Glaucoma, Ocular Hypertension
Conditions
Keywords
Tafluprost, Glaucoma, Ocular Hypertension, Timolol, Eye Disorder, Preservative-Free, Prostaglandin Analogue
Brief summary
This study will test the hypothesis that preservative-free tafluprost (MK-2452) is non-inferior to preservative-free timolol maleate with respect to the diurnal intraocular pressure (IOP) change from baseline after 4 weeks of therapy in participants with open-angle glaucoma or ocular hypertension.
Interventions
DRUGPreservative-Free Tafluprost or vehicle
Preservative-free tafluprost (0.0015%) ophthalmic solution; Preservative-free vehicle ophthalmic solution (contains no active drug)
DRUGPreservative-Free Timolol maleate
Preservative-free timolol maleate (0.5%) ophthalmic solution
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Participant has been diagnosed with primary open-angle glaucoma, pigmentary glaucoma, capsular glaucoma/pseudoexfoliation, or ocular hypertension * Has been using ocular hypotensive medication on a stable treatment regimen for at least 30 days prior to screening, or is treatment-naive (has never used or has not used ocular hypotensive medication for the last 4 weeks prior to screening) * Able to discontinue all topical and/or systemic ocular hypotensive medication during the washout period (up to 4 weeks pre-study) * Best-corrected early treatment of diabetic retinopathy study (ETDRS) visual acuity of 20/80 or better in each eye * Willing and able to avoid wearing contact lenses from 4 weeks prior to dosing with study medication through 24 hours after final dosing * Willing and able to self-administer or has an able person available on a daily basis to assist with administration of study medications * Participant with reproductive potential must agree to remain abstinent (unless abstinence is not a locally acceptable method of contraception) or use highly effective methods of birth control (hormonal contraceptives, intrauterine device, diaphragm, condoms and vasectomy) within the projected duration of the study * Able to refrigerate study drug at home.
Exclusion criteria
* Mean IOP \>36 mmHg in either eye at screening * Unable to use study medication in the affected eye(s) * History of any inflammatory ocular surface disease or a history of anterior or posterior uveitis in either eye within 6 months prior to screening * History of retinal detachment, proliferative diabetic retinopathy, or any progressive retinal disease * Significant visual field loss or evidence of progressive visual loss within the last year * Intraocular surgery in either eye in the last 4 months * Any glaucoma surgery, refractive surgery, or penetrating keratoplasty in either eye * Currently on two or more anti-glaucoma medications (except Cosopt™ or its generic formulation) * Previously used tafluprost * History of cardiovascular disorder within 6 months of screening * History of bronchial asthma, wheezing, chronic obstructive pulmonary disease (COPD) or other pulmonary disease, abnormal chest x-ray, or has current active pneumonia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Diurnal IOP Change From Baseline at Week 4 - Study Eye | Baseline and Week 4 | IOP was measured at baseline, Week 2 and Week 4 using a Goldmann applanation tonometer. At each of these visits, IOP measurement was performed at 0800, 1000 and 1600 hours. At each IOP assessment time point during a visit, 2 consecutive IOP measurements were made. If these 2 measurements differed by ≤2 mmHg, then the average of the 2 IOP values was recorded. If the 2 measurements differed by \>2 mmHg, then a third measurement was obtained and the median of these 3 measurements was recorded. The IOP value for a visit (e.g., Week 4) was the mean of the values recorded at the 3 time points during the visit. For each participant, one study eye was identified for data summarization and analysis for this primary efficacy outcome measure. The study eye was the eye with the higher (i.e., worse) IOP at baseline, or if both eyes had the same baseline IOP value, the right eye was designated the study eye. Change from baseline in IOP at Week 4 = Week 4 IOP value - baseline IOP value. |
| Number of Participants With an Adverse Event (AE) | Up to 14 days after Week 4 visit | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Participants with one or more AEs during the study are counted once in this summary. |
| Number of Participants Who Discontinued Study Drug Due to an AE | Up to Week 4 | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Participants who discontinued study drug treatment due to an AE are counted once in this summary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With ≥25% Reduction in IOP From Baseline to Week 4 - Study Eye | Baseline and Week 4 | IOP was measured at baseline, Week 2 and Week 4 using a Goldmann applanation tonometer. At each of these visits, IOP measurement was performed at 0800, 1000 and 1600 hours. At each IOP assessment time point during a visit, 2 consecutive IOP measurements were made. If these 2 measurements differed by ≤2 mmHg, then the average of the 2 IOP values was recorded. If the 2 measurements differed by \>2 mmHg, then a third measurement was obtained and the median of these 3 measurements was recorded. The IOP value for a visit (e.g., Week 4) was the mean of the values recorded at the 3 time points during the visit. For each participant, one study eye was identified for data summarization and analysis. The study eye was the eye with the higher (i.e., worse) IOP at baseline, or if both eyes had the same baseline IOP value, the right eye was designated the study eye. Percent reduction in IOP at Week 4 = (\[baseline IOP value - Week 4 IOP value\]/Baseline IOP value)\*100. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tafluprost One drop of preservative-free vehicle (contains no active drug) per eye in the morning, and one drop of preservative-free tafluprost (0.0015%) per eye in the evening for four weeks. | 93 |
