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

• Sponsor: Wills Eye (Other)
• Overall Status: Completed
• CT.gov ID: NCT03034772
• Collaborator: Mid Atlantic Retina (Other)
• Enrollment: 52
• Locations: 5
• Arms: 2
• Actual Duration (Months): 28.8
• Patients Per Site: 10.4
• Patients Per Site Per Month: 0.4

Study Details

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
• 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: Feb 8, 2017
• Actual Primary Completion Date: Feb 8, 2019
• Actual Study Completion Date: Jul 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 Names: 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) [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 [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 [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 [Baseline and 18 weeks]

   Change in mean best available visual acuity from baseline to final visit.

4. Change in Mean Intraocular Pressure (IOP) [Baseline and 18 weeks]

   Change in mean IOP from baseline to final visit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	Palo Alto Medical Foundation	Palo Alto	California	United States	94301
2	Ophthalmic Consultants of Boston	Boston	Massachusetts	United States	02114
3	Associated Retinal Consultants	Royal Oak	Michigan	United States	48073
4	Mid Atlantic Retina- Wills Eye Institute	Philadelphia	Pennsylvania	United States	19107
5	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)

• Study Protocol and Statistical Analysis Plan - Feb 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.

• Responsible Party: Jason Hsu, MD, Co-director of Retina Research, Wills Eye
• ClinicalTrials.gov Identifier: NCT03034772
• Other Study ID Numbers: 16-596
• First Posted: Jan 27, 2017
• Last Update Posted: Jun 19, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• 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, Co-director of Retina Research, Wills Eye: neovascular; wet; age-related; macular degeneration; dorzolamide; timolol
• Additional relevant MeSH terms: Macular Degeneration; Wet Macular Degeneration; Timolol; Dorzolamide; Lubricant Eye Drops

Study Results

Participant Flow

Pre-assignment Detail	Since multiple centers were enrolling simultaneously, two more patients then anticipated were randomized

Arm/Group Title	Dorzolamide-timolol	Artificial Tears
Arm/Group Description	Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration	Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration
Period Title: Overall Study
STARTED	27	25
COMPLETED	27	23
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Dorzolamide-timolol	Artificial Tears	Total
Arm/Group Description	Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration	Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration	Total of all reporting groups
Overall Participants	27	23	50
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	79.7 (7.5)	77.5 (6.3)	78.4 (7)
Sex: Female, Male (Count of Participants)
Female	18 66.7%	16 69.6%	34 68%
Male	9 33.3%	7 30.4%	16 32%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
United States	27 100%	23 100%	50 100%
Intravitreal anti-vascular endothelial growth factor agent used (Count of Participants)
Aflibercept	13 48.1%	14 60.9%	27 54%
Ranibizumab	14 51.9%	9 39.1%	23 46%
Number of prior anti-vascular endothelial growth factor (VEGF) injections (injections) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [injections]	20 (15.6)	21.1 (11.6)	20.5 (14)
Injection interval before enrollment (Count of Participants)
Every 4 weeks	17 63%	12 52.2%	29 58%
Every 5 weeks	3 11.1%	8 34.8%	11 22%
Every 6 weeks	7 25.9%	3 13%	10 20%
Visual Acuity (logarithm of the minimum angle of resolution, logMAR) (logMAR) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [logMAR]	0.37 (0.31)	0.348 (0.19)	0.361 (0.26)
Intraocular Pressure (mm Hg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm Hg]	14.37 (2.9)	14.22 (3.1)	14.3 (2.95)
Baseline Optical Coherence Tomography (OCT) Measurements (microns) [Mean (Standard Deviation) ]
Central subfield thickness	348.3 (75.5)	321.3 (80.5)	335.9 (78.2)
Maximum pigment epithelial detachment height	230.2 (116.4)	178.9 (111)	206.1 (115.7)
Maximum subretinal fluid height	103.15 (68.5)	90 (70.5)	96.98 (69.1)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dorzolamide-timolol	Artificial Tears
Arm/Group Description	Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration	Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration
Measure Participants	27	23
Mean (Standard Deviation) [microns]	-36.6 (54)	1.7 (52.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dorzolamide-timolol, Artificial Tears
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	ANCOVA
	Comments	Mean difference between the 2 groups derived using analysis of covariance, with the baseline value and type of anti-VEGF drug used as covariates.

2. Secondary Outcome

Title	Change in Mean Maximum Subretinal Fluid (SRF) Height
Description	Change in mean maximum SRF height on spectral domain optical coherence tomography from baseline to final visit.
Time Frame	Baseline and 18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dorzolamide-timolol	Artificial Tears
Arm/Group Description	Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration	Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration
Measure Participants	27	23
Mean (Standard Deviation) [microns]	-49.4 (55)	-22.2 (56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dorzolamide-timolol, Artificial Tears
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	ANCOVA
	Comments	Mean difference between the 2 groups derived using analysis of covariance, with the baseline value and type of anti-VEGF drug used as covariates.

3. Secondary Outcome

Title	Change in Mean Maximum Pigment Epithelial Detachment (PED) Height
Description	Change in mean maximum PED height on spectral domain optical coherence tomography from baseline to final visit.
Time Frame	Baseline and 18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dorzolamide-timolol	Artificial Tears
Arm/Group Description	Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration	Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration
Measure Participants	27	23
Mean (Standard Deviation) [microns]	-39.1 (65)	1.1 (16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dorzolamide-timolol, Artificial Tears
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	ANCOVA
	Comments	Mean difference between the 2 groups derived using analysis of covariance, with the baseline value and type of anti-VEGF drug used as covariates.

4. Secondary Outcome

Title	Change in Visual Acuity
Description	Change in mean best available visual acuity from baseline to final visit.
Time Frame	Baseline and 18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dorzolamide-timolol	Artificial Tears
Arm/Group Description	Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration	Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration
Measure Participants	27	23
Mean (Standard Deviation) [logMAR]	0.031 (0.15)	0.018 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dorzolamide-timolol, Artificial Tears
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Change in Mean Intraocular Pressure (IOP)
Description	Change in mean IOP from baseline to final visit.
Time Frame	Baseline and 18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dorzolamide-timolol	Artificial Tears
Arm/Group Description	Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration	Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration
Measure Participants	27	23
Mean (Standard Deviation) [mm Hg]	-1.81 (3.8)	-0.78 (2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dorzolamide-timolol, Artificial Tears
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.24
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	20 months
Arm/Group Title	Dorzolamide-timolol		Artificial Tears
Arm/Group Description	Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration		Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration
All Cause Mortality
	Dorzolamide-timolol		Artificial Tears
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/25 (0%)
Serious Adverse Events
	Dorzolamide-timolol		Artificial Tears
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Dorzolamide-timolol		Artificial Tears
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		1/25 (4%)
Eye disorders
Eyelid edema	0/27 (0%)	0	1/25 (4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.