A Phase 2 Study Of The 24-Hour Intraocular Pressure Lowering And Systemic Exposure Of PF-04217329

Study Overview
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Brief Summary
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This study will characterize the effect of PF-04217329, alone and in combination with latanoprost, on circadian intraocular pressure and blood pressure in glaucoma patients. Blood samples will be collected to measure the amount of active metabolite of PF-04217329 in the plasma following dosing.

Official Title
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A Phase 2, Single-masked, Randomized, Crossover Study Of The 24-hour Intraocular Pressure Lowering And Systemic Exposure of Pf-04217329 Alone And In Combination With Latanoprost

Conditions
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Glaucoma, Open-Angle, Ocular Hypertension

Intervention / Treatment
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* Drug: PF-04217329
* Drug: latanoprost vehicle
* Drug: PF-04217329
* Drug: latanoprost


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of primary open-angle glaucoma or ocular hypertension in one or both eyes Intraocular Pressure (IOP) of at least 22 mmHg and not more than 30 mmHg in either eye at 8 AM after discontinuing previous glaucoma treatment Visual acuity correctable to 20/100 or better in each eye. Exclusion Criteria: Closed/barely open anterior chamber angle or a history of acute angle closure in either eye. Diagnosis of a clinically significant or progressive retinal disease (eg, diabetic retinopathy, macular degeneration) in either eye. Advanced glaucoma or a history of severe central visual field loss in either eye. History of ocular surgery or trauma in either eye within 6 months of the screening visit. History of ocular infection, ocular inflammation, or laser surgery in either eye within 3 months of the screening visit.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-04217329 + placebo<br>Active study drug + latanoprost vehicle | Drug: PF-04217329<br>* Topical ocular solution, once-daily for 14 days<br>Drug: latanoprost vehicle<br>* Topical ocular solution, once-daily for 14 days<br>|
| Experimental: PF-04217329 + latanoprost<br>Active study drug + latanoprost | Drug: PF-04217329<br>* Topical ocular solution, once-daily for 14 days<br>Drug: latanoprost<br>* Topical ocular solution, once-daily for 14 days<br>* Other names: Xalatan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 14: 8 Ante Meridiem (AM) (0 Hour) | IOP was measured using Perkins applanation tonometer at Day -8, Day 14 and using standard Goldmann applanation tonometer at eligibility visit. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 visit was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), mean of the 2 readings was recorded as the IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 8 AM on Day -8 as baseline for 8 AM value on Day 14. | 8 AM on Baseline (Day -8), 8 AM on Day 14 (0 Hour) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 14: 10 AM (2 Hours) | IOP was measured using Perkins applanation tonometer at Day -8, Day 14 and using standard Goldmann applanation tonometer at eligibility visit. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 visit was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury, mean of the 2 readings was recorded as the IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 10 AM on Day -8 as baseline for 10 AM value on Day 14. | 10 AM on Baseline (Day -8), 10 AM on Day 14 (2 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 14: 12 Post Meridiem (PM) (4 Hours) | IOP was measured using Perkins applanation tonometer at Day -8, Day 14 and using standard Goldmann applanation tonometer at eligibility visit. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 visit was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in the same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), mean of 2 readings was recorded as IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 12 PM on Day -8 as baseline for 12 PM value on Day 14. | 12 PM on Baseline (Day -8), 12 PM on Day 14 (4 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 14: 2 PM (6 Hours) | IOP was measured using Perkins applanation tonometer at Day -8, Day 14 and using standard Goldmann applanation tonometer at eligibility visit. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 visit was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), mean of the 2 readings was recorded as the IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 2 PM on Day -8 as baseline for 2 PM value on Day 14. | 2 PM on Baseline (Day -8), 2 PM on Day 14 (6 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 14: 4 PM (8 Hours) | IOP was measured using Perkins applanation tonometer at Day -8, Day 14 and using standard Goldmann applanation tonometer at eligibility visit. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 visit was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), mean of the 2 readings was recorded as the IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 4 PM on Day -8 as baseline for 4 PM value on Day 14. | 4 PM on Baseline (Day -8), 4 PM on Day 14 (8 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 14: 6 PM (10 Hours) | IOP was measured using Perkins applanation tonometer at Day -8, Day 14 and using standard Goldmann applanation tonometer at eligibility visit. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 visit was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), mean of the 2 readings was recorded as the IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 6 PM on Day -8 as baseline for 6 PM value on Day 14. | 6 PM on Baseline (Day -8), 6 PM on Day 14 (10 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 14: 8 PM (12 Hours) | IOP was measured using Perkins applanation tonometer at Day -8, Day 14 and using standard Goldmann applanation tonometer at eligibility visit. IOP was measured in both the eyes, and eye with higher IOP reading across eligibility visit and Day -8 visit was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), mean of the 2 readings was recorded as the IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 8 PM on Day -8 as baseline for 8 PM value on Day 14. | 8 PM on Baseline (Day -8), 8 PM on Day 14 (12 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 14: 10 PM (14 Hours) | IOP was measured using Perkins applanation tonometer at Day -8, Day 14 and using standard Goldmann applanation tonometer at eligibility visit. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 visit was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in the same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), mean of 2 readings was recorded as the IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 10 PM on Day -8 as baseline for 10 PM value on Day 14. | 10 PM on Day -8 (Baseline), 10 PM on Day 14 (14 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 15: 12 AM (16 Hours) | IOP was measured using Perkins applanation tonometer at Day -8 and using standard Goldmann applanation tonometer at eligibility visit, Day -7 and Day 15. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in the same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), mean of 2 readings was recorded as IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 12 AM on Day -7 as baseline for 12 AM value on Day 15. | 12 AM on Baseline (Day -7), 12 AM on Day 15 (16 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 15: 4 AM (20 Hours) | IOP was measured using Perkins applanation tonometer at Day -8 and using standard Goldmann applanation tonometer at eligibility visit, Day -7 and Day 15. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in the same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), mean of 2 readings was recorded as IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 4 AM on Day -7 as baseline for 4 AM value on Day 15. | 4 AM on Baseline (Day -7), 4 AM on Day 15 (20 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 15: 6 AM (22 Hours) | IOP was measured using Perkins applanation tonometer at Day -8 and using standard Goldmann applanation tonometer at eligibility visit, Day -7 and Day 15. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in the same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), mean of 2 readings was recorded as the IOP at that time point. If difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 6 AM on Day -7 as baseline for 6 AM value on Day 15. | 6 AM on Baseline (Day -7), 6 AM on Day 15 (22 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 15: 8 AM (24 Hours) | IOP was measured using Perkins applanation tonometer at Day -8 and using standard Goldmann applanation tonometer at eligibility visit, Day -7 and Day 15. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in the same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), mean of 2 readings was recorded as IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 8 AM on Day -7 as baseline for 8 AM value on Day 15. | 8 AM on Baseline (Day -7), 8 AM on Day 15 (24 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 16: 8 AM (48 Hours) | IOP was measured using Perkins applanation tonometer at Day -8 and using standard Goldmann applanation tonometer at eligibility visit and Day 16. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in the same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), the mean of 2 readings was recorded as the IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 8 AM on Day -8 as baseline for 8 AM value on Day 16. | 8 AM on Baseline (Day -8), 8 AM on Day 16 (48 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 17: 8 AM (72 Hours) | IOP was measured using Perkins applanation tonometer at Day -8 and using standard Goldmann applanation tonometer at eligibility visit and Day 17. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in the same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), the mean of 2 readings was recorded as the IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 8 AM on Day -8 as baseline for 8 AM value on Day 17. | 8 AM on Baseline (Day -8), 8 AM on Day 17 (72 Hours) | 
