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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 (GVHD ASED)

This study has been terminated.
(Investigational product unavailable due to manufacturing issues)
Sponsor:
Collaborator:
The EMMES Corporation
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Eye Institute (NEI) )
ClinicalTrials.gov Identifier:
NCT01972438
First received: October 23, 2013
Last updated: July 25, 2016
Last verified: July 2016
  Purpose

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.


Condition Intervention Phase
Graft vs Host Disease
Drug: ASEDs
Drug: Saline
Phase 2

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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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. [ Time Frame: Baseline and 3 months ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Number of Systemic and Ocular Toxicities and Adverse Events [ Time Frame: Study Duration, up to 24 months ] [ Designated as safety issue: Yes ]
  • Number of Participants Withdrawn From the Study Treatment Due to Vision Loss, Adverse Events or Treatment Failure [ Time Frame: Study Duration, up to 24 months ] [ Designated as safety issue: Yes ]
  • 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 [ Time Frame: Baseline and 3 Months ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Baseline and 3 Months ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Baseline and 6 Months ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Baseline and 6 Months ] [ Designated as safety issue: No ]
    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.

  • Mean Change in the Chronic Ocular GVHD Composite Assessment Scale (CAS) Score in the Study Eye at 3 Months Compared to Baseline [ Time Frame: Baseline and 3 Months ] [ Designated as safety issue: No ]

    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.


  • Mean Change in the Chronic Ocular GVHD Composite Assessment Scale (CAS) Score in the Fellow Eye at 3 Months Compared to Baseline [ Time Frame: Baseline and 3 Months ] [ Designated as safety issue: No ]

    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.


  • Mean Change in the Chronic Ocular GVHD Composite Assessment Scale (CAS) Score in the Study Eye at 6 Months Compared to Baseline [ Time Frame: Baseline and 6 Months ] [ Designated as safety issue: No ]

    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.


  • Mean Change in the Chronic Ocular GVHD Composite Assessment Scale (CAS) Score in the Fellow Eye at 6 Months Compared to Baseline [ Time Frame: Baseline and 6 Months ] [ Designated as safety issue: No ]

    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.


  • Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 3 Months Compared to Baseline. [ Time Frame: Baseline and 3 Months ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Fellow Eye at 3 Months Compared to Baseline [ Time Frame: Baseline and 3 Months ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 6 Months Compared to Baseline [ Time Frame: Baseline and 6 Months ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Fellow Eye at 6 Months Compared to Baseline. [ Time Frame: Baseline and 6 Months ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Tear Stability (Tear Break-up Time) in the Study Eye at 3 Months Compared to Baseline [ Time Frame: Baseline and 3 Months ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Tear Stability (Tear Break-up Time) in the Fellow Eye at 3 Months Compared to Baseline [ Time Frame: Baseline and 3 Months ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Tear Stability (Tear Break-up Time) in the Study Eye at 6 Months Compared to Baseline [ Time Frame: Baseline and 6 Months ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Tear Stability (Tear Break-up Time) in the Fellow Eye at 6 Months Compared to Baseline [ Time Frame: Baseline and 6 Months ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Tear Composition (Tear Osmolarity) in the Study Eye at 3 Months Compared to Baseline [ Time Frame: Baseline and 3 Months ] [ Designated as safety issue: No ]
    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).

  • Mean Change in Tear Composition (Tear Osmolarity) in the Study Eye at 6 Months Compared to Baseline [ Time Frame: Baseline and 6 Months ] [ Designated as safety issue: No ]
    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).

  • Mean Change in Tear Composition (Tear Osmolarity) in the Fellow Eye at 3 Months Compared to Baseline [ Time Frame: Baseline and 3 Months ] [ Designated as safety issue: No ]
    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).

  • Mean Change in Tear Composition (Tear Osmolarity) in the Fellow Eye at 6 Months Compared to Baseline [ Time Frame: Baseline and 6 Months ] [ Designated as safety issue: No ]
    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).


Enrollment: 18
Study Start Date: November 2013
Study Completion Date: January 2016
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01972438

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Eye Institute (NEI)
The EMMES Corporation
Investigators
Principal Investigator: Manuel B Datiles, M.D. National Eye Institute (NEI)
  More Information

Additional Information:
Publications:
Responsible Party: National Eye Institute (NEI)
ClinicalTrials.gov Identifier: NCT01972438     History of Changes
Other Study ID Numbers: 130206  13-EI-0206 
Study First Received: October 23, 2013
Results First Received: May 24, 2016
Last Updated: July 25, 2016
Health Authority: United States: Federal Government
United States: Food and Drug Administration
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by National Institutes of Health Clinical Center (CC):
Graft Versus Host Disease
Hematopoietic Stem Cell Transplant

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Ophthalmic Solutions
Tetrahydrozoline
Pharmaceutical Solutions
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Nasal Decongestants
Vasoconstrictor Agents
Respiratory System Agents

ClinicalTrials.gov processed this record on September 27, 2016