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Impact of Timolol/Dorzolamide Therapy on Autoregulation in Glaucoma Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02053298
Recruitment Status : Unknown
Verified January 2014 by Universitaire Ziekenhuizen Leuven.
Recruitment status was:  Recruiting
First Posted : February 3, 2014
Last Update Posted : December 3, 2014
Information provided by (Responsible Party):
Universitaire Ziekenhuizen Leuven

Brief Summary:

Glaucoma is an optic neuropathy in which the main risk factor is intraocular pressure (IOP). The search for other variables involved in glaucoma pathogenesis and progression has identified both systemic and ocular signs of vascular dysfunction in glaucoma patients, such as migraine, peripheral vasospasm, systemic hypotension and cerebral microvascular ischemia. Ocular blood flow studies using Color Doppler Imaging (CDI) technology has demonstrated blood velocities and increased vascular resistance (RI) to exist in such patients when compared to healthy controls. However, a CDI examination provides far more additional information, such as arterial pulsatility (PI) and mean blood velocities (MFV). While these have been used for decades now to study cerebral arteries vasoreactivity, little is known about how these variables are changed in glaucoma patients. We have recently demonstrated that these variables can be used to identify a change in the normal vascular activity when there is increased resistance. In glaucoma patients, a cutpoint in RI of the retrobulbar arteries could be determined beyond which PI increased significantly. This sharp increase in the PI has been used as an indirect signal that the vessel's ability to buffer a decreased perfusion pressure has been surpassed. The normal response to a decreased perfusion in a vascular territory with autoregulation is an increase in dilation in the downstream microcirculation, increasing cross section area in an attempt to keep a steady MFV. As PI is calculated using the vessel's MFV [PI = (PSV-EDV)/MFV], it is highly sensitive to changes in this variable. As such, the cutpoints we have identified in glaucoma patients are therefore an indirect assessment of the vessel's autoregulation limit.

While our data could provide the rational as to why these RI values are associated with progression, the clinical question arises as to whether these cutpoints can be modulated by topical glaucoma therapy. As some medications such as carbonic anhydrase inhibitors have been found to have a positive effect in disease progression in what appears to be a non-IOP related effect, we considered the hypothesis that these drugs could have a positive impact on the ocular's microcirculation vasoactive response, potentially enabling to keep a steady MFV into higher values of vascular resistance.

Condition or disease Intervention/treatment Phase
Open Angle Glaucoma Drug: Timolol & Dorzolamide Phase 4

Detailed Description:

Patients will be recruited from the glaucoma clinic at the department of Ophthalmology in the Leuven University Hospital.

General study setup:

Two cohorts of subjects will be included in the study: primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) patients. At the screening visit, eligible patients will have their topical therapy replaced by timolol 0.5% bid. At week 4, dorzolamide 2% will be added to the existing treatment in a fixed combination therapy (timolol 0.5%+dorzolamide 2% bid). A final visit at week 8.

At the screening visit (day 0), the patients will undergo a complete ophthalmic investigation with visual acuity, slit lamp biomicroscopy, tonometry, 90 D fundoscopy, automated perimetry, Heidelberg retinal tomography and color Doppler imaging. Blood pressure will also be measured. Topical monotherapy will be replaced by timolol 0.5% bid.

At visit 1 and 2 (timolol - week 4, timolol+dorzolamide week 8, respectively), the patients will undergo ophthalmic investigation with visual acuity, slit lamp biomicroscopy, tonometry, 90 D fundoscopy, blood pressure measurement and color Doppler imaging.

Only one eye will be selected for the study (eye with worst glaucomatous damage). Mann-Whitney test will be used in pairwise comparisons. Restricted cubic sp-lines will be used to verify if there is any evidence for nonlinearity in the relation between the RI and PI. Piecewise linear regression models will be used to determine the optimal cutpoint (i.e. the cutpoint yielding the highest likelihood) in all three visits (baseline, timolol and timolol/dorzolamide). Sensitivity analyses will be performed to verify if the result is not due to an (influential) subject with a high RI value. All data will be expressed in mean ± standard deviation. A two sided p-value <0.05 is considered significant.

Sample size calculations were made to address the primary outcome (i.e., a change in the RI cutpoints between baseline and last study visit) in the overall glaucoma population (POAG+NTG patients). Based on our previous results10, setting an α error to 5%, power at 80% and the allowable difference at 10% would require the recruitment of 40 patients. Further post hoc analysis will be made to identify differences between the two study cohorts.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Impact of Timolol/Dorzolamide Therapy on Autoregulation in Glaucoma Patients
Study Start Date : January 2014
Estimated Primary Completion Date : May 2015
Estimated Study Completion Date : May 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Glaucoma

Arm Intervention/treatment
Experimental: Timolol & Dorzolamide
Topical preservative-free fixed combination of timolol 0.5%+dorzolamide 2% to be applied bid for 1 month
Drug: Timolol & Dorzolamide
Topical preservative-free fixed combination of timolol 0.5%+dorzolamide 2% to be applied bid for 1 month
Other Name: Cosopt UD

Primary Outcome Measures :
  1. Retrobulbar vascular resistance cutpoint change [ Time Frame: 2 months ]
    The retrobulbar vascular resistance point at which the pulsatility changes will be measured before (baseline), under topical timolol 0.5% and under topical timolol 0.5+dorzolamide 2%

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • individuals over 18 years old
  • willing to sign an informed consent and able to comply with the requirements of the study
  • having no other ocular diseases besides glaucoma associated with hemodynamic disturbances
  • being either under no topical therapy (naïve patients) or under IOP-lowering monotherapy

Exclusion Criteria:

  • history of ocular trauma
  • intraocular surgery (except for cataract surgery)
  • eye disease associated with hemodynamic disturbances (except glaucoma)
  • systemic diseases with ocular involvement like diabetes
  • contra-indications to the use of topical beta-blockers or carbonic anhydrase inhibitors

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02053298

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Contact: Ingeborg Stalmans, MD, PhD

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University Hospitals Leuven Recruiting
Leuven, Flemish Brabant, Belgium, 3000 Leuven
Principal Investigator: Ingeborg Stalmans, MD, PhD         
Sub-Investigator: Evelien Vandewalle, MD, PhD         
Sub-Investigator: Luis Abegão Pinto, MD, PhD         
Sponsors and Collaborators
Universitaire Ziekenhuizen Leuven
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Principal Investigator: Ingeborg Stalmans, MD, PhD UZ Leuven
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Responsible Party: Universitaire Ziekenhuizen Leuven Identifier: NCT02053298    
Other Study ID Numbers: S - 54854
First Posted: February 3, 2014    Key Record Dates
Last Update Posted: December 3, 2014
Last Verified: January 2014
Keywords provided by Universitaire Ziekenhuizen Leuven:
Additional relevant MeSH terms:
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Glaucoma, Open-Angle
Ocular Hypertension
Eye Diseases
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Carbonic Anhydrase Inhibitors
Enzyme Inhibitors