Trial Outcomes & Findings for Effect of Topical Naltrexone Ophthalmic Solution on the Signs and Symptoms of Dry Eye in Diabetic Subjects (NCT NCT03660475)

Results Overview

The OSDI is a 12-item questionnaire designed to provide a rapid assessment of the symptoms of ocular irritation consistent with dry eye disease and their impact on vision-related functioning. It is a scale of 0-4 for each of the 12 questions. A minimum value would be "0" and a maximum value would be "48". The higher the value the worse the outcome.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

60 participants

Primary outcome timeframe

Day 29

Results posted on

2022-12-02

Participant Flow

Sixty subjects (30 subjects per treatment arm) were planned. For this number, it was anticipated that 120 subjects would be screened. A total of 87 subjects were screened to enroll 60 subjects who were analyzed for efficacy and safety.

Participant milestones

Participant milestones
Measure	Naltrexone Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Overall Study STARTED	30	30
Overall Study COMPLETED	30	30
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Effect of Topical Naltrexone Ophthalmic Solution on the Signs and Symptoms of Dry Eye in Diabetic Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution	Total n=60 Participants Total of all reporting groups
Age, Continuous	65.64 years STANDARD_DEVIATION 7.86 • n=5 Participants	62.64 years STANDARD_DEVIATION 10.97 • n=7 Participants	64.14 years STANDARD_DEVIATION 9.58 • n=5 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	18 Participants n=7 Participants	35 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	12 Participants n=7 Participants	25 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	20 Participants n=5 Participants	21 Participants n=7 Participants	41 Participants n=5 Participants
Race (NIH/OMB) White	10 Participants n=5 Participants	9 Participants n=7 Participants	19 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	30 participants n=5 Participants	30 participants n=7 Participants	60 participants n=5 Participants

PRIMARY outcome

Timeframe: Day 29

The OSDI is a 12-item questionnaire designed to provide a rapid assessment of the symptoms of ocular irritation consistent with dry eye disease and their impact on vision-related functioning. It is a scale of 0-4 for each of the 12 questions. A minimum value would be "0" and a maximum value would be "48". The higher the value the worse the outcome.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Total Ocular Surface Disease Index	21.17 score on a scale Standard Deviation 17.72	21.36 score on a scale Standard Deviation 17.16

SECONDARY outcome

Timeframe: Day 29

Lissamine green staining; regions: inferior, superior, central, corneal sum, temporal, nasal, conjunctival sum, total eye will be measured using an ocular discomfort score on a scale of 0 (no staining) to 4 (confluent staining). The total eye score is presented. A minimum score would be "0" and a maximal score would be "8". The higher the value the worse the outcome.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Lissamine Green Staining	2.65 score on a scale Standard Deviation 1.10	2.59 score on a scale Standard Deviation 1.25

SECONDARY outcome

Timeframe: Day 29

Tear film break-up time is the time taken for the first dry spot to appear on the cornea after a complete blink.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Tear Film Break-up Time	2.76 seconds Standard Deviation 0.98	3.48 seconds Standard Deviation 2.49

SECONDARY outcome

Timeframe: Day 29

Conjunctival redness will be assessed and conjunctival pain will be assessed using a visual analog scale ranging from "0" (none: normal without vasodilation) to "5" (severe: broad ciliary and prominent, horizontal conjunctival vasodilation). A minimal score would be "0" and a maximal score would be "10". The higher the value the worse the outcome .

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Conjunctival Redness	1.0 score on a scale Standard Deviation 0.41	1.0 score on a scale Standard Deviation 0.45

SECONDARY outcome

Timeframe: Day 29

Schirmer's Test (without anesthesia) ) involves placing a Schirmer test strip in the lower temporal lid margin of each eye such that the strip fits tightly. Subjects will be instructed to close their eyes. After 5 minutes have elapsed, the Schirmer strip will be removed. The length of the moistened area will be recorded (mm) for each eye. A normal reading is ≥10 mm wetting of the paper after 5 minutes. Tear deficiency is \<5 mm wetting of the paper after 5 minutes.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Schirmer's Test	8.97 mm Standard Deviation 8.00	12.48 mm Standard Deviation 9.20

SECONDARY outcome

Timeframe: Day 29

After extending the Cochet-Bonnet corneal sensitivity device (containing a thin, retractable, nylon monofilament) up to 6 cm in length and pressing against the cornea, the monofilament is slowly retracted incrementally in 0.5 cm steps until the patient can feel its contact and the length is recorded. The greater the length indicates increased sensation and the shorter the length indicates decreased sensation.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Cochet-Bonnet Corneal Sensitivity Test	59.78 cm Standard Deviation 0.95	59.37 cm Standard Deviation 1.44

SECONDARY outcome

Timeframe: Day 29

Normal tear osmolarity is defined as \< 300 mOsm/L in both eyes and an inter-eye difference of \< 8 mOsm/L. Values greater than 300 mOsm/L are suggestive of dry eye.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Tear Osmolarity	304.31 mOsm/L Standard Deviation 14.11	310.66 mOsm/L Standard Deviation 12.16

SECONDARY outcome

Timeframe: Day 29

Levels of MMP-9 will be measured in each eye using InflammaDry at Visit 5. The test will be recorded as either positive or negative. Dry eye patients generally exhibit positive levels of MMP-9., so the number of subjects testing positive for MMP-9 at Day 29 will be recorded.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Matrix Metalloprotienase-9 (MMP-9) is a Marker of Inflammation.	3 Participants	3 Participants

