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The objective of this exploratory study is to determine the safety and efficacy of 0.002% Naltrexone Ophthalmic Solution, compared to placebo for the treatment of the signs and symptoms of dry eye in diabetic subjects.
This is a Phase 2, single-center, double-masked, randomized, placebo-controlled study to compare the safety and efficacy of Naltrexone Ophthalmic Solution, 0.002% to placebo for the treatment of the signs and symptoms of dry eye in diabetic subjects. Subjects eligible to be randomized will receive one of the following treatments to be administered bilaterally BID for 29 days (from Visit 2 to Visit 5): Naltrexone Ophthalmic Solution, 0.002% or Placebo Ophthalmic Solution (Vehicle). During a 10-day study run-in period (for the purpose of subject selection) prior to randomization, all subjects will receive Placebo Ophthalmic Solution (Vehicle) bilaterally BID. Participants who terminate early during the application period will be asked to complete safety assessments (if the participants agree) prior to study exit. Participants who are terminated early from the study will not be replaced.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Naltrexone | Experimental | Naltrexone Ophthalmic Solution 0.002% |
|
| Placebo | Placebo Comparator | Placebo Ophthalmic Solution |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Naltrexone | Drug | naltrexone formulated as ophthalmic solution |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Total Ocular Surface Disease Index | 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. | Day 29 |
| Measure | Description | Time Frame |
|---|---|---|
| Lissamine Green Staining | 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. | Day 29 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events | 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). | Adverse events will be collected from first dose of study drug to 30 days after treatment discontinuation (Day 29 + 4 weeks). |
Inclusion Criteria:
Provide written informed consent;
Have a diagnosis of type 1 or type 2 diabetes mellitus prior to Visit 1;
Have a reported history of dry eye for at least 6 months prior to Visit 1;
Have a history of use or desire to use eye drops for dry eye symptoms within 6 months of Visit 1;
Have a corneal fluorescein staining score of ≥ 2 in any region (inferior, superior, or central regions) in at least one eye at Visits 1 and 2 (must be the same eye at Visits 1 and 2);
Have at least one of the following at Visits 1 and 2:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Eugene B McLaurin, M.D. | Total Eye Care | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Total Eye Care | Memphis | Tennessee | 38119 | United States |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Naltrexone | Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution |
| FG001 | Placebo | Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Naltrexone | Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution |
| BG001 | Placebo | Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Total Ocular Surface Disease Index | 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. | Posted | Mean | Standard Deviation | score on a scale | Day 29 |
|
Through Day 29 + four week follow-up period
Deaths and adverse events were not reported on during the Run-In Period
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Naltrexone | Naltrexone Ophthalmic Solution 0.002% Naltrexone: naltrexone formulated as ophthalmic solution |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Swelling of upper lip | Skin and subcutaneous tissue disorders | MedDRA 10.0 | Non-systematic Assessment |
Please note that no specific primary endpoint was identified in the protocol. The study was exploratory in nature looking at both efficacy and safety parameters to help inform future studies.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Joseph Sassani, MD, MHA | Penn State Hershey Medical Center | 717 531 8783 | jsassani@pennstatehealth.psu.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 21, 2018 | Sep 12, 2022 | Prot_SAP_001.pdf |
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| ID | Term |
|---|---|
| D015352 | Dry Eye Syndromes |
| ID | Term |
|---|---|
| D007766 | Lacrimal Apparatus Diseases |
| D005128 | Eye Diseases |
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| ID | Term |
|---|---|
| D009271 | Naltrexone |
| ID | Term |
|---|---|
| D009270 | Naloxone |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006571 |
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| Placebos |
| Drug |
Placebo ophthalmic solution |
|
| Tear Film Break-up Time | Tear film break-up time is the time taken for the first dry spot to appear on the cornea after a complete blink. | Day 29 |
