Conditions: Corneal Endothelial Dystrophy Corneal Edema
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 70
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess off-label use of loteprednol etabonate 0.25% ophthalmic suspension (Eysuvis) for prevention of immunologic rejection in the first year after Descemet membrane endothelial keratoplasty (DMEK). Topical corticosteroids have long been the mainstay for preventing and treating cornea transplant rejection although none are specifically approved for this purpose. The rates of immunologic rejection episodes and steroid-induced ocular hypertension will be compared with the respective rates observed in earlier studies with prednisolone acetate 1% suspension, loteprednol etabonate 0.5% gel, and fluorometholone 0.1% suspension after DMEK.

Detailed description:

Arms:
arm 1: Loteprednol etabonate ophthalmic suspension 0.25% dosed 4 times daily for 2 months, 3 times daily for one month, twice daily for one month, and once daily until the 1 year postop exam.

Interventions: intervention 1: loteprednol etabonate 0.25% ophthalmic suspension
Intervention descriptions: intervention 1: tapering dose

Protocol document:
Prot_SAP_000.pdf: 
PROSPECTIVE ANALYSIS OF LOTEPREDNOL ETABONATE OPHTHALMIC SUSPENSION 0.25% 
FOR PREVENTION OF IMMUNOLOGIC REJECTION AFTER DESCEMET MEMBRANE 
ENDOTHELIAL KERATOPLASTY 
 
 
NCT05136443 
 
 
DOCUMENT DATE: NOVEMBER 3, 2021 
 


 
 
 
 
- CLINICAL PROTOCOL - 
 
 
 
 
 
PROSPECTIVE ANALYSIS OF LOTEPREDNOL ETABONATE OPHTHALMIC SUSPENSION 
0.25% FOR PREVENTION OF IMMUNOLOGIC REJECTION AFTER DESCEMET MEMBRANE 
ENDOTHELIAL KERATOPLASTY 
 
 
Protocol # 2021-002 
Version Date 11/3/21 
 
 
 
Principal Investigator and Sponsor 
 
Francis W. Price, Jr. MD 
9002 N. Meridian St., Suite 100 
Indianapolis, IN  46260 
Phone: 317-814-2990,  
FAX: 317-814-2806 
 
 
 


1. Purpose of the Study and Background 
 
1.1  Purpose of the Study:  
The purpose of this study is to assess off-label use of loteprednol etabonate 0.25% 
ophthalmic suspension for prevention of immunologic rejection after Descemet 
membrane endothelial keratoplasty (DMEK). 
 
1.2  Background 
Topical corticosteroids have long been the mainstay for preventing and treating corneal 
graft rejection.[1] Typically, topical corticosteroids are dosed 4 times a day for several 
months, followed by tapered dosing for an extended period of time, sometimes 
indefinitely, after surgery.[1] If a patient experiences an immunologic graft rejection 
episode, corticosteroid use is increased in an effort to save the graft. 
 
A number of side effects are associated with long-term corticosteroid use. In 
particular, up to one third of patients with no previous diagnosis of glaucoma experience 
intraocular pressure elevation with prolonged use of prednisolone acetate 0.1% 
ophthalmic suspension,[2] which is commonly used to prevent rejection following 
corneal transplantation.[1]  
 
In our earlier studies, DMEK recipients used prednisolone acetate 1% four times 
daily for 1 month and then were randomized to a tapering dose of prednisolone acetate 
1% ophthalmic suspension, fluorometholone 0.1% ophthalmic suspension, or loteprednol 
etabonate 0.5% gel. The loteprednol etabonate 0.5% gel and fluorometholone 0.1% 
suspension were as effective as prednisolone acetate 1% at preventing immunologic 
rejection episodes and were associated with significantly lower rates of steroid-induced 
ocular hypertension. [3,4] 
 
This study will assess the use of a tapering dose of loteprednol etabonate 0.25% 
suspension from one month to one year after DMEK. The rates of immunologic rejection 
episodes and steroid-induced ocular hypertension will be compared with the respective 
rates observed in the earlier studies with use of prednisolone acetate 1% suspension, 
loteprednol etabonate 0.5% gel, or fluorometholone 0.1% suspension.  
 
