Study of Brimonidine Tartrate Nanoemulsion Eye Drop Solution in the Treatment of Dry Eye Disease (DED)

• Sponsor: Ocugen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03785340
• Collaborator: (none)
• Enrollment: 252
• Locations: 16
• Arms: 2
• Actual Duration (Months): 2.8
• Patients Per Site: 15.8
• Patients Per Site Per Month: 5.7

Study Details

Study Description

Brief Summary

This study evaluates the use of Brimonidine tartrate nanoemulsion eye drop solution in the treatment of Dry Eye Disease (DED). Half of participants will receive Brimonidine and half will receive ophthalmic buffered saline (placebo).

Condition or Disease	Intervention/Treatment	Phase
Dry Eye	Drug: Brimonidine Tartrate; Drug: Placebos	Phase 3

Detailed Description

Dry eye disease (DED) is a common ocular disorder involving the aberrant production and instability of tear film, which results in damage to the ocular surface and is correlated with symptoms of ocular discomfort.

This study will be a randomized, placebo-controlled, double-masked, multicenter phase 3 study in the United States conducted at approximately 25 centers. Upon meeting the eligibility criteria, enrolled subjects will be randomly assigned in a 1:1 (test:control) fashion to receive either Brimonidine Nanoemulsion Eye Drops 0.20% investigational product (test) or ophthalmic buffered saline (placebo).

Study Design

• Study Type: Interventional
• Actual Enrollment: 252 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Randomized, Placebo-Controlled, Double-Masked, Multicenter, Safety and Efficacy Study of Brimonidine Tartrate 0.2% Nanoemulsion Eye Drops in Patients With Dry Eye Disease (DED)
• Actual Study Start Date: Dec 3, 2018
• Actual Primary Completion Date: Feb 25, 2019
• Actual Study Completion Date: Feb 25, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: OCU-310 Brimonidine Tartrate Nanoemulsion Eye Drops 0.20% given 2 times a day for 4 weeks	Drug: Brimonidine Tartrate; Brimonidine Tartrate Nanoemulsion Eye Drops 0.20% given 2 times a day for 4 weeks.; Other Names: OCU-310
Placebo Comparator: Placebos Ophthalmic buffered saline Eye Drops given 2 times a day for 4 weeks	Drug: Placebos; Ophthalmic buffered saline Eye Drops given 2 times a day for 4 weeks.; Other Names: Ophthalmic buffered saline solution

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to 4 Weeks (Day 28) in Symptom Assessment in Dry Eye (SANDE) Questionnaire Score [Baseline, 4 weeks (Day 28)]

   The SANDE questionnaire is a short Visual Analog Scale (VAS) assessment that quantifies both severity and frequency of current dry eye symptoms. The SANDE is comprised of two questions, and each question employs a 100-mm horizontal linear VAS. The measurement of symptom frequency ranges from "rarely" to "all of the time", and the symptom severity from "very mild" to "very severe". Data collected from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root. The result is the Overall SANDE score which ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.

2. Change From Baseline to 4 Weeks (Day 28) in Lissamine Green Conjunctival Staining Scores [Baseline, 4 Weeks (Day 28)]

   Conjunctival staining with Lissamine Green dye (1%; LG) staining in each eye was conducted using the slit lamp. A single drop of 1% Lissamine Green dye was applied to the inferior conjunctival fornix of both eyes. The conjunctivae was examined with the slit lamp at ×10 magnification, using a neutral-density filter. The conjunctiva was graded for each eye from 0 to 3 based on the density of punctate staining in the nasal-bulbar and temporal-bulbar zones. Total scores ranged from 0 (no staining) to 6 (most severe staining) with a lower score representing a more desirable outcome.

Secondary Outcome Measures

1. Change From Baseline to 2 Weeks (Day 14) in SANDE Score [Baseline, 2 weeks (Day 14)]

   The SANDE questionnaire is a short Visual Analog Scale (VAS) assessment that quantifies both severity and frequency of current dry eye symptoms. The SANDE is comprised of two questions, and each question employs a 100-mm horizontal linear VAS. The measurement of symptom frequency ranges from "rarely" to "all of the time", and the symptom severity from "very mild" to "very severe". Data collected from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root. The result is the Overall SANDE score which ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.

2. Change From Baseline to 2 Weeks (Day 14) in Lissamine Green Conjunctival Staining Scores [Baseline, 2 Weeks (Day 14)]

   Conjunctival staining with Lissamine Green dye (1%; LG) staining in each eye was conducted using the slit lamp. A single drop of 1% Lissamine Green dye was applied to the inferior conjunctival fornix of both eyes. The conjunctivae was examined with the slit lamp at ×10 magnification, using a neutral-density filter. The conjunctiva was graded for each eye from 0 to 3 based on the density of punctate staining in the nasal-bulbar and temporal-bulbar zones. Total scores ranged from 0 (no staining) to 6 (most severe staining) with a lower score representing a more desirable outcome.

