Safety and Efficacy of Ophthalmic Phentolamine Mesylate to Reverse Pharmacologically Induced Mydriasis

Study Overview
=================
Brief Summary
-----------------
The objectives of this study are: To evaluate the efficacy of Nyxol (phentolamine mesylate ophthalmic solution 1%) to expedite the reversal of pharmacologic mydriasis To evaluate the safety of Nyxol To evaluate the effect of Lumify® to suppress conjunctival hyperemia (redness) potentially associated with administration of Nyxol

Detailed Description
-----------------
Randomized, 2-arm cross-over, double-masked Phase 2b study in approximately 32 healthy subjects, evaluating safety and efficacy of Nyxol in subjects with pharmacologically induced mydriasis. At the first visit subjects will be screened for study eligibility. After screening, eligible subjects will be randomized 1:1 to one of the two treatment sequences: Treatment sequence 1: Placebo (Visit 1), Nyxol (Visit 2). Treatment sequence 2: Nyxol (Visit 1), Placebo (Visit 2). Randomization will be stratified by mydriatic agent (2.5% phenylephrine or 1% tropicamide). Approximately one half of the randomized subjects will receive 2.5% phenylephrine and one half will receive 1% tropicamide. Subjects will receive their mydriatic agent 1 hour before treatment. Each subject will receive the same mydriatic agent throughout the study. At each visit, pupil diameter (PD), accommodation, near and distance visual acuity (VA) and redness in each eye will be measured before (-1 hour/baseline) and 1 hour after (maximum/0 minutes) the mydriatic agent instillation in each eye (i.e., right before the study treatment is administered), and at 30 minutes, 1 hour, 2 hours, 4 hours and 6 hours after treatment dosing. As needed, two hours post treatment, subjects may request the administration of Lumify® in the non-study eye.

Official Title
-----------------
Randomized, Cross-Over, Double-Masked, Placebo-Controlled Study of the Safety and Efficacy of Phentolamine Mesylate Ophthalmic Solution to Reverse Pharmacologically Induced Mydriasis in Normal Healthy Subjects

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

Intervention / Treatment
-----------------
* Drug: Phentolamine Mesylate Ophthalmic Solution 1%
* Other: Phentolamine Mesylate Ophthalmic Solution Vehicle (Placebo)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or females ≥ 18 and ≤ 45 years of age with brown irides (irises) only Otherwise healthy and well controlled subjects Able to comply with all protocol mandated procedures and to attend all scheduled office visits Willing to give written informed consent to participate in this study Exclusion Criteria Clinically significant ocular disease as deemed by the Investigator (e.g., cataract, glaucoma, corneal edema, uveitis, severe keratoconjunctivitis sicca) that might interfere with the study Unwilling or unable to discontinue use of contact lenses during treatment visits Ocular trauma, ocular surgery or non-refractive laser treatment within the 6 months prior to screening Ocular medication of any kind within 30 days of screening, with the exception of a) lid scrubs (which may have been used prior to, but not after screening) or b) lubricating drops for dry eye (preservative-free artificial tears), which may be used in between the study treatment days Recent or current evidence of ocular infection or inflammation. Current evidence of clinically significant blepharitis, conjunctivitis, or a history of herpes simplex or herpes zoster keratitis at screening History of diabetic retinopathy Closed or very narrow angles that in the Investigator's opinion are potentially occludable if the subject's pupil is dilated History of any traumatic (surgical or nonsurgical) or non-traumatic condition affecting the pupil or iris (e.g., irregularly shaped pupil, neurogenic pupil disorder, iris atrophy, iridotomy) Known allergy or contraindication to any component of the mydriatic agents or the vehicle formulation Known hypersensitivity or contraindication to α- and/or β-adrenoceptor antagonists (e.g., chronic obstructive pulmonary disease or bronchial asthma; abnormally low blood pressure (BP) or heart rate (HR); second- or third-degree heart blockage or Congestive Heart Failure (CHF); severe diabetes) Clinically significant systemic disease (e.g., uncontrolled diabetes, myasthenia gravis, cancer, hepatic, renal, endocrine or cardiovascular disorders) that might interfere with the study Initiation of treatment with or any changes to the current dosage, drug or regimen of any topical or systemic adrenergic or cholinergic drugs up to 7 days prior to screening, or during the study Participation in any investigational study within 30 days prior to screening Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a medically acceptable form of birth control. Acceptable methods include the use of at least one of the following: intrauterine device (IUD), hormonal (oral, injection, patch, implant, ring), barrier with spermicide (condom, diaphragm), or abstinence. An adult woman is considered to be of childbearing potential unless she is 1 year postmenopausal or 3 months post-surgical sterilization. All females of childbearing potential must have a negative urine pregnancy test result at Visit 1/Screening and Visit 2 examinations and must intend to not become pregnant during the study Resting heart rate (HR) outside the normal range (50-110 beats per minute) at the Screening Visit. HR may be repeated only once if outside the normal range following at least a 5-minute rest period in the sitting position Hypertension with resting diastolic BP > 105 mmHg or systolic BP > 160 mmHg at the Screening Visit. BP may be repeated only once if outside the specified range following at least a 5-minute rest period in the sitting position

