Phase 2/3 Dose-Ranging Study of the Safety and Efficacy of OTX-101 in the Treatment of Keratoconjunctivitis Sicca

• Sponsor: Sun Pharmaceutical Industries Limited (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02254265
• Collaborator: (none)
• Enrollment: 455
• Location: 1
• Arms: 3
• Duration (Months): 8
• Patients Per Site Per Month: 57.2

Study Details

Study Description

Brief Summary

This is a Phase 2/3 study to evaluate the safety and efficacy of 2 different dose concentrations of OTX-101 dosed twice a day in both eyes for 84 days compared to placebo (vehicle) in patients with keratoconjunctivitis sicca (dry eye disease).

Condition or Disease	Intervention/Treatment	Phase
Keratoconjunctivitis Sicca; Dry Eye Disease	Drug: OTX-101 0.05%; Drug: OTX-101 0.09%; Drug: Vehicle	Phase 2/Phase 3

Detailed Description

Keratoconjunctivitis sicca (KCS) is a common multifactorial ophthalmologic disorder of the tears and ocular surface characterized by symptoms of burning, stinging, itching, grittiness, scratchiness, foreign body sensation, dryness, stickiness and tired eye sensation.

This study is the first clinical safety and efficacy study with OTX-101 and is designed to compare two dose concentrations of OTX-101 against vehicle (placebo) in reducing the signs and symptoms of KCS and evaluate safety when dosed twice a day in both eyes over an 84 day period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 455 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Multicenter, Double-Masked, Vehicle-Controlled, Dose-Ranging Study of the Safety and Efficacy of OTX-101 in the Treatment of Keratoconjunctivitis Sicca
• Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: OTX-101 0.05% OTX-101 0.05% ophthalmic solution 1 drop in both eyes BID for 84 days	Drug: OTX-101 0.05%; OTX-101 0.05% Ophthalmic Solution
Experimental: OTX-101 0.09% OTX-101 0.09% ophthalmic solution 1 drop in both eyes BID for 84 days	Drug: OTX-101 0.09%; OTX-101 0.09% Ophthalmic Solution
Placebo Comparator: Vehicle Vehicle of OTX-101 ophthalmic solution 1 drop in both eyes BID for 84 days	Drug: Vehicle; Vehicle of OTX-101 Ophthalmic Solution

Outcome Measures

Primary Outcome Measures

1. Conjunctival Staining [Baseline to 84 days]

   Mean change from baseline at day 84 for the lissamine green conjunctival staining score in the designated study eye. The Investigator recorded a score for each area of each eye on a 0 (No punctate stain in zone) to 3 (Densely concentrated micropunctate stain spots) scale

2. Global Symptom Score [Baseline to 84 days]

   Mean change from baseline at day 84 for the global symptom score. The freuency and severy of dry eye and irritation scores were used to calculate symptom score as follows: Frequency of dry eye/irritation based on a scale of 0 (rarely) to 100 (all the time) Severity of dryness or irritation based on a scale of 0 (very mildly) to 100 (very severe). The global symptom score was calculated as the square root of the frequency score times the severity score

Secondary Outcome Measures

1. Tear Film Break up Time (TBUT) [Baseline to 84 days]

   Mean change from baseline in TBUT in the study eye from baseline at Day 84

2. Corneal Staining Score [Baseline to 84 days]

   Mean Change from Baseline in Corneal Staining Score in the Study Eye. Expanded National Eye Institute Scale for Corneal Staining Score was used to grade each of the 5 areas of the cornea on a 0 (No punctate stain in area) to 4 (Severe diffuse (coalescent) macropunctate stain of the area) scale

3. Schirmer's Test [Baseline to 84 days]

   Change from Baseline in Categorized Schirmer's Test Score. Schirmer's test was performed with strips placed in both eyes at the same time. Strips were removed after 5 minutes and the amount of wetting (in mm) was recorded as scores from 1 to 5. 1: < 3 mm, 3 - 6 mm, 7 - 10 mm, 11 - 14 mm, and 5: > 14 mm

4. Patient Satisfaction [Baseline to 84 days]

   Patient satisfaction with treatment score using 5-point scale (1=extremely dissatisfied to 5=extremely satisfied)

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Subjects age 18 years or older on the date of informed consent.

