Clinical trial NCT03034772
Conditions: Neovascular Age-related Macular Degeneration Wet Macular Degeneration
Keywords: neovascular wet age-related macular degeneration dorzolamide timolol
Sponsor: Wills Eye
Start date: 2017-02-08; Completion date: 2019-07-05
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals. arm 2: Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.
Interventions: intervention 1: Dorzolamide-timolol intervention 2: Artificial tears
Intervention descriptions: intervention 1: Topical eye drop (active comparator) used twice daily for study duration intervention 2: Topical eye drop (placebo comparator) used twice daily for study duration

Protocol documents:
Prot_SAP_001.pdf: 
  
 
 
 
 
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 
 
 
NCT03034772 
 
 
Document Date: 5/30/17 (statistical analysis finalized 2/4/20) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
A Randomized Controlled Trial Comparing the Effect of Topical 
DorzolamideTimolol 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 Principal 
Investigator: Jason Hsu, MD1  
  
Sub-investigators: Chirag Shah, MD MPH2; Andre Witkin, MD3; Jeremy Wolfe, MD4;  
Eric Chen, MD5; Francis C. Decroos, MD6; Ehsan Rahimy, MD7  
  
1The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia,  
Pennsylvania  
2Ophthalmic Consultants of Boston, Boston, Massachusetts  
3Tufts Medical Center, Boston, Massachusetts  
4Associated Retinal Consultants at William Beaumont Hospital, Royal Oak, Michigan  
5Retina Consultants of Houston, Houston, Texas  
6Southeastern Retina Associates, Chattanooga, Tennessee  
7Palo Alto Medical Foundation, Palo Alto, California  
  
INTRODUCTION  
Intravitreal anti-vascular endothelial growth factor (VEGF) agents, including 
bevacizumab, ranibizumab, and aflibercept, remain the standard of care treatment for 
neovascular age-related macular degeneration (AMD).1–4 Various treatment modalities 
using these agents have been proposed, including monthly, pro re nata, and treat-
andextend regimens.5,6 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).7,8  
  
Clinical Data   
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.9-12 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.13 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.  
  
Trial Rationale  
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.  
  
  
TRIAL OBJECTIVES  
Objective  
The objective of this study is to compare the efficacy of adding topical 
dorzolamidetimolol versus a topical placebo in combination with intravitreal anti-VEGF 
injections in patients with neovascular AMD who are anti-VEGF incomplete responders.  
  
Endpoints  
Primary Efficacy Endpoint:  
The primary efficacy endpoint is change in mean central subfield thickness (CST) on 
spectral domain optical coherence tomography (SD-OCT) from baseline to the final visit.  
  
Secondary Endpoints:  
The secondary endpoints are change in mean maximum subretinal fluid height (SRF), 
mean maximum pigment epithelial detachment (PED) height, mean intraocular pressure 
(IOP) and mean pinhole Snellen visual acuity from baseline to final visit.  
  
 
TRIAL DESIGN  
Subjects will be randomized in a 1:1 ratio to the following groups:  
• 
Topical dorzolamide-timolol 1 drop in study eye twice daily  
• 
Topical artificial tears (placebo group) 1 drop in study eye twice daily  
  
Subjects in both groups will continue to receive the same anti-VEGF drug at the same 
interval (± 1 week) as the 2 visits prior to study enrollment. Once enrolled, subjects will 
continue on the same drop as initially assigned (dorzolamide-timolol or artificial tears) 
for the entire study duration starting at baseline and continuing through 3 follow-up 
visits.   
  
 
 


  
PROCEDURES  
Vision Testing  
Pinhole Snellen visual acuity will be obtained at each visit.  
  
Tonometry  
Tonometry will be performed using either a Tonopen or Goldmann applanation at each 
visit. If the IOP is ≥ 25 mm Hg, Goldmann applanation tonometry must be used to verify 
the reading.  
  
Ophthalmologic Examination  
The following examination will be performed at the baseline visit.  
• 
Inspection of the eyelids   
• 
Examination of the extra-ocular muscle movement   
• 
Inspection of the cornea   
• 
Examination of the anterior chamber for inflammation  
• 
Examination of the pupils   
• 
Examination of the iris   
• 
Inspection of the lens   
• 
Inspection of the vitreous body  
• 
Inspection of the retina and optic disc   
  
Optical Coherence Tomography  
Spectral domain optical coherence tomography will be performed at all timepoints. 
Tracking features should be enabled to allow direct comparison of a given B-scan from 
one visit to another. In addition, the scan algorithm must allow for automated generation 
of the central subfield (1 mm circle) thickness.  
  
