Safety and Efficacy of Nyxol Eye Drops as a Single Agent and With Adjunctive Low-Dose Pilocarpine Eye Drops in Subjects With Presbyopia

Study Overview
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Brief Summary
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The objectives of this study are: To evaluate the safety and efficacy of Nyxol alone and with adjunctive low dose pilocarpine to improve distance-corrected near visual acuity (DCNVA) in subjects with presbyopia.

Official Title
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Randomized, Double-Masked, Placebo-Controlled, Multicenter, Phase 3 Study of the Safety and Efficacy of Nyxol (Phentolamine Ophthalmic Solution 0.75%) as a Single Agent and With Adjunctive Low-Dose Pilocarpine Hydrochloride Ophthalmic Solution 0.4% in Subjects With Presbyopia

Conditions
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Presbyopia

Intervention / Treatment
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* Drug: Phentolamine Opthalmic Solution 0.75%
* Other: Placebo
* Drug: Low dose pilocarpine
* Other: Low dose pilocarpine vehicle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females ≥ 40 and ≤ 64 years of age. BCDVA of 0.1 LogMAR (20/25 Snellen equivalent) or better in each eye in photopic conditions. DCNVA of 0.4 LogMAR (20/50 Snellen equivalent) or worse but not > 0.7 LogMAR (20/100 Snellen equivalent) in photopic conditions in each eye and binocularly. For subjects who depend on reading glasses or bifocals, binocular best-corrected near VA is 0.1 LogMAR (20/25 Snellen equivalent) or better. Photopic PD of ≥ 3 mm in either eye. Exclusion Criteria: Ophthalmic (in either eye): Use of any topical prescription or over-the-counter (OTC) ophthalmic medications of any kind within 7 days of Screening until study completion, with the exception of lid scrubs with OTC products and artificial tears as specified in Exclusion # 2 below. Use of any OTC artificial tears (preserved or unpreserved) during Visit days or 15 min before or after instillation of study medication. Current use of any topical ophthalmic therapy for dry eye. Tear break-up time of < 5 seconds or corneal fluorescein staining Grade ≥ 2 in the inferior zone or Grade ≥ 1 in the central zone using the National Eye Institute scale.. Clinically significant ocular disease that might interfere with the study as deemed by the Investigator. Recent or current evidence of ocular infection or inflammation in either eye. Any history of herpes simplex or herpes zoster keratitis. Known allergy, hypersensitivity, or contraindication to any component of the phentolamine, pilocarpine, or vehicle formulations. Prior participation in a study involving the use of Nyxol for the treatment of presbyopia. History of cauterization of the punctum or punctal plug (silicone or collagen) insertion or removal. Ocular trauma within 6 months prior to Screening. Ocular surgery or any ocular laser treatment within 6 months prior to Screening. Subjects with surgical monovision, multifocal or extended depth of focus intraocular lenses (IOLs) are excluded. History of any traumatic (surgical or nonsurgical) or nontraumatic condition affecting the pupil or iris. Contact lens wear on the day of any study visit and contact lenses must be removed for home dosing and for at least 10 minutes following dosing. Systemic: Known hypersensitivity or contraindication to alpha- and/or beta-adrenoceptor antagonists . Known hypersensitivity or contraindication to any systemic cholinergic parasympathomimetic agent. Clinically significant systemic disease that might interfere with the study as deemed by the judgment of the Investigator. Initiation of treatment with, or any changes to, the current dosage, drug, or regimen of any systemic adrenergic or cholinergic drugs within 7 days prior to Screening or during the study. Participation in any investigational study within 30 days prior to Screening. Females of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a medically acceptable form of birth control. Resting HR outside the range of 50 to 110 beats per min. Hypertension with resting diastolic BP > 105 mmHg or systolic BP > 160 mmHg.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nyxol + low dose pilocarpine<br> | Drug: Phentolamine Opthalmic Solution 0.75%<br>* phentolamine ophthalmic solution 0.75% (Nyxol), a non-selective alpha-1 and alpha-2 adrenergic antagonist<br>* Other names: Nyxol;Drug: Low dose pilocarpine<br>* Pilocarpine hydrochloride ophthalmic solution 0.4%<br>* Other names: LDP;|
| Experimental: Nyxol + low dose pilocarpine vehicle<br> | Drug: Phentolamine Opthalmic Solution 0.75%<br>* phentolamine ophthalmic solution 0.75% (Nyxol), a non-selective alpha-1 and alpha-2 adrenergic antagonist<br>* Other names: Nyxol;Other: Low dose pilocarpine vehicle<br>* Vehicle for low dose pilocarpine<br>|
| Experimental: Placebo + low dose pilocarpine<br> | Other: Placebo<br>* Vehicle for Phentolamine Ophthalmic Solution<br>* Other names: Phentolamine Ophthalmic Solution Vehicle;Drug: Low dose pilocarpine<br>* Pilocarpine hydrochloride ophthalmic solution 0.4%<br>* Other names: LDP;|