2. All subjects must provide signed written consent prior to participation in any study-related procedures.

3. Patient-reported history of KCS for a period of at least 6 months.

4. Clinical diagnosis of bilateral KCS supported by OTX-101-2014-001 study assessments.

5. Lissamine green conjunctival staining sum score of ≥ 3 to ≤ 9 out of a total possible score of 12 (scoring excludes superior zones 2 and 4) in the same eye at Screening and Baseline.

6. Global symptom score ≥ 40 at both Screening and Baseline.

7. Corrected Snellen VA of better than 20/200 in each eye.

8. Willing to discontinue use of current dry eye therapy (including artificial tears or ocular lubricants) during the study as of the run-in period.

9. Female subjects of childbearing potential must have a negative urine pregnancy test at Screening. Women of childbearing potential (ie, women who are not either postmenopausal for one year or surgically sterile) must use an acceptable form of contraception throughout the study.

Exclusion Criteria:

1. Use of cyclosporine ophthalmic emulsion 0.05% (Restasis®) within 3 months prior to Screening.

2. Previous treatment failure (lack of efficacy) on cyclosporine ophthalmic emulsion 0.05% (Restasis).

3. Diagnosed with Sjögren's disease ˃5 years prior to Screening.

4. Clinical diagnosis of seasonal and perennial allergic conjunctivitis.

5. Use of systemic and topical medications that are known to cause dry eye within 7 days prior to Screening and throughout the study period. These include the following medications:

• Immunomodulators (permitted if dose is stable for 3 months prior to screening and does not change during the study period)

• Antihistamines (including over-the counter (OTC))

• Cholinergics

• Antimuscarinics

• Tricyclic antidepressants

• Phenothiazines

• Retinoids

1. Oral omega-3 fatty acids (permitted if dose is stable for 3 months prior to Screening and does not change during the study period)

2. Use of any topical ophthalmic medications, prescription (including antiglaucoma medications) or OTC (including artificial tears), other than the assigned study medication during the study period.

3. Current active eye disease other than KCS (i.e., any disease for which topical or systemic ophthalmic medication is necessary).

4. History of herpes keratitis.

5. Unstable macular disease (e.g., age-related macular degeneration, diabetic maculopathy). Stable macular disease is defined as no reduction in central VA within 6 months prior to Screening.

6. Diagnosis of chronic uveitis.

7. Corneal transplant (e.g., penetrating keratoplasty, lamellar keratoplasty, Descemet's stripping endothelial keratoplasty (DSEK) ).

8. Corneal refractive surgery (e.g., laser-assisted in situ keratomileusis (LASIK]) photo refractive keratectomy (PRK), limbal relaxing incision (LRI) ) within 6 months prior to screening or postoperative refractive surgery symptoms of dryness that have not resolved.

9. Cataract surgery within 3 months prior to Screening.

10. Non-laser glaucoma surgery at any time; glaucoma laser procedures within 3 months prior to Screening.

11. Presence of punctal plugs or past history of permanent punctal occlusion (e.g., cautery).

12. Lagophthalmos or clinically significant eyelid margin irregularity of the study eye whether congenital or acquired.

13. Presence of conjunctivochalasis (i.e., mechanical blockage of the lower lid punctum by redundant conjunctiva).

14. Presence of pterygium in the study eye.

15. Unwilling to discontinue use of contact lenses during the duration of the study.

16. Preplanned elective surgery or hospitalization during the study period.

17. HIV-positive.

18. Unable to reliably report symptoms and history.

19. Has known hypersensitivity or contraindication to the study medication(s) or their components.

20. Has a history or presence of chronic generalized systemic disease that the Investigator feels might increase the risk to the subject or confound the result(s) of the study.

21. Has a severe/serious ocular condition, or any other unstable medical condition that, in the Investigator's opinion, may preclude study treatment or follow-up.

22. Women who are pregnant or breastfeeding.

23. Participation in any drug or device clinical investigation within 30 days prior to entry into this study and/or during the period of study participation.

