Clinical trial NCT04168112
Conditions: Keratoconus, Unstable Collagen Crosslinking Postoperative Pain
Keywords: Collagen Crosslinking Keratoconus Dexamethasone Intracanalicular Insert
Sponsor: Sight Medical Doctors PLLC
Start date: 2020-02-12; Completion date: 2023-04-05
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
There is no standard of care medication regimen for the management of pain and inflammation post-corneal crosslinking (CXL), although most cornea specialists agree on use of an antibiotic and steroid eye drop in the immediate postoperative period. However, steroid tapering schedule and use of additional topical non-steroidal anti-inflammatory (NSAID) eyedrops vary amongst practitioners. The goal of this study is to compare postoperative pain scores between patients receiving a tapering dose of topical steroids over 1-month post-CXL, versus those receiving an intracanalicular dexamethasone insert.

Detailed description:
Keratoconus is a progressive ectatic disease of the cornea, leading to worsening of astigmatism and vision over time. With FDA approval of corneal collagen cross-linking (CXL), we now have the ability to halt the progression of keratoconus and prevent further vision loss in these patients. Although CXL has now become standard of care, the immediate post-operative period can be quite painful despite use of anti-inflammatory medications/eye drops. The goal of this study is to evaluate the efficacy of an intracanalicular dexamethasone insert in reduction of post-CXL pain as compared to routine steroid eye drop therapy.

To date, no studies have been performed evaluating the success of an intracanalicular dexamethasone insert for the treatment of postoperative inflammation and pain in corneal cross-linking patients. Oftentimes, patients experience a great deal of discomfort post-CXL, which may also make it difficult to apply eye drops in the correct fashion. Use of a dexamethasone insert alleviates the need for postoperative steroid eye drops and may provide increased pain relief post-CXL as compared to topical therapy. This will be a head-to-head study where steroid therapy (topical or insert) will begin in a standard fashion on the date of CXL. This will allow for accurate comparison of a 4-week taper of topical steroids, versus a dexamethasone insert designed to release steroid for 30 days.

Arms: arm 1: Intracanalicular dexamethasone insert is placed on day of crosslinking (CXL); patients will still receive postoperative fluoroquinolone (or other class in case of allergy) antibiotic eye drops with instructions for use (i.e. 1 drop in operative eye QID x 10 days). arm 2: Patients are placed on standard postoperative regimen of postoperative fluoroquinolone (or other class in case of allergy) antibiotic eye drops with instructions for use (i.e. 1 drop in operative eye QID x 10 days) and Prednisolone acetate 1% ophthalmic solution tapered over 1 month in the following schedule: QID x1 week, TID x 1 week, BID x 1 week, and Qday x 1 week.
Interventions: intervention 1: Dextenza intervention 2: Prednisolone Acetate
Intervention descriptions: intervention 1: Placement of intracanalicular dexamethasone insert for post-crosslinking inflammation and pain intervention 2: post-crosslinking eye drop prednisolone acetate given in a tapering schedule over 1 month

Protocol documents:
Prot_SAP_000.pdf: 
11/20/2023 
 
 
Dear FDA Clinical Trials Review Board, 
 
Please find attached the study protocol and statistical analysis plan document as requested on the 
PRS System.  
This is for the study: Intracanalicular Dexamethasone Insert for Post-Corneal Cross-Linking 
Inflammation and Pain- The LINK Study (IND 146603; NCT04168112) 
Please do not hesitate to contact me with any questions or concerns regarding this document. 
Thank you for your time and consideration. 
 
Sincerely, 
 
 
 
 
Alanna Nattis, DO 
SightMD 
500 W Main Street, Ste 210 
Babylon NY 11702 
631-957-2816 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Intracanalicular Dexamethasone Insert for Post-Corneal Cross-Linking Inflammation and Pain- 
The LINK Study 
Protocol in brief: This prospective, open-label, single-center, randomized, investigator-
sponsored clinical study sought to investigate the efficacy of dexamethasone intracanalicular 
insert on post-corneal crosslinking inflammation and pain in keratoconus patients. This study 
planned to enroll 20 patients and follow patients over the course of several study visits 
[(postoperative day (POD) 1, POD-3, POD4-7, POW2, POW3 and POW4]. It is anticipated that 
corneal re-epithelialization will occur within the first postoperative week, but patients were be 
followed closely for documentation of therapeutic effect for 30 days due to duration of steroid 
therapy (i.e. dexamethasone intracanalicular insert or use of Prednisolone acetate 1% ophthalmic 
solution tapered over 1 month in the following schedule: 4 times daily x1 week, 3 times daily x 1 
week, 2 times daily x 1 week, and daily x 1 week). All patients will receive postoperative 
fluoroquinolone antibiotic eye drops with instructions for use (i.e. 1 drop in operative eye 4 times 
daily x 10 days). All patients were evaluated for pain scores, rate of corneal re-epithelialization, 
ease of use of the post-crosslinking regimen, and need for rescue pain medication after standard 
bilateral epithelium-off crosslinking.  
Biostatistics  
Study variables were analyzed by appropriate statistical methods to assess for the differences 
between eyes treated as an entire group, and as broken down between dexamethasone implant 
and traditional prednisolone drop groups. Correlations between ease of use, intraocular 
inflammation, and epithelial healing were assessed using χ2, t-test, Pearson, and the Fisher Z-
transformation test, evaluating the sample correlation r for significance. For independent 
samples, the t-test or Mann-Whitney-U test will be used for scaled data based on the outcome of 
the Kolmogorov-Smirnov test for normality of distribution.  Ordinal data was analyzed using the 
Mann-Whitney-U test and chi-square or Fisher’s Exact test for nominal data. P-values less than 
or equal to 0.05 were considered statistically significant. For non-inferiority or equivalency data, 
95% confidence intervals were formulated and compared with equivalency margins. Sample size 
is small secondary to the incidence of the disease (1:2,000) 
For any patient deciding to withdraw from the follow-up, the reasons for the withdrawal were 
recorded for the subsequent analysis in the interpretation of the results. 
Reasons behind drop out were investigated and included in study results. The authors only 
analyzed complete cases, as imputing the missing data using single or multiple imputation 
methods would be confounded by the small sample size. ITT for ease of use was calculated 
utilizing extremely conservative estimates of a 70% +/- 10% for drops and 90% for 
dexamethasone insert, while utilizing a two independent sample study with a continuous 
endpoint, 1:1 enrollment ratio, alpha/beta of 0.05, and power of 95%. We calculated the 
minimum number of patients needed to enroll as 12. 
 
