Ocular Hypertension, Open-angle Glaucoma
Conditions
Keywords
Glaucoma
Brief summary
To evaluate the ocular hypotensive efficacy and ocular and systemic safety of AR-13324 Ophthalmic Solution, 0.02% compared to the active comparator Timolol maleate Ophthalmic Solution, 0.5%
Interventions
1 drop BID, AM/PM, OU
1 drop once daily (QD), PM, OU
OTHERPlacebo
1 drop QD, AM, 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
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) IOP (Intraocular Pressure) \>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 (individuals who are excluded for this criterion are not allowed to attempt requalification), 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 IOP |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Extent of Exposure | 3 months | Exposure to study medication in days for all treatment groups. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited at 35 clinical trial sites starting in June of 2014. The first participant was enrolled in July of 2014 and the last participant was enrolled in December of 2014.
Pre-assignment details
Prior to enrollment, adult participants were to have a Screening Visit and 2 Qualification Visits to allow for washout of ocular hypotensive medication if needed. The Randomized Population includes all subjects who were randomized to treatment. Baseline variables and demographic characteristics were summarized for this population.
Participants by arm
| Arm | Count |
|---|---|
| AR-13324 Ophthalmic Solution 0.02% & Placebo 1 drop AR-13324 in the evening (PM) & 1 drop placebo in the morning (AM) in both eyes (OU) | 202 |
| 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) | 209 |
| Total | 411 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 20 | 4 |
| Overall Study | Lack of Efficacy | 3 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliant | 0 | 1 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Protocol Violation | 3 | 5 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Timolol Maleate Ophthalmic Solution 0.5% BID | Total | AR-13324 Ophthalmic Solution 0.02% & Placebo |
|---|---|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 11.34 | 65.0 years STANDARD_DEVIATION 11.5 | 65.8 years STANDARD_DEVIATION 11.65 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 55 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 181 Participants | 356 Participants | 175 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 51 Participants | 94 Participants | 43 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 153 Participants | 310 Participants | 157 Participants |
| Sex: Female, Male Female | 136 Participants | 250 Participants | 114 Participants |
| Sex: Female, Male Male | 73 Participants | 161 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 203 | 0 / 208 |
| other Total, other adverse events | 145 / 203 | 75 / 208 |
| serious Total, serious adverse events | 3 / 203 | 4 / 208 |
Outcome results
Primary
Intraocular Pressure (IOP)
The primary efficacy outcome is mean IOP
Time frame: 3 months
Population: Per-Protocol (PP) Population. The PP population includes subjects who did not have major protocol violations likely to seriously affect the primary outcome of the study. The PP population summarizes subjects as treated for purpose of analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 15, 1000 hours | 17.29 mmHg | Standard Deviation 3.303 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 1, 0800 hours | 23.42 mmHg | Standard Deviation 1.756 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 1, 1000 hours | 22.28 mmHg | Standard Deviation 2.128 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 1, 1600 hours | 21.78 mmHg | Standard Deviation 2.385 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 15, 0800 hours | 18.68 mmHg | Standard Deviation 3.342 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 15, 1600 hours | 17.24 mmHg | Standard Deviation 3.294 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 43, 0800 hours | 19.35 mmHg | Standard Deviation 3.629 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 43, 1000 hours | 18.14 mmHg | Standard Deviation 3.502 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 43, 1600 hours | 17.86 mmHg | Standard Deviation 3.58 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 90 (month 3), 0800 hours | 19.81 mmHg | Standard Deviation 3.647 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 90 (month 3), 1000 hours | 18.92 mmHg | Standard Deviation 3.702 |
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Intraocular Pressure (IOP) | Day 90 (month 3), 1600 hours | 18.48 mmHg | Standard Deviation 3.595 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 90 (month 3), 1000 hours | 17.96 mmHg | Standard Deviation 2.674 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 43, 0800 hours | 18.24 mmHg | Standard Deviation 2.924 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 1, 0800 hours | 23.37 mmHg | Standard Deviation 1.658 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 90 (month 3), 0800 hours | 18.47 mmHg | Standard Deviation 2.711 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 1, 1000 hours | 21.92 mmHg | Standard Deviation 2.053 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 43, 1000 hours | 17.44 mmHg | Standard Deviation 2.725 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 1, 1600 hours | 21.45 mmHg | Standard Deviation 2.365 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 90 (month 3), 1600 hours | 17.74 mmHg | Standard Deviation 2.546 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 15, 0800 hours | 18.33 mmHg | Standard Deviation 2.566 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 15, 1000 hours | 17.55 mmHg | Standard Deviation 2.57 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 43, 1600 hours | 17.71 mmHg | Standard Deviation 2.82 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Intraocular Pressure (IOP) | Day 15, 1600 hours | 17.70 mmHg | Standard Deviation 2.661 |
Comparison: Assuming zero difference between AR-13324 and timolol, a 2-tailed alpha of 0.05 at each of 9 time points, a common SD of 3.0 mmHg, and a correlation between time points of 0.60 or less, 170 PP subjects per arm were necessary to have 90% power to show clinical noninferiority of AR-13324 to timolol in mean IOP.p-value: <0.0001ANCOVA
Secondary
Extent of Exposure
Exposure to study medication in days for all treatment groups.
Time frame: 3 months
Population: Safety Population: all randomized subjects who received at least 1 dose of study medication. The safety population summarizes subjects as treated for purpose of analysis. Three (3) subjects received incorrect study medication from that to which they were randomized, shown in the Participant Flow.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AR-13324 Ophthalmic Solution 0.02% & Placebo | Extent of Exposure | 82.8 days | Standard Deviation 21.44 |
| Timolol Maleate Ophthalmic Solution 0.5% BID | Extent of Exposure | 87.4 days | Standard Deviation 15.53 |