1.3 Study Design 
 Prospective, open-label clinical study  
 Main Outcome Measures 
o Rate of intraocular pressure elevation 
o Rate of initial immunologic graft rejection episodes 


 
2.0 Characteristics of the Research Population 
 
2.1 
 Number of Subjects: up to 75 DMEK recipients may enroll 1 eye into the study 
at the 1-month postoperative exam. 
2.2 
 Gender of Subjects: both men and women will be enrolled 
2.3 
 Age of Subjects: 18-90 years of age. The rationale for not including minors is 
that DMEK is performed to treat endothelial dysfunction, a condition usually seen in 
adults over 40 years of age. 
2.4 
 Racial and Ethnic Origin: Subjects may be of any racial or ethnic origin. 
 
2.5 
 Inclusion criteria: the following are requirements for study inclusion: 
o At least 18 years of age 
o Male or female patient who had DMEK within the past 1 to 7 weeks.  
o Patient is able and willing to administer eye drops. 
o Patient is able to comprehend and has signed the Informed Consent form. 
o Patient is likely to complete the 11-month study duration. 
 
2.6: Exclusion criteria:  
o A history of a previous rejection episode in the study eye 
o A patient exhibiting intraocular inflammation.  
o A patient with a known sensitivity to any of the ingredients in the study 
medications  
o A patient who has a condition (i.e., UNCONTROLLED systemic disease) or is 
in a situation which in the investigator’s opinion may put the patient at 
significant risk, may confound the study results, or may interfere 
significantly with the patient’s participation in the study 
o A patient with abnormal eyelid function. 
o A patient that is exhibiting active corneal ulceration, keratitis, or 
conjunctivitis, or who has a history of herpetic keratitis.  
o A patient with primary open angle glaucoma. 
o Presence of any ocular disease that would interfere with the evaluation of 
the study treatment.  However, patients with a history of cystoid macular 
edema, age-related macular degeneration, corneal neovascularization, and 
other non-interfering comorbidities may be enrolled. 


o A patient with a history of non-compliance with using prescribed 
medication. 
o Patients who are pregnant or planning to become pregnant within the 
duration of the study 
 
2.7 Vulnerable Subjects: No potentially vulnerable subjects will be enrolled because 
there may be no direct benefit to the patient; rather, important knowledge which may 
benefit future subjects is being sought. As such, the direct benefit would not outweigh 
risks for vulnerable populations.  
 
Minors will not be enrolled into this study because the conditions being studied under this 
protocol are not typical problems for minors. Endothelial keratoplasty is performed to 
treat endothelial dysfunction, a condition usually seen only in older (>40 years of age) 
adults.) 
 
Pregnant women will not be enrolled into this study as potential risks and harm to the 
fetus is unknown.  
 
This study plans to exclude any person who does not speak English as non- English 
speaking patients are not normally seen at the study site so a translator would not be 
available to translate the consent form into the patient’s native language. 
 
3.0  Methods & Procedures 
 
3.1 Study procedures and assessments. 
 
Screening:  Prospective subjects, who have recently undergone DMEK, will be 
considered for entry into the study.  
 
 
Enrollment: Subjects meeting the inclusion and exclusion criteria will be 
informed of the opportunity to participate in the study. Subjects will be entered into the 
study after providing written informed consent.  Each subject will be instructed that if 
they decide not to participate, they may withdraw at any time.  
 
 
Study Treatment Regimen: At one month after DMEK (or at the time of study 
enrollment if that is more than one month after DMEK) participants will discontinue use 
of the prednisolone acetate 1% ophthalmic suspension that was prescribed for use after 


DMEK, and they will be provided with loteprednol etabonate 0.25% ophthalmic 
suspension for use 4 times daily for 2 months, 3 times daily for a month, twice daily for a 
month, then once daily until the 12-month postoperative exam.  
 
