Safety and Efficacy of Nyxol (0.75% Phentolamine Ophthalmic Solution) to Reverse Pharmacologically-Induced Mydriasis (MIRA-3)

Study Overview
=================
Brief Summary
-----------------
The objectives of this study are: To evaluate the efficacy of Nyxol to expedite the reversal of pharmacologically-induced mydriasis across multiple mydriatic agents with an emphasis on phenylephrine To evaluate the efficacy of Nyxol to return subjects to baseline accommodation after worsening (with cycloplegic agents tropicamide and Paremyd) To evaluate the safety of Nyxol To evaluate any additional benefits of the reversal of pharmacologically-induced mydriasis To evaluate the systemic exposure of Nyxol on pharmacokinetic (PK) sampling

Detailed Description
-----------------
A randomized, parallel arm, double-masked, placebo-controlled Phase 3 study in at least 330 randomized subjects, evaluating the safety and efficacy of Nyxol in subjects with pharmacologically-induced mydriasis. Following the successful completion of screening, each subject will be stratified by eye color and then simultaneously be randomized to mydriatic agent (unmasked) and treatment (masked). Treatment randomization will be 2:1, Nyxol or placebo (vehicle). Stratification by iris color will be 1:1, light or dark rides. The mydriatic agent randomization will be 3:1:1 (2.5% phenylephrine, 1% tropicamide, and Paremyd). At the treatment visit, subjects who have been randomized and stratified by iris color (1:1 [light/dark]) will receive one of three approved mydriatic agents approximately 1 hour prior to receiving study treatment. Measurements will be measured before (-1 hour /baseline) and 60 minutes after (maximum/0 minutes) the mydriatic agent instillation in each eye (i.e. right before the study treatment is administered), and at 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, and 6 hours after treatment dosing. Measurements will include pupil diameter (PD), distance and near visual acuity (VA), accommodation, and redness in each eye. Blood sampling for Nyxol PK measurements will be conducted in a subset of approximately 30 adult subjects at approximately two select study sites. At the Follow-Up Visit, which is 1 day after Visit 1, measurements will again be recorded 24 hours after treatment dosing.

Official Title
-----------------
Randomized, Parallel Arm, Double-Masked, Placebo-Controlled Study of the Safety and Efficacy of Nyxol (0.75% Phentolamine Ophthalmic Solution) to Reverse Pharmacologically-Induced Mydriasis in Healthy Subjects

Conditions
-----------------
Mydriasis, Dilation

Intervention / Treatment
-----------------
* Drug: Phentolamine Ophthalmic Solution 0.75%
* Drug: Phentolamine Ophthalmic Solution Vehicle


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or females ≥ 12 years of age Ability to comply with all protocol-mandated procedures independently and to attend all scheduled office visits Exclusion Criteria: Clinically significant ocular disease as deemed by the Investigator (eg, glaucoma, corneal edema, uveitis, severe keratoconjunctivitis sicca) that might interfere with the study Unwilling or unable to discontinue use of contact lenses at screening until study completion Unwilling or unable to suspend use of topical medication at screening until study completion Ocular trauma, ocular surgery, or non-refractive laser treatment within the 6 months prior to screening Use of any topical prescription or over-the-counter (OTC) ophthalmic medications of any kind within 7 days of screening, with the exception of lid scrubs with OTC products (eg, OCuSOFT® lid scrub, SteriLid®, baby shampoo, etc.) Recent or current evidence of ocular infection or inflammation in either eye (such as current evidence of clinically significant blepharitis, conjunctivitis, or keratitis). Subjects must be symptom-free for at least 7 days prior to screening Closed or very narrow-angle that in the Investigator's opinion is potentially occludable if the subject's pupil is dilated Prior participation in a study involving the use of Nyxol for the reversal of mydriasis Known hypersensitivity or contraindication to α- and/or β-adrenoceptor antagonists Clinically significant systemic disease (eg, uncontrolled diabetes, myasthenia gravis, cancer, hepatic, renal, endocrine, or cardiovascular disorders) that might interfere with the study Participation in any investigational study within 30 days prior to screening Resting heart rate (HR) outside the normal range (50-110 beats per minute) at the Screening Visit. Hypertension with resting diastolic blood pressure (BP)>105 mmHg or systolic BP > 160 mmHg at the Screening Visit.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Phentolamine Ophthalmic Solution 0.75%<br>2 drops in study eye and 1 drop in non-study eye, 1 hour post pharmacologically-induced mydriasis | Drug: Phentolamine Ophthalmic Solution 0.75%<br>* 0.75% phentolamine ophthalmic solution (Nyxol), a non-selective alpha-1 and alpha-2 adrenergic antagonist<br>* Other names: Nyxol;|
| Placebo Comparator: Phentolamine Ophthalmic Solution Vehicle<br>2 drops in study eye and 1 drop in non-study eye, 1 hour post pharmacologically-induced mydriasis | Drug: Phentolamine Ophthalmic Solution Vehicle<br>* Phentolamine Ophthalmic Solution Vehicle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Subjects' Study Eyes With Pupil Diameter Returning to Baseline | Percentage of subjects' study eyes returning to less than or equal to 0.2 mm from baseline pupil diameter | 90 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Subjects' Study Eyes With Pupil Diameter Returning to Baseline | Percentage of subjects' study eyes returning to less than or equal to 0.2 mm from baseline pupil diameter | 30 minutes to 24 hours | 
| Pupil Diameter (Change From Max) | Change (mm) from maximum pharmacologically-induced mydriatic pupil diameter (0 minutes) | 30 minutes to 24 hours | 
| Percent of Subjects With Unchanged Accommodation From Baseline | Percentage of subjects with unchanged accommodation from baseline (-1 hour) | 90 minutes to 6 Hours | 
| Change From Baseline in Best-Corrected Distance Visual Acuity (BCDVA) Under Normal Photopic Lighting Without Glare Conditions | Change from Baseline in best-corrected distance visual acuity (BCDVA) under normal photopic lighting without glare conditions | 6 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Nyxol, Pharmacologically Induced Mydriasis, Dilation