24. Previous randomization into this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Cleveland	Ohio	United States

Sponsors and Collaborators

• Sun Pharmaceutical Industries Limited

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sun Pharmaceutical Industries Limited
• ClinicalTrials.gov Identifier: NCT02254265
• Other Study ID Numbers: OTX-101-2014-001
• First Posted: Oct 1, 2014
• Last Update Posted: Nov 19, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Dry Eye Syndromes; Eye Diseases; Keratoconjunctivitis Sicca; Keratoconjunctivitis

Study Results

Participant Flow

Arm/Group Title	OTX-101 0.05%	OTX-101 0.09%	Vehicle
Arm/Group Description	OTX-101 0.05% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.05%: OTX-101 0.05% Ophthalmic Solution	OTX-101 0.09% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.09%: OTX-101 0.09% Ophthalmic Solution	Vehicle of OTX-101 ophthalmic solution 1 drop in both eyes BID for 84 days Vehicle: Vehicle of OTX-101 Ophthalmic Solution
Period Title: Overall Study
STARTED	151	152	152
COMPLETED	142	140	144
NOT COMPLETED	9	12	8

Baseline Characteristics

Arm/Group Title	OTX-101 0.05%	OTX-101 0.09%	Vehicle	Total
Arm/Group Description	OTX-101 0.05% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.05%: OTX-101 0.05% Ophthalmic Solution	OTX-101 0.09% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.09%: OTX-101 0.09% Ophthalmic Solution	Vehicle of OTX-101 ophthalmic solution 1 drop in both eyes BID for 84 days Vehicle: Vehicle of OTX-101 Ophthalmic Solution	Total of all reporting groups
Overall Participants	151	152	152	455
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.9 (13.27)	59.2 (14.55)	59.3 (13.75)	60.1 (13.90)
Sex: Female, Male (Count of Participants)
Female	119 78.8%	122 80.3%	120 78.9%	361 79.3%
Male	32 21.2%	30 19.7%	32 21.1%	94 20.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.7%	0 0%	0 0%	1 0.2%
Asian	8 5.3%	7 4.6%	3 2%	18 4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	2 1.3%	2 0.4%
Black or African American	11 7.3%	13 8.6%	20 13.2%	44 9.7%
White	128 84.8%	126 82.9%	120 78.9%	374 82.2%
More than one race	3 2%	6 3.9%	7 4.6%	16 3.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Conjunctival Staining
Description	Mean change from baseline at day 84 for the lissamine green conjunctival staining score in the designated study eye. The Investigator recorded a score for each area of each eye on a 0 (No punctate stain in zone) to 3 (Densely concentrated micropunctate stain spots) scale
Time Frame	Baseline to 84 days

Outcome Measure Data

Analysis Population Description

Intent to treat population, last observed carried forward approach

Arm/Group Title	OTX-101 0.05%	OTX-101 0.09%	Vehicle
Arm/Group Description	OTX-101 0.05% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.05%: OTX-101 0.05% Ophthalmic Solution	OTX-101 0.09% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.09%: OTX-101 0.09% Ophthalmic Solution	Vehicle of OTX-101 ophthalmic solution 1 drop in both eyes BID for 84 days Vehicle: Vehicle of OTX-101 Ophthalmic Solution
Measure Participants	151	152	152
Mean (Standard Deviation) [score on a scale]	-1.9 (2.17)	-1.8 (2.27)	-1.2 (2.17)

2. Primary Outcome

Title	Global Symptom Score
Description	Mean change from baseline at day 84 for the global symptom score. The freuency and severy of dry eye and irritation scores were used to calculate symptom score as follows: Frequency of dry eye/irritation based on a scale of 0 (rarely) to 100 (all the time) Severity of dryness or irritation based on a scale of 0 (very mildly) to 100 (very severe). The global symptom score was calculated as the square root of the frequency score times the severity score
Time Frame	Baseline to 84 days

