Glaucoma
Conditions
Keywords
Glaucoma, Ocular Hypertension, Timolol®, Latanoprost® and Dorzolamide®
Brief summary
This study is designed to identify physiological, pharmacological and pathological circadian fluctuations in aqueous humor inflow and outflow, systemic blood pressure and ocular blood flow in humans.
Detailed description
Glaucoma is a progressive optic neuropathy and a leading cause of blindness in the United States. In glaucoma, vision is lost through apoptosis (programmed cell death) of retinal ganglion cells, a type of cell in the retina that transmits visual information to the brain. Diagnosis of glaucoma is usually based on a combination of progressive, characteristic vision loss (measured using visual field testing) and progressive optic nerve head damage (as detected through dilated fundus examinations or disc photography). While a high pressure inside the eye (ocular hypertension, OHT) is not sufficient for a diagnosis of glaucoma, it is the greatest single risk factor for disease onset. Currently, the only effective treatment to prevent disease progression is lowering of the intraocular pressure (IOP). IOP is determined by the balance between aqueous production (flow) and aqueous outflow through either the trabecular meshwork or uveoscleral pathway. Diurnal rhythms in aqueous humor dynamics and nocturnal fluctuations in IOP and aqueous flow have been studied in some detail9 but little is known about the nocturnal rhythms of aqueous humor outflow. Usually, clinical IOP measurement is performed during the day; little is known about nocturnal IOP fluctuations in relation to glaucoma management . A recent surge of interest in nocturnal IOPs stems from the hypothesis that significant glaucomatous damage may occur at night. In response, some investigators have advocated particular classes of glaucoma medications based on their nocturnal IOP effects. The most efficacious drug on the market may not be the preferred treatment if it is ineffective at night. Therefore, the understanding of nighttime IOP and the aqueous humor dynamics that control it has important scientific, clinical, and commercial implications. Additionally, previous research on glaucoma medications has been limited to the effects ocular hypotensive drugs on 24-hour IOP or daytime aqueous humor dynamics; few studies have addressed their effect on nocturnal aqueous humor dynamics. Beta-blockers have been proven effective in lowering IOP during the day by decreasing aqueous flow. However, limitations have been found in their IOP-lowering effect overnight. Prostaglandins, which increase uveoscleral outflow, seem to possess a hypotensive effect that is constant throughout the 24-hour period. Dorzolamide reduces aqueous flow to lower IOP but few studies have addressed its effect at night. This study is designed to elucidate the physiological mechanisms driving the efficacy of these drugs throughout the 24-hour period, i.e. circadian rhythms in aqueous humor dynamics. In studies of new glaucoma medications the preferred study population includes ocular hypertensive subjects. These people have high IOP but no optic nerve damage and no glaucoma. They may be taking prescribed IOP lowering drugs for this condition or they may not. Those taking ocular drugs are asked to stop taking them. Since each of the glaucoma drugs affects aqueous humor dynamics in different ways, it is essential that no residual medical effect remains from these drugs. Standard washout periods of 6-weeks will be utilized in between drug assessments. This period of time is based on the methods of other published studies which determined a necessary period of 4-8 weeks for ocular washout of prostaglandins. A concern for patient safety exists when OHT patients are taken off of glaucoma medications, as IOP may rise during the washout. In order to monitor IOP in these patients, most study methods utilize a biweekly check of the IOP. If pressure rises above the ophthalmologist's preset target pressure at any point, then the patient is removed from the study and returned to their previous medical regimen.
Interventions
Sponsors
Pfizer
University of Nebraska
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Subjects must be nineteen (19) years of age or older. Subjects must be able and willing to give written informed consent \[i.e., each subject will be given ample time to read (or have read to them) the consent form, ask any questions they may have regarding the study, and have a clear understanding of the study as well as the procedures involved, prior to signing the consent form\]. * Subjects must exhibit a willingness to comply with the protocol and investigator's instructions. * Subjects must have been previously diagnosed with unilateral or bilateral ocular hypertension at least six months prior to the screening visit. * Subjects must exhibit baseline IOPs between 21 and 35 mmHg (inclusive); the average IOP between eyes must be ≤ 5 mmHg * Subjects will be age matched to ocular hypotensive subjects * Subjects must exhibit baseline IOPs between 12 and 20 mmHg (inclusive); the average IOP between eyes must be ≤ 5 mmHg