 
SUBJECT POPULATION  
Sample Size  
Approximately 50 subjects will be enrolled in the study.   
  
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 (ranibizumab or aflibercept) 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. Anticipated use of intravitreal bevacizumab during the study period  
2. History of uveitis.  
3. 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.  
4. Any ophthalmic surgery within previous 6 months, including cataract extraction.  
5. Any history of vitrectomy or glaucoma surgery (e.g., trabeculectomy, tube shunt).  
6. Current prescription eye drop usage (e.g., glaucoma drops, corticosteroid drops, 
etc.).  
7. Any contraindication for topical use of a beta-blocker (e.g., bradycardia, 
decompensated heart failure, chronic obstructive pulmonary disease, reactive 
airway disease, asthma, etc.).  
8. Any history of sulfonamide allergy.  
  
  
TRIAL CONDUCT  
Subjects should adhere to the scheduled study visits which will take place at the same 
interval (± 1 week) that they were being injected between the visit prior to enrollment and 
the enrollment visit (i.e., every 4, 5, or 6 weeks).   
   
Overview of Study Assessments  
Assessment  
Baseline  
Study Visit 1*  
Study Visit 2*  
Study Visit 3*  
Informed Consent  
X  
  
  
  
Medical &  
Ophthalmic History  
X  
  
  
  
Vision Testing  
X  
X  
X  
X  
Tonometry  
X  
X  
X  
X  
Ophthalmologic 
Examination  
X  
  
  
  
Optical Coherence 
Tomography  
X  
X  
X  
X  
Randomization  
X  
  
  
  
Subjects Randomized 
to 
DorzolamideTimolol 
Reminded to  
Use Drops and Given  
Bottle  
X  
X  
X  
  


  
Subjects Randomized 
to Artificial Tears  
Reminded to Use 
Drops and Given  
Bottle  
X  
X  
X  
  
*Interval between each visit will be based upon the interval between the visit prior to 
enrollment and the enrollment visit. Subjects should be encouraged to follow-up at this 
same interval (± 1 week) for the duration of the study.  
  
Study Assessments  
The following evaluations will be performed at the visits specified below.  
  
Baseline (Day of Enrollment in Study)  
Pre-injection  
• 
Vision testing  
• 
Ophthalmologic examination and tonometry  
• 
Optical coherence tomography  
Injection  
• 
Optional if patient consents separately: Aqueous humor sample prior to 
antiVEGF injection   
• 
Intravitreal injection of same anti-VEGF drug used at the two visits prior to 
enrollment (i.e., ranibizumab or aflibercept).   
Post-injection  
• 
Instruct patient on use of topical drop (dorzolamide-timolol vs. artificial tears as 
assigned at randomization, 1 drop twice daily for study duration) to begin same 
day.  
  
Study Visit 1  
Pre-injection  
• 
Vision testing and tonometry  
• 
Optical coherence tomography  
Injection  
• 
Optional if patient consents separately: Aqueous humor sample prior to 
antiVEGF injection   
• 
Intravitreal injection of same anti-VEGF drug used previously (i.e., ranibizumab 
or aflibercept ).  
Post-injection  
• 
Instruct patient on continuing use of topical drop (dorzolamide-timolol vs. 
artificial tears as previously assigned, 1 drop twice daily for study duration) to 
begin same day.  
  
Study Visit 2  
Pre-injection  
• 
Vision testing and tonometry  
• 
Optical coherence tomography  


  
  
Injection  
• Intravitreal injection of same anti-VEGF drug used previously (i.e.,  ranibizumab or 
aflibercept).  
Post-injection  
• 
Instruct patient on continuing use of topical drop (dorzolamide-timolol vs. 
artificial tears as previously assigned, 1 drop twice daily for study duration) to 
begin same day.  
  
