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Safety and Efficacy of Topical Tacrolimus 0.05% in the Treatment of Ocular Graft-Versus-Host Disease

Primary Purpose

Ocular GVHD

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Tacrolimus
Methylprednisolone Sodium Succinate
Sponsored by
Massachusetts Eye and Ear Infirmary
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ocular GVHD focused on measuring GVHD, Ocular GVHD, Tacrolimus, Methylprednisolone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age ≥18 years.
  • Willing and able to provide written informed consent.
  • Willing and able to comply with study assessments for the full duration of the study.
  • Diagnosis of ocular GVHD.
  • Minimum corneal fluorescein staining of 4 (NEI grading scheme, 0-15) in at least one eye.
  • Ocular Surface Disease Index score >22.
  • In good stable overall health.

Exclusion Criteria:

  • History of immune disease other than GVHD.
  • Ocular or periocular malignancy.
  • Significant change, as judged by the principal investigator, in systemic immunosuppressive regimen within 2 weeks of study entry.
  • Any history of topical tacrolimus use.
  • Any change in dosage of tetracycline compounds (tetracycline, doxycycline, and minocycline) within the last month.
  • Any change in frequency of preserved anti-glaucoma medications within 2 weeks of study entry.
  • Current use of topical steroids more than twice a day.
  • Change in frequency of serum tears, topical cyclosporine and/or topical kineret within the last month.
  • Corneal epithelial defect >1mm2.
  • Any history of herpetic keratitis.
  • Participation in another simultaneous medical research study.
  • Signs of current infection, including fever and current treatment with antibiotics.
  • Intra-ocular surgery or ocular laser surgery within 3 months.
  • Pregnancy (positive pregnancy test) or lactating
  • Has worn contact lenses, except for bandage contact lens or rigid gas permeable lens, for the last 2 weeks prior to the study or would be unable to stay off contact lenses for the study duration.
  • Any condition (including language barrier) that precludes patient's ability to comply with study requirements including completion of study.

Sites / Locations

  • Massachusetts Eye and Ear Infirmary

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Tacrolimus

Methylprednisolone Sodium Succinate

Arm Description

Topical tacrolimus suspension will be formulated and aseptically prepared from commercially available intravenous tacrolimus, PROGRAF® (Astellas Pharma US, Inc), and transferred into a sterile dropper container by the MEEI pharmacy. A formulation of 0.05% (5mg/10ml) concentration of tacrolimus with diluting solvent, LiquiTears Ophthalmic Solution (Major Pharmaceuticals, Inc.) will be used. Patients will be instructed to keep refrigerated each bottle after opening for 9 days and keep frozen the unopened bottles up to 45 days. They will also be instructed to shake the bottles at least 20 times before using it.

Topical methylprednisolone sodium succinate suspension will be formulated and aseptically prepared from commercially available sterile dry powder vial preservative-free for intravenous use, SOLU-MEDROL® (Pfizer, Inc.). A formulation of 0.5% (5mg/1ml) concentration of methylprednisolone with diluting solvents, LiquiTears Ophthalmic Solution (Major Pharmaceuticals, Inc.) will be used. Patients will be instructed to keep refrigerated each bottle after opening for 9 days and keep frozen the unopened bottles up to 45 days. They will also be instructed to shake the bottles at least 20 times before using it.

Outcomes

Primary Outcome Measures

Ocular Burning Sensation, Ocular Discharge, Ocular Redness, Ocular Itching, Foreign Body Sensation
Ocular burning sensation, ocular discharge, ocular redness, ocular Itching, and foreign body sensation were measured to evaluate the safety and tolerability of topical tacrolimus 0.05% twice a day in the treatment of patients with ocular GVHD. Safety and tolerability of topical tacrolimus 0.05% twice a day will be monitored by the occurrence of systemic and ocular adverse events in addition to symptoms directly related to the instillation or use of the investigational medication. Subjects will be monitored at each study visit for the occurrence of any adverse events found through examination or patient reports. Tolerability will be evaluated at every visit with a self-response questionnaire that assessed burning sensation, discharge, redness, itchiness, and foreign body sensation on a scale from 0 to 4 (none = 0, trace = 1, mild = 2, moderate = 3, and severe = 4). Where a higher value represents more symptoms (less tolerability).

