Ocular Hypertension, Open Angle Glaucoma
Conditions
Brief summary
The study is intended to test the effectiveness and safety of Netarsudil / Latanoprost 0.02% / 0.005% Ophthalmic Solution, relative to GANFORT® for lowering of intraocular pressure (IOP) in patients with elevated intraocular pressure
Interventions
DRUGNetarsudil/Latanoprost 0.02%/0.005%
Topical sterile ophthalmic solution
DRUGGANFORT®
Topical sterile ophthalmic solution
Sponsors
Aerie Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Must be 18 years of age or older. 2. Diagnosis of OAG or OHT in both eyes (OAG in one eye and OHT in the fellow eye is acceptable). 3. Subjects insufficiently controlled and/or subjects considered in need for combination therapy by the investigators. 4. Medicated intraocular pressure ≥ 17 mmHg in at least one eye and \< 28mmHg in both eyes at screening visit. 5. Unmedicated (post-washout) IOP \>20mmHg in at least one eye and \< 36mmHg in both eyes at 2 qualification visits at 08:00 hour, 2-7 days apart. At the second qualification visit, have IOP \>17mmHg in at least one eye and \< 36mmHg in both eyes at 10:00 and 16:00 hours. Note: For purposes of determining eligibility of subjects to be enrolled, the non-integral IOP mean number will be used. Any non-integral mean IOP number should not be rounded. If only one eye qualifies at the second qualification visit it MUST be the same eye that qualified on the first visit and this will be the study eye for the duration of the study. 6. Best corrected visual acuity +1.0 logMAR or better by ETDRS in each eye (equivalent to 20/200 or better Snellen visual acuity in each eye). 7. Be able and willing to give signed informed consent and follow study instruction. 8. Women must be either of non-childbearing potential, or women with childbearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study. 9. Women of childbearing potential must have a negative urine pregnancy test within 7 days of first dose of study treatment and agree to use highly effective contraception during the study and for 3 months after the last dose of study medication. 10. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use an effective form of contraception from time of randomization and for 3 months following the last dose of study medication. 11. In France, a subject will be eligible for inclusion in this study only if either affiliated to or as a beneficiary of a social security number.
Exclusion criteria
Ophthalmic: 1. Clinically significant ocular disease (e.g., corneal edema, uveitis, or severe keratoconjunctivitis sicca) which might interfere with interpretation of the study efficacy endpoints or with safety assessments, including subjects with glaucomatous damage so severe that washout of ocular hypotensive medications for 4 weeks or longer if needed is not judged safe as it would put the subject at risk for further vision loss. 2. Pseudoexfoliation or pigment dispersion component glaucoma, history of angle closure glaucoma, or narrow angles i.e. Grade 2 Shaffer (Chan 1981) or less extreme narrow angle with complete or partial closure. Note: Previous laser peripheral iridotomy is NOT acceptable. 3. Intraocular pressure ≥ 36mmHg (unmedicated) in either eye (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 combination medications, for the purpose of this exclusion criterion, count as one medication. However, subjects currently taking 2 fixed dose combination products are excluded. 4. Treatment-naïve subjects. 5. Prior treatment with GANFORT® topical eye drops where the subjects IOP did not achieve the target IOP and was considered either a therapeutic failure or to have insufficient response. Subjects currently (immediately prior to screening visit) being treated with GANFORT® are excluded from the study. 6. Known hypersensitivity to any component of the investigational formulations to be used (e.g., benzalkonium chloride) or to fluorescein. 7. Previous glaucoma intraocular surgery, including SLT or ALT in either eye. 8. Refractive surgery in either eye (e.g., radial keratotomy, PRK, LASIK, corneal cross-linking, keratoplasty). 9. Ocular trauma within the six months prior to screening, or ocular surgery or non-refractive laser treatment within the three months prior to screening. 10. Recent or current evidence of ocular infection or inflammation in either eye. Current evidence of clinically significant blepharitis, conjunctivitis, keratitis, current evidence or history of herpes simplex or zoster keratitis in either eye at screening. 11. Use of ocular medication in either eye of any kind within 30 days of screening and throughout the study, with the exception of a) ocular hypotensive medications which must have been the same medication for 30 days prior to screening (which must be washed out according to the provided schedule), b) lid scrubs (which may be used prior to, but not after, screening), c) lubricating drops for dry eye (which may be used throughout the study), as prescribed by the Investigator. 12. Mean central corneal thickness greater than 620μm at screening. 13. Any abnormality preventing reliable Goldmann applanation tonometry of either eye (e.g., keratoconus). Systemic: 14. Clinically significant abnormalities in laboratory tests at screening. 15. Known hypersensitivity or contraindication to GANFORT® (Appendix 3 Marketed Product Medication Information Section 4.3) and to β-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, cardiac failure, cardiac shock and severe diabetes). 16. Clinically significant systemic disease which might interfere with the study. 17. Participation in any investigational study within 30 days prior to screening. 18. Systemic medication including corticosteroid containing drugs that could have a substantial effect on IOP which HAVE NOT been maintained at a consistent dose and regime within 30 days prior to screening, and are anticipated to change in dose and/or regime during the study. 19. Use of topical steroid containing medications on the face or in or around the eyes will exclude the subject (see Section 5.6 Concomitant Medications). 20. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a medically acceptable and highly effective form of birth control. An adult woman is considered to be of childbearing potential unless she is one year post-menopausal (1 year without menses with appropriate clinical profile, e.g. age appropriate, \> 45 years in the absence of HRT. In questionable cases the subject must have FSH value \> 40mIU/mL and an estradiol value \< 40pg/mL (\< 140pmol/L)) or three months post-surgical sterilization. 21. Vulnerable subjects such as minors, adults under legal protection or unable to express their consent (e.g. hospitalized persons in coma), persons deprived of liberty (prisoners from jails), or persons subject to psychiatric care.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Diurnal Intraocular Pressure by Goldmann Applanation Tonometry | Day 90 | Comparison of PG324 to Ganfort for mean intraocular pressure at specified timepoints at Week 2, Week 6 and Month 3. |
Countries
Austria, Belgium, Czechia, France, Germany, Hungary, Italy, Latvia, Poland, Spain, United Kingdom
Participant flow
Recruitment details
Recruitment took place in 11 European countries between September 2017 and May 2020.