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. Sign and date informed consent form approved by the IRB

3. History of Dry Eye Disease for ≥6 months

4. Demonstrate the following 2 signs of DED in the same eye at Screening and Baseline (Day 1):

5. Conjunctival staining at ≥3 (out of a possible score of 6 per eye), and

6. Schirmer test (with anesthesia) at ≥1 to ≤7mm in 5 minutes

7. Symptomatic evidence of DED by having a global symptom score (Overall SANDE) ≥40 mm at Screening and Baseline (Day 1) visit

8. Intraocular pressure (IOP) ≥ 5 mmHg and ≤22 mmHg in each eye

9. Women who satisfy one of the following:

8a. Are of child-bearing potential (WOCP) who are not pregnant or lactating and who are either abstinent or sexually active on an acceptable method of birth control for at least 4 weeks prior to Visit 1 and throughout the study (i.e., until Day 28), OR 8b. Are post-menopausal or have undergone a sterilization procedure

Exclusion Criteria:

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

2. Use of contact lenses within 14 days prior to Screening visit or planned use during study

3. Currently receiving brimonidine or other treatment for glaucoma or ocular hypertension or history of glaucoma surgery.

4. Receiving or have received any experimental or investigational drug or device within 30 days prior to Screening visit

5. Intraocular pressure <5 mmHg or >22 mmHg in either eye

6. Active ocular infection or history of ocular herpetic keratitis

7. History of neurotrophic keratitis or ocular neuropathic pain

8. Any history of eyelid surgery or intraocular/ocular surgery within the past 3 months

9. Punctal occlusion within 3 months prior to Screening visit or during study

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

11. Have active drug/alcohol dependence or abuse history

12. Are neonates, pregnant/lactating women, children, or others who may be considered vulnerable populations

13. Received corticosteroid-containing eye drops within 14 days prior to Screening visit or planned use during study

14. Any change in systemic corticosteroids/immunosuppressives, cyclosporine ophthalmic emulsion 0.05% (Restasis®), cyclosporine ophthalmic solution 0.09% (Cequa™), or lifitegrast ophthalmic solution 5% (Xiidra®) within 30 days prior to Screening visit or planned change during study

15. In the opinion of Investigator or Study Coordinator, be unwilling or unable to comply with study protocol or unable to successfully instill eye drops

16. Disease, condition, or disorder that in the judgement of Investigator could confound study assessments or limit compliance to study protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aesthetic Eye Care Institute/David Wirta, MD and Associates	Newport Beach	California	United States	92663
2	Martel Medical Eye Group	Rancho Cordova	California	United States	95670
3	Rand Eye Institute	Pompano Beach	Florida	United States	33064
4	Chicago Cornea Consultants	Hoffman Estates	Illinois	United States	60169
5	Heart of America Eye Care, P. A.	Mission	Kansas	United States	66204
6	Ophthalmology Associates	Saint Louis	Missouri	United States	63131
7	Apex Eye- Kenwood	Cincinnati	Ohio	United States	45236
8	Apex Eye-Montgomery	Cincinnati	Ohio	United States	45242
9	Abrams Eye Center	Cleveland	Ohio	United States	44115
10	Scott and Christie Eyecare Associates	Cranberry Township	Pennsylvania	United States	16066
11	Total Eye Care	Memphis	Tennessee	United States	38119
12	Toyos Clinic	Nashville	Tennessee	United States	37215
13	Midtown Eye Physicans & Associates	Houston	Texas	United States	77004
14	Advanced Laser Vision & Surgical Institute	Houston	Texas	United States	77034
15	Revolution Research, Inc; Lake Travis Eye and Laser Center	Lakeway	Texas	United States	78734
16	The Eye Institute of Utah	Salt Lake City	Utah	United States	84107

Sponsors and Collaborators

• Ocugen

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Aug 12, 2018

More Information

Publications

None provided.