| Change From Baseline in Mean Intra Ocular Pressure (IOP) in Study Eye at Day 21: 8 AM (168 Hours) | IOP was measured using Perkins applanation tonometer at Day -8 and using standard Goldmann applanation tonometer at eligibility visit and Day 21. IOP was measured in both eyes, and the eye with higher IOP reading across eligibility visit and Day -8 was referred as 'study eye' for efficacy assessment. If both measurements were equal, right eye was selected as study eye. IOP was measured twice in the same eye, and if difference between 2 measurements was less than or equal to 2 millimeter of mercury (mmHg), the mean of 2 readings was recorded as the IOP at that time point. If the difference between 2 readings was greater than 2 mmHg, a third consecutive reading was taken and the median IOP was recorded as the IOP at that time point. Mean IOP was reported as the average of individual participants' mean or median IOP values. Change from baseline in IOP = baseline IOP - post-baseline IOP. Change was calculated using the value at 8 AM on Day -8 as baseline for 8 AM value on Day 21. | 8 AM on Day -8 (Baseline), 8 AM on Day 21 (168 Hours) | 
| Plasma Concentration for PF-04217329 Active Metabolite (CP-544326) at 5 Minutes on Day 14 |  | 5 minutes post-dose on Day 14 | 
| Plasma Concentration for PF-04217329 Active Metabolite (CP-544326) at 0.25 Hours on Day 14 |  | 0.25 hours post-dose on Day 14 | 
| Plasma Concentration for PF-04217329 Active Metabolite (CP-544326) at 0.5 Hours on Day 14 |  | 0.5 hours post-dose on Day 14 | 
| Plasma Concentration for PF-04217329 Active Metabolite (CP-544326) at 0.75 Hours on Day 14 |  | 0.75 hours post-dose on Day 14 | 
| Plasma Concentration for PF-04217329 Active Metabolite (CP-544326) at 1 Hour on Day 14 |  | 1 hour post-dose on Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diastolic Ocular Perfusion Pressure (DOPP) | DOPP = diastolic blood pressure minus IOP of the study eye. IOP was measured using Perkins applanation tonometer at Day -8, Day 14 and using standard Goldmann applanation tonometer at eligibility visit and Day 15. IOP was measured in both the eyes, and the eye with higher IOP reading across eligibility visit and Day -8 was referred as 'study eye' for efficacy assessment. If both the measurements were equal, right eye was selected as the study eye. | 8 AM, 10 AM, 12 PM, 2 PM, 4 PM, 6 PM, 8 PM, 10 PM on Day 14; 12 AM, 4 AM, 6 AM, 8 AM on Day 15 | 
| Change From Baseline in Diastolic Ocular Perfusion Pressure (DOPP) at Day 14 (8 AM, 10 AM, 12 PM, 2 PM, 4 PM, 6 PM, 8 PM, 10 PM) and Day 15 (12 AM, 2 AM, 4 AM, 6 AM and 8 AM) | DOPP=diastolic blood pressure minus IOP of the study eye. IOP was measured using Perkins applanation tonometer at Day -8, Day 14 and using standard Goldmann applanation tonometer at eligibility visit, Day -7 and Day 15. IOP was measured in both the eyes, and the eye with higher IOP reading across eligibility visit and Day -8 was referred as 'study eye' for efficacy assessment. If both the measurements were equal, right eye was selected as the study eye. Change at various post-dose time points on Day 14 and Day 15 was calculated from the values at same time points on Day -8 and Day -7 respectively (for example, value at 8 AM on Day -8 was used as baseline value for 8 AM value on Day 14 and value at 8 AM on Day -7 was used as baseline value for 8 AM value on Day 15). | 8 AM, 10 AM, 12 PM, 2 PM, 4 PM, 6 PM, 8 PM, and 10 PM on Day -8 (Baseline), Day 14; 12 AM, 4 AM, 6 AM, 8 AM on Day -7 (Baseline), Day 15 | 
| Number of Participants With Ocular and Systemic Adverse Events (AEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study medication and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Number of participants with ocular (AE related to eye) and systemic (all AEs including eye) AEs were reported. | Baseline up to 28 days after last dose of study medication (up to 58 Days) | 
| Percentage of Participants With Photophobia and Iritis | Percentage of participants with treatment emergent photophobia (abnormal sensitivity or intolerance of eye towards light) and iritis (inflammation of the iris of eye) were reported. Treatment-emergent are events between first dose of study medication and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to 28 days after last dose of study medication (up to 58 Days) | 
| Change From Baseline in Corneal Thickness at Day 7, 13, 16, 21, 28 and 35 | Corneal thickness was measured using an ultrasonic pachymeter. Corneal thickness in both study eye and fellow eye were reported. Study eye: IOP was measured in both the eyes, and the eye with higher IOP reading across eligibility visit and Day -8 was referred as 'study eye'. If both the measurements were equal, right eye was selected as the study eye. The other eye was referred as 'fellow eye'. | 8 AM on Day 1 (Baseline), Days 7, 13, 16, 21, 28, 35 | 
| Change From Baseline in Corneal Endothelial Cell Counts at Day 13 and 35 | Endothelial cell count was defined as the number of cells per millimeter square (cells/mm^2) of endothelium and was calculated using confocal microscopy for both study eye and fellow eye. Study eye: IOP was measured in both the eyes, and the eye with higher IOP reading across eligibility visit and Day -8 was referred as 'study eye'. If both the measurements were equal, right eye was selected as the study eye. The other eye was referred as 'fellow eye'. | 8 AM on Day 1 (Baseline), Day 13, 35 |