Pre-assignment details
All participants underwent a period of washout for their pre-study ocular hypotensive medication for a prescribed period (up to 4 weeks or longer), depending on the medication, before receiving study medication. From the total 436 participants, 6 were not included in the analysis due to serious GCP breaches (2 from the Netarsudil/Latanoprost 0.02%/0.005% arm and 4 from the Ganfort arm). The remaining 430 participants (218 and 212 respectively) were included in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| Netarsudil/Latanoprost 0.02%/0.005% PG324 Ophthalmic Solution (netarsudil 0.02% / latanoprost 0.005%) one drop daily to each eye for 180 days.
Netarsudil/Latanoprost 0.02%/0.005%: Topical sterile ophthalmic solution | 218 |
| GANFORT® GANFORT® (bimatoprost 0.03%/timolol 0.5%) Ophthalmic solution one drop daily to each eye for 180 days.
GANFORT®: Topical sterile ophthalmic solution | 212 |
| Total | 430 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 40 | 4 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Disallowed Concurrent Medication | 1 | 1 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other - Reason not reported in CSR | 4 | 3 |
| Overall Study | Protocol Violation | 3 | 3 |
| Overall Study | Withdrawal by Subject | 5 | 1 |
Baseline characteristics
| Characteristic | GANFORT® | Netarsudil/Latanoprost 0.02%/0.005% | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 133 Participants | 147 Participants | 280 Participants |
| Age, Categorical Between 18 and 65 years | 79 Participants | 71 Participants | 150 Participants |
| Age, Continuous Mean | 67.0 years | 67.3 years | 67.2 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 56 Participants | 61 Participants | 117 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 156 Participants | 157 Participants | 313 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 | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 4 Participants | 9 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 | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) White | 200 Participants | 210 Participants | 410 Participants |
| Region of Enrollment Austria | 17 participants | 17 participants | 34 participants |
| Region of Enrollment Belgium | 5 participants | 5 participants | 10 participants |
| Region of Enrollment Czechia | 31 participants | 30 participants | 61 participants |
| Region of Enrollment France | 4 participants | 2 participants | 6 participants |
| Region of Enrollment Germany | 36 participants | 38 participants | 74 participants |
| Region of Enrollment Hungary | 11 participants | 8 participants | 19 participants |
| Region of Enrollment Italy | 21 participants | 21 participants | 42 participants |
| Region of Enrollment Latvia | 8 participants | 8 participants | 16 participants |
| Region of Enrollment Poland | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Spain | 61 participants | 66 participants | 127 participants |
| Region of Enrollment United Kingdom | 15 participants | 20 participants | 35 participants |
| Sex: Female, Male Female | 92 Participants | 131 Participants | 223 Participants |
| Sex: Female, Male Male | 120 Participants | 87 Participants | 207 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 218 | 1 / 212 |
| other Total, other adverse events | 117 / 218 | 53 / 212 |
| serious Total, serious adverse events | 7 / 218 | 7 / 212 |
Outcome results
Primary
Mean Diurnal Intraocular Pressure by Goldmann Applanation Tonometry
Comparison of PG324 to Ganfort for mean intraocular pressure at specified timepoints at Week 2, Week 6 and Month 3.
Time frame: Day 90
Population: A total of 430 (100%) participants were included in the Safety and Intent-to-Treat populations.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Netarsudil/Latanoprost 0.02%/0.005% | Mean Diurnal Intraocular Pressure by Goldmann Applanation Tonometry | Week 2 | 15.39 mmHg |
| Netarsudil/Latanoprost 0.02%/0.005% | Mean Diurnal Intraocular Pressure by Goldmann Applanation Tonometry | Week 6 | 15.64 mmHg |
| Netarsudil/Latanoprost 0.02%/0.005% | Mean Diurnal Intraocular Pressure by Goldmann Applanation Tonometry | Month 3 | 15.61 mmHg |
| GANFORT® | Mean Diurnal Intraocular Pressure by Goldmann Applanation Tonometry | Week 2 | 15.56 mmHg |
| GANFORT® | Mean Diurnal Intraocular Pressure by Goldmann Applanation Tonometry | Week 6 | 15.25 mmHg |
| GANFORT® | Mean Diurnal Intraocular Pressure by Goldmann Applanation Tonometry | Month 3 | 15.19 mmHg |
Comparison: Assuming no difference between PG324 and Ganfort, a two-tailed alpha of 0.05 (2-sided 95% CI) at each of 9 time points, a common SD of 3.5 mmHg, and a correlation between time points of ≤ 0.60, 200 ITT subjects per arm were necessary to have 85% power to show clinical non-inferiority of PG324 to Ganfort in the mean change from baseline IOP.p-value: <0.05Regression, Linear