Outcome Measure Data

Analysis Population Description

Intent to treat population, observed data

Arm/Group Title	OTX-101 0.05%	OTX-101 0.09%	Vehicle
Arm/Group Description	OTX-101 0.05% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.05%: OTX-101 0.05% Ophthalmic Solution	OTX-101 0.09% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.09%: OTX-101 0.09% Ophthalmic Solution	Vehicle of OTX-101 ophthalmic solution 1 drop in both eyes BID for 84 days Vehicle: Vehicle of OTX-101 Ophthalmic Solution
Measure Participants	143	140	144
Mean (Standard Deviation) [score on a scale]	-19.78 (23.791)	-18.86 (22.810)	-19.16 (22.973)

3. Secondary Outcome

Title	Tear Film Break up Time (TBUT)
Description	Mean change from baseline in TBUT in the study eye from baseline at Day 84
Time Frame	Baseline to 84 days

Outcome Measure Data

Analysis Population Description

Intent to treat population - observed data

Arm/Group Title	OTX-101 0.05%	OTX-101 0.09%	Vehicle
Arm/Group Description	OTX-101 0.05% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.05%: OTX-101 0.05% Ophthalmic Solution	OTX-101 0.09% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.09%: OTX-101 0.09% Ophthalmic Solution	Vehicle of OTX-101 ophthalmic solution 1 drop in both eyes BID for 84 days Vehicle: Vehicle of OTX-101 Ophthalmic Solution
Measure Participants	143	140	144
Mean (Standard Deviation) [seconds]	0.43 (2.032)	0.53 (2.590)	0.39 (2.149)

4. Secondary Outcome

Title	Corneal Staining Score
Description	Mean Change from Baseline in Corneal Staining Score in the Study Eye. Expanded National Eye Institute Scale for Corneal Staining Score was used to grade each of the 5 areas of the cornea on a 0 (No punctate stain in area) to 4 (Severe diffuse (coalescent) macropunctate stain of the area) scale
Time Frame	Baseline to 84 days

Outcome Measure Data

Analysis Population Description

Intent to treat population, Last observed carried forward approach

Arm/Group Title	OTX-101 0.05%	OTX-101 0.09%	Vehicle
Arm/Group Description	OTX-101 0.05% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.05%: OTX-101 0.05% Ophthalmic Solution	OTX-101 0.09% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.09%: OTX-101 0.09% Ophthalmic Solution	Vehicle of OTX-101 ophthalmic solution 1 drop in both eyes BID for 84 days Vehicle: Vehicle of OTX-101 Ophthalmic Solution
Measure Participants	151	152	152
Mean (Standard Deviation) [score on a scale]	-1.4 (3.23)	-1.4 (2.87)	-0.6 (2.76)

5. Secondary Outcome

Title	Schirmer's Test
Description	Change from Baseline in Categorized Schirmer's Test Score. Schirmer's test was performed with strips placed in both eyes at the same time. Strips were removed after 5 minutes and the amount of wetting (in mm) was recorded as scores from 1 to 5. 1: < 3 mm, 3 - 6 mm, 7 - 10 mm, 11 - 14 mm, and 5: > 14 mm
Time Frame	Baseline to 84 days

Outcome Measure Data

Analysis Population Description

Intent to treat population (with both eyes averaged)

Arm/Group Title	OTX-101 0.05%	OTX-101 0.09%	Vehicle
Arm/Group Description	OTX-101 0.05% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.05%: OTX-101 0.05% Ophthalmic Solution	OTX-101 0.09% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.09%: OTX-101 0.09% Ophthalmic Solution	Vehicle of OTX-101 ophthalmic solution 1 drop in both eyes BID for 84 days Vehicle: Vehicle of OTX-101 Ophthalmic Solution
Measure Participants	143	140	144
Mean (Standard Deviation) [score on a scale]	0.41 (1.263)	0.37 (1.260)	-0.08 (1.307)

6. Secondary Outcome

Title	Patient Satisfaction
Description	Patient satisfaction with treatment score using 5-point scale (1=extremely dissatisfied to 5=extremely satisfied)
Time Frame	Baseline to 84 days

Outcome Measure Data

Analysis Population Description

Intent to treat population (Observed)