In order to account for type I errors over multiple endpoints Bonferroni adjustment method was 
utilized.  


Study results: Twenty patients (40 eyes) were enrolled in the study. In the prednisolone group, 
there was 60% male and 40% female (n=6, n=4, respectively). In the dexamethasone group, 
there was 40% male and 60% female (n=4, n=6, respectively). One patient in the prednisolone 
group dropped out from the study after POW1 as her family moved out of state and is 
continually followed by a cornea specialist in her new location. Another patient in the 
prednisolone group was lost to follow up after POW1 and despite multiple attempts at contacting 
her, including a certified letter she did not return for follow up. Results were analyzed for the 
remaining patients who completed the full study course (8 patients (16 eyes) in prednisolone 
group, 10 (20 eyes) in dexamethasone insert group).  
Mean age in the prednisolone group was 26±3.89 years (range: 19-27), mean age in the 
dexamethasone group was 36.3±10.29 years (range: 25-47). Mean best corrected visual acuity 
(BCVA) at baseline was 20/40 (range: 20/20-20/100) in the prednisolone group and 20/40 
(range: 20/20 to 20/400) in the dexamethasone insert group. There was no statistical difference 
between age, sex and whether or not patient received dexamethasone insert or prednisolone. In 
addition, there was no significant correlation between sex and final BCVA (t-test, p=0.543). No 
correlation was found between age and final BCVA (Pearson correlation, p=0.372) 
No significant difference was found between BCVA at POW4 and whether the patient received 
dexamethasone or prednisolone (t-test, p=0.554). Mean POW4 BCVA was 20/40 in the 
prednisolone group and 20/30 in the dexamethasone insert group. There was no significant 
change in BCVA at POW4 as compared with baseline. 
When assessing pain scores, a standardized visual analog pain scale (0-10) was used for each 
patient. Mean pain score on POD0 was 6.4±1.3 and 6.6±1.62 for the prednisolone and 
dexamethasone insert groups, respectively. Pain scores fell significantly on POD1 to 1.3±0.45 
and 2±1.18 in the prednisolone and dexamethasone groups, respectively. By POD7, no patient 
complained of pain or discomfort (i.e., pain scale rating was “0”).  No patient used ‘rescue 
medications’ longer than 2 days (POD0 and POD1) – the most commonly used self-reported 
medications were ibuprofen and acetaminophen. Seventy percent of patients in the prednisolone 
group vs. 60% of those patients in the dexamethasone insert group self-administered pain 
medications to help manage postoperative discomfort. No narcotics were prescribed or deemed 
necessary to help manage post-CXL pain in our study. Though not a large difference in pain 
scores, those in the prednisolone group reported statistically significantly lower pain scores at 
POD0(t-test, p=0.021) and POD1 (t-test, p=0.036) vs. those in the dexamethasone insert group. 
Ocular surface inflammation was noted to be quite mild over the course of the study. Most 
patients demonstrated clear conjunctiva that was free of injection by POD1; only 4 eyes (2 in the 
prednisolone group, 2 in dexamethasone group) had trace injection noted at time of exam. No 
conjunctival injection was noted at the remainder of the study visits for any subject.  
Trend in intraocular pressure (IOP) was assessed from baseline to POW4. There was no 
significant difference in baseline IOP between groups (t-test, p=0.518); mean IOP was noted to 
be 13.5±1.28mmHg and 13.9±1.64 mmHg at POD1 in prednisolone and dexamethasone insert 
groups, respectively. By POW4, mean IOP measured 14.25±1.64mmHg in the prednisolone 


group and 13.65±2.26mmHg in the dexamethasone insert group. There was no significant rise or 
difference in intraocular pressure over time across both groups. 
 
Rate of corneal re-epithelialization was assessed between groups. There was no significant 
difference between groups and rate of epithelial defect resolution at POD1 (t-test, p=0.152) and 
POD3 (p=0.061). Epithelial defect was noted to be resolved by POD7 in all subjects 
Central corneal pachymetry (CCT) will often change over the course of post-CXL healing and as 
such was assessed at baseline and at the completion of the study between groups. As expected, 
there was no significant difference in mean CCT between groups at baseline (505.4±47.6µm in 
prednisolone group and 509±44.11µm in dexamethasone group), nor at POW4 (459±33.89 µm in 
prednisolone group; 473.15±43.78 µm in dexamethasone group).  
At the end of the study, the patients were asked to complete an “ease of use” questionnaire 
regarding postoperative medications. The first question asked “Were directions regarding eye 
drop use post-CXL easy to follow”? All patients in both groups responded “yes” to this. The 
second question asked, “Was it cumbersome to use eye drops for more than 10 days” (this 
pertained to the prednisolone group), however 100% responded “no”. The final question asked 
“Was it difficult to remember to use postoperative drops?”; 100% of patients responded “no”.  
No patient experienced any adverse results in relation to treatment or CXL.