Circadian Ocular Perfusion Pressure and Ocular Blood Flow

Study Overview
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Brief Summary
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The purpose of this study was to compare the short term effects of two intraocular pressure (IOP) lowering medications on ocular perfusion pressure (OPP), ocular blood flow, intraocular pressure, and blood pressure in patients with glaucoma. Ocular perfusion pressure (OPP) is defined as the difference between arterial blood pressure (diastolic and systolic) and intraocular pressure. The primary efficacy assessment is based on diastolic ocular perfusion pressure.

Official Title
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Effects of Topical Hypotensive Drugs on Circadian Ocular Perfusion Pressure and Ocular Blood Flow in Patients With Open-Angle Glaucoma

Conditions
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Glaucoma

Intervention / Treatment
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* Drug: Brinzolamide 10 mg/ml/Timolol 5 mg/ml eye drops suspension
* Drug: Brimonidine 20 mg/ml/Timolol 5 mg/ml eye drops solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sign Informed Consent. Diagnosis of open-angle glaucoma in at least one eye. Requires more than one IOP-lowering medication. IOP measurements at Screening, Safety, and Eligibility/Period 1 Baseline Visits as specified in protocol. Able to discontinue all IOP-lowering medication prior to Eligibility Visit and for 4 weeks between treatment periods. Willing to complete all required study visits. Other protocol-defined inclusion criteria may apply. Exclusion Criteria: Female of child-bearing potential if pregnant, lactating, or not using highly effective birth control measures. Severe central visual field loss in either eye. Previous glaucoma surgery in the study eye. Intraocular surgery in the study eye within 3 months prior to the Screening Visit. Wears contact lenses. Allergy/hypersensitivity to study medication. Cannot safely discontinue use of glucocorticoid medication. Uses medication that could affect IOP or blood pressure. Recent use of high-dose aspirin. Bronchial asthma or severe chronic obstructive pulmonary disease. Diabetic retinopathy. Any abnormality preventing reliable tonometry. Any severe illness or condition unsuitable for the study, in the opinion of the investigator. Other protocol-defined exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: AZARGA/COMBIGAN<br>AZARGA, followed by COMBIGAN, as randomized. Each fixed combination instilled in the study eye, one drop twice daily (9:00 and 21:00), for six weeks, with a 4-week washout period separating the two treatment periods. | Drug: Brinzolamide 10 mg/ml/Timolol 5 mg/ml eye drops suspension<br>* Fixed combination ophthalmic suspension<br>* Other names: AZARGA™;Drug: Brimonidine 20 mg/ml/Timolol 5 mg/ml eye drops solution<br>* Fixed combination ophthalmic solution<br>* Other names: COMBIGAN®;|
| Other: COMBIGAN/AZARGA<br>COMBIGAN, followed by AZARGA, as randomized. Each fixed combination instilled in the study eye, one drop twice daily (9:00 and 21:00), for six weeks, with a 4-week washout period separating the two treatment periods. | Drug: Brinzolamide 10 mg/ml/Timolol 5 mg/ml eye drops suspension<br>* Fixed combination ophthalmic suspension<br>* Other names: AZARGA™;Drug: Brimonidine 20 mg/ml/Timolol 5 mg/ml eye drops solution<br>* Fixed combination ophthalmic solution<br>* Other names: COMBIGAN®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Overall Diastolic Ocular Perfusion Pressure at Week 6 | Diastolic ocular perfusion pressure (DOPP) is defined as the difference between diastolic arterial pressure and intraocular pressure. Diastolic arterial pressure was measured with a calibrated automated sphygmomanometer. Intraocular pressure was measured with a calibrated pneumatonometer. A lower DOPP indicates a lower optic blood supply, which can be a risk factor for developing glaucoma or glaucoma progression (leading to optic nerve damage). | Week 0, Week 6 (period-based) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Circadian Diastolic Ocular Perfusion Pressure at Week 6 | Circadian diastolic ocular perfusion pressure (COPP) is defined as the variations in diastolic OPP during the day and night. Diastolic ocular perfusion pressure was calculated at 7 timepoints over a 24-hour period. Changes in the diastolic ocular perfusion pressure rhythm throughout the day (outside the normal range) may affect glaucoma progression. | Week 0, Week 6 (period-based) | 