Exclusion criteria
* Age less than nineteen years old. * Women who are pregnant, lactating or of childbearing potential who are not using highly effective birth control measures. * Aphakia or pseudophakia * Best corrected visual acuity worse than 20/60 in either eye. * Chronic or recurrent severe ocular inflammatory disease. * Ocular infection or inflammation within three (3) months of screening visit. * History of clinically significant or progressive retinal disease such as retinal degeneration, diabetic retinopathy or retinal detachment. * Any abnormality preventing reliable tonometry of either eye. * Previous exposure to: beta-adrenergic antagonists, topical prostaglandin analogues (including latanoprost, unoprostone, travoprost and bimatoprost) within six (6) weeks of the baseline visit; α-adrenergic agonists within two (2) weeks of the baseline visit; and cholinergic agonists and carbonic anhydrase inhibitors within five (5) days of the treatment initiation visit * History of any severe ocular pathology (including severe dry eye) that would preclude the administration of a topical beta blocker, carbonic anhydrase inhibitor, or a topical prostaglandin. * Any eye with a cup-to-disc ratio greater than 0.8. * History of intraocular surgery. * History of ocular laser surgery. * History of severe or serious hypersensitivity to topical or systemic beta blockers, prostaglandins, or sulfa drugs. * History of severe, unstable or uncontrolled cardiovascular, hepatic or renal disease. * History of bronchial asthma or chronic obstructive pulmonary disease (COPD). * Less than one month (prior to baseline) stable dosing regimen of any non-glaucoma medication that would affect IOP. * Gonioscopy angle \< 2. * Inability to be dosed with treatment medication. * Inability to discontinue contact lens wear. * Therapy with any investigational agent within 30 days of screening. * Use of any additional topical or systemic adjunctive ocular hypotensive medications during the study. * History of open angle glaucoma (either primary open angle glaucoma or other cause of open angle glaucoma) or narrow angle glaucoma.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Outflow Facility | 2 weeks | outflow facility was calculated using fluorophotometry and tonography |
| Uvescleral Outflow | 2 weeks | uvescleral outflow was calulated using goldmann equation |
| Intraocular Pressure | 2 weeks | Intra-ocular Pressure was measured by applanation tonometry |
| Aqueous Flow | 2 weeks | aqueous flow measurements was calculated using fluorophotometry measurements. |
| Central Corneal Thickness | 2 weeks | central corneal thickness was measured by ultrasound pachymetry |
| Anterior Chamber Volume | 2 weeks | Anterior chamber volume was measured by A-scan ultrasound biometry, daytime |
| Blood Pressure | 2 weeks | blood pressure was measured by sphygmomanometry |
| Episcleral Venous Pressure | 2 weeks | Episcleral venous pressure was measured by venomenometry |
Countries
United States
Participant flow
Pre-assignment details
One patient who was taking latanoprost for ocular hypertension did not have an IOP rise greater than 20mmHg after discontinuing treatment for up to 12 weeks. A second patient who initially expressed interest chose to withdraw from the study.
Participants by arm
| Arm | Count |
|---|---|
| Latanoprost/Dorzolamide/Timolol The participants received latanoprost at night and vehicle in the morning for two weeks, then 6 week washout, then Dorzolamide BID for two weeks, then 6 week washout, then Timolol BID for two weeks. The order in which the participants received the three different drugs was random. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Latanoprost/Dorzolamide/Timolol |
|---|---|
| Age, Continuous | 59 years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 30 | 0 / 30 | 0 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 | 0 / 30 |
Outcome results
Primary
Anterior Chamber Volume
Anterior chamber volume was measured by A-scan ultrasound biometry, daytime
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Latanoprost | Anterior Chamber Volume | 191 μL | Standard Deviation 45 |
| Timolol | Anterior Chamber Volume | 191 μL | Standard Deviation 33 |
| Dorzolamide | Anterior Chamber Volume | 198 μL | Standard Deviation 38 |
p-value: 0.84ANOVA
Primary
Aqueous Flow
aqueous flow measurements was calculated using fluorophotometry measurements.
Time frame: 2 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Latanoprost | Aqueous Flow | day time | 2.09 μL/min | Standard Deviation 0.71 |
| Latanoprost | Aqueous Flow | night time | 1.1 μL/min | Standard Deviation 0.38 |
| Timolol | Aqueous Flow | day time | 1.57 μL/min | Standard Deviation 0.44 |
| Timolol | Aqueous Flow | night time | 1.1 μL/min | Standard Deviation 0.38 |
| Dorzolamide | Aqueous Flow | day time | 1.75 μL/min | Standard Deviation 0.54 |
| Dorzolamide | Aqueous Flow | night time | 1.1 μL/min | Standard Deviation 0.38 |
p-value: <0.05ANOVA
Primary
Blood Pressure
blood pressure was measured by sphygmomanometry
Time frame: 2 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Latanoprost | Blood Pressure | diastolic night time | 83 mmHg | Standard Deviation 11 |