• Responsible Party: Ocugen
• ClinicalTrials.gov Identifier: NCT03785340
• Other Study ID Numbers: OCU-310-301
• First Posted: Dec 24, 2018
• Last Update Posted: Jul 18, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ocugen: Dry Eye Disease
• Additional relevant MeSH terms: Dry Eye Syndromes; Keratoconjunctivitis Sicca; Eye Diseases; Brimonidine Tartrate

Study Results

Participant Flow

Arm/Group Title	OCU-310	Placebo
Arm/Group Description	Brimonidine Tartrate Nanoemulsion Eye Drops 0.20% given 2 times a day (BID) for 4 weeks	Placebo (ophthalmic buffered saline) Eye Drops given 2 times a day (BID) for 4 weeks
Period Title: Overall Study
STARTED	126	126
Received at Least 1 Study Treatment	126	126
COMPLETED	123	126
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	OCU-310	Placebo	Total
Arm/Group Description	Brimonidine Tartrate Nanoemulsion Eye Drops 0.20% given 2 times a day (BID) for 4 weeks	Placebo (ophthalmic buffered saline) Eye Drops given 2 times a day (BID) for 4 weeks	Total of all reporting groups
Overall Participants	126	126	252
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	61.7	62.1	62
Sex: Female, Male (Count of Participants)
Female	106 84.1%	105 83.3%	211 83.7%
Male	20 15.9%	21 16.7%	41 16.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 9.5%	11 8.7%	23 9.1%
Not Hispanic or Latino	114 90.5%	115 91.3%	229 90.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.8%	0 0%	1 0.4%
Asian	4 3.2%	3 2.4%	7 2.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	19 15.1%	11 8.7%	30 11.9%
White	101 80.2%	111 88.1%	212 84.1%
More than one race	1 0.8%	1 0.8%	2 0.8%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to 4 Weeks (Day 28) in Symptom Assessment in Dry Eye (SANDE) Questionnaire Score
Description	The SANDE questionnaire is a short Visual Analog Scale (VAS) assessment that quantifies both severity and frequency of current dry eye symptoms. The SANDE is comprised of two questions, and each question employs a 100-mm horizontal linear VAS. The measurement of symptom frequency ranges from "rarely" to "all of the time", and the symptom severity from "very mild" to "very severe". Data collected from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root. The result is the Overall SANDE score which ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.
Time Frame	Baseline, 4 weeks (Day 28)

Outcome Measure Data

Analysis Population Description

The Intention-to-treat (ITT) set is the primary analysis set for the efficacy endpoints and includes all randomized participants who have at least one post-baseline efficacy measurement. Here, the overall number of participants analyzed is the number of participants with evaluable data at each time point.

Arm/Group Title	OCU-310	Placebo
Arm/Group Description	Brimonidine Tartrate Nanoemulsion Eye Drops 0.20% given 2 times a day (BID) for 4 weeks	Placebo (ophthalmic buffered saline) Eye Drops given 2 times a day (BID) for 4 weeks
Measure Participants	124	124
Baseline	73.0 (13.6)	72.7 (12.4)
4 weeks (Day 28)	56.6 (23.2)	57.2 (19.8)
Change from Baseline at 4 weeks (Day 28)	-16.4 (20.9)	-15.5 (19.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OCU-310, Placebo
	Comments	Four endpoints (two primary and two secondary) were to be tested in a fixed sequence, proceeding to the next endpoint until a p-value >0.05 was found. The analysis of the four outcomes employed a repeated measures mixed model with mean change from baseline score at the stated time point as the response with baseline score as a covariate and treatment, visit, and their interaction as fixed effects. The least squares mean difference (OCU 310 - placebo) at the stated time point was tested.
	Type of Statistical Test	Superiority
	Comments	The endpoints were tested in a fixed sequence, proceeding to the next endpoint until a p-value >0.05 was found: Change from baseline to 4 weeks (Day 28) in SANDE score Change from baseline to 4 weeks (Day 28) in Lissamine Green conjunctival staining scores Change from baseline to 2 weeks (Day 14) in SANDE score Change from baseline to 2 weeks (Day 14) in Lissamine Green conjunctival staining scores
Statistical Test of Hypothesis	p-Value	0.739
	Comments
	Method	Mixed Model Repeated Measures Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.844
	Confidence Interval	(2-Sided) 95%; -5.823 to 4.134
	Parameter Dispersion	Type: Value:
	Estimation Comments	Change from baseline to 4 weeks (Day 28) in SANDE score; OCU-310 vs. Placebo

2. Primary Outcome

Title	Change From Baseline to 4 Weeks (Day 28) in Lissamine Green Conjunctival Staining Scores
Description	Conjunctival staining with Lissamine Green dye (1%; LG) staining in each eye was conducted using the slit lamp. A single drop of 1% Lissamine Green dye was applied to the inferior conjunctival fornix of both eyes. The conjunctivae was examined with the slit lamp at ×10 magnification, using a neutral-density filter. The conjunctiva was graded for each eye from 0 to 3 based on the density of punctate staining in the nasal-bulbar and temporal-bulbar zones. Total scores ranged from 0 (no staining) to 6 (most severe staining) with a lower score representing a more desirable outcome.
Time Frame	Baseline, 4 Weeks (Day 28)

Outcome Measure Data

Analysis Population Description

The ITT set is the primary analysis set for the efficacy endpoints and includes all randomized participants who have at least one post-baseline efficacy measurement. Here, the overall number of participants analyzed is the number of participants with evaluable data at each time point.

