Effect of Myocilin Genetic Variants on Intraocular Pressure and Pressure Variation in Sitting and Supine Positions

Phase 4

Completed

Conditions: Glaucoma

Interventions: Drug: Cosopt (combination eyedrop of dorzolamide and timolol)

Registration Number: NCT00906087

Lead Sponsor: University of Michigan

Brief Summary: The purpose of this study is to determine if one of the genes that can cause glaucoma, called myocilin, are associated with larger eye pressure and blood pressure changes in sitting and lying down positions without glaucoma drug treatment and with glaucoma drug treatment with a combination medication called Cosopt® (Merck \& Co., Inc.).

Detailed Description: Glaucoma is an important public health issue, and identifying new markers to improve treatment outcomes is a high priority. Progress in Mendelian genetic approaches has led to identifying 15 genes and 31 loci (http://www.ncbi.nlm.nih.gov/); however, since these monogenic forms of glaucoma are uncommon, other approaches are needed to identify genetic markers that contribute to common risk factors, such as elevated eye pressure, eye pressure fluctuation, and drug response variation.

It is well known that eye pressure varies over a 24-hour period,1-6 but the mechanisms that regulate this eye pressure rhythm are not yet fully known. Drance reported that 84% of normal eyes (N=320 eyes) had eye pressure fluctuations of less than 5 mmHg in contrast to only 6% of untreated glaucomatous eyes (N=138).7 Drance clearly recognized that eye pressure factors were more variable in eyes with glaucoma. Attention to this eye pressure fluctuation during glaucoma treatment is important because fluctuation leads to progression. The variation in eye pressure drug response profiles measured at selected times over a 24-hour period is related to the mechanism of action of these drugs, endogenous circadian rhythms, and glaucoma. The molecular and genetic tools are now available to identify potential genetic markers for these variable traits.

Advancing clinical research to the "translational" level is an important step to integrate our ever increasing knowledge base in genomics and proteinomics with clinical trials and clinical studies. Given the infrastructure at the University of Michigan with the strength in both glaucoma genetics and our resources in the clinic, it is possible to test for relationships between glaucoma genes and eye pressure. Although it is known that myocilin (MYOC) mutations cause the phenotype of high pressure open-angle glaucoma, the effect of these MYOC mutations in "pre-symptomatic" subjects and patients with early open-angle glaucoma on eye pressure variation is not known.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

Inclusion Criteria

Early OAG, as determined by a comprehensive ophthalmic examination
Greater than or equal to 18 years of age
Either gender
Any race
Both eyes meet eligibility criteria
Cup to disc ratio less than 0.8 determined by fundoscopy and confirmed by disc photos
Visual field parameters in the study eye: Pattern Standard Deviation (PSD) greater than 1.0 dB but less than 6.0 dB
Ability to cooperate for an outpatient study involving at least five visits over a four month study period
Ability to comply with Cosopt treatment regimen

Exclusion Criteria

Less than or equal to 18 years old
Refusal to be genotyped or sign Informed Consent for Protocol 1991-144
Pregnant or lactating women
Medical conditions of severe pulmonary compromise with asthma or emphysema or cardiac contraindications to beta-blockers
Ocular disease of chronic angle-closure glaucoma, iridocorneal endothelial disease, posterior polymorphous corneal dystrophy, epithelial downgrowth, uveitic glaucoma, or neovascular glaucoma
Ocular surgery for glaucoma, including trabeculectomy, other glaucoma filtration surgery, glaucoma drainage implant, or laser cyclophotocoagulation
Current use of systemic steroids or chemotherapeutic agents that non-selectively inhibit dividing cells
Proliferative diabetic retinopathy, history of panretinal photocoagulation treatment, diabetic macular edema, or history of macular grid laser treatment
History of changing treatment involving the use oral beta-blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, or oral alpha 2-agonists in the prior two months or in the next month (i.e., must be on stable treatment with any of these drugs for at least two months)
Patients taking erectile dysfunction drugs (i.e., Viagra, Cialis, Levitra)
Contradictions:
- bronchial asthma or a history of bronchial asthma
- severe chronic obstructive pulmonary disease
- sinus bradycardia
- second or third degree atrioventricular block
- overt cardiac failure
- cardiogenic shock
- hypersensitivity to any component of Cosopt

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cosopt	Cosopt (combination eyedrop of dorzolamide and timolol)	Intraocular pressure and blood pressure measurements will be compared under the following conditions: 1) after washout of clinical treatment, 2) after treatment with Cosopt, and 3) after another washout of Cosopt.

Primary Outcome Measures

Name	Time	Method
Intraocular Pressure in Sitting and Supine Positions.	10 weeks	Effect of Cosopt treatment on intraocular pressure changes in sitting to supine positions.
Blood Pressure in Sitting to Supine Positions	10 weeks	Effect of Cosopt treatment on blood pressure changes in sitting to supine positions.

Secondary Outcome Measures