Ocular Hypertension, Open-angle Glaucoma
Conditions
Keywords
Glaucoma
Brief summary
Evaluation of the ocular hypotensive efficacy and safety of Netarsudil (AR-13324) Ophthalmic Solution compared to Timolol Maleate Ophthalmic Solution
Interventions
1 drop once daily (QD), PM, OU
1 drop BID, AM/PM, OU
OTHERPlacebo
1 drop QD, AM, OU
1 drop BID, AM/PM, OU
Sponsors
Aerie Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 99 Years
Healthy volunteers
No
Inclusion criteria
Subject inclusion criteria 1. 0-2 years of age and 18 years or greater 2. Diagnosis of open angle glaucoma or ocular hypertension 3. Unmedicated (post-washout) intraocular pressure (IOP) \>20 mm Hg and \< 27 mm Hg in the study eye at 2 qualification visits 4. Corrected visual acuity in each eye equivalent to 20/200 5. Able and willing to give signed informed consent (parent or guardian consent for pediatric patient) and follow study instructions Subject
Exclusion criteria
Ophthalmic: 1. Glaucoma: pseudoexfoliation or pigment dispersion component, history of angle closure, or narrow angles. Note: Previous laser peripheral iridotomy is NOT acceptable. 2. Intraocular pressure ≥27 mm Hg (unmedicated) in both eyes or use of more than two ocular hypotensive medications within 30 days of screening. Note: fixed dose combinations count as two medications. 3. Known hypersensitivity to any component of the formulations to be used (benzalkonium chloride, etc.), to topical anesthetics or beta-adrenoceptor antagonists. 4. Previous glaucoma intraocular surgery or glaucoma laser procedures in either eye 5. Refractive surgery in either eye. 6. Ocular trauma in either eye within the six months prior to screening, or ocular surgery or non-refractive laser treatment within the three months prior to screening. 7. Recent or current evidence of ocular infection or inflammation in either eye. Current evidence of clinically significant blepharitis, conjunctivitis, or a history of herpes simplex or zoster keratitis at screening in either eye. 8. Ocular medication in either eye of any kind within 30 days of screening. 9. Clinically significant ocular disease in either eye (e.g., corneal edema, uveitis, severe keratoconjunctivitis sicca) which might interfere with the study, including glaucomatous damage so severe that washout of ocular hypotensive medications for one month is not judged safe. 10. Central corneal thickness in either eye greater than 600 µm at screening. 11. Any abnormality in either eye preventing reliable applanation tonometry of either eye. Systemic: 12. Clinically relevant abnormalities (as determined by the investigator) in laboratory tests at screening which may impact the study. 13. Known hypersensitivity or contraindication to beta-adrenoceptor antagonists (e.g., chronic obstructive pulmonary disease or bronchial asthma; abnormally low blood pressure or heart rate; second or third degree heart block or congestive heart failure; severe diabetes). 14. Clinically significant systemic disease (e.g., uncontrolled diabetes, myasthenia gravis, hepatic, renal, endocrine or cardiovascular disorders) which might interfere with the study. 15. Participation in any investigational study within 30 days prior to screening. 16. Changes of systemic medication that could have an effect on intraocular pressure within 30 days prior to screening, or anticipated during the study. 17. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a medically acceptable form of birth control. An adult woman is considered to be of childbearing potential unless she is one year post-menopausal or three months post-surgical sterilization. All females of childbearing potential must have a negative urine pregnancy test result at the screening examination and must not intend to become pregnant during the study..
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intraocular Pressure (IOP) | 3 months | The primary efficacy outcome is mean intraocular pressure (IOP) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Extent of Exposure | 12 Months | Exposure to study medication in days for all treatment groups |
Countries
United States
Participant flow
Recruitment details
62 clinical trial sites participated in this study, of which 60 clinical trial sites enrolled participants. Screening started in June 2014. Enrollment started in July 2014. The last participant was enrolled in March 2015.
Pre-assignment details
Prior to enrollment, adult participants were required to have a Screening Visit and 2 Qualification Visits to allow for washout of ocular hypotensive medication.
