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

• ClinicalTrials.gov Identifier: NCT03034772
• Recruitment Status: Completed
• First Posted: January 27, 2017
• Results First Posted: June 19, 2020
• Last Update Posted: June 19, 2020
• Sponsor: Wills Eye
• Collaborator: Mid Atlantic Retina
• Information provided by (Responsible Party): Jason Hsu, MD, Wills Eye

Study Description

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 52 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
• Actual Primary Completion Date: February 8, 2019
• Actual Study Completion Date: July 5, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Change in Mean Central Subfield Thickness (CST) [ Time Frame: Baseline and 18 weeks ]
   Change in mean CST on spectral domain optical coherence tomography from baseline to the final visit

Secondary Outcome Measures :

1. Change in Mean Maximum Subretinal Fluid (SRF) Height [ Time Frame: Baseline and 18 weeks ]
   Change in mean maximum SRF height on spectral domain optical coherence tomography from baseline to final visit.
2. Change in Mean Maximum Pigment Epithelial Detachment (PED) Height [ Time Frame: Baseline and 18 weeks ]
   Change in mean maximum PED height on spectral domain optical coherence tomography from baseline to final visit.
3. Change in Visual Acuity [ Time Frame: Baseline and 18 weeks ]
   Change in mean best available visual acuity from baseline to final visit.
4. Change in Mean Intraocular Pressure (IOP) [ Time Frame: Baseline and 18 weeks ]
   Change in mean IOP from baseline to final visit.

Eligibility Criteria

• 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.

Contacts and Locations

Locations

United States, California

Palo Alto Medical Foundation

Palo Alto, California, United States, 94301

United States, Massachusetts

Ophthalmic Consultants of Boston

Boston, Massachusetts, United States, 02114

United States, Michigan

Associated Retinal Consultants

Royal Oak, Michigan, United States, 48073

United States, Pennsylvania

Mid Atlantic Retina- Wills Eye Institute

Philadelphia, Pennsylvania, United States, 19107

United States, Texas

Retina Consultants of Houston

Houston, Texas, United States, 77030

Sponsors and Collaborators

Wills Eye

Mid Atlantic Retina

Investigators

• Principal Investigator: Jason Hsu, MD; Wills Eye

  Study Documents (Full-Text)

Documents provided by Jason Hsu, MD, Wills Eye:

Study Protocol and Statistical Analysis Plan  [PDF] February 4, 2020

More Information

Publications:

Sridhar J, Hsu J, Shahlaee A, Garg SJ, Spirn MJ, Fineman MS, Vander J. Topical Dorzolamide-Timolol With Intravitreous Anti-Vascular Endothelial Growth Factor for Neovascular Age-Related Macular Degeneration. JAMA Ophthalmol. 2016 Apr;134(4):437-43. doi: 10.1001/jamaophthalmol.2016.0045.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hsu J, Patel SN, Wolfe JD, Shah CP, Chen E, Jenkins TL, Wibbelsman TD, Obeid A, Mikhail M, Garg SJ, Ho AC, Chiang A, Spirn MJ, Vander JF. Effect of Adjuvant Topical Dorzolamide-Timolol vs Placebo in Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial. JAMA Ophthalmol. 2020 May 1;138(5):560-567. doi: 10.1001/jamaophthalmol.2020.0724.

• Responsible Party: Jason Hsu, MD, Co-director of Retina Research, Wills Eye
• ClinicalTrials.gov Identifier: NCT03034772
• Other Study ID Numbers: 16-596
• First Posted: January 27, 2017
• Results First Posted: June 19, 2020
• Last Update Posted: June 19, 2020
• Last Verified: June 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Macular Degeneration; Wet Macular Degeneration; Retinal Degeneration; Retinal Diseases; Eye Diseases; Timolol; Dorzolamide; Lubricant Eye Drops; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Antihypertensive Agents; Ophthalmic Solutions; Pharmaceutical Solutions; Carbonic Anhydrase Inhibitors; Enzyme Inhibitors