Safety and Efficacy of Thymosin Beta 4 Ophthalmic Solution in Patients With Dry Eye

• Sponsor: ReGenTree, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01387347
• Collaborator: ORA, Inc. (Industry)
• Enrollment: 72
• Arms: 2
• Duration (Months): 4

Study Details

Study Description

Brief Summary

Thymosin Beta 4 (Tβ4) is a synthetic copy of the naturally-occurring 43-amino acid peptide that is found in a variety of tissues. Tβ4 promotes/accelerates wound repair in dermal, ocular, and cardiac animal models. Two recent pre-clinical evaluations have demonstrated that Tβ4 promotes corneal ocular surface defects healing in animal models of dry eye. RGN-259 (formulation of Tβ4 ophthalmic solution) mechanism of action offers potential to be a product that meets a major unmet medical need in patients with dry eye.

Condition or Disease	Intervention/Treatment	Phase
Dry Eye Syndrome; Dry Eye	Drug: Thymosin beta 4; Drug: Placebo	Phase 2

Detailed Description

Tβ4 promotes wound repair and regeneration in various tissues. In the eye, it promotes corneal epithelial cell migration, decreases inflammation and has anti-apoptotic activities. It up-regulates the gene expression of laminin-5, a major subepithelial adhesion protein, located in the basement membrane region of the cornea, conjunctiva, and important in wound healing. In compassionate-use cases, Tβ4 has demonstrated efficacy in repairing non-healing neurotrophic corneal ulcers and other corneal epithelial wounds. In twenty-four nonclinical toxicology and safety pharmacology studies, the safety of Tβ4 has been demonstrated for its current and planned uses in man. The results of the two recent dry eye murine mouse model studies show that Tβ4 reduced corneal staining more than positive controls and demonstrated statistically significant reduction in staining compared to vehicle control. The results of these studies, in addition to data from compassionate use studies in patients with non-healing corneal surface defects, suggests that Tβ4 has a significant potential to be an important new safe and effective therapeutic in the treatment of dry eye syndrome.

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Masked, Randomized, Single-Center Study Evaluating the Safety and Efficacy of 0.1% Tβ4 Ophthalmic Solution Compared to Vehicle on the Signs and Symptoms of Dry Eye in the Controlled Adverse Environment (CAE) Model
• Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Thymosin Beta 4 RGN-259 is a preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4	Drug: Thymosin beta 4; A preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.; Other Names: Tβ4 RGN-259 (eye drop formulation of Tβ4)
Placebo Comparator: Placebo The placebo solution is composed of the same excipients as RGN-259 but does not contain Tβ4. The Placebo is identical to the RGN-259 eye drops in color, consistency, and odor.	Drug: Placebo; A preservative-free, sterile eye drop solution containing 0.0% (w/w) Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.; Other Names: Vehicle Control

Outcome Measures

Primary Outcome Measures

1. Corneal Staining (Inferior Region) in the Worst Eye in the Controlled Adverse Environment (CAE) Model, Which is a Regulated Environmental Setting Aimed at Exacerbating the Signs and Symptoms of Dry Eye [Day 29 (end of treatment)]

   This is a test that uses orange dye (fluorescein) and a blue light to detect ocular surface defects associated with dry eye. If the test result is normal, the dye remains in the tear film on the surface of the eye and does not adhere to the eye itself. The test is carried out throughout the study till end of treatment Day 29. However, the primary outcome measure itself is determined on Day 29. The scale used to determine the difference in corneal fluorescein staining between RGN-259 and placebo is the ORA scale: 0= no staining (no detectable ocular defect)to 4= confluent staining( severe ocular defect). Worst eye: In the case that both eyes were eligible for analysis, the worst eye was chosen as the eye with the greater increase of inferior corneal staining from Visit 1 to Visit 2. If both eyes were equal, the eye with greater ocular discomfort at Visit 2 was chosen as the worst eye. If both eyes were equal at Visit 2, then the right eye was chosen as the worst eye.

2. Ocular Discomfort in the Worst Eye in the Controlled Adverse Environment(CAE) Model, Which is a Regulated Environmental Setting Aimed at Exacerbating the Signs and Symptoms of Dry Eye. [Day 29 (end of treatment)]

   Dry eye causes ocular discomfort, which is measured using a validated 4-point ORA Scale from the start of the dosing till the end of treatment (Day 29). 0 = no discomfort to 4 = constant discomfort. If the measurement is lower, then improvement of ocular discomfort can be inferred. The test is carried out throughout the study till end of treatment Day 29. However, the primary outcome measure itself is determined on Day 29. Worst eye: In the case that both eyes were eligible for analysis, the worst eye was chosen as the eye with the greater increase of inferior corneal staining from Visit 1 to Visit 2. If both eyes were equal, the eye with greater ocular discomfort at Visit 2 was chosen as the worst eye. If both eyes had were equal at Visit 2, then the right eye was chosen as the worst eye.

