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Dorzolamide-timolol in Combination With Anti-vascular Endothelial Growth Factor Injections for Wet Age-related Macular Degeneration (DAWN)

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ClinicalTrials.gov Identifier: NCT03034772
Recruitment Status : Recruiting
First Posted : January 27, 2017
Last Update Posted : April 19, 2018
Sponsor:
Collaborator:
Mid Atlantic Retina
Information provided by (Responsible Party):
Jason Hsu, MD, Wills Eye

Brief Summary:
A previous pilot study demonstrated that commonly available glaucoma drops (dorzolamide-timolol) might decrease the amount of chronic swelling in patient with wet age-related macular degeneration who have been receiving anti-vascular endothelial growth factor (VEGF) injections. This will be a larger study where subjects are randomly assigned to receive the glaucoma drops or a placebo (artificial tears) in order to confirm whether this previous finding is valid. Subjects will continue to receive the normally scheduled anti-VEGF injections at regular intervals as done prior to enrollment. The only addition to the regimen will be the daily use of eye drops (dorzolamide-timolol or artificial tears) twice daily for the duration of the study. At the end of the study, the swelling in the retina will be compared to the amount before starting the drops to see if there is any difference between the group using dorzolamide-timolol versus artificial tears.

Condition or disease Intervention/treatment Phase
Neovascular Age-related Macular Degeneration Wet Macular Degeneration Drug: Dorzolamide-timolol Other: Artificial tears Phase 2 Phase 3

Detailed Description:
Intravitreal anti-vascular endothelial growth factor (VEGF) agents, including ranibizumab and aflibercept, remain the standard of care treatment for neovascular age-related macular degeneration (AMD). Various treatment modalities using these agents have been proposed, including monthly, pro re nata, and treat-and-extend regimens. Despite frequent and consistent treatment with anti-VEGF therapy, there is a subset of patients who are incomplete responders and have persistent exudation, including intraretinal edema, subretinal fluid (SRF), and/or retinal pigment epithelial detachment (PED) on spectral-domain optical coherence tomography (SD-OCT). While clearance of intravitreal anti-VEGF drugs is not completely understood, some studies have suggested that outflow through the anterior chamber may play a role. We hypothesized that by decreasing aqueous production, outflow may also be reduced which could subsequently slow the clearance of intravitreal drugs. In a prior pilot study with 10 eyes of 10 patients who were incomplete responders with neovascular AMD, the effect of topical dorzolamide-timolol in combination with continued intravitreal anti-VEGF injections was explored. Patients were kept on the same anti-VEGF drug as well as the same interval between injections for the 2 visits before enrollment and through the course of the pilot study in order to minimize the chances that any changes noted might be the result of altering one of these variables. The mean central subfield thickness (CST) decreased from 419.7 μm at enrollment to 334.1 μm at the final visit (p=0.012). Mean maximum subretinal fluid (SRF) height decreased from 126.6 μm at enrollment to 56.5 μm at the final visit (p=0.020). This decrease in mean CST and SRF was significant beginning at the first visit after initiation of the drops. Based on this initial pilot data, dorzolamide-timolol appears to be a promising adjuvant treatment in combination with anti-VEGF injections for incomplete anti-VEGF responders with neovascular AMD. However, since there was no control group in the pilot study, it is possible that the decreased exudation seen was a result of the continued anti-VEGF therapy alone rather than an effect of the topical therapy. As a result, a randomized, placebo-controlled clinical trial will be better able to assess the efficacy of dorzolamide-timolol in this setting.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Masking Description: Single-blind
Primary Purpose: Treatment
Official Title: A Randomized Controlled Trial Comparing the Effect of Topical Dorzolamide-Timolol Versus Placebo Combined With Intravitreal Anti-Vascular Endothelial Growth Factor (VEGF) Injections in Patients With Neovascular Age-Related Macular Degeneration Who Are Incomplete Anti-VEGF Responders
Actual Study Start Date : February 8, 2017
Estimated Primary Completion Date : November 28, 2018
Estimated Study Completion Date : November 28, 2019


Arm Intervention/treatment
Active Comparator: Dorzolamide-timolol
Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.
Drug: Dorzolamide-timolol
Topical eye drop (active comparator) used twice daily for study duration
Other Name: Cosopt

Placebo Comparator: Artificial tears
Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.
Other: Artificial tears
Topical eye drop (placebo comparator) used twice daily for study duration




Primary Outcome Measures :
  1. Mean central subfield thickness (CST) on spectral domain optical coherence tomography [ Time Frame: 18 weeks ]
    Change in mean central subfield thickness (CST) on spectral domain optical coherence tomography (SD-OCT) from baseline to the final visit


Secondary Outcome Measures :
  1. Mean maximum subretinal fluid (SRF) height on spectral domain optical coherence tomography [ Time Frame: 18 weeks ]
    Change in mean maximum SRF height on spectral domain optical coherence tomography from baseline to final visit.

