Nebivolol 0.5, 1.0, or Timolol 0.5 Suspension Compared to Timolol 0.5 Solution to Treat Glaucoma/Ocular Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety (in the eye and throughout the body) and effectiveness of nebivolol (0.5 and 1 percent) and timolol (0.5 percent) eye drop suspensions. These eye drops will be compared to timolol 0.5 percent eye drop solution in participants with open angle glaucoma (the most common type of glaucoma) or high eye pressure (ocular hypertension).

Detailed Description
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The study will enroll 240 participants (60 in each treatment arm) who will be treated for 84 days (12 weeks). Participants will have OAG (open angle glaucoma) or OHT (ocular hypertension) in both eyes (OAG in one eye and OHT in the follow eye is acceptable) that requires therapy and elevated IOP (intraocular pressure) adequately controlled on no more than 2 ocular hypertensive medications. Participants with OHT on no ocular hypotensive medications are acceptable. After being informed about the study and potential risks, participants giving written informed consent will undergo an washout period, if required, from previous glaucoma medications (28 days for prostaglandin analogs, rho-associated protein kinase inhibitors, or beta blockers; 14 days for adrenergic agonists; and 5 days for muscarinic agonists or carbonic anhydrase inhibitors). Eligible participants must have unmedicated IOP measurements at Visit 3/Baseline ≥ 22 and ≤ 34 mm Hg at 8:00 AM and ≥ 18 and ≤ 34 mm Hg at 10:00 AM and 4:00 PM (each qualifying eye must fall within the required IOP range at all 3 time points and must be at least 22 mm Hg at each consecutive measurement at the 8:00 AM time point). Both eyes will be treated twice daily. Study visits will comprise Visit 1/Screening/Day -35 to -1, Visit 2/Washout Safety Check/Day -14 ± 3 (performed for participants undergoing 28-day washout periods at the Investigator's discretion), Visit 3/Qualification/Baseline/Day 1, Visit 4/Day 15 ± 3, Visit 5/Day 42 ± 3, and Visit 6/Day 84 ± 3. At Visits 4, 5, and 6, participants will be evaluated at 8:00 AM, at 2 hours after study medication dosing at the clinical site (approximately 10:00 AM), and at 4:00 PM (each ± 30 minutes). All ophthalmic assessments will be performed bilaterally.

Official Title
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Randomized, Multicenter, Observer-Masked Study to Compare Safety/Efficacy of Nebivolol Suspension 0.5% or 1.0%, or Timolol Suspension 0.5% to Timolol Solution 0.5% in Participants With Primary Open Angle Glaucoma or Ocular Hypertension

Conditions
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Open-Angle Glaucoma, Ocular Hypertension

Intervention / Treatment
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* Drug: Nebivolol Ophthalmic Suspension 1 Percent
* Drug: Nebivolol Ophthalmic Suspension 0.5 Percent
* Drug: Timolol Ophthalmic Suspension 0.5 Percent
* Drug: Timolol Ophthalmic Solution 0.5 Percent