| Mean Change From Baseline in Mean Flow Value in the Superotemporal Peripapillary Retina at Week 6 | Retinal perfusion assessments were made using Heidelberg Retinal Flowmetry (HRF). Assessments were made at 4 timepoints over a 12-hour period. Intensity of blood flow was measured in arbitrary units, with a higher number indicating an increased blood flow. An increase in ocular blood flow may reduce the risk of glaucoma progression. | Week 0, Week 6 (period-based) | 
| Mean Change From Baseline in Mean Flow Value in the Inverotemporal Peripapillary Retina at Week 6 | Retinal perfusion assessments were made using Heidelberg Retinal Flowmetry (HRF). Assessments were made at 4 timepoints over a 12-hour period. Intensity of blood flow was measured in arbitrary units, with a higher number indicating an increased blood flow. An increase in ocular blood flow may reduce the risk of glaucoma progression. | Week 0, Week 6 (period-based) | 
| Mean Change From Baseline in Intraocular Pressure (IOP) at Week 6 | Intraocular pressure (IOP) is defined as the fluid pressure inside the eye. Intraocular pressure was measured with a calibrated pneumatonometer at 7 time points over a 24-hour period. High IOP (outside the normal range) can be a risk factor for developing glaucoma or glaucoma progression (leading to optic nerve damage). | Week 0, Week 6 (period-based) | 
| Mean Change From Baseline in Diastolic Blood Pressure at Week 6 | Blood pressure is defined as the pressure exerted by circulating blood upon the walls of the blood vessels, that is, arterial pressure of the systemic circulation of blood. Diastolic blood pressure refers to the minimum pressure, that is, the pressure between heartbeats. Diastolic glood pressure was measured at 7 timepoints in a 24-hour period using a calibrated sphygmomonometer. Higher blood pressure (outside the normal range) can be a risk factor for developing cardiovascular events, such as heart attack, stroke, or heart failure. Lower blood pressure (outside the normal range) can be a risk factor for dizziness or fainting. | Week 0, Week 6 (period-based) | 
| Mean Change From Baseline in Systolic Blood Pressure at Week 6 | Blood pressure is defined as the pressure exerted by circulating blood upon the walls of the blood vessels, that is, arterial pressure of the systemic circulation of blood. Systolic blood pressure refers to the maximum pressure, that is, the pressure while the heart is beating, and was measured at 7 timepoints in a 24-hour period using a calibrated sphygmomonometer. Higher blood pressure (outside the normal range) can be a risk factor for developing cardiovascular events, such as heart attack, stroke, or heart failure. Lower blood pressure (outside the normal range) can be a risk factor for dizziness or fainting. | Week 0, Week 6 (period-based) | 
| Mean Change From Baseline in Vascular Resistance in the Central Retinal Artery at Week 6 | Vascular resistance in the central retinal artery was assessed using Color Doppler Imaging (CDI). Assessments were made at 7 time points over a 24-hour period. | Week 0, Week 6 (period-based) | 
| Mean Change From Baseline in Vascular Resistance in the Ophthalmic Artery at 6 Weeks | Vascular resistance in the ophthalmic artery was assessed using Color Doppler Imaging (CDI). Assessments were made at 7 time points over a 24-hour period. | Week 0, Week 6 (period-based) | 
| Mean Change From Baseline in End Diastolic Velocity in the Ophthalmic Artery at Week 6 | End diastolic velocity in the ophthalmic artery was assessed using Color Doppler Imaging (CDI). Assessments were made at 7 time points over a 24-hour period. | Week 0, Week 6 (period-based) | 
| Mean Change From Baseline in Peak Systolic Velocity in the Ophthalmic Artery at Week 6 | Peak systolic velocity in the ophthalmic artery was assessed using Color Doppler Imaging (CDI). Assessments were made at 7 time points over a 24-hour period. | Week 0, Week 6 (period-based) | 
| Mean Change From Baseline in Peak Systolic Velocity in the Central Retinal Artery at Week 6 | Peak systolic velocity in the central retinal artery was assessed using Color Doppler Imaging (CDI). Assessments were made at 7 time points over a 24-hour period. | Week 0, Week 6 (period-based) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glaucoma, ocular perfusion pressure, ocular blood flow, open angle glaucoma requiring more than one IOP-lowering medication