  2. Mean maximum pigment epithelial detachment (PED) height on spectral domain optical coherence tomography [ Time Frame: 18 weeks ]
    Change in mean maximum PED height on spectral domain optical coherence tomography from baseline to final visit.

  3. Visual acuity [ Time Frame: 18 weeks ]
    Change in mean best available visual acuity from baseline to final visit.

  4. Mean intraocular pressure (IOP) [ Time Frame: 18 weeks ]
    Change in mean IOP from baseline to final visit.



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Ages Eligible for Study:   45 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Active choroidal neovascularization (CNV) due to AMD.
  2. Prior treatment with at least 4 injections of anti-VEGF agents in the past 6 months and persistent intraretinal and/or subretinal fluid on SD-OCT at each visit during this period.
  3. Baseline CST ≥ 270 µm on SD-OCT automated retinal thickness map.
  4. Injection of the same anti-VEGF agent at each of the two visits immediately preceding study enrollment.
  5. Time interval of 5 weeks (± 1 week) between visits for at least two visits immediately preceding study enrollment.
  6. Subjects of either gender aged ≥ 45 years.
  7. Provide written informed consent
  8. Ability to comply with study and follow-up procedures and return for study visits.

Exclusion Criteria:

  1. History of uveitis.
  2. Presence of intraocular inflammation, significant epiretinal membrane (causing distortion of macular anatomy per investigator discretion), significant vitreomacular traction (per investigator discretion), macular hole, or vitreous hemorrhage.
  3. Any ophthalmic surgery within previous 6 months, including cataract extraction.
  4. Any history of vitrectomy or glaucoma surgery (e.g., trabeculectomy, tube shunt).
  5. Current prescription eye drop usage (e.g., glaucoma drops, corticosteroid drops, etc.).
  6. Any contraindication for topical use of a beta-blocker (e.g., bradycardia, decompensated heart failure, chronic obstructive pulmonary disease, reactive airway disease, asthma, etc.).
  7. Any history of sulfonamide allergy.

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 ClinicalTrials.gov identifier (NCT number): NCT03034772


Contacts
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Contact: Michele Formoso 215-928-3092 mformoso@midatlanticretina.com
Contact: Kelly Diienno 215-928-3092 kdiienno@midatlanticretina.com

Locations
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United States, California
Palo Alto Medical Foundation Recruiting
Palo Alto, California, United States, 94301
Contact: Ehsan Rahimy, MD    650-853-2974      
United States, Massachusetts
Ophthalmic Consultants of Boston Recruiting
Boston, Massachusetts, United States, 02114
Contact: Chirag Shah, MD    800-635-0489      
United States, Michigan
Associated Retinal Consultants Recruiting
Royal Oak, Michigan, United States, 48073
Contact: Jeremy Wolfe, MD    248-288-2280      
United States, Pennsylvania
Mid Atlantic Retina- Wills Eye Institute Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Michele Formoso    215-928-3092    mformoso@midatlanticretina.com   
Principal Investigator: Jason Hsu, MD         
United States, Texas
Retina Consultants of Houston Recruiting
Houston, Texas, United States, 77030
Contact: Eric Chen, MD    800-833-5921      
Sponsors and Collaborators
Wills Eye
Mid Atlantic Retina
Investigators
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Principal Investigator: Jason Hsu, MD Wills Eye

Publications:
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Responsible Party: Jason Hsu, MD, Co-director of Retina Research, Wills Eye
ClinicalTrials.gov Identifier: NCT03034772     History of Changes
Other Study ID Numbers: 16-596
First Posted: January 27, 2017    Key Record Dates
Last Update Posted: April 19, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jason Hsu, MD, Wills Eye:
neovascular
wet
age-related
macular degeneration
dorzolamide
timolol

Additional relevant MeSH terms:
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Macular Degeneration
Wet Macular Degeneration
Retinal Degeneration
Retinal Diseases
Eye Diseases
Mitogens
Timolol
Dorzolamide
Bevacizumab
Endothelial Growth Factors
Lubricant Eye Drops
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Ophthalmic Solutions
Pharmaceutical Solutions
Carbonic Anhydrase Inhibitors
Enzyme Inhibitors