| Timolol One drop of preservative-free timolol maleate (0.05%) per eye twice daily (morning and evening) for four weeks. | 94 |
| Total | 187 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Timolol | Tafluprost | Total |
|---|---|---|---|
| Age, Continuous | 54.9 years STANDARD_DEVIATION 13.42 | 56.7 years STANDARD_DEVIATION 11.54 | 55.8 years STANDARD_DEVIATION 12.52 |
| Intraocular Pressure (IOP) - Study Eye | 24.9 mmHg STANDARD_DEVIATION 2.6 | 24.8 mmHg STANDARD_DEVIATION 3 | 24.9 mmHg STANDARD_DEVIATION 2.8 |
| Sex: Female, Male Female | 22 Participants | 34 Participants | 56 Participants |
| Sex: Female, Male Male | 72 Participants | 59 Participants | 131 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 93 | 15 / 94 |
| serious Total, serious adverse events | 0 / 93 | 1 / 94 |
Outcome results
Primary
Mean Diurnal IOP Change From Baseline at Week 4 - Study Eye
IOP was measured at baseline, Week 2 and Week 4 using a Goldmann applanation tonometer. At each of these visits, IOP measurement was performed at 0800, 1000 and 1600 hours. At each IOP assessment time point during a visit, 2 consecutive IOP measurements were made. If these 2 measurements differed by ≤2 mmHg, then the average of the 2 IOP values was recorded. If the 2 measurements differed by \>2 mmHg, then a third measurement was obtained and the median of these 3 measurements was recorded. The IOP value for a visit (e.g., Week 4) was the mean of the values recorded at the 3 time points during the visit. For each participant, one study eye was identified for data summarization and analysis for this primary efficacy outcome measure. The study eye was the eye with the higher (i.e., worse) IOP at baseline, or if both eyes had the same baseline IOP value, the right eye was designated the study eye. Change from baseline in IOP at Week 4 = Week 4 IOP value - baseline IOP value.
Time frame: Baseline and Week 4
Population: Per Protocol population: Participants who received at least one dose of study drug, had at least one efficacy measurement available for an analysis endpoint and did not have any protocol violations that may substantially affect the results of the primary efficacy endpoint
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tafluprost | Mean Diurnal IOP Change From Baseline at Week 4 - Study Eye | -8.3 mmHg |
| Timolol | Mean Diurnal IOP Change From Baseline at Week 4 - Study Eye | -6.6 mmHg |
Comparison: The study hypothesis was that tafluprost is non-inferior to timolol with respect to change from baseline in diurnal IOP at Week 4 in participants with open-angle glaucoma or ocular hypertension. The study hypothesis would be met if the upper bound of the two-sided 95% confidence interval for the between-treatment difference in mean diurnal IOP change from baseline at Week4 (tafluprost - timolol) was ≤1.5 mmHg.95% CI: [-2.6, -0.7]ANCOVA
Primary
Number of Participants Who Discontinued Study Drug Due to an AE
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Participants who discontinued study drug treatment due to an AE are counted once in this summary.
Time frame: Up to Week 4
Population: APaT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tafluprost | Number of Participants Who Discontinued Study Drug Due to an AE | 3 participants |
| Timolol | Number of Participants Who Discontinued Study Drug Due to an AE | 2 participants |
95% CI: [-3.5, 5.7]Miettinen and Nurminen
Primary
Number of Participants With an Adverse Event (AE)
An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Participants with one or more AEs during the study are counted once in this summary.
Time frame: Up to 14 days after Week 4 visit
Population: APaT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tafluprost | Number of Participants With an Adverse Event (AE) | 28 participants |
| Timolol | Number of Participants With an Adverse Event (AE) | 32 participants |
95% CI: [-17.3, 9.4]Miettinen and Nurminen
Secondary
Number of Participants With ≥25% Reduction in IOP From Baseline to Week 4 - Study Eye
IOP was measured at baseline, Week 2 and Week 4 using a Goldmann applanation tonometer. At each of these visits, IOP measurement was performed at 0800, 1000 and 1600 hours. At each IOP assessment time point during a visit, 2 consecutive IOP measurements were made. If these 2 measurements differed by ≤2 mmHg, then the average of the 2 IOP values was recorded. If the 2 measurements differed by \>2 mmHg, then a third measurement was obtained and the median of these 3 measurements was recorded. The IOP value for a visit (e.g., Week 4) was the mean of the values recorded at the 3 time points during the visit. For each participant, one study eye was identified for data summarization and analysis. The study eye was the eye with the higher (i.e., worse) IOP at baseline, or if both eyes had the same baseline IOP value, the right eye was designated the study eye. Percent reduction in IOP at Week 4 = (\[baseline IOP value - Week 4 IOP value\]/Baseline IOP value)\*100.
Time frame: Baseline and Week 4
Population: Per Protocol population: Participants who received at least one dose of study drug, had at least one efficacy measurement available for an analysis endpoint and did not have any protocol violations that may substantially affect the results of the primary efficacy endpoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tafluprost | Number of Participants With ≥25% Reduction in IOP From Baseline to Week 4 - Study Eye | 65 participants |
| Timolol | Number of Participants With ≥25% Reduction in IOP From Baseline to Week 4 - Study Eye | 48 participants |
95% CI: [5.7, 33.4]Stratified Miettinen and Nurminen method