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to understand and sign an informed consent form prior to any study related procedures. Able to administer or have a caregiver accurately administer an eye drop. Have POAG or OHT in both eyes that requires therapy for IOP and is adequately controlled, in the opinion of the Investigator, on no more than 2 ocular hypotensive medications (fixed dose combinations count as 2 medications). Subjects with OHT on no ocular hypotensive medication are acceptable. Presence of POAG in one eye and OHT in the fellow eye is acceptable. 3. Able, in the opinion of the Investigator, to safely discontinue use of ocular hypotensive medications, if applicable, and undergo the appropriate required washout period for ocular hypotensive medications prior to Visit 3/Qualification/Baseline. 4. At Visit 3/Qualification/Baseline, at least one eye must have unmedicated (post washout) IOP ≥ 22 and ≤ 34 mm Hg at 8:00 AM and ≥ 18 and ≤ 34 mm Hg at 10:00 AM and 4:00 PM in the same eye(s) qualifying at the Visit 3 8:00 AM time point. The IOP must be at least 22 mm Hg at each consecutive measurement at the 8:00 AM time point. 5. No significant VF (visual field) loss, defined as a mean deviation in either eye greater than - 12 dB or a central point of fixation < 5 dB in either eye. If the VF performed at or within 90 days prior to Visit 1 does not meet study required parameters, it may be repeated (test should be prior to randomization at Visit 3/Qualification/Baseline). 6. Best corrected visual acuity (BCVA) of +0.6 logMAR or better in both eyes at Visit 1/Screening and Visit 3/Qualification/Baseline. 7. Central corneal thickness ≥ 480 and ≤ 600 μm in both eyes. Pachymetry within 90 days prior to Screening is acceptable. 8. Shaffer gonioscopic grade ≥ 3 (in at least 3 quadrants) in both eyes. Gonioscopy within 90 days prior to randomization is acceptable. 9. Female subjects must be 1-year postmenopausal, surgically sterilized (total hysterectomy, bilateral oophorectomy or bilateral tubal ligation > 90 days prior to Visit 1/Screening), or women of childbearing potential with a negative urine pregnancy test at Visit 1/Screening and Visit 3/Qualification/Baseline who are not breastfeeding or planning a pregnancy during the study. Women of childbearing potential must use an acceptable form of contraception throughout the study. Acceptable methods include the use of at least one of the following: Intrauterine (IUD) device Hormonal contraceptive (oral, injection, patch, implant, ring); subjects must have been on the same hormonal contraceptive for ≥ 90 days prior to Visit 1/Screening Double barrier method (spermicide used with either a condom or diaphragm) Abstinence Exclusion Criteria: Ocular Intraocular pressure ˃ 34 mm Hg in either eye at Visit 1/Screening, Visit 2/Washout Safety Check, or Visit 3/Qualification/Baseline. Other forms of glaucoma in either eye, e.g., congenital glaucoma, closed-angle glaucoma, uveitic glaucoma, pseudoexfoliation or pigment dispersion syndrome, or history of angle closure. Narrow angles treated with peripheral iridotomy are allowed if at least 4 months status post iridotomy. Current or recent (within 30 days prior to Visit 1/Screening) clinically significant ocular infection or inflammation, in the opinion of the Investigator, in either eye. History of conjunctivitis within 90 days prior to Visit 1/Screening, or history of herpes simplex or herpes zoster in either eye. Clinically significant ocular disease, in the opinion of the Investigator, in either eye (including, but not limited to corneal edema, uveitis, severe dry eye, proliferative diabetic retinopathy or macular degeneration) that might interfere with the study, confound study results, or put the subject at increased risk. Have a cup-to disc (CD) ratio > 0.8 at Visit 1/Screening in either eye. Intravitreal steroid injections within 6 months prior to Visit 1/Screening. Subconjunctival or subtenon steroid injections within 90 days prior to Visit 1/Screening. Use of topical ocular medications within 30 days prior to Visit 1/Screening other than ocular hypotensive medications and medications used as part of an eye examination. Artificial tears may be used during this period provided the use is not required for severe dry eye disease. Clinically significant ocular trauma or incisional ocular surgery (including routine cataract surgery) in either eye within 6 months prior to Visit 1/Screening. Glaucoma filtering surgery, or minimally invasive glaucoma surgery within 12 months prior to Visit 1/Screening. Laser surgery for IOP reduction within 6 months prior to Visit 1/Screening. Non-incisional ocular surgery or non-glaucomatous laser treatment within 90 days prior to Visit 1/Screening. Refractive surgery in either eye (i.e., radial keratotomy, photorefractive keratectomy [PRK], laser-assisted in situ keratomileusis [LASIK], corneal cross-linking, limbal relaxing incision) within 6 months prior to Visit 1/Screening. Any ocular (e.g., corneal) abnormality