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

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

Status

Completed

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03034772

Acronym

DAWN

Enrollment

Registered

2017-01-27

Start date

2017-02-08

Completion date

2019-07-05

Last updated

2020-06-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neovascular Age-related Macular Degeneration, Wet Macular Degeneration

Keywords

neovascular, wet, age-related, macular degeneration, dorzolamide, timolol

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.

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.

Interventions

DRUGDorzolamide-timolol

Topical eye drop (active comparator) used twice daily for study duration

OTHERArtificial tears

Topical eye drop (placebo comparator) used twice daily for study duration

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

SINGLE (Subject)

Masking description

Single-blind

Eligibility

Sex/Gender

ALL

Age

45 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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.
Change in Visual Acuity	Baseline and 18 weeks	Change in mean best available visual acuity from baseline to final visit.
Change in Mean Intraocular Pressure (IOP)	Baseline and 18 weeks	Change in mean IOP from baseline to final visit.

Countries

United States

Participant flow

Pre-assignment details

Since multiple centers were enrolling simultaneously, two more patients then anticipated were randomized

Participants by arm

Arm	Count
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. Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration	27
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. Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration	23
Total	50

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	1
Overall Study	Withdrawal by Subject	0	1

Baseline characteristics

Characteristic	Dorzolamide-timolol	Artificial Tears	Total
Age, Continuous	79.7 years STANDARD_DEVIATION 7.5	77.5 years STANDARD_DEVIATION 6.3	78.4 years STANDARD_DEVIATION 7
Baseline Optical Coherence Tomography (OCT) Measurements Central subfield thickness	348.3 microns STANDARD_DEVIATION 75.5	321.3 microns STANDARD_DEVIATION 80.5	335.9 microns STANDARD_DEVIATION 78.2
Baseline Optical Coherence Tomography (OCT) Measurements Maximum pigment epithelial detachment height	230.2 microns STANDARD_DEVIATION 116.4	178.9 microns STANDARD_DEVIATION 111	206.1 microns STANDARD_DEVIATION 115.7
Baseline Optical Coherence Tomography (OCT) Measurements Maximum subretinal fluid height	103.15 microns STANDARD_DEVIATION 68.5	90 microns STANDARD_DEVIATION 70.5	96.98 microns STANDARD_DEVIATION 69.1
Injection interval before enrollment Every 4 weeks	17 Participants	12 Participants	29 Participants
Injection interval before enrollment Every 5 weeks	3 Participants	8 Participants	11 Participants
Injection interval before enrollment Every 6 weeks	7 Participants	3 Participants	10 Participants
Intraocular Pressure	14.37 mm Hg STANDARD_DEVIATION 2.9	14.22 mm Hg STANDARD_DEVIATION 3.1	14.3 mm Hg STANDARD_DEVIATION 2.95
Intravitreal anti-vascular endothelial growth factor agent used Aflibercept	13 Participants	14 Participants	27 Participants
Intravitreal anti-vascular endothelial growth factor agent used Ranibizumab	14 Participants	9 Participants	23 Participants
Number of prior anti-vascular endothelial growth factor (VEGF) injections	20 injections STANDARD_DEVIATION 15.6	21.1 injections STANDARD_DEVIATION 11.6	20.5 injections STANDARD_DEVIATION 14
Race and Ethnicity Not Collected	—	—	0 Participants
Region of Enrollment United States	27 Participants	23 Participants	50 Participants
Sex: Female, Male Female	18 Participants	16 Participants	34 Participants
Sex: Female, Male Male	9 Participants	7 Participants	16 Participants
Visual Acuity (logarithm of the minimum angle of resolution, logMAR)	0.37 logMAR STANDARD_DEVIATION 0.31	0.348 logMAR STANDARD_DEVIATION 0.19	0.361 logMAR STANDARD_DEVIATION 0.26

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 27	0 / 25
other Total, other adverse events	0 / 27	1 / 25
serious Total, serious adverse events	0 / 27	0 / 25