 
Rescue medication: if a study subject experiences inflammation or a 
questionable immunologic rejection episode in the study eye within the first month after 
enrollment, they will be instructed to use prednisolone acetate 1% ophthalmic suspension 
up to 8x/day for one week, 6x/day for 1 week, 4x/day for one week and 3x/day for one 
week). The study subject will then restart the study dosing schedule.  The month of rescue 
treatment will allow those with greater than average inflammation to remain in the study 
by providing an additional month of increased steroid strength before resuming a weaker 
steroid regimen. 
  
 
Examinations:  
o Schedule: Each subject will be examined at 1, 3, 6 and 12 months after 
DMEK as detailed in Table 1. The examination schedule and procedures 
are standard of care for DMEK patients. 
o Procedures: At each exam, medical and ophthalmic histories will be 
updated, adverse events will be recorded, and measurements of manifest 
refraction, visual acuity, corneal thickness (pachymetry) and intraocular 
pressure will be made. Corneal endothelial cell density will be measured 
by specular or confocal microscopy if possible. A slit lamp examination 
will be performed to assess the health of the transplant and document any 
conjunctival or lid hyperemia, stromal inflammation, superficial punctate 
keratitis, other surface toxicity of the cornea, neovascularization of the 
cornea, cells or flare in the anterior chamber, or evidence of transplant 
rejection. 
o Records release: Subjects may be asked to sign a records release form in 
case the subject sees another eye specialist while enrolled in the study. 
This will allow the investigator to determine if there is a rejection episode 
or elevated intraocular pressure at examinations made with other 
physicians. Since the primary and secondary outcome measures (slit lamp 
examination for evidence of rejection and intraocular pressure 
measurement) are routine ophthalmic exams, the subject may have some 
of the exams performed by a local eye doctor if getting back to the study 
site is too burdensome. 


o Unscheduled examinations: Subjects will be instructed to return for extra 
examinations if they note any problems with the eye or any early signs of a 
possible rejection episode, such as a change in vision, redness to the eye, 
increased light sensitivity, burning sensation, or foreign body sensation. 
o Study completion: Subjects will be considered to have completed the 
study after they complete the one-year postoperative examination. 
o Subject withdrawal or discontinuation:  Each subject may voluntarily 
discontinue the study at any time they choose. Subjects who cannot 
complete the study for administrative reasons (e.g., non-compliance, 
failure to meet visit schedule, etc.) will be discontinued from the study. 
Discontinued subjects may be replaced. For subjects withdrawn from the 
study, the same measurements and assessments should be performed as 
done at one year. Adverse events should be followed up until resolution or 
stabilization of the adverse event.  
Table 1 
 
Screening 
(~1 month 
after DMEK) 
3 months 
after DMEK 
6 months 
after 
DMEK 
One year 
after 
DMEK 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
Medical and 
ophthalmic history 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
Uncorrected visual 
acuity (Snellen) 
X 
X 
X 
X 
Corrected Distance 
visual acuity (Snellen) 
X 
X 
X 
X 
Manifest refraction 
X 
X 
X 
X 
Endothelial cell density 
(if possible) 
X 
X 
X 
X 
Intraocular Pressure  
X 
X 
X 
X 
Ultrasonic Pachymetry 
X 
X 
X 
X 
 
3.2 Data Analysis and Data Monitoring: The primary outcome measures are the 
incidence of clinically significant intraocular pressure (IOP) elevation (defined as IOP ≥ 
24mmHg or a relative increase over the pre-transplant IOP of ≥ 10mmHg), and the 
incidence of initial allograft rejection episodes or necessity to increase corticosteroids 


because of breakthrough corneal or anterior chamber inflammation. The data will be 
analyzed using Kaplan Meier survival analysis and the log rank test.  
 