Arm/Group Title	OCU-310	Placebo
Arm/Group Description	Brimonidine Tartrate Nanoemulsion Eye Drops 0.20% given 2 times a day (BID) for 4 weeks	Placebo (ophthalmic buffered saline) Eye Drops given 2 times a day (BID) for 4 weeks
Measure Participants	124	124
Baseline	4.2 (1.1)	4.1 (1.0)
4 Weeks (Day 28)	3.6 (1.6)	3.2 (1.3)
Change from Baseline at 4 Weeks (Day 28)	-0.6 (1.4)	-0.9 (1.1)

3. Secondary Outcome

Title	Change From Baseline to 2 Weeks (Day 14) in SANDE Score
Description	The SANDE questionnaire is a short Visual Analog Scale (VAS) assessment that quantifies both severity and frequency of current dry eye symptoms. The SANDE is comprised of two questions, and each question employs a 100-mm horizontal linear VAS. The measurement of symptom frequency ranges from "rarely" to "all of the time", and the symptom severity from "very mild" to "very severe". Data collected from the SANDE questionnaire was calculated by multiplying the frequency score by the severity score and obtaining the square root. The result is the Overall SANDE score which ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.
Time Frame	Baseline, 2 weeks (Day 14)

Outcome Measure Data

Analysis Population Description

The ITT set is the primary analysis set for the efficacy endpoints and includes all randomized participants who have at least one post-baseline efficacy measurement. Here, the overall number of participants analyzed are those evaluable for this Outcome Measure and the Number Analyzed per Row is the number of participants with evaluable data at each time point.

Arm/Group Title	OCU-310	Placebo
Arm/Group Description	Brimonidine Tartrate Nanoemulsion Eye Drops 0.20% given 2 times a day (BID) for 4 weeks	Placebo (ophthalmic buffered saline) Eye Drops given 2 times a day (BID) for 4 weeks
Measure Participants	124	124
Baseline	73.0 (13.6)	72.7 (12.4)
2 weeks (Day 14)	61.3 (20.5)	58.6 (17.5)
Change from Baseline at 2 weeks (Day 14)	-11.6 (18.3)	-14.1 (16.3)

4. Secondary Outcome

Title	Change From Baseline to 2 Weeks (Day 14) in Lissamine Green Conjunctival Staining Scores
Description	Conjunctival staining with Lissamine Green dye (1%; LG) staining in each eye was conducted using the slit lamp. A single drop of 1% Lissamine Green dye was applied to the inferior conjunctival fornix of both eyes. The conjunctivae was examined with the slit lamp at ×10 magnification, using a neutral-density filter. The conjunctiva was graded for each eye from 0 to 3 based on the density of punctate staining in the nasal-bulbar and temporal-bulbar zones. Total scores ranged from 0 (no staining) to 6 (most severe staining) with a lower score representing a more desirable outcome.
Time Frame	Baseline, 2 Weeks (Day 14)

Outcome Measure Data

Analysis Population Description

The ITT set is the primary analysis set for the efficacy endpoints and includes all randomized participants who have at least one post-baseline efficacy measurement. Here, the overall number of participants analyzed are those evaluable for this Outcome Measure and the Number Analyzed per Row is the number of participants with evaluable data at each time point.

Arm/Group Title	OCU-310	Placebo
Arm/Group Description	Brimonidine Tartrate Nanoemulsion Eye Drops 0.20% given 2 times a day (BID) for 4 weeks	Placebo (ophthalmic buffered saline) Eye Drops given 2 times a day (BID) for 4 weeks
Measure Participants	124	124
Baseline	4.2 (1.1)	4.1 (1.0)
2 Weeks (Day 14)	3.8 (1.4)	3.4 (1.3)
Change from Baseline at 2 Weeks (Day 14)	-0.4 (1.2)	-0.7 (1.0)

Adverse Events

Time Frame	Adverse events were collected from the time of informed consent completion, throughout the study, and at early termination (Up to 28 Days)
Arm/Group Title	OCU-310		Placebo
Arm/Group Description	Brimonidine Tartrate Nanoemulsion Eye Drops 0.20% given 2 times a day (BID) for 4 weeks		Placebo (ophthalmic buffered saline) Eye Drops given 2 times a day (BID) for 4 weeks
All Cause Mortality
	OCU-310		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/126 (0%)		0/126 (0%)
Serious Adverse Events
	OCU-310		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/126 (0%)		0/126 (0%)
Other (Not Including Serious) Adverse Events
	OCU-310		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/126 (0%)		0/126 (0%)

Limitations/Caveats

[Not Specified]

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.