Arm/Group Title	OTX-101 0.05%	OTX-101 0.09%	Vehicle
Arm/Group Description	OTX-101 0.05% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.05%: OTX-101 0.05% Ophthalmic Solution	OTX-101 0.09% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.09%: OTX-101 0.09% Ophthalmic Solution	Vehicle of OTX-101 ophthalmic solution 1 drop in both eyes BID for 84 days Vehicle: Vehicle of OTX-101 Ophthalmic Solution
Measure Participants	143	140	144
Mean (Standard Deviation) [score on a scale]	3.8 (1.17)	3.7 (1.17)	3.9 (1.08)

Adverse Events

Arm/Group Title	OTX-101 0.09%		OTX-101 0.05%		Vehicle
Arm/Group Description	OTX-101 0.09% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.09%: OTX-101 0.09% Ophthalmic Solution		OTX-101 0.05% ophthalmic solution 1 drop in both eyes BID for 84 days OTX-101 0.05%: OTX-101 0.05% Ophthalmic Solution		Vehicle of OTX-101 ophthalmic solution 1 drop in both eyes BID for 84 days Vehicle: Vehicle of OTX-101 Ophthalmic Solution
All Cause Mortality
	OTX-101 0.09%		OTX-101 0.05%		Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/152 (0%)		0/151 (0%)		0/152 (0%)
Serious Adverse Events
	OTX-101 0.09%		OTX-101 0.05%		Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/152 (0.7%)		0/151 (0%)		4/152 (2.6%)
Injury, poisoning and procedural complications
Humerus fracture	0/152 (0%)		0/151 (0%)		1/152 (0.7%)
Metabolism and nutrition disorders
Hypokalaemia	0/152 (0%)		0/151 (0%)		1/152 (0.7%)
Nervous system disorders
Cerebrovascular accident	0/152 (0%)		0/151 (0%)		1/152 (0.7%)
Psychiatric disorders
Bipolar disorder	0/152 (0%)		0/151 (0%)		1/152 (0.7%)
Surgical and medical procedures
Peripheral nerve decompression	1/152 (0.7%)		0/151 (0%)		0/152 (0%)
Other (Not Including Serious) Adverse Events
	OTX-101 0.09%		OTX-101 0.05%		Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/151 (24.5%)		31/152 (20.4%)		30/152 (19.7%)
Eye disorders
Eye irritation	3/151 (2%)		2/152 (1.3%)		1/152 (0.7%)
Lacrimation increased	3/151 (2%)		2/152 (1.3%)		1/152 (0.7%)
Meibomian gland dysfunction	2/151 (1.3%)		0/152 (0%)		1/152 (0.7%)
Conjunctival haemorrhage	1/151 (0.7%)		2/152 (1.3%)		2/152 (1.3%)
Eye discharge	1/151 (0.7%)		2/152 (1.3%)		0/152 (0%)
Eye pruritus	1/151 (0.7%)		3/152 (2%)		4/152 (2.6%)
Vitreous floaters	1/151 (0.7%)		1/152 (0.7%)		2/152 (1.3%)
Eye pain	0/151 (0%)		0/152 (0%)		2/152 (1.3%)
Eyelid pain	0/151 (0%)		2/152 (1.3%)		0/152 (0%)
Vision blurred	0/151 (0%)		1/152 (0.7%)		4/152 (2.6%)
Vitreous detachment	0/151 (0%)		3/152 (2%)		0/152 (0%)
Corneal abrasion	0/151 (0%)		0/152 (0%)		2/152 (1.3%)
General disorders
Instillation site pain	23/151 (15.2%)		20/152 (13.2%)		5/152 (3.3%)
Instillation site reaction	0/151 (0%)		2/152 (1.3%)		1/152 (0.7%)
Pyrexia	0/151 (0%)		0/152 (0%)		2/152 (1.3%)
Infections and infestations
Conjunctivitis viral	0/151 (0%)		0/152 (0%)		2/152 (1.3%)
Sinusitis	0/151 (0%)		3/152 (2%)		0/152 (0%)
Nasopharyngitis	2/151 (1.3%)		1/152 (0.7%)		4/152 (2.6%)
Injury, poisoning and procedural complications
Fall	0/151 (0%)		0/152 (0%)		2/152 (1.3%)
Nervous system disorders
Tremor	0/151 (0%)		0/152 (0%)		2/152 (1.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/151 (0.7%)		2/152 (1.3%)		2/152 (1.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.