SECONDARY outcome

Timeframe: Day 29

Ocular discomfort scores will be subjectively graded by the subjects according to the following scale, rating each eye separately on a scale from 0-4. A score of "0" represents no discomfort and a score of "4" represents constant discomfort. A minimum score would be "0" and a maximum score would be "8". The higher the value the worse the outcome.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Ocular Discomfort (Scale 1)	1.03 score on a scale Standard Deviation 1.10	1.07 score on a scale Standard Deviation 1.13

SECONDARY outcome

Timeframe: Day 29

Subjects will rate the severity of each of the following symptoms, with regard to how both their eyes feel: overall ocular discomfort, burning, dryness, grittiness and stinging according to the following 6-point (0 to 5) scale where 0 = none and 5 = worst. A minimum score would be "0" and a maximum score would be "10". The higher the value the worse the outcome.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Ocular Discomfort (Scale 2)	1.40 score on a scale Standard Deviation 1.25	1.45 score on a scale Standard Deviation 1.57

SECONDARY outcome

Timeframe: Day 29

Standard scale assessing a patient's level of pain on a scale of 0-100. The subject will be asked to rate each ocular symptom due to ocular dryness by placing a vertical mark on the horizontal line to indicate the level of discomfort. 0% corresponds to "no discomfort" and 100% corresponds to "maximal discomfort". The following parameters will be assessed: burning/stinging, itching, foreign body sensation, blurred vision, eye dryness, photophobia, and pain, with a total score for each eye reported. A minimal score would be "0" and a maximum score would be "200". The higher the value the worse the outcome.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Visual Analog Scale for Pain	16.27 score on a scale Standard Deviation 22.82	25.07 score on a scale Standard Deviation 31.32

SECONDARY outcome

Timeframe: Day 29

The following regions of each eye will be assessed for fluorescein staining: inferior, superior, central, corneal sum, temporal, nasal, conjunctival sum, and a total eye score recorded. A score of "0" represents no staining and a score of "4" represents confluent staining. A minimum score would be "0" and a maximum score would be "8". A higher values represent a worse outcome.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Fluorescein Staining	7.70 score on a scale Standard Deviation 2.53	7.14 score on a scale Standard Deviation 3.23

SECONDARY outcome

Timeframe: Day 29

Population: Mean change in visual acuity for both eyes measured by LogMAR units (0-1.0)

Mean change in visual acuity (LogMAR units 0-1.0) for both eyes at Day 29 was determined for each treatment arm and considered a measure of safety.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Visual Acuity Measured by Assessing Average Change in LogMAR Units for Both Eyes at Day 29. LogMAR Units Range From 0-1.0, With the Higher the Number Indicating a Worsening in Vision.	0.08 units on a scale Standard Deviation 0.11	0.07 units on a scale Standard Deviation 0.13

OTHER_PRE_SPECIFIED outcome

Timeframe: Adverse events will be collected from first dose of study drug to 30 days after treatment discontinuation (Day 29 + 4 weeks).

An adverse event is defined as any untoward medical occurrence associated with the use of the investigational agent (or placebo) regardless of whether or not it is considered related to the investigational drug (or placebo).

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Number of Participants With Treatment-related Adverse Events	0 Participants	1 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 29

The binocular slit-lamp examination provides a stereoscopic magnified view of the eye structures in detail, enabling anatomical diagnoses to be made of the cornea, conjunctiva, anterior chamber, iris, lens and lid for both eyes. The number of subjects in each treatment arm that have changes in the cornea, conjunctiva, anterior chamber, iris, lens and lid for both eyes at Day 29 will be reported.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Slit-lamp Biomicroscopy	0 participants	0 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 29

Intraocular pressure is the fluid pressure inside the eye.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Intraocular Pressure	14.95 mmHg Standard Deviation 3.30	14.65 mmHg Standard Deviation 2.90

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 29

Dilated fundus examination is a diagnostic procedure that employs the use of mydriatic eye drops to dilate the pupil in order to obtain a better view of the fundus of the eye. The number of subjects that demonstrate clinically significant abnormalities in the vitreous, choroid, macula, and optic nerve at Day 29 in either treatment arm will be reported.

Outcome measures

Outcome measures
Measure	Naltrexone n=30 Participants Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 Participants Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Dilated Fundoscopy	0 participants	0 participants

Adverse Events

Naltrexone

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Naltrexone n=30 participants at risk Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution	Placebo n=30 participants at risk Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution
Skin and subcutaneous tissue disorders Swelling of upper lip	0.00% 0/30 • Through Day 29 + four week follow-up period Deaths and adverse events were not reported on during the Run-In Period	3.3% 1/30 • Through Day 29 + four week follow-up period Deaths and adverse events were not reported on during the Run-In Period
Metabolism and nutrition disorders Increase in A1C	0.00% 0/30 • Through Day 29 + four week follow-up period Deaths and adverse events were not reported on during the Run-In Period	3.3% 1/30 • Through Day 29 + four week follow-up period Deaths and adverse events were not reported on during the Run-In Period
Musculoskeletal and connective tissue disorders Rotator cuff pain	0.00% 0/30 • Through Day 29 + four week follow-up period Deaths and adverse events were not reported on during the Run-In Period	3.3% 1/30 • Through Day 29 + four week follow-up period Deaths and adverse events were not reported on during the Run-In Period

Additional Information

Joseph Sassani, MD, MHA

Penn State Hershey Medical Center

Phone: 717 531 8783

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place