Purpose
To evaluate off-label use of netarsudil 0.02% for treatment of corneal edema associated with Fuchs dystrophy.
Design
Prospective, randomized clinical trial.
Methods
Twenty-nine subjects with symptomatic Fuchs dystrophy were enrolled and randomized to use netarsudil or placebo eye drops once daily for 3 months. The primary outcomes were the change in central corneal thickness between baseline and 1 month and between baseline and 3 months. Secondary outcomes included change in scotopic corrected distance visual acuity (CDVA) at 3 months and change in scores on a visual disability questionnaire validated for use with Fuchs dystrophy.
Results
Compared with use of placebo, use of netarsudil produced significant reduction in central corneal thickness at 1 month (mean difference, -20 µm; 95% confidence interval, -32 to -9 µm) and 3 months (mean difference, -26 µm; 95% confidence interval, -39 to -12 µm) and significant improvement in scotopic CDVA at 3 months (mean difference +1.6 lines; 95% confidence interval, 0.2-3.0 lines). Scores on the visual disability questionnaire did not change significantly in either arm or differ significantly between arms. One subject assigned to netarsudil had baseline epithelial bullae and withdrew from the study because of disabling glare.
Conclusions
Use of netarsudil was associated with reduction of corneal edema and improvement in scotopic CDVA in Fuchs dystrophy patients. Further study is needed to more fully assess patient satisfaction and visual acuity under various lighting conditions and to compare use of netarsudil with other treatment options such as endothelial keratoplasty.
T T he leading reason for corneal transplantation in the United States is Fuchs endothelial corneal dystrophy (FECD), which is characterized by deposition of abnormal, vision-distorting deposits on Descemet membrane and subsequent apoptosis of corneal endothelial cells, resulting in corneal edema. A treatment that could bolster the corneal endothelium’s ability to maintain appropriate corneal hydration in FECD and thereby postpone or prevent the need for a cornea transplant would be very useful, even if it only resolved corneal edema for a relatively short time. The age of onset of symptomatic Fuchs dystrophy overlaps the age of onset of symptomatic cataracts, so Fuchs dystrophy patients often undergo cataract surgery before or combined with corneal transplantation. However, it is significantly more difficult to hit the refractive target when cataract surgery is performed in an eye with corneal edema, because it distorts the preoperative imaging needed to calculate the optimal intraocular lens power. , Therefore, it would be valuable to find a treatment that could resolve corneal edema, even short-term, to refine the preoperative imaging and refractive outcomes for these patients.
Netarsudil is a drug known as a ROCK inhibitor, because it inhibits the Rho family of small G-protein kinases. It has been shown to increase aqueous outflow through the trabecular meshwork and is approved for treatment of glaucoma. ROCK inhibitors also activate corneal endothelial cell migration and possibly proliferation. Some corneal surgeons have reported anecdotally that they tried Rhopressa in patients with FECD and it seemed to reduce corneal edema (unpublished data). The purpose of this study was to test the hypothesis that off-label use of Rhopressa could reduce corneal edema in patients with FECD.
Methods
This prospective, randomized, double-masked, placebo-controlled clinical trial was conducted at a single site (Price Vision Group, Indianapolis, Indiana, USA). The study and informed consent document were prospectively approved by an independent review board (IRBCo, Inc, Buena Park, California, USA), complied with the Declaration of Helsinki and the Health Insurance Portability and Accountability Act (HIPAA), and was registered on the clinical trials website ( www.clinicaltrials.gov , NCT04051463). Participants were recruited between July 2019 and March 2020 and follow-up was completed in June 2020. All participants completed an informed consent process.
Inclusion and Exclusion Criteria
The study inclusion criteria were patients of any sex or racial or ethnic origin, who were at least 18 years of age, diagnosed with FECD, and able and willing to administer the study medication. The exclusion criteria were active intraocular inflammation, corneal ulceration, keratitis, or conjunctivitis; known sensitivity to any of the ingredients in the study medication; abnormal eyelid function; history of herpetic keratitis; history of noncompliance with using prescribed medication; current or planned pregnancy within the study duration; concurrent involvement or participation in another randomized clinical trial within 30 days prior to enrollment in this study; and any ocular or systemic condition that, in the investigator’s opinion, might put the patient at significant risk, confound the study results, or interfere significantly with the patient’s participation in the study.
Randomization and Study Treatment Regimen
Netarsudil ophthalmic solution 0.02% and placebo (netarsudil vehicle) eye drops were provided in 2.5 mL bottles, identical in appearance, by Aerie Pharmaceuticals, Durham, NC, USA. An unmasked dosing coordinator applied a coded label to each bottle. After completing the informed consent process, study subjects were randomized to receive netarsudil or placebo using a computer-generated randomization table. Both the subject and the evaluators remained masked to the assigned treatment. Six participants already had endothelial keratoplasty in 1 eye, 11 wanted to schedule endothelial keratoplasty in 1 eye between 1 and 3 months after enrollment, and 1 had an amblyopic eye, so the contralateral eye was automatically designated as the study eye. In 11 of 29 participants, both eyes qualified for the study, so 1 eye was randomized as the study eye using a computer-generated randomization table. Subjects were allowed to use the assigned medication in the fellow eye if it had not had a transplant. Subjects were instructed to refrigerate the study drops and instill 1 drop in the study eye each evening for the study duration.