Secondary Outcome Measures

1. Number of Adverse Events as a Measure of Safety and Tolerability [Throughout the study till Day 29]

   The Adverse events, which will be followed, are: impairment of visual acuity, an increase in intraocular pressure (IOP), and an increase in corneal sensitivity in both eyes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Have given a written, informed consent.

2. Be able and willing to follow instructions, including participation in study assessments, and be present for the required study visits for the duration of the study.

3. Have a best corrected visual acuity.

4. Have a patient-reported history of dry eye in both eyes.

5. Use and/or desire to use an artificial tear substitute for dry eye symptoms within the past 6 months.

6. A negative urine pregnancy test if female of childbearing potential.

7. Have a corneal fluorescein staining score of ≥ 2 in any corneal surface segment in at least one eye at Visit 1.

Exclusion Criteria:

1. Have contraindications to the use of the study drug.

2. Have known allergy or sensitivity to the study drug or components thereof.

3. Have anterior blepharitis.

4. Be diagnosed with an on-going ocular infection or active ocular inflammation.

5. Use contact lenses within 1 week before Visit 1 or during the course of the study.

6. Have previously had Laser-Assisted in Situ Keratomileusis (LASIK) surgery within 12 months prior to Visit 1.

7. Be currently taking any topical ophthalmic prescription or over-the-counter (OTC) solutions, artificial tears, gels, or scrubs and cannot discontinue these medications for the duration of the trial.

8. Have used topical ocular cyclosporine within 30 days prior to Visit 1.

9. Have had a past or present evidence of malignancy.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• ReGenTree, LLC
• ORA, Inc.

Investigators

• Principal Investigator: Gail Torkildsen, MD, Ora Clinical Research and Development

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: ReGenTree, LLC
• ClinicalTrials.gov Identifier: NCT01387347
• Other Study ID Numbers: RGN-DE-202
• First Posted: Jul 4, 2011
• Last Update Posted: Jul 10, 2015
• Last Verified: Dec 1, 2012

• Keywords provided by ReGenTree, LLC: Thymosin beta 4; Dry eye syndrome; Dry eye
• Additional relevant MeSH terms: Dry Eye Syndromes; Keratoconjunctivitis Sicca; Ophthalmic Solutions

Study Results

Participant Flow

Recruitment Details	The study took place at Ora Clinical Research and Development (a medical clinic)by Dr. Gail Torkildsen.The first subject was screened on 13 August 2011 and the last subject last visit to the clinic was on 20 September 2011.
Pre-assignment Detail	Subjects who initially qualified for study entry, had adequate baseline staining and redness and positive controlled adverse environment response, were instructed to discontinue all ophthalmic medications and instill a commercially-available sterile irrigating (balanced salt) solution (i.e., the run-in solution) twice a day until Visit 2, Day 0.

Arm/Group Title	Placebo	Thymosin Beta 4
Arm/Group Description	The placebo solution is composed of the same excipients as RGN-259 but does not contain Tβ4. The Placebo is identical to the RGN-259 eye drops in color, consistency, and odor. Placebo : A preservative-free, sterile eye drop solution containing 0.0% (w/w) Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.	RGN-259 is a preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4. Thymosin beta 4 : A preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.
Period Title: Overall Study
STARTED	36	36
COMPLETED	34	35
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Placebo	Thymosin Beta 4	Total
Arm/Group Description	The placebo solution is composed of the same excipients as RGN-259 but does not contain Tβ4. The Placebo is identical to the RGN-259 eye drops in color, consistency, and odor. Placebo : A preservative-free, sterile eye drop solution containing 0.0% (w/w) Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.	RGN-259 is a preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4 Thymosin beta 4 : A preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.	Total of all reporting groups
Overall Participants	36	36	72
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	27 75%	27 75%	54 75%
>=65 years	9 25%	9 25%	18 25%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.3 (12.76)	57.1 (12.07)	56.02 (12.37)
Sex: Female, Male (Count of Participants)
Female	25 69.4%	29 80.6%	54 75%
Male	11 30.6%	7 19.4%	18 25%
Region of Enrollment (participants) [Number]
United States	36 100%	36 100%	72 100%

Outcome Measures

1. Primary Outcome

Title	Corneal Staining (Inferior Region) in the Worst Eye in the Controlled Adverse Environment (CAE) Model, Which is a Regulated Environmental Setting Aimed at Exacerbating the Signs and Symptoms of Dry Eye
Description	This is a test that uses orange dye (fluorescein) and a blue light to detect ocular surface defects associated with dry eye. If the test result is normal, the dye remains in the tear film on the surface of the eye and does not adhere to the eye itself. The test is carried out throughout the study till end of treatment Day 29. However, the primary outcome measure itself is determined on Day 29. The scale used to determine the difference in corneal fluorescein staining between RGN-259 and placebo is the ORA scale: 0= no staining (no detectable ocular defect)to 4= confluent staining( severe ocular defect). Worst eye: In the case that both eyes were eligible for analysis, the worst eye was chosen as the eye with the greater increase of inferior corneal staining from Visit 1 to Visit 2. If both eyes were equal, the eye with greater ocular discomfort at Visit 2 was chosen as the worst eye. If both eyes were equal at Visit 2, then the right eye was chosen as the worst eye.
Time Frame	Day 29 (end of treatment)