Study Visit 3  
Pre-injection  
• 
Vision testing  
• 
Ophthalmologic examination and tonometry  
• 
Optical coherence tomography  
  
Aqueous Humor Samples (optional)  
Anterior chamber (aqueous humor) samples will be collected from all patients who 
provide additional consent to participate. Where patient consents to aqueous humor 
sampling, all efforts should be made to collect a baseline aqueous humor sample on the 
Baseline visit and Study Visit 1.   
  
Withdrawal from Trial  
Subjects have the right to withdraw from the trial at any time for any reason. The 
investigator also has the right to withdraw subjects from the trial in the event of 
concurrent illness, adverse events, treatment failure after a prescribed procedure, protocol 
violations, cure, administrative or other reasons.  
  
  
STATISTICAL METHODS  
Experimental Design  
This is a randomized clinical trial in which 50 subjects will be randomly assigned to 
receive topical dorzolamide-timolol or artificial tears (1 drop twice daily for the study 
duration) in combination with continuing intravitreal anti-VEGF injections for 
neovascular AMD.  
  
Sample Size  
Assuming a power of 0.9 and an alpha of 0.05, approximately 44 patients will be required 
to demonstrate a CST improvement of 400 to 350 microns with a standard deviation of 
50 microns. Estimating a 10% drop out rate, approximately 50 patients will be targeted 
for enrollment.  
 
Statistical Analysis (finalized 2/4/20) 
Statistical analyses were not pre-specified. Snellen VA was converted to logMAR for 
analysis. For continuous variables, the mean difference and 95% confidence intervals 


  
between the two groups were derived using analysis of covariance (ANCOVA) with the 
baseline value and type of anti-VEGF drug used as covariates. For binary outcomes, a 
logistic regression was used with the baseline value as a covariate. Missing data were 
excluded from analyses such that complete-case analysis was conducted and multiple 
secondary outcomes were evaluated without formal control for multiplicity, i.e., without 
adjustment for multiple analyses. All P values were two-sided. A P value < .05 was 
considered statistically significant for the primary outcome, and a P value <.001 was 
considered statistically significant for any other outcomes since there was no adjustment 
for multiple analyses. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


  
References  
1. 
Moshfeghi AA, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab 
(Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week 
results of an uncontrolled open-label clinical study. Ophthalmology 2006;113:2002.e1–
12.  
2. 
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-
related macular degeneration. N Engl J Med 2006;355:1419–1431.  
3. 
Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in 
wet age-related macular degeneration. Ophthalmology 2012;119:2537–2548.  
4. 
Bressler NM. Antiangiogenic approaches to age-related macular degeneration 
today. Ophthalmology 2009;116:S15–23.  
5. 
Brown DM, Regillo CD. Anti-VEGF agents in the treatment of neovascular 
agerelated macular degeneration: applying clinical trial results to the treatment of 
everyday patients. Am J Ophthalmol 2007;144:627–637.  
6. 
Arnold JJ, Campain A, Barthelmes D, et al. Two-year outcomes of “treat and 
extend” intravitreal therapy for neovascular age-related macular degeneration. 
Ophthalmology 2015;122:1212–1219.  
7. 
Krebs I, Glittenberg C, Ansari-Shahrezaei S, et al. Non-responders to treatment 
with antagonists of vascular endothelial growth factor in age-related macular 
degeneration. Br J Ophthalmol 2013;97:1443–1446.  
8. 
Barthelmes D, Walton R, Campain AE, et al. Outcomes of persistently active 
neovascular age-related macular degeneration treated with VEGF inhibitors: 
observational study data. Br J Ophthalmol 2015;99:359–364.  
9. 
Byeon SH, Kwon OW, Song JH, et al. Prolongation of activity of single 
intravitreal bevacizumab by adjuvant topical aqueous depressant (Timolol-Dorzolamide). 
Graefes Arch Clin Exp Ophthalmol 2009;247:35–42.  
10. 
Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal 
bevacizumab (Avastin). Ophthalmology 2007;114:855–859.  
11. 
Stewart MW. Predicted biologic activity of intravitreal bevacizumab. Retina 
2007;27:1196–1200.  
12. 
Gaudreault J, Fei D, Rusit J, et al. Preclinical pharmacokinetics of Ranibizumab 
(rhuFabV2) after a single intravitreal administration. Invest Ophthalmol Vis Sci 
2005;46:726–733.  
  


  
13. 
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 Feb 25. doi:  
10.1001/jamaophthalmol.2016.0045