Brimonidine Eye Drops for Treatment of Ocular Graft-vs-Host Disease (oGVHD)

• Sponsor: Sandeep Jain, MD (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02975557
• Collaborator: Ocugen (Industry)
• Enrollment: 15
• Locations: 2
• Arms: 3
• Actual Duration (Months): 11.4
• Patients Per Site: 7.5
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The objective of this study is to establish whether patients with dry eye disease (DED) are able to tolerate receiving Brimonidine: 0.15% eye drops two times a day for twelve weeks (primary tolerability objective) and to investigate the preliminary efficacy of Brimonidine 0.15% topical eye drop solution in treating Meibomian Gland Dysfunction (MGD) (primary efficacy objective).

Meibomian Gland dysfunction can happen with numerous conditions such as Rosacea, Sjögren's syndrome, and oGVHD. In order to limit the influence of differing etiologies on the outcome of this trial, the investigator has limited the screening to MGD that accompanies oGVHD.

Condition or Disease	Intervention/Treatment	Phase
Dry Eye; Ocular Graft vs Host Disease; Meibomian Gland Dysfunction	Drug: Brimonidine 0.15%; Drug: Brimonidine 0.075%; Drug: Placebo	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Randomized, Placebo-Controlled, Double-Blind, Single-Center, Tolerability And Preliminary Efficacy Study Of Use of Brimonidine Eye Drops for Treatment of Ocular Graft-vs-Host Disease (oGVHD)
• Actual Study Start Date: May 1, 2016
• Actual Primary Completion Date: Apr 13, 2017
• Actual Study Completion Date: Apr 13, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Brimonidine 0.15% Brimonidine 0.15% eye drops 2 times a day for 12 weeks	Drug: Brimonidine 0.15%; Brimonidine 0.15% eye drops 2 times a day for 12 weeks; Other Names: Alphagan P
Active Comparator: Brimonidine 0.075% Brimonidine 0.075% (1:1 dilution will be performed using 0.15% Alphagan-P solution with Refresh Plus Artificial Tears solution) eye drops 2 times a day for 12 weeks.	Drug: Brimonidine 0.075%; Brimonidine 0.075% (1:1 dilution will be performed using 0.15% Alphagan-P solution with Refresh Plus Artificial Tears solution) eye drops 2 times a day for 12 weeks.; Other Names: Alphagan P
Placebo Comparator: Placebo Placebo (Refresh plus Artificial Tear) dispensed in Brimonidine bottles 2 times a day for 12 weeks.	Drug: Placebo; Placebo (Refresh plus Artificial Tear) dispensed in Brimonidine bottles 2 times a day for 12 weeks.; Other Names: Refresh plus Artificial Tear

Outcome Measures

Primary Outcome Measures

1. Primary Tolerability End Point: The Test Substance Tolerance (Visual Analog Scale) at 12 Weeks. [12 weeks]

   Subjects assessed their tolerance to the administration of the study drug, utilizing a Visual Analog Scale (VAS). The VAS is a 100 mm horizontal line with verbal descriptors at either end and marks at an equal distance starting from 0 mm and leading up to 100 mm (0 10 20 30 40 50 60 70 80 90 100). The VAS ratings will be completed after administration of the study drug on Day 1 (post-dose), week 3, week 6, week 9 and week 12. Subjects will place a single slash mark across the horizontal line between the end labeled "completely intolerable" (0 mm) and "easily tolerable" (100mm).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Aged 18 years or older.

2. Capable of giving informed consent and does provide informed consent.

3. Diagnosis of Meibomian Gland Disease

4. Women must be post-menopausal ≥ 1 year, or surgically sterilized. If not, a negative urine pregnancy test is required within 7 days of the participant receiving first dose of study drug along with definite evidence of contraceptive use during the duration of the study. Women of reproductive age should use a method of birth control that is acceptable to the participant and the study doctor. This may include oral contraceptive pills, birth control implants, barrier methods or abstinence. If a participant suspects pregnancy after being enrolled, another pregnancy test will be administered. If the test is positive, the participant will be discontinued from the study immediately.