Outcome Measure Data

Analysis Population Description

Intent to Treat population

Arm/Group Title	Thymosin Beta 4	Placebo
Arm/Group Description	RGN-259 is a preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4 Thymosin beta 4 : A preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.	Placebo is a preservative-free, sterile eye drop solution containing 0% Tβ4 Thymosin beta 4 : A preservative-free, sterile eye drop solution containing 0% Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.
Measure Participants	36	36
Mean (Standard Deviation) [units on a scale]	2.08 (0.71)	1.9 (0.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thymosin Beta 4, Placebo
	Comments	Inferior corneal fluorescein staining score at Day 29(primary sign) was summarized using descriptive statistics (number of observations, mean, standard deviation, median, minimum, and maximum). Active treatment was compared to placebo using a two-sample t-test assuming unequal variances, assessed at the α = 0.05 level
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2596
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.18
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Thymosin Beta 4, Placebo
	Comments	Comparison of central corneal fluorescein staining score between the placebo and Thymosin beta 4 groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0075
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Thymosin Beta 4, Placebo
	Comments	Comparison of superior corneal fluorescein staining score between the placebo and Thymosin beta 4 groups
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0210
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Ocular Discomfort in the Worst Eye in the Controlled Adverse Environment(CAE) Model, Which is a Regulated Environmental Setting Aimed at Exacerbating the Signs and Symptoms of Dry Eye.
Description	Dry eye causes ocular discomfort, which is measured using a validated 4-point ORA Scale from the start of the dosing till the end of treatment (Day 29). 0 = no discomfort to 4 = constant discomfort. If the measurement is lower, then improvement of ocular discomfort can be inferred. The test is carried out throughout the study till end of treatment Day 29. However, the primary outcome measure itself is determined on Day 29. Worst eye: In the case that both eyes were eligible for analysis, the worst eye was chosen as the eye with the greater increase of inferior corneal staining from Visit 1 to Visit 2. If both eyes were equal, the eye with greater ocular discomfort at Visit 2 was chosen as the worst eye. If both eyes had were equal at Visit 2, then the right eye was chosen as the worst eye.
Time Frame	Day 29 (end of treatment)

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT)

Arm/Group Title	Placebo	Thymosin Beta 4
Arm/Group Description	The placebo solution is composed of the same excipients as RGN-259 but does not contain Tβ4. The Placebo is identical to the RGN-259 eye drops in color, consistency, and odor. Placebo : A preservative-free, sterile eye drop solution containing 0.0% (w/w) Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.	Thymosin beta 4 solution is a sterile eye drop solution containing 0.1%(w/w) Tβ4. Thymosin beta 4 : A preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.
Measure Participants	36	36
Mean (Standard Deviation) [Units on a Scale]	1.3 (1.1)	1.6 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thymosin Beta 4, Placebo
	Comments	Comparison between the groups uses a two-sample t-test assuming unequal variances, assessed at the alpha = 0.05 level.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3734
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Thymosin Beta 4, Placebo
	Comments	Comparison of discomfort score between the placebo and Thymosin beta 4 groups on Day 28
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0244
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Number of Adverse Events as a Measure of Safety and Tolerability
Description	The Adverse events, which will be followed, are: impairment of visual acuity, an increase in intraocular pressure (IOP), and an increase in corneal sensitivity in both eyes.
Time Frame	Throughout the study till Day 29

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT)

Arm/Group Title	Placebo	Thymosin Beta 4
Arm/Group Description	Placebo is a preservative-free, sterile eye drop solution containing 0% Tβ4 (w/w) for direct instillation into each eye twice a day for 29 days.	RGN-259 is a preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4 for direct instillation into each eye twice a day for 29 days.
Measure Participants	36	36
Number [Events]	2	0

Adverse Events

Arm/Group Title	Placebo		Thymosin Beta 4
Arm/Group Description	The placebo solution is composed of the same excipients as RGN-259 but does not contain Tβ4. The Placebo is identical to the RGN-259 eye drops in color, consistency, and odor. Placebo : A preservative-free, sterile eye drop solution containing 0.0% (w/w) Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.		RGN-259 is a preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4 Thymosin beta 4 : A preservative-free, sterile eye drop solution containing 0.1% (w/w) Tβ4 for direct instillation into each eye, twice a day (BID) for 28 days.
All Cause Mortality
	Placebo		Thymosin Beta 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Thymosin Beta 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/36 (0%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Thymosin Beta 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/36 (5.6%)		0/36 (0%)
Eye disorders
General disorder ocular and administration site conditions AND Instillation site pain,	2/36 (5.6%)	4	0/36 (0%)	0

Limitations/Caveats

There were no limitations to trial RGN-DE-202 entitled:"Safety and Efficacy of Thymosin beta 4 Ophthalmic Solution in Patients with Dry Eye". All subjects were enrolled.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.