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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Graft vs Host Disease

Intervention / Treatment
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* Drug: ASEDs
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Participant must be 18 years of age or older. Participant must understand and sign the protocol's informed consent document. 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: Combined score of modified Oxford punctate keratopathy grading and National Institutes of Health (NIH)/National Eye Institute (NEI) visual analogue scale of ≥ 4, and Composite assessment scale (CAS) score of ≥ 3, and Schirmer's tear test without anesthesia of ≤ 5 mm, and 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. Participant is enrolled in an NIH study at the National Cancer Institute (NCI) or National Heart, Lung and Blood Institute (NHLBI). Participant is willing and able to supply an adequate amount of blood to create the autologous serum eye drops (ASEDs). Exclusion Criteria Participant is unable to comply with study procedures or follow-up visits. 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. Participant has GVHD proliferative keratopathy, uveitis or GVHD retinopathy in either eye. Participant has an active ocular infection in either eye. Participant has an allergy to dilating or anesthetic eye drops. 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.

Ages Eligible for Study
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Minimum Age: 18 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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASEDs - Saline<br>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<br>* Experimental Intervention<br>Drug: Saline<br>* Control Intervention<br>|
| Placebo Comparator: Saline - ASEDs<br>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<br>* Experimental Intervention<br>Drug: Saline<br>* Control Intervention<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft Versus Host Disease, Hematopoietic Stem Cell Transplant