A statistical power analysis indicated that a sample size of 70 participants would provide 
80% power to detect a statistically significant difference in the rate of IOP elevation 
between loteprednol etabonate 0.25% and prednisolone acetate 1%, based on observed 
rates of IOP elevation in an earlier study that compared loteprednol 0.5% gel with 
prednisolone 1% suspension.4  
 
3.3 Data Storage and Confidentiality: Research data will be stored in a locked cabinet 
or locked room and on a password protected server to prevent unauthorized access to 
data. The investigators and research staff will have access to the data. Subject identifiers 
will be removed from study data released to the Sponsor or for publication.   
 
4.0  Risk/Benefit Assessment 
 
4.1 Risks and Anticipated Adverse Events: 
Risks: This study is considered to entail minimal risk for study subjects because topical 
corticosteroids are routinely used off label to prevent cornea transplant rejection.  
  
A number of complaints and complications are anticipated in patients who have received 
a cornea transplant, regardless of whether they participate in this study.  Therefore, the 
presence or absence of the following anticipated complaints and complications in the 
study eye will be recorded on the electronic case report form (eCRF) for each exam rather 
than on separate adverse event forms.  
 Complaints of ocular discomfort: (examples include: eye pain, irritation, burning, 
itching, scratchy feeling, foreign body sensation, tired/fatigued feeling, 
achy/tender/sore feeling, pressure sensation, tightness, twinge/twitchy feeling, 
dry eyes, tearing/watering, eye redness) 
 Complaints of visual symptoms or disturbances: (examples include: glare or 
fluctuating vision, haloes around lights, diplopia, blurry, hazy, cloudy, filmy or 
out of focus vision, ghosting or shadowing, difficulty reading, difficulty with 
night driving, floaters, spots in vision, light sensitivity, decreased vision, light 
reflections from intraocular lens or peripheral iridotomy).   
 Increased ptosis (within the first 6 months of surgery) 


 Puffy eyelids (within the first 3 months of surgery) 
 Delayed resolution of corneal haze or edema (within the first 6 months of surgery) 
 Subconjuntival hemorrhage (within the first 3 months of surgery) 
 Epithelial defect (within the first month of surgery) 
 Folds in the transplant 
 Partial graft detachment without further intervention 
 Development of capsular haze without further intervention 
 Superficial punctate keratitis 
 Pupillary block (within the first 3 months of surgery) 
Adverse events: The type, severity, duration and frequency of the following anticipated 
adverse experiences and any other unanticipated ocular adverse events will be tabulated. 
If a patient experiences an adverse reaction, appropriate medical treatment will be 
provided.  Examples may include:  
 Graft detachment which requires intervention 
 Immunologic graft rejection episode 
 Graft failure and/or regraft 
 Intraocular pressure elevation which requires intervention 
 Development of capsular haze which requires intervention 
 Iris synechia 
 Cystoid macular edema 
 Iritis 
Anticipated rare adverse events include retinal detachment, iris synechiae/atrophy, 
epiretinal membrane, infectious keratitis or conjunctivitis, branch retinal vein occlusion, 
or endophthalmitis.  
Serious Adverse Event: A serious adverse event is one that results in any of the following 
outcomes: death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/ incapacity, 
or a congenital anomaly/birth defect. In the event of a serious adverse event, the 
investigator will maintain complete documentation and promptly inform the governing 
Institutional Review Board (IRB) of the serious adverse event within their required 
reporting period. 
 


Fellow eye: Each subject may enroll one eye into the study. Patients in this population 
tend to be affected with the eye condition bilaterally, so many of the study subjects may 
undergo surgery on the fellow eye during the year of study participation.  Routine 
fellow-eye post-transplant complications will not be transcribed to the eCRF. 
 
4.2 
Protection Against Risks: Every effort will be made to minimize any risks or 
discomforts to study subjects. The investigator will ensure appropriate training of study 
personnel and monitoring of subjects and will provide appropriate treatment for 
eye-related adverse events or referral for treatment of non-eye-related adverse events. 
The subject and or their health insurance plan will be responsible for payment for 
treatment, counseling or follow up.   
 