Study Procedures
The study visits included a baseline, 1-month, and 3-month examination. At each visit, the study procedures included manifest refraction and assessment of scotopic corrected distance visual acuity with a Snellen chart, slit-lamp examination, intraocular pressure measurement by Goldmann tonometry, completion of a 15-item visual disability questionnaire validated for use with FECD, and imaging with anterior segment optical coherence tomography (AS-OCT, Avanti; Optovue, Inc, Fremont, California, USA), Scheimpflug corneal tomography (Pentacam; Oculus, Wetzlar, Germany), corneal topography (TMS-4; Tomey Corporation, Nagoya, Japan), and optical biometry (Lenstar; Haag-Streit, Koniz, Switzerland). At each examination, participants were asked whether any adverse events were experienced since the last examination, and participants were encouraged to call with any concerns between scheduled visits. All participant-reported ocular adverse events were tabulated.
Outcome Measures
The prespecified primary outcomes were the change in central corneal thickness from baseline to 1 month and from baseline to 3 months after randomization. The change in corrected distance visual acuity (CDVA) from baseline to 3 months after randomization was a secondary outcome. An additional secondary outcome was the change in FECD disability questionnaire score; this outcome was assessed at 1 month rather than 3 months to avoid potential confounding from fellow-eye surgery that was allowed after the 1-month visit. The change in the corneal surface asymmetry index (assessed by corneal topography) and change in intraocular pressure from baseline to 3 months were exploratory outcomes.
Sample Size Determination and Statistical Analysis
We anticipated that a sample size of 13 eyes per arm would provide 80% power to detect a 70-µm between-group difference in central corneal thickness reduction, assuming a 2-tailed alpha of 0.05 and a standard deviation of 60 µm. The assumptions regarding the mean and standard deviation of the potential central corneal thickness reduction were based on historical observations in FECD patients who underwent Descemet membrane endothelial keratoplasty at our center.
As prespecified, subjects who withdrew before the 1-month visit were replaced but included in the safety analysis. One subject in each arm did not make the 1-month visit and 2 in each arm did not make the 3-month visit because of COVID-19.
Between-group differences at the prespecified time points were assessed using the Student t test. The analyses were 2-tailed and conducted on an intention-to-treat basis; P values less than .05 were considered significant. Sensitivity analyses consisted of examining box plots to detect any outliers in the main, secondary, or exploratory outcomes and repeating the analyses without the outlier(s) to determine whether or not this affected the findings. The data were analyzed with Statistical Analysis Software (SAS Version 9.4; SAS Institute, Cary, North Carolina, USA).
Results
Twenty-nine subjects were enrolled and assigned to treatment. One subject assigned to the netarsudil arm withdrew because she experienced severe glare after using the study drop the first night, and 1 subject per arm withdrew for extraneous personal reasons before the 1-month examination. Safety was assessed in 29 subjects and efficacy was assessed in 26 eyes of 26 subjects (13 per study arm) ( Figure 1 ). The baseline participant characteristics and follow-up data are shown in Table 1 .
| Netarsudil | Placebo | |
|---|---|---|
| Demographics | ||
| Sex, n | 5 male, 6 female | 6 male, 7 female |
| Age, years | 68 ± 5 | 69 ± 7 |
| Central corneal thickness by biometry, µm | ||
| Baseline | 590 ± 43 | 611 ± 35 |
| 1 month | 568 ± 46 | 609 ± 37 |
| 3 months | 563 ± 40 | 607 ± 29 |
| Corrected distance visual acuity, logMAR | ||
| Baseline | 0.34 ± 0.24 | 0.38 ±0.33 |
| 1 month | 0.27 ± 0.27 | 0.32 ± 0.25 |
| 3 months | 0.15 ± 0.18 | 0.34 ± 0.28 |
| Topographic surface asymmetry index | ||
| Baseline | 0.9 ± 0.8 | 0.6 ± 0.5 |
| 3 months | 0.7 ± 0.6 | 0.6 ± 0.4 |
| Intraocular pressure, mm Hg | ||
| Baseline | 14.1 ± 2.3 | 14.5 ± 1.9 |
| 3 months | 12.4 ± 1.6 | 14.5 ± 3.4 |
| Disability questionnaire score | ||
| Baseline | 35 ± 15 (range, 8-56) | 36 ± 12 (range, 14-52) |
| 1 month | 39 ± 15 (range, 11-60) | 33 ± 14 (range, 10-45) |
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