preventing accurate assessment of IOP. Contact lens wear within 1 week prior to Visit 1/Screening or unwillingness to discontinue wear of contacts lenses prior to and during the study period. Aphakia. General Pregnancy or lactation. Known hypersensitivity or contraindication to β-blockers (i.e., chronic obstructive pulmonary disease, bronchial asthma, unstable or abnormally low blood pressure or heart rate, second or third degree heart block or congestive heart failure, severe or unstable diabetes mellitus) that in the opinion of the Investigator may put the subject at risk from a topical ocular beta-blocker. Have a condition or be in a situation which, in the Investigator's opinion, may put the subject at significant risk, confound study results, or interfere with the subject's participation in the study. Clinically significant systemic disease (myasthenia gravis, hepatic, renal, endocrine, or cardiovascular disorders) that in the opinion of the Investigator might interfere with the study. Use of systemic beta-adrenergic antagonists unless the dosage has been stable for 1 month prior to Visit 1/Screening and is expected to remain stable through the study period. Use of systemic (oral, injectable, inhaled) or topical steroids within 30 days prior to Visit 1/Screening; topical dermatologic or intranasal steroids are acceptable provided the usage meets the criteria outlined in the Summary of Prohibited Medications and Procedures in the protocol. Contraindication to the use of timolol, nebivolol, or any of the components of the investigational products. Changes to systemic medication that could have an effect on IOP within 28 days prior to Visit 3/Qualification/Baseline. Participation in any study of an investigational product within 30 days prior to Visit 1/Screening. History of substance abuse within 1 year prior to Visit 1/Screening. Screening and enrollment of employees or relatives of employees of the clinical site.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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
Interventional Model Description: Eligible participants will be randomized in a 1:1:1:1 ratio to 4 treatment arms: nebivolol 0.5% ophthalmic suspension; nebivolol 1.0% ophthalmic suspension; timolol 0.5% ophthalmic suspension; and timolol 0.5% ophthalmic solution.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nebivolol Ophthalmic Suspension 1 Percent<br>Administered twice daily to both eyes for 84 days (12 weeks) | Drug: Nebivolol Ophthalmic Suspension 1 Percent<br>* 1 drop instilled into each eye twice daily<br>|
| Experimental: Nebivolol Ophthalmic Suspension 0.5 Percent<br>Administered twice daily to both eyes for 84 days (12 weeks) | Drug: Nebivolol Ophthalmic Suspension 0.5 Percent<br>* 1 drop instilled into each eye twice daily<br>|
| Experimental: Timolol Ophthalmic Suspension 0.5 Percent<br>Administered twice daily to both eyes for 84 days (12 weeks) | Drug: Timolol Ophthalmic Suspension 0.5 Percent<br>* 1 drop instilled into each eye twice daily<br>|
| Active Comparator: Timolol Ophthalmic Solution 0.5 Percent<br>Administered twice daily to both eyes for 84 days (12 weeks) | Drug: Timolol Ophthalmic Solution 0.5 Percent<br>* 1 drop instilled into each eye twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intraocular Pressure Over 84 Days | Measured utilizing a calibrated Goldmann tonometer; two consecutive IOP measurements of each eye will be performed. If the 2 measurements differ by more than 2 mm Hg, a third measurement will be taken. The primary efficacy analysis will be the between-group comparison of the mean IOP values in the study eye at 10AM, 2 hours postdose, and 4PM, at each of the Visit 4/Day 15, Visit 5/Day 42, and Visit 6/Day 84 visits (ie, a total of 9 between-group comparisons). A hierarchical analysis will be conducted to compare each of the investigational products against the comparator, timolol 0.5% ophthalmic solution, as follows: (1) nebivolol 1% ophthalmic suspension, (2) nebivolol 0.5% ophthalmic suspension, and (3) timolol ophthalmic suspension. | Over 84 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intraocular Pressure: Change from Baseline in Diurnal IOP at Each Visit | Change from baseline (Visit 3/Qualification/Baseline) in the average of the 3 daily IOP measurements at Day 15, Day 42, and Day 84 | Day 15: 8 AM ± 30 minutes, 2 hours post-dose ± 30 minutes, 4 PM ± 30 minutes; Day 42: 8 AM ± 30 minutes, 2 hours post-dose ± 30 minutes, 4 PM ± 30 minutes; Day 84: 8 AM ± 30 minutes, 2 hours post-dose ± 30 minutes, 4 PM ± 30 minutes | 
| Intraocular Pressure: Change from Baseline at All Time Points at Each Visit | Time-matched change from baseline (Visit 3/Qualification/Baseline) in the 3 daily IOP measurements at Day 15, Day 42 and Day 84 | Day 15: 8 AM ± 30 minutes, 2 hours post-dose ± 30 minutes, 4 PM ± 30 minutes; Day 42: 8 AM ± 30 minutes, 2 hours post-dose ± 30 minutes, 4 PM ± 30 minutes; Day 84: 8 AM ± 30 minutes, 2 hours post-dose ± 30 minutes, 4 PM ± 30 minutes |