| Experimental: Placebo + low dose pilocarpine vehicle<br> | Other: Placebo<br>* Vehicle for Phentolamine Ophthalmic Solution<br>* Other names: Phentolamine Ophthalmic Solution Vehicle;Other: Low dose pilocarpine vehicle<br>* Vehicle for low dose pilocarpine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of subjects with ≥ 15 letters of improvement in photopic binocular DCNVA and with < 5 letters of loss in photopic binocular BCDVA in Nyxol-treated subjects | The primary efficacy endpoint is the percent of subjects with ≥ 15 letters of improvement in photopic binocular DCNVA and with < 5 letters of loss in photopic binocular BCDVA from Baseline at 30 min post-LDP/vehicle comparing subjects treated with Nyxol + LDP to subjects treated with placebo + LDP vehicle at Visit 5 (Stage 2 Day 8). | Baseline at 30 min post-LDP/vehicle comparing subjects treated with Nyxol + LDP to subjects treated with placebo + LDP vehicle at Visit 5 (Stage 2 Day 8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of subjects with ≥ 15 letters improvement in photopic binocular DCNVA and with < 5 letters of loss in photopic binocular BCDVA in LDP+Nyxol-treated subjects | The percent of subjects with ≥ 15 letters of improvement in photopic binocular DCNVA and with < 5 letters of loss in photopic binocular BCDVA at 30 min post-LDP/vehicle comparing Nyxol + LDP to Nyxol alone at Visit 5 (Stage 2 Day 8). | At 30 min post-LDP/vehicle comparing Nyxol + LDP to Nyxol alone at Visit 5 (Stage 2 Day 8) | 
| Percentage of subjects with ≥ 15 letters of improvement in binocular photopic DCNVA and with < 5 letters of loss in binocular photopic BCDVA from Baseline (excluding primary and key secondary outcome timepoints) | Percentage of subjects with ≥ 15 letters of improvement in binocular photopic DCNVA and with < 5 letters of loss in binocular photopic BCDVA from Baseline (excluding primary and key secondary outcome timepoints) | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Percentage of subjects with ≥ 5, ≥ 10, and ≥ 15 letters of improvement in photopic DCNVA from Baseline (monocular and binocular) | Percentage of subjects with ≥ 5, ≥ 10, and ≥ 15 letters of improvement in photopic DCNVA from Baseline (monocular and binocular) | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Change in photopic DCNVA from Baseline (monocular and binocular) | Change in photopic DCNVA from Baseline (monocular and binocular) | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Percentage of subjects with loss or improvement in photopic and mesopic BCDVA from Baseline (monocular and binocular) | Percentage of subjects with loss or improvement in photopic and mesopic BCDVA from Baseline (monocular and binocular) | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Change in photopic and mesopic BCDVA from Baseline (monocular and binocular) | Change in photopic and mesopic BCDVA from Baseline (monocular and binocular) | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Percentage of subjects with ≥ 5, ≥ 10, and ≥ 15 letters of improvement in mesopic binocular DCNVA from Baseline | Percentage of subjects with ≥ 5, ≥ 10, and ≥ 15 letters of improvement in mesopic binocular DCNVA from Baseline | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Change in mesopic binocular DCNVA from Baseline | Change in mesopic binocular DCNVA from Baseline | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Change and percent change in photopic PD from Baseline | Change and percent change in photopic PD from Baseline | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Percentage of subjects with photopic PD of < 3.5, < 3.0, < 2.5, < 2.0, and < 1.5 mm | Percentage of subjects with photopic PD of < 3.5, < 3.0, < 2.5, < 2.0, and < 1.5 mm | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Percentage of subjects with photopic PD of 1.5 to < 2.0 mm, 2.0 to < 2.5 mm, 2.5 to < 3.0 mm, and 3.0 to < 3.5 mm | Percentage of subjects with photopic PD of 1.5 to < 2.0 mm, 2.0 to < 2.5 mm, 2.5 to < 3.0 mm, and 3.0 to < 3.5 mm | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Change and percent change in mesopic PD from Baseline | Change and percent change in mesopic PD from Baseline | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Percentage of subjects with mesopic PD of < 3.5, < 3.0, < 2.5, < 2.0, and < 1.5 mm | Percentage of subjects with mesopic PD of < 3.5, < 3.0, < 2.5, < 2.0, and < 1.5 mm | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Percentage of subjects with mesopic PD of 1.5 to < 2.0 mm, 2.0 to < 2.5 mm, 2.5 to < 3.0 mm, and 3.0 to < 3.5 mm | Percentage of subjects with mesopic PD of 1.5 to < 2.0 mm, 2.0 to < 2.5 mm, 2.5 to < 3.0 mm, and 3.0 to < 3.5 mm | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Percentage of subjects with Baseline photopic DCNVA ≤ 20/63, ≤ 20/80, ≤ 20/100, ≤ 20/125, and ≤ 20/160, with a ≥ 10-letter and ≥ 15-letter improvement in photopic DCNVA | Percentage of subjects with Baseline photopic DCNVA ≤ 20/63, ≤ 20/80, ≤ 20/100, ≤ 20/125, and ≤ 20/160, with a ≥ 10-letter and ≥ 15-letter improvement in photopic DCNVA | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Percentage of subjects with Baseline photopic DCNVA from 20/50 to 20/63, 20/50 to 20/80, 20/50 to 20/100, 20/50 to 20/125, and 20/50 to 20/160, with a ≥ 10-letter and ≥ 15-letter improvement in photopic DCNVA | Percentage of subjects with Baseline photopic DCNVA from 20/50 to 20/63, 20/50 to 20/80, 20/50 to 20/100, 20/50 to 20/125, and 20/50 to 20/160, with a ≥ 10-letter and ≥ 15-letter improvement in photopic DCNVA | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 
| Subject questionnaire responses related to change in near vision and satisfaction with near vision. | Subject questionnaire responses related to change in near vision and satisfaction with near vision. | At various timepoints and visits by treatment arms in Stage 1 and Stage 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nyxol, Presbyopia, Pilocarpine