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 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: Crossover Assignment
Interventional Model Description: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phentolamine Mesylate Ophthalmic Solution 1%<br>1 drop in each eye, 1 hour post medically-induced mydriasis | Drug: Phentolamine Mesylate Ophthalmic Solution 1%<br>* 1% phentolamine mesylate ophthalmic solution (Nyxol), a non-selective alpha-1 and alpha-2 adrenergic antagonist<br>* Other names: Nyxol;|
| Placebo Comparator: Phentolamine Mesylate Ophthalmic Solution Vehicle<br>1 drop in each eye, 1 hour post medically-induced mydriasis | Other: Phentolamine Mesylate Ophthalmic Solution Vehicle (Placebo)<br>* Topical Sterile Ophthalmic Solution<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pupil Diameter (Change From Max) | Change in pharmacologically-induced mydriatic (maximum) pupil diameter at 2 hours post-treatment in the study eye. | 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pupil Diameter (Change From Max) | Change in pharmacologically-induced mydriatic (maximum) pupil diameter at remaining timepoints (30 min, 1 hours, 4 hours, 6 hours) | 30 min, 1 hours, 4 hours, 6 hours | 
| Pupil Diameter Return to Baseline | Percent of Subjects Achieving Pupil Diameter No More Than 0.5 mm Above Baseline by Time Point with either phenylephrine or tropicamide | 0 min, 1 hour, 2 hours, 4 hours, 6 hours | 
| Accommodation Measured by the Near Point Rule (Diopters) (Change From Baseline), Percent With Unchanged Accommodation | Change from baseline (-1 hour) in accommodation at each time point (0 min, 2 hours, 4 hours) with Tropicamide and Phenylephrine Worsening of accommodation is defined as an amplitude decrease of greater than 1 diopter compared to baseline | 0 min, 2 hours, 4 hours | 
| Conjunctival Hyperemia (Eye Redness) Assessed Visually With the Brien Holden Vision Institute (Formerly Corneal and Contact Lens Research Unit, or CCLRU) Bulbar Redness Scale (0-3) | Conjunctival hyperemia at each timepoint (0 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours), for study eye; in all subjects. Scale 0-3 (None, Mild, Moderate, Severe) | 0 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours | 
| Best Corrected Distance Visual Acuity (BCDVA) Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Light Box Chart (Letters) at 4 Meters (Change From Baseline) | Change from baseline (-1 hour) in Best Corrected Distance Visual Acuity at each time point (0 min, 30 mins, 1 hour, 2 hours, 6 hours) in Study Eye | 0 mins, 30 mins, 1 hour, 2 hours, 4 hours, 6 hours | 
| Distance-Corrected Near Visual Acuity (DCNVA) Measured by Standard Reading Card (Original Series Sloan Letter ETDRS Card at 16 Inches, LogMAR Units) (Change From Baseline) | Change from baseline (-1 hour) in Distance Corrected Near Visual Acuity at each time point (0 min, 30 mins, 1 hour, 2 hours, 6 hours) in Study Eye | 0 mins, 30 mins, 1 hour, 2 hours, 4 hours, 6 hours | 

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