| Conjunctival Redness | 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 . | Day 29 |
| Schirmer's Test | 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. | Day 29 |
| Cochet-Bonnet Corneal Sensitivity Test | 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. | Day 29 |
| Tear Osmolarity | 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. | Day 29 |
| Matrix Metalloprotienase-9 (MMP-9) is a Marker of Inflammation. | 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. | Day 29 |
| Ocular Discomfort (Scale 1) | 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. | Day 29 |
| Ocular Discomfort (Scale 2) | 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. | Day 29 |
| Visual Analog Scale for Pain | 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. | Day 29 |
| Fluorescein Staining | 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. | Day 29 |
| 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. | 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. | Day 29 |
| Slit-lamp Biomicroscopy | 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. | Day 29 |
| Intraocular Pressure | Intraocular pressure is the fluid pressure inside the eye. | Day 29 |
| Dilated Fundoscopy | 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. | Day 29 |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
|
| Secondary | Lissamine Green Staining | 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. | Posted | Mean | Standard Deviation | score on a scale | Day 29 |
|
|
|
|
| Secondary | Tear Film Break-up Time | Tear film break-up time is the time taken for the first dry spot to appear on the cornea after a complete blink. | Posted | Mean | Standard Deviation | seconds | Day 29 |
|
|
|
|
| Secondary | Conjunctival Redness | 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 . | Posted | Mean | Standard Deviation | score on a scale | Day 29 |
|
|
|
|
| Secondary | Schirmer's Test | 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. | Posted | Mean | Standard Deviation | mm | Day 29 |
|
|
|
|
| Secondary | Cochet-Bonnet Corneal Sensitivity Test | 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. | Posted | Mean | Standard Deviation | cm | Day 29 |
|
|
|
|
| Secondary | Tear Osmolarity | 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. | Posted | Mean | Standard Deviation | mOsm/L | Day 29 |
|
|
|
|
| Secondary | Matrix Metalloprotienase-9 (MMP-9) is a Marker of Inflammation. | 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. | Posted | Count of Participants | Participants | Day 29 |
|
|
|
| Secondary | Ocular Discomfort (Scale 1) | 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. | Posted | Mean | Standard Deviation | score on a scale | Day 29 |
|
|
|
|
| Secondary | Ocular Discomfort (Scale 2) | 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. | Posted | Mean | Standard Deviation | score on a scale | Day 29 |
|
|
|
|
| Secondary | Visual Analog Scale for Pain | 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. | Posted | Mean | Standard Deviation | score on a scale | Day 29 |
|
|
|
|
| Secondary | Fluorescein Staining | 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. | Posted | Mean | Standard Deviation | score on a scale | Day 29 |
|
|
|
|
| Secondary | 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. | 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. | Mean change in visual acuity for both eyes measured by LogMAR units (0-1.0) | Posted | Mean | Standard Deviation | units on a scale | Day 29 |
|
|
|
| Other Pre-specified | Number of Participants With Treatment-related Adverse Events | 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). | Posted | Count of Participants | Participants | Adverse events will be collected from first dose of study drug to 30 days after treatment discontinuation (Day 29 + 4 weeks). |
|
|
|
| Other Pre-specified | Slit-lamp Biomicroscopy | 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. | Posted | Number | participants | Day 29 |
|
|
|
| Other Pre-specified | Intraocular Pressure | Intraocular pressure is the fluid pressure inside the eye. | Posted | Mean | Standard Deviation | mmHg | Day 29 |
|
|
|
| Other Pre-specified | Dilated Fundoscopy | 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. | Posted | Number | participants | Day 29 |
|
|
|
| 0 |
| 30 |
| 0 |
| 30 |
| 0 |
| 30 |
| EG001 | Placebo | Placebo Ophthalmic Solution Placebos: Placebo ophthalmic solution | 0 | 30 | 0 | 30 | 1 | 30 |
| Increase in A1C | Metabolism and nutrition disorders | MedDRA 10.0 | Non-systematic Assessment |
|
| Rotator cuff pain | Musculoskeletal and connective tissue disorders | MedDRA 10.0 | Non-systematic Assessment |
|
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| Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |