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

Phase 1

Completed

Conditions: Ocular GVHD

Interventions: Drug: Methylprednisolone Sodium Succinate
Drug: Tacrolimus

Registration Number: NCT01977781

Lead Sponsor: Massachusetts Eye and Ear Infirmary

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Methylprednisolone Sodium Succinate	Methylprednisolone Sodium Succinate	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.
Tacrolimus	Tacrolimus	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.

Primary Outcome Measures

Name	Time	Method
Ocular Burning Sensation, Ocular Discharge, Ocular Redness, Ocular Itching, Foreign Body Sensation	10 weeks	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

Name	Time	Method
Tear Film Break-Up Time	10 weeks	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.
Corneal Epitheliopathy (Corneal Fluorescein Staining Using the NEI Grading Scheme)	10 weeks	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)	10 weeks	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.
Ocular Surface Disease Index (OSDI) Questionnaire	10 weeks	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.
Visual Acuity	10 weeks	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	10 weeks	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.