| Latanoprost | Blood Pressure | diastolic day time | 78 mmHg | Standard Deviation 12 |
| Latanoprost | Blood Pressure | systolic night time | 143 mmHg | Standard Deviation 17 |
| Latanoprost | Blood Pressure | systolic day time | 136 mmHg | Standard Deviation 20 |
| Timolol | Blood Pressure | diastolic day time | 81 mmHg | Standard Deviation 12 |
| Timolol | Blood Pressure | systolic night time | 136 mmHg | Standard Deviation 15 |
| Timolol | Blood Pressure | systolic day time | 138 mmHg | Standard Deviation 22 |
| Timolol | Blood Pressure | diastolic night time | 79 mmHg | Standard Deviation 11 |
| Dorzolamide | Blood Pressure | systolic night time | 138 mmHg | Standard Deviation 17 |
| Dorzolamide | Blood Pressure | systolic day time | 139 mmHg | Standard Deviation 19 |
| Dorzolamide | Blood Pressure | diastolic night time | 82 mmHg | Standard Deviation 12 |
| Dorzolamide | Blood Pressure | diastolic day time | 83 mmHg | Standard Deviation 11 |
p-value: <0.05ANOVA
Primary
Central Corneal Thickness
central corneal thickness was measured by ultrasound pachymetry
Time frame: 2 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Latanoprost | Central Corneal Thickness | day time | 564 μm | Standard Deviation 40 |
| Latanoprost | Central Corneal Thickness | night time | 585 μm | Standard Deviation 46 |
| Timolol | Central Corneal Thickness | day time | 568 μm | Standard Deviation 43 |
| Timolol | Central Corneal Thickness | night time | 586 μm | Standard Deviation 45 |
| Dorzolamide | Central Corneal Thickness | day time | 564 μm | Standard Deviation 44 |
| Dorzolamide | Central Corneal Thickness | night time | 582 μm | Standard Deviation 43 |
p-value: 0.93ANOVA
Primary
Episcleral Venous Pressure
Episcleral venous pressure was measured by venomenometry
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Latanoprost | Episcleral Venous Pressure | 9.4 mmHg | Standard Deviation 1.4 |
| Timolol | Episcleral Venous Pressure | 9.6 mmHg | Standard Deviation 1.3 |
| Dorzolamide | Episcleral Venous Pressure | 9.4 mmHg | Standard Deviation 1 |
p-value: 0.89ANOVA
Primary
Intraocular Pressure
Intra-ocular Pressure was measured by applanation tonometry
Time frame: 2 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Latanoprost | Intraocular Pressure | Daytime | 17.6 mmHg | Standard Deviation 3.7 |
| Latanoprost | Intraocular Pressure | Night time | 17.0 mmHg | Standard Deviation 3.2 |
| Timolol | Intraocular Pressure | Daytime | 16.4 mmHg | Standard Deviation 2.3 |
| Timolol | Intraocular Pressure | Night time | 17.1 mmHg | Standard Deviation 2.5 |
| Dorzolamide | Intraocular Pressure | Daytime | 20.2 mmHg | Standard Deviation 4.8 |
| Dorzolamide | Intraocular Pressure | Night time | 17.6 mmHg | Standard Deviation 2.4 |
p-value: <0.05ANOVA
Primary
Outflow Facility
outflow facility was calculated using fluorophotometry and tonography
Time frame: 2 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Latanoprost | Outflow Facility | daytime tonography | 0.22 µL/min per mm Hg | Standard Deviation 0.1 |
| Latanoprost | Outflow Facility | day time fluorophotometry | 0.23 µL/min per mm Hg | Standard Deviation 0.18 |
| Latanoprost | Outflow Facility | night tonography | 0.21 µL/min per mm Hg | Standard Deviation 0.11 |
| Timolol | Outflow Facility | daytime tonography | 0.18 µL/min per mm Hg | Standard Deviation 0.08 |
| Timolol | Outflow Facility | day time fluorophotometry | 0.23 µL/min per mm Hg | Standard Deviation 0.12 |
| Timolol | Outflow Facility | night tonography | 0.17 µL/min per mm Hg | Standard Deviation 0.08 |
| Dorzolamide | Outflow Facility | day time fluorophotometry | 0.21 µL/min per mm Hg | Standard Deviation 0.11 |
| Dorzolamide | Outflow Facility | night tonography | 0.18 µL/min per mm Hg | Standard Deviation 0.08 |
| Dorzolamide | Outflow Facility | daytime tonography | 0.20 µL/min per mm Hg | Standard Deviation 0.08 |
p-value: <0.05Kruskal-Wallis
Primary
Uvescleral Outflow
uvescleral outflow was calulated using goldmann equation
Time frame: 2 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Latanoprost | Uvescleral Outflow | daytime tonography | 0.90 µL/min per mm Hg | Standard Deviation 1.46 |
| Latanoprost | Uvescleral Outflow | day time fluorophotometry | 0.43 µL/min per mm Hg | Standard Deviation 1.64 |
| Latanoprost | Uvescleral Outflow | night tonography | 0.26 µL/min per mm Hg | Standard Deviation 1.1 |
| Timolol | Uvescleral Outflow | day time fluorophotometry | -0.16 µL/min per mm Hg | Standard Deviation 1.13 |
| Timolol | Uvescleral Outflow | daytime tonography | 0.70 µL/min per mm Hg | Standard Deviation 1.52 |
| Timolol | Uvescleral Outflow | night tonography | 0.50 µL/min per mm Hg | Standard Deviation 1.38 |
| Dorzolamide | Uvescleral Outflow | day time fluorophotometry | 0.14 µL/min per mm Hg | Standard Deviation 1.21 |
| Dorzolamide | Uvescleral Outflow | night tonography | 0.12 µL/min per mm Hg | Standard Deviation 1.45 |
| Dorzolamide | Uvescleral Outflow | daytime tonography | 0.58 µL/min per mm Hg | Standard Deviation 1.62 |
p-value: <0.05Kruskal-Wallis