Intraocular Pressure
Conditions
Keywords
Aqueous Humor Dynamics, Aqueous Humor Dynamics and Circadian Rhythms
Brief summary
This single-center, investigator-masked, crossover study is designed to investigate the circadian rhythms of aqueous humor dynamics in human subjects with ocular hypertension (OHT) before and after intervention with a commonly used ocular hypotensive medication, brimonidine for six weeks.
Detailed description
Currently, the only effective treatment to prevent disease progression is lowering of the intraocular pressure (IOP).2 Usually, clinical IOP measurements are performed during the day with little information collected on nocturnal IOP. A recent surge of interest in nocturnal IOPs stems from the hypothesis that significant glaucomatous damage may occur at night.4,5 In response, some investigators have advocated particular classes of glaucoma medications based on their nocturnal IOP effects.6-8 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. Previous research on glaucoma medications has been limited to the effects of ocular hypotensive drugs on 24-hour IOP or daytime aqueous humor dynamics. Few studies have evaluated nocturnal aqueous humor dynamics. The investigators recently completed studies of day and night differences in aqueous humor dynamics in patients treated with drugs from three different classes that include a prostaglandin analog, a beta blocker and a carbonic anhydrase inhibitor. The current study is designed to elucidate the physiological mechanisms driving the efficacy of brimonidine, an alpha 2 adrenergic agonist, throughout the 24-hour period, i.e. circadian rhythms in aqueous humor dynamics. Based on what the investigators know of 24 hour IOPs this drug is expected to work well at night potentially by enhancing uveoscleral outflow. This study will test this hypothesis. This single-center, investigator-masked, crossover study is designed to investigate the circadian rhythms of aqueous humor dynamics in human subjects with ocular hypertension (OHT) before and after intervention with a commonly used ocular hypotensive medication, brimonidine. Thirty participants with ocular hypertension (intraocular pressure greater than 20mmHg) will be enrolled. The subjects will undergo a baseline phase and medication phase using brimonidine. At both phases, they will attend a daytime and a nighttime study visit in which fluorophotometry will be used to calculate aqueous flow (production), trabecular outflow facility, and uveoscleral outflow. At the completion of the study, subjects will return to their previous ophthalmic clinic.
Interventions
DRUGBrimonidine
One drop of brimonidine in each eye three times a day for six weeks.
DRUGArtificial tears
Lubricating drops added three times a day for six weeks
Sponsors
University of Nebraska
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must be 19 years of age or older * Subjects must exhibit a history of untreated IOPs between 21 and 35 mmHg (inclusive)
Exclusion criteria
* Age less than nineteen years old * Women who are pregnant, lactating or of childbearing potential who are not using 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 (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 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 prelude 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 brimonidine or its vehicle. * 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 |
|---|---|---|
| Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | 6 weeks | Seated day-time and supine day-time IOP was measured by pneumatonometer at 9 am and 11 am. Seated night-time IOP was measured at 9 pm and 11 pm. |
| Supine Night-time & Day-time Seated Episcleral Venous Pressure (EVP) | 6 weeks plus 2 days | The episcleral venous pressure was measured using the episcleral venomanometer |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Aqueous Flow | 6 weeks | Measured by fluorophotometry during the day and night on 29 participants. |
| Uveoscleral Outflow | 6 weeks | Calculated from the modified Goldmann equation using data obtained at 9 am and 11 am. Goldmann equation involves data from aqueous flow, tonography/outflow facility, episcleral venous pressure and IOP. Tonography/outflow facility data on 2 participants were not reliable, therefore uveosleral outflow analysis was performed on 27 participants. |
| Outflow Facility | 6 weeks | Calculated from the measurement taken during the day and night. Tonography/outflow facility data was not reliable in 2 of the participants, therefore analysis was conducted on data from 27 participants. |
Countries
United States
Participant flow
Pre-assignment details
2 subjects consented and then dropped out prior to assignment.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants participants were randomized to receive both IOP lowering drug and lubricating drops in a randomized order | 29 |
| Total | 29 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 1.7 |
| Race/Ethnicity, Customized African American | 6 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants |
| Race/Ethnicity, Customized Native American | 1 Participants |
| Race/Ethnicity, Customized White | 21 Participants |
| Region of Enrollment United States | 29 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 33 | 4 / 33 |
| serious Total, serious adverse events | 0 / 33 | 0 / 33 |
Outcome results
Primary
Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm
Seated day-time and supine day-time IOP was measured by pneumatonometer at 9 am and 11 am. Seated night-time IOP was measured at 9 pm and 11 pm.