Secondary Outcome Measures

Ocular Surface Disease Index (OSDI) Questionnaire
The OSDI questionnaire is a 12-question survey used to measure the symptoms of dry eye disease. Each of the 12 individual questions rate each of the dry eye symptoms on a 0-4 scale, with 4 meaning that the symptom is present all of the time and 0 meaning the symptom is present none of the time. The overall ODSI score is calculated by adding all of the values from the 12 questions, multiplying that value by 25, and dividing the resulting value by the number of questions answered. This results in an overall scale that ranges from 0-100, with 100 being severe dry eye symptoms and 0 being no dry eye symptoms.
Corneal Epitheliopathy (Corneal Fluorescein Staining Using the NEI Grading Scheme)
Corneal fluorescein staining is used to assess the level of corneal epitheliopathy that is related to dry eye disease. The corneal fluorescein staining scale ranges from 0 to 15, with 0 representing the minimum level of corneal epitheliopathy and 15 representing the maximum level of epitheliopathy.
Schirmer Tear Test (mm)
Schirmer tear test measures the amount of tear secretion produced by a patient in millimeters (mm). Generally, the greater amounts of tear secretion is better than smaller amounts of tear secretion. The minimum value of this scale is 0 mm of tear secretion and there is no maximum value to this scale.
Tear Film Break-Up Time
Tear Film Break-Up Time measures the amount of time, in seconds, that the tear film completely coats the ocular surface after each blink. The longer the amount of time the tear film completely coats the ocular surface is considered to be better than a shorter amount of time.
Visual Acuity
Visual acuity is measured by asking subjects to read letters on a chart that consists of different rows of letters. Each row of letters corresponds to different levels of visual acuity. The Logarithm of the Minimum Angle of Resolution (LogMAR) scale generally ranges from 0 to 1, with 0 corresponding to 20/20 vision and 1 corresponding to 20/200 vision. The range from 0-1 is not absolute, however, as patients who have vision better than 20/20 or vision worse than 20/200 will score out side of the 0 to 1 range.
Intraocular Pressure
Intraocular pressure is the measure of the fluid pressure within the eye as measured by tonometry. Intraocular pressure is normally measured in millimeters of mercury (mmHg). The normal range for intraocular pressure is 12-20 mmHg, there is no better or worse measurement.

Full Information

First Posted
October 31, 2013
Last Updated
May 2, 2017
Sponsor
Massachusetts Eye and Ear Infirmary
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1. Study Identification

Unique Protocol Identification Number
NCT01977781
Brief Title
Safety and Efficacy of Topical Tacrolimus 0.05% in the Treatment of Ocular Graft-Versus-Host Disease
Official Title
Safety and Efficacy of Topical Tacrolimus 0.05% in the Treatment of Ocular Graft-Versus-Host Disease
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
December 2013 (undefined)
Primary Completion Date
September 2014 (Actual)
Study Completion Date
September 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts Eye and Ear Infirmary

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to evaluate the safety and tolerability of topical tacrolimus 0.05% twice a day in the treatment of ocular graft versus host disease (GVHD).
Detailed Description
The objective of this study is to compare the safety and efficacy of topical tacrolimus 0.05% drops compared with topical methylprednisolone sodium succinate 0.5% drops in patients with ocular GVHD. 40 patients with ocular GVHD who meet the inclusion criteria of the study as determined by a screening visit will be divided into two equal groups. In addition to their current medication, one group will receive the topical tacrolimus 0.05% drops and the other group will receive the topical methylprednisolone sodium succinate 0.5% drops. The participants will then have two follow-up visits at the week 5 and week 10 markers after their screening visit. To evaluate the purpose of the study as well as the patient's safety, the following procedures will be performed at each visit: a comprehensive eye examination, tear break-up time (TBUT), Schirmer's test, intraocular pressure (IOP), fundoscopy and grading scores of lid margin and corneal fluorescein staining. The following questionnaires will be administered at each visit: Ocular Surface Disease Index (OSDI) and Symptom Assessment in Dry Eye (SANDE). Impression cytology specimens will be taken only at the screening visit and at the week 10 visit.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ocular GVHD
Keywords
GVHD, Ocular GVHD, Tacrolimus, Methylprednisolone

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
Investigator
Allocation
Randomized
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tacrolimus
Arm Type
Experimental
Arm Description
Topical tacrolimus suspension will be formulated and aseptically prepared from commercially available intravenous tacrolimus, PROGRAF® (Astellas Pharma US, Inc), and transferred into a sterile dropper container by the MEEI pharmacy. A formulation of 0.05% (5mg/10ml) concentration of tacrolimus with diluting solvent, LiquiTears Ophthalmic Solution (Major Pharmaceuticals, Inc.) will be used. Patients will be instructed to keep refrigerated each bottle after opening for 9 days and keep frozen the unopened bottles up to 45 days. They will also be instructed to shake the bottles at least 20 times before using it.
Arm Title
Methylprednisolone Sodium Succinate
Arm Type
Active Comparator
Arm Description
Topical methylprednisolone sodium succinate suspension will be formulated and aseptically prepared from commercially available sterile dry powder vial preservative-free for intravenous use, SOLU-MEDROL® (Pfizer, Inc.). A formulation of 0.5% (5mg/1ml) concentration of methylprednisolone with diluting solvents, LiquiTears Ophthalmic Solution (Major Pharmaceuticals, Inc.) will be used. Patients will be instructed to keep refrigerated each bottle after opening for 9 days and keep frozen the unopened bottles up to 45 days. They will also be instructed to shake the bottles at least 20 times before using it.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
Compounded tacrolimus (FK-506, Prograf, Protopic) in vehicle
Intervention Description
Topical bilateral application of 0.05% Tacrolimus BID for 10 weeks
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone Sodium Succinate
Other Intervention Name(s)
Compounded methlyprednisolone sodium succinate in vehicle
Intervention Description
Topical bilateral application of 0.5% methylprednisolone sodium succinate BID for 10 weeks
Primary Outcome Measure Information:
Title
Ocular Burning Sensation, Ocular Discharge, Ocular Redness, Ocular Itching, Foreign Body Sensation
Description
Ocular burning sensation, ocular discharge, ocular redness, ocular Itching, and foreign body sensation were measured to evaluate the safety and tolerability of topical tacrolimus 0.05% twice a day in the treatment of patients with ocular GVHD. Safety and tolerability of topical tacrolimus 0.05% twice a day will be monitored by the occurrence of systemic and ocular adverse events in addition to symptoms directly related to the instillation or use of the investigational medication. Subjects will be monitored at each study visit for the occurrence of any adverse events found through examination or patient reports. Tolerability will be evaluated at every visit with a self-response questionnaire that assessed burning sensation, discharge, redness, itchiness, and foreign body sensation on a scale from 0 to 4 (none = 0, trace = 1, mild = 2, moderate = 3, and severe = 4). Where a higher value represents more symptoms (less tolerability).
Time Frame
10 weeks
Secondary Outcome Measure Information:
Title
Ocular Surface Disease Index (OSDI) Questionnaire
Description
The OSDI questionnaire is a 12-question survey used to measure the symptoms of dry eye disease. Each of the 12 individual questions rate each of the dry eye symptoms on a 0-4 scale, with 4 meaning that the symptom is present all of the time and 0 meaning the symptom is present none of the time. The overall ODSI score is calculated by adding all of the values from the 12 questions, multiplying that value by 25, and dividing the resulting value by the number of questions answered. This results in an overall scale that ranges from 0-100, with 100 being severe dry eye symptoms and 0 being no dry eye symptoms.
Time Frame
10 weeks
Title
Corneal Epitheliopathy (Corneal Fluorescein Staining Using the NEI Grading Scheme)
Description
Corneal fluorescein staining is used to assess the level of corneal epitheliopathy that is related to dry eye disease. The corneal fluorescein staining scale ranges from 0 to 15, with 0 representing the minimum level of corneal epitheliopathy and 15 representing the maximum level of epitheliopathy.
Time Frame
10 weeks
Title
Schirmer Tear Test (mm)
Description
Schirmer tear test measures the amount of tear secretion produced by a patient in millimeters (mm). Generally, the greater amounts of tear secretion is better than smaller amounts of tear secretion. The minimum value of this scale is 0 mm of tear secretion and there is no maximum value to this scale.
Time Frame
10 weeks
Title
Tear Film Break-Up Time
Description
Tear Film Break-Up Time measures the amount of time, in seconds, that the tear film completely coats the ocular surface after each blink. The longer the amount of time the tear film completely coats the ocular surface is considered to be better than a shorter amount of time.
Time Frame
10 weeks
Title
Visual Acuity
Description
Visual acuity is measured by asking subjects to read letters on a chart that consists of different rows of letters. Each row of letters corresponds to different levels of visual acuity. The Logarithm of the Minimum Angle of Resolution (LogMAR) scale generally ranges from 0 to 1, with 0 corresponding to 20/20 vision and 1 corresponding to 20/200 vision. The range from 0-1 is not absolute, however, as patients who have vision better than 20/20 or vision worse than 20/200 will score out side of the 0 to 1 range.
Time Frame
10 weeks
Title
Intraocular Pressure
Description
Intraocular pressure is the measure of the fluid pressure within the eye as measured by tonometry. Intraocular pressure is normally measured in millimeters of mercury (mmHg). The normal range for intraocular pressure is 12-20 mmHg, there is no better or worse measurement.
Time Frame
10 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥18 years. Willing and able to provide written informed consent. Willing and able to comply with study assessments for the full duration of the study. Diagnosis of ocular GVHD. Minimum corneal fluorescein staining of 4 (NEI grading scheme, 0-15) in at least one eye. Ocular Surface Disease Index score >22. In good stable overall health. Exclusion Criteria: History of immune disease other than GVHD. Ocular or periocular malignancy. Significant change, as judged by the principal investigator, in systemic immunosuppressive regimen within 2 weeks of study entry. Any history of topical tacrolimus use. Any change in dosage of tetracycline compounds (tetracycline, doxycycline, and minocycline) within the last month. Any change in frequency of preserved anti-glaucoma medications within 2 weeks of study entry. Current use of topical steroids more than twice a day. Change in frequency of serum tears, topical cyclosporine and/or topical kineret within the last month. Corneal epithelial defect >1mm2. Any history of herpetic keratitis. Participation in another simultaneous medical research study. Signs of current infection, including fever and current treatment with antibiotics. Intra-ocular surgery or ocular laser surgery within 3 months. Pregnancy (positive pregnancy test) or lactating Has worn contact lenses, except for bandage contact lens or rigid gas permeable lens, for the last 2 weeks prior to the study or would be unable to stay off contact lenses for the study duration. Any condition (including language barrier) that precludes patient's ability to comply with study requirements including completion of study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Reza Dana, MD, MPH, MSc
Organizational Affiliation
Massachusetts Eye and Ear Infirmary
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts Eye and Ear Infirmary
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes

Learn more about this trial

Safety and Efficacy of Topical Tacrolimus 0.05% in the Treatment of Ocular Graft-Versus-Host Disease

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