A Data Safety Monitoring Committee (DSMC) will be chaired by Dr. Gerald 
Clarke, an independent ophthalmologist practicing in Menasha, Wisconsin. The DSMC 
will review any serious adverse events as they occur. The DSMC will also review the 
interim data (including adverse events and subject compliance) every 6 months, to 
determine if any modifications to the original study plan may be warranted. Urgent data 
and safety monitoring reports (e.g. reports indicating an unanticipated problem involving 
risk) will be reported to the IRB within 10 business days of the Sponsor receipt of the 
report. Routine reports will be submitted to the IRB with the Sponsor’s Study Status 
Report. 
 
4.3 
Potential Benefits to the Subjects: Study subjects may not realize any direct 
benefit from participation in the research; rather, important knowledge which may benefit 
future subjects is being sought. 
 
4.4 
Study termination: The study may be prematurely terminated if, in the opinion 
of the investigator or the Sponsor, there is sufficient reasonable cause. Written 
notification, documenting the reason for study termination, will be provided to the 
investigator or Sponsor by the terminating party. Circumstances that may warrant 
termination include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to subjects. 
 Insufficient adherence to protocol requirements. 
 Data that is not sufficiently complete or evaluable. 
 Plans to modify, suspend or discontinue marketing of the Study Product. 
 
5.0 Method of Subject Identification and Recruitment 


 
5.1 Process of Consent The process of obtaining the consent consists of explaining the 
eye condition and explaining the risks and benefits of the proposed   treatment and 
alternatives. In addition, the patient will be allowed to read the consent and ask questions 
prior to signing the informed consent form. The patient may take home an unsigned copy 
of this consent form to think about or discuss with family or friends before making a 
decision.  
Study coordinators, who have been trained in obtaining consent by the investigator and 
who have experience in consenting subjects for clinical trials, will obtain informed 
consent. Consent will be obtained in a private exam room with the door closed to protect 
the privacy of participants. The study will be explained to participants and if subjects 
have specific questions which the study coordinator cannot address, the principal 
investigator will be available to answer the questions. 
5.2 Subject Capacity: All subjects will be evaluated for capacity to consent through the 
use of the Cornea Research Foundation of America Evaluation to Sign a Consent Form. 
Any subjects who do not answer the Evaluation questions satisfactorily will be 
considered cognitively impaired and will not be enrolled into the study as they would not 
meet the study's inclusion/exclusion criteria. 
5.3 Subject/Representative Comprehension: Subjects will be given time to ask any 
questions, and study information will be explained until it is clear that all information 
presented is understood.   
5.4 Debriefing Procedures: Not applicable; this is not a psychological study and no 
information will be purposely withheld from the subject. 
6.0 Consent Forms 
6.1 Documentation of Consent Patient's medical records and informed consent 
documents will be maintained and stored with access limited to the authorized 
personnel. All research records will be kept separate and locked with limited access by 
research personnel only. 
6.2 Costs to the Subject: The subject and or their health insurance plan will be 
responsible for payment for treatment, counseling or follow up. 


6.3 Payment for Participation: Subjects will be provided with the assigned topical 
corticosteroid for the duration of the study. Subjects will not receive any payment for 
study participation. 
7.0 References 
1.   Price FW, Price DA, Ngakeng V, Price MO. Survey of steroid usage patterns during 
and after low-risk penetrating keratoplasty. Cornea 2009;28:865-70. 
2.  Vajaranant TS, Price MO, Price FW, Gao W, Wilensky JT, Edward DP. Visual acuity 
and intraocular pressure after Descemet’s stripping endothelial keratoplasty in 
patients with and without pre-existing glaucoma, Ophthalmology 2009;116:1644-50. 
 3. Price MO, Feng MT, Scanameo A, Price FW Jr. Loteprednol etabonate 0.5% gel vs. 
prednisolone acetate 1% solution after Descemet membrane endothelial 
keratoplasty: prospective randomized trial. Cornea 2015;34:853-8. 
 4.  Price MO