Time frame: 6 weeks
Population: some patients were consented but did not participate due to various reasons
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intraocular Pressure Lowering Drug | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Seated day-time 9 am | 18.1 mmHg | Standard Error 0.7 |
| Intraocular Pressure Lowering Drug | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Seated day-time 11 am | 18.0 mmHg | Standard Error 0.7 |
| Intraocular Pressure Lowering Drug | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Supine day-time 9 am | 23.1 mmHg | Standard Error 0.7 |
| Intraocular Pressure Lowering Drug | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Supine day-time 11 am | 23.1 mmHg | Standard Error 0.7 |
| Intraocular Pressure Lowering Drug | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Seated night-time 9 pm | 16.0 mmHg | Standard Error 0.6 |
| Intraocular Pressure Lowering Drug | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Seated night-time 11 pm | 16.7 mmHg | Standard Error 0.7 |
| Artificial Tears | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Seated night-time 9 pm | 18.0 mmHg | Standard Error 0.7 |
| Artificial Tears | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Seated day-time 9 am | 20.3 mmHg | Standard Error 0.7 |
| Artificial Tears | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Supine day-time 11 am | 24.7 mmHg | Standard Error 0.8 |
| Artificial Tears | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Seated day-time 11 am | 19.9 mmHg | Standard Error 0.8 |
| Artificial Tears | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Seated night-time 11 pm | 18.4 mmHg | Standard Error 0.7 |
| Artificial Tears | Seated Day-time IOP 9 am and 11 am, Supine Day-time IOP 9 am and 11 am, and Seated Night-time IOP 9 pm and 11 pm | Supine day-time 9 am | 25.4 mmHg | Standard Error 0.7 |
Primary
Supine Night-time & Day-time Seated Episcleral Venous Pressure (EVP)
The episcleral venous pressure was measured using the episcleral venomanometer
Time frame: 6 weeks plus 2 days
Population: some patients were consented but did not participate due to various reasons
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intraocular Pressure Lowering Drug | Supine Night-time & Day-time Seated Episcleral Venous Pressure (EVP) | Daytime Seated | 10.3 mmHg | Standard Error 0.2 |
| Intraocular Pressure Lowering Drug | Supine Night-time & Day-time Seated Episcleral Venous Pressure (EVP) | Nighttime Supine | 11.3 mmHg | Standard Error 0.3 |
| Artificial Tears | Supine Night-time & Day-time Seated Episcleral Venous Pressure (EVP) | Daytime Seated | 10.3 mmHg | Standard Error 0.2 |
| Artificial Tears | Supine Night-time & Day-time Seated Episcleral Venous Pressure (EVP) | Nighttime Supine | 11.2 mmHg | Standard Error 0.2 |
Secondary
Aqueous Flow
Measured by fluorophotometry during the day and night on 29 participants.
Time frame: 6 weeks
Population: Measurements were taken in the day and night for each group and analysis was done comparing the difference between and within both groups in the day and night respectively.~some patients were consented but did not participate due to various reasons
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intraocular Pressure Lowering Drug | Aqueous Flow | day-time measurement | 2.4 µl/min | Standard Error 0.1 |
| Intraocular Pressure Lowering Drug | Aqueous Flow | night-time measurement | 1.5 µl/min | Standard Error 0.1 |
| Artificial Tears | Aqueous Flow | day-time measurement | 2.3 µl/min | Standard Error 0.1 |
| Artificial Tears | Aqueous Flow | night-time measurement | 1.5 µl/min | Standard Error 0.1 |
Secondary
Outflow Facility
Calculated from the measurement taken during the day and night. Tonography/outflow facility data was not reliable in 2 of the participants, therefore analysis was conducted on data from 27 participants.
Time frame: 6 weeks
Population: Tonography/outflow facility data was not reliable in 2 of the participants, therefore analysis was conducted on data from 27 participants.~some patients were consented but did not participate due to various reasons
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intraocular Pressure Lowering Drug | Outflow Facility | 0.28 μL/min | Standard Error 0.02 |
| Artificial Tears | Outflow Facility | 0.28 μL/min | Standard Error 0.02 |
| Artificial Tears (Day) | Outflow Facility | 0.29 μL/min | Standard Error 0.02 |
| Artificial Tears (Night) | Outflow Facility | 0.29 μL/min | Standard Error 0.02 |
Secondary
Uveoscleral Outflow
Calculated from the modified Goldmann equation using data obtained at 9 am and 11 am. Goldmann equation involves data from aqueous flow, tonography/outflow facility, episcleral venous pressure and IOP. Tonography/outflow facility data on 2 participants were not reliable, therefore uveosleral outflow analysis was performed on 27 participants.
Time frame: 6 weeks
Population: Tonography/outflow facility data on 2 participants were not reliable, therefore uveosleral outflow analysis was performed on 27 participants.~some patients were consented but did not participate due to various reasons
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intraocular Pressure Lowering Drug | Uveoscleral Outflow | 0.84 μL/min |
| Artificial Tears | Uveoscleral Outflow | 0.72 μL/min |