Exclusion Criteria:

1. Allergic to Brimonidine or any similar products, or excipients of Brimonidine

2. Currently receiving any Brimonidine preparation as a part of glaucoma management

3. Receiving or have received within 30 days any experimental systemic medication.

4. Active ocular infection or ocular allergies.

5. Any history of eyelid surgery or ocular surgery within the past 3 months.

6. Corneal epithelial defect larger than 1 mm2 in either eye.

7. Have active drug/alcohol dependence or abuse history.

8. Vulnerable populations, such as neonates, pregnant women, children, prisoners, institutionalized individuals, or others who may be considered vulnerable populations.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Illinois Eye and Ear Infirmary, University of Illinois	Chicago	Illinois	United States	60612
2	Translational Clinic of Corneal Neurobiology Laboratory, Illinois Eye and Ear Infirmary, University of Illinois	Chicago	Illinois	United States	60612

Sponsors and Collaborators

• Sandeep Jain, MD
• Ocugen

Investigators

• Principal Investigator: Sandeep Jain, MD, University of Illinois at Chicago

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 9, 2017
• Informed Consent Form - Feb 10, 2017

More Information

Additional Information:

• Principal Investigator description
• Dry Eye and ocular GVHD Clinic at University of Illinois at Chicago
• Corneal Neurobiology Laboratory (National Eye Institute funded)

Publications

• Sonawane S, Khanolkar V, Namavari A, Chaudhary S, Gandhi S, Tibrewal S, Jassim SH, Shaheen B, Hallak J, Horner JH, Newcomb M, Sarkar J, Jain S. Ocular surface extracellular DNA and nuclease activity imbalance: a new paradigm for inflammation in dry eye disease. Invest Ophthalmol Vis Sci. 2012 Dec 17;53(13):8253-63. doi: 10.1167/iovs.12-10430.
• Tibrewal S, Sarkar J, Jassim SH, Gandhi S, Sonawane S, Chaudhary S, Byun YS, Ivanir Y, Hallak J, Horner JH, Newcomb M, Jain S. Tear fluid extracellular DNA: diagnostic and therapeutic implications in dry eye disease. Invest Ophthalmol Vis Sci. 2013 Dec 11;54(13):8051-61. doi: 10.1167/iovs.13-12844.

• Responsible Party: Sandeep Jain, MD, Professor of Ophthalmology, University of Illinois at Chicago
• ClinicalTrials.gov Identifier: NCT02975557
• Other Study ID Numbers: 2015-0278
• First Posted: Nov 29, 2016
• Last Update Posted: Nov 8, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Sandeep Jain, MD, Professor of Ophthalmology, University of Illinois at Chicago: Brimonidine; Dry Eye; oGVHD; MGD
• Additional relevant MeSH terms: Dry Eye Syndromes; Meibomian Gland Dysfunction; Graft vs Host Disease; Brimonidine Tartrate; Lubricant Eye Drops

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from the clinical practice of the investigator at the time of their routine eye examination visit. The clinical practice is located in the Illinois Eye and Ear Infirmary (EEI), the University of Illinois at Chicago (UIC). The first participant was enrolled in May 2016, and the last participant was enrolled in February 2017.

Arm/Group Title	Brimonidine 0.15%	Brimonidine 0.075%	Placebo
Arm/Group Description	Brimonidine 0.15% eye drops 2 times a day for 12 weeks Brimonidine 0.15%: Brimonidine 0.15% eye drops 2 times a day for 12 weeks	Brimonidine 0.075% (1:1 dilution will be performed using 0.15% Alphagan-P solution with Refresh Plus Artificial Tears solution) eye drops 2 times a day for 12 weeks. Brimonidine 0.075%: Brimonidine 0.075% (1:1 dilution will be performed using 0.15% Alphagan-P solution with Refresh Plus Artificial Tears solution) eye drops 2 times a day for 12 weeks.	Placebo (Refresh plus Artificial Tear) dispensed in Brimonidine bottles 2 times a day for 12 weeks. Placebo: Placebo (Refresh plus Artificial Tear) dispensed in Brimonidine bottles 2 times a day for 12 weeks.
Period Title: Overall Study
STARTED	4	5	6
COMPLETED	3	2	5
NOT COMPLETED	1	3	1

Baseline Characteristics

Arm/Group Title	Brimonidine 0.15%	Brimonidine 0.075%	Placebo	Total
Arm/Group Description	Brimonidine 0.15% eye drops 2 times a day for 12 weeks Brimonidine 0.15%: Brimonidine 0.15% eye drops 2 times a day for 12 weeks	Brimonidine 0.075% (1:1 dilution will be performed using 0.15% Alphagan-P solution with Refresh Plus Artificial Tears solution) eye drops 2 times a day for 12 weeks. Brimonidine 0.075%: Brimonidine 0.075% (1:1 dilution will be performed using 0.15% Alphagan-P solution with Refresh Plus Artificial Tears solution) eye drops 2 times a day for 12 weeks.	Placebo (Refresh plus Artificial Tear) dispensed in Brimonidine bottles 2 times a day for 12 weeks. Placebo: Placebo (Refresh plus Artificial Tear) dispensed in Brimonidine bottles 2 times a day for 12 weeks.	Total of all reporting groups
Overall Participants	4	5	6	15
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 75%	4 80%	6 100%	13 86.7%
>=65 years	1 25%	1 20%	0 0%	2 13.3%
Sex: Female, Male (Count of Participants)
Female	1 25%	2 40%	2 33.3%	5 33.3%
Male	3 75%	3 60%	4 66.7%	10 66.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	1 16.7%	1 6.7%
White	4 100%	5 100%	5 83.3%	14 93.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	4 100%	5 100%	6 100%	15 100%
Ocular Surface Disease Index (OSDI) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	48.4 (8.32)	61.36 (22.42)	56.03 (22.99)	55.72 (20.28)
Schirmer I Test (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	6.75 (8.42)	2 (4.47)	0.33 (0.74)	1.4 (2.60)

