, Bishop MR, Childs R, Barrett AJ, Csaky KG. Topical Corticosteroid Therapy for Cicatricial Conjunctivitis Associated with Chronic Graft Versus Host Disease. Bone Marrow Transplant. 2004; 18:567-9.	Baseline and 6 Months
Mean Change in the Chronic Ocular GVHD Composite Assessment Scale (CAS) Score in the Fellow Eye at 6 Months Compared to Baseline	The fellow eye is the untreated eye. The CAS score is the sum of the scores on three separate assessments: Schirmer's tear test without anesthesia, punctate keratopathy and conjunctival inflammation and scarring (scored according to Robinson et. al*). Each assessment was scored 0-3 with 0 = none, 1 = mild, 2 = moderate and 3 = severe. The higher values represent a worse outcome. The CAS score was a number between 0-9 with the higher number representing a worse outcome. *Robinson MR, Lee SS, Rubin BI, Wayne AS, Pavletic SZ, Bishop MR, Childs R, Barrett AJ, Csaky KG. Topical Corticosteroid Therapy for Cicatricial Conjunctivitis Associated with Chronic Graft Versus Host Disease. Bone Marrow Transplant. 2004; 18:567-9.	Baseline and 6 Months
Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 3 Months Compared to Baseline.	Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.	Baseline and 3 Months
Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Fellow Eye at 3 Months Compared to Baseline	The fellow eye is the untreated eye. Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.	Baseline and 3 Months
Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 6 Months Compared to Baseline	Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.	Baseline and 6 Months
Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Fellow Eye at 6 Months Compared to Baseline.	The fellow eye is the untreated eye. Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.	Baseline and 6 Months
Mean Change in Tear Stability (Tear Break-up Time) in the Study Eye at 3 Months Compared to Baseline	Sodium fluorescein dye was added to the eye and the tear film was observed under the slit lamp while the participant avoided blinking until tiny dry spots develop. Three measurements were taken and averaged for a more reproducible score.	Baseline and 3 Months
Mean Change in Tear Stability (Tear Break-up Time) in the Fellow Eye at 3 Months Compared to Baseline	The fellow eye is the untreated eye. Sodium fluorescein dye was added to the eye and the tear film was observed under the slit lamp while the participant avoided blinking until tiny dry spots develop. Three measurements were taken and averaged for a more reproducible score.	Baseline and 3 Months
Mean Change in Tear Stability (Tear Break-up Time) in the Study Eye at 6 Months Compared to Baseline	Sodium fluorescein dye was added to the eye and the tear film was observed under the slit lamp while the participant avoided blinking until tiny dry spots develop. Three measurements were taken and averaged for a more reproducible score.	Baseline and 6 Months
Mean Change in Tear Stability (Tear Break-up Time) in the Fellow Eye at 6 Months Compared to Baseline	The fellow eye is the untreated eye. Sodium fluorescein dye was added to the eye and the tear film was observed under the slit lamp while the participant avoided blinking until tiny dry spots develop. Three measurements were taken and averaged for a more reproducible score.	Baseline and 6 Months
Mean Change in Tear Composition (Tear Osmolarity) in the Study Eye at 3 Months Compared to Baseline	The tear composition test consists of the measurement of tear osmolarity using the Tearlab Osmolarity System (San Diego, California) by collecting a small 50 nanoliter (nL) tear sample which, with the use of laboratory test calculations, can derive the tear osmolarity in milliosmole per liter (mOsm/L).	Baseline and 3 Months
Mean Change in Tear Composition (Tear Osmolarity) in the Study Eye at 6 Months Compared to Baseline	The tear composition test consists of the measurement of tear osmolarity using the Tearlab Osmolarity System (San Diego, California) by collecting a small 50 nanoliter (nL) tear sample which, with the use of laboratory test calculations, can derive the tear osmolarity in milliosmole per liter (mOsm/L).	Baseline and 6 Months
Mean Change in Tear Composition (Tear Osmolarity) in the Fellow Eye at 3 Months Compared to Baseline	The fellow eye is the untreated eye. The tear composition test consists of the measurement of tear osmolarity using the Tearlab Osmolarity System (San Diego, California) by collecting a small 50 nanoliter (nL) tear sample which, with the use of laboratory test calculations, can derive the tear osmolarity in milliosmole per liter (mOsm/L).	Baseline and 3 Months
Mean Change in Tear Composition (Tear Osmolarity) in the Fellow Eye at 6 Months Compared to Baseline	The fellow eye is the untreated eye. The tear composition test consists of the measurement of tear osmolarity using the Tearlab Osmolarity System (San Diego, California) by collecting a small 50 nanoliter (nL) tear sample which, with the use of laboratory test calculations, can derive the tear osmolarity in milliosmole per liter (mOsm/L).	Baseline and 6 Months

Collaborators and Investigators

• Sponsor: National Eye Institute (NEI)
• Collaborators: The Emmes Company, LLC
• Investigators: Principal Investigator: Manuel B Datiles, M.D., National Eye Institute (NEI)

Publications and helpful links

General Publications

• 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. doi: 10.1016/j.bbmt.2005.09.004.
• 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. doi: 10.1097/00003226-200310000-00008.
• 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.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: October 23, 2013
• First Submitted That Met QC Criteria: October 24, 2013
• First Posted (Estimate): October 30, 2013

Study Record Updates

• Last Update Posted (Estimate): December 8, 2016
• Last Update Submitted That Met QC Criteria: October 26, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Hematopoietic Stem Cell Transplant; Graft Versus Host Disease
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: 130206; 13-EI-0206

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No