Participants by arm
| Arm | Count |
|---|---|
| AR-13324 Ophthalmic Solution 0.02% & Placebo 1 drop AR-13324 in the evening (PM) and 1 drop placebo in the morning (AM) in both eyes (OU) | 251 |
| Timolol Maleate Ophthalmic Solution 0.5% BID 1 drop Timolol maleate twice daily (BID) in the morning (AM) and evening (PM) in both eyes (OU) | 251 |
| AR-13324 Ophthalmic Solution 0.02% BID 1 drop AR-13324 twice daily (BID) in the morning (AM) and evening (PM) in both eyes (OU) | 254 |
| Total | 756 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 71 | 15 | 132 |
| Overall Study | Death | 2 | 0 | 0 |
| Overall Study | Disallowed Concurrent Medication | 2 | 5 | 2 |
| Overall Study | Lack of Efficacy | 10 | 2 | 4 |
| Overall Study | Lost to Follow-up | 1 | 0 | 3 |
| Overall Study | Non-Compliant | 3 | 3 | 1 |
| Overall Study | Other(Site,Sponsor and Subject request) | 2 | 1 | 5 |
| Overall Study | Physician Decision | 1 | 2 | 2 |
| Overall Study | Protocol Violation | 4 | 10 | 6 |
| Overall Study | Withdrawal by Subject | 9 | 9 | 13 |
Baseline characteristics
| Characteristic | AR-13324 Ophthalmic Solution 0.02% & Placebo | Timolol Maleate Ophthalmic Solution 0.5% BID | AR-13324 Ophthalmic Solution 0.02% BID | Total |
|---|---|---|---|---|
| Age, Continuous | 65.3 Years STANDARD_DEVIATION 11.48 | 63 Years STANDARD_DEVIATION 11.81 | 64.1 Years STANDARD_DEVIATION 12.46 | 64.1 Years STANDARD_DEVIATION 11.95 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 41 Participants | 42 Participants | 43 Participants | 126 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 210 Participants | 209 Participants | 211 Participants | 630 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 6 Participants | 6 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 69 Participants | 76 Participants | 69 Participants | 214 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 178 Participants | 166 Participants | 177 Participants | 521 Participants |
| Sex: Female, Male Female | 148 Participants | 150 Participants | 165 Participants | 463 Participants |
| Sex: Female, Male Male | 103 Participants | 101 Participants | 89 Participants | 293 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 251 | 0 / 251 | 0 / 253 |
| other Total, other adverse events | 198 / 251 | 96 / 251 | 213 / 253 |
| serious Total, serious adverse events | 17 / 251 | 12 / 251 | 7 / 253 |
Outcome results
Primary
Intraocular Pressure (IOP)
The primary efficacy outcome is mean intraocular pressure (IOP)
Time frame: 3 months
Population: The Per Protocol (PP) population includes all subjects who did not have a major protocol violation likely to seriously affect the primary outcome of the study. This is the primary population for efficacy analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 90 (Month 3), 1600 hours | 17.73 mmHg | Standard Deviation 3.386 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 1, 1600 hours | 21.56 mmHg | Standard Deviation 2.338 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 90 (Month 3), 0800 hours | 19.43 mmHg | Standard Deviation 3.761 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 43, 1600 hours | 17.88 mmHg | Standard Deviation 2.888 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 15, 0800 hours | 19.01 mmHg | Standard Deviation 2.979 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 43, 0800 hours | 19.37 mmHg | Standard Deviation 3.749 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 90 (Month 3), 1000 hours | 18.18 mmHg | Standard Deviation 3.571 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 15, 1000 hours | 17.74 mmHg | Standard Deviation 3.089 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 1, 1000 hours | 22.31 mmHg | Standard Deviation 2.131 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 1, 0800 hours | 23.51 mmHg | Standard Deviation 1.654 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 15, 1600 hours | 17.37 mmHg | Standard Deviation 2.83 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 43, 1000 hours | 18.10 mmHg | Standard Deviation 3.335 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 15, 1600 hours | 17.59 mmHg | Standard Deviation 2.935 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 43, 0800 hours | 18.08 mmHg | Standard Deviation 2.614 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 43, 1600 hours | 17.25 mmHg | Standard Deviation 2.813 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 90 (Month 3), 0800 hours | 18.21 mmHg | Standard Deviation 2.819 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 1, 1000 hours | 22.18 mmHg | Standard Deviation 2.089 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 90 (Month 3), 1000 hours | 17.52 mmHg | Standard Deviation 2.777 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 1, 1600 hours | 21.61 mmHg | Standard Deviation 2.369 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 90 (Month 3), 1600 hours | 17.67 mmHg | Standard Deviation 2.879 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 15, 0800 hours | 18.25 mmHg | Standard Deviation 2.736 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 43, 1000 hours | 17.31 mmHg | Standard Deviation 2.805 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 15, 1000 hours | 17.49 mmHg | Standard Deviation 2.796 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 1, 0800 hours | 23.45 mmHg | Standard Deviation 1.601 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 90 (Month 3), 1000 hours | 17.81 mmHg | Standard Deviation 3.33 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 43, 1000 hours | 17.09 mmHg | Standard Deviation 3.028 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 90 (Month 3), 1600 hours | 17.08 mmHg | Standard Deviation 3.112 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 1, 0800 hours | 23.50 mmHg | Standard Deviation 1.671 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 1, 1000 hours | 22.26 mmHg | Standard Deviation 2.103 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 1, 1600 hours | 21.49 mmHg | Standard Deviation 2.279 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 15, 0800 hours | 18.20 mmHg | Standard Deviation 3.491 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 15, 1000 hours | 16.91 mmHg | Standard Deviation 3.087 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 15, 1600 hours | 16.28 mmHg | Standard Deviation 2.925 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 43, 0800 hours | 18.57 mmHg | Standard Deviation 3.206 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 43, 1600 hours | 16.58 mmHg | Standard Deviation 3.095 |
| AR-13324 Ophthalmic Solution 0.02% BID | Intraocular Pressure (IOP) | Day 90 (Month 3), 0800 hours | 18.66 mmHg | Standard Deviation 3.46 |
Secondary
Extent of Exposure
Exposure to study medication in days for all treatment groups
Time frame: 12 Months
Population: The Safety Population included all randomized subjects who received at least 1 dose of study medication and was used to summarize safety variables. The safety population summarized subjects as treated for purpose of analysis. One (1) subject did not receive study drug as randomized, shown in the Participant Flow
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Extent of Exposure | 259.7 days | Standard Deviation 133.34 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Extent of Exposure | 324.5 days | Standard Deviation 90.73 |
| AR-13324 Ophthalmic Solution 0.02% BID | Extent of Exposure | 185.2 days | Standard Deviation 144.56 |