Outcome Measures

1. Primary Outcome

Title	Primary Tolerability End Point: The Test Substance Tolerance (Visual Analog Scale) at 12 Weeks.
Description	Subjects assessed their tolerance to the administration of the study drug, utilizing a Visual Analog Scale (VAS). The VAS is a 100 mm horizontal line with verbal descriptors at either end and marks at an equal distance starting from 0 mm and leading up to 100 mm (0 10 20 30 40 50 60 70 80 90 100). The VAS ratings will be completed after administration of the study drug on Day 1 (post-dose), week 3, week 6, week 9 and week 12. Subjects will place a single slash mark across the horizontal line between the end labeled "completely intolerable" (0 mm) and "easily tolerable" (100mm).
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

The sponsor terminated the research early citing slow accrual of subjects and ceased sponsorship. At this point, the available valid sample size was 11 subjects at 12 weeks for assessing the tolerability at 12 weeks.

Arm/Group Title	Brimonidine 0.15%	Brimonidine 0.075%	Placebo
Arm/Group Description	Brimonidine 0.15% eye drops 2 times a day for 12 weeks Brimonidine 0.15%: Brimonidine 0.15% eye drops 2 times a day for 12 weeks	Brimonidine 0.075% (1:1 dilution will be performed using 0.15% Alphagan-P solution with Refresh Plus Artificial Tears solution) eye drops 2 times a day for 12 weeks. Brimonidine 0.075%: Brimonidine 0.075% (1:1 dilution will be performed using 0.15% Alphagan-P solution with Refresh Plus Artificial Tears solution) eye drops 2 times a day for 12 weeks.	Placebo (Refresh plus Artificial Tear) dispensed in Brimonidine bottles 2 times a day for 12 weeks. Placebo: Placebo (Refresh plus Artificial Tear) dispensed in Brimonidine bottles 2 times a day for 12 weeks.
Measure Participants	3	2	6
Tolerability (100%)	3 75%	1 20%	4 66.7%
Tolerability (95%)	0 0%	0 0%	1 16.7%
Tolerability (90%)	0 0%	1 20%	1 16.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brimonidine 0.15%, Brimonidine 0.075%, Placebo
	Comments	We evaluated if the categorical type of tolerability measure is different between control (Artificial Tears) and intervention (Brimonidine, including both 0.15% high and 0.075% low doses groups).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1
	Comments
	Method	Fisher Exact
	Comments	The type I error was adjusted by using the alpha spending function approach with O'Brien-Fleming type boundaries.

Adverse Events

Time Frame	4 months.
Arm/Group Title	Brimonidine 0.15%		Brimonidine 0.075%		Placebo
Arm/Group Description	Brimonidine 0.15% eye drops 2 times a day for 12 weeks Brimonidine 0.15%: Brimonidine 0.15% eye drops 2 times a day for 12 weeks		Brimonidine 0.075% (1:1 dilution will be performed using 0.15% Alphagan-P solution with Refresh Plus Artificial Tears solution) eye drops 2 times a day for 12 weeks. Brimonidine 0.075%: Brimonidine 0.075% (1:1 dilution will be performed using 0.15% Alphagan-P solution with Refresh Plus Artificial Tears solution) eye drops 2 times a day for 12 weeks.		Placebo (Refresh plus Artificial Tear) dispensed in Brimonidine bottles 2 times a day for 12 weeks. Placebo: Placebo (Refresh plus Artificial Tear) dispensed in Brimonidine bottles 2 times a day for 12 weeks.
All Cause Mortality
	Brimonidine 0.15%		Brimonidine 0.075%		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/5 (0%)		0/6 (0%)
Serious Adverse Events
	Brimonidine 0.15%		Brimonidine 0.075%		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/5 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Brimonidine 0.15%		Brimonidine 0.075%		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/5 (0%)		0/6 (0%)

Limitations/Caveats

Given the inadequate power to detect efficacy (due to 40% enrollment), we did not perform an analysis to determine whether the drug had any beneficial effect. Due to slow accrual of subjects in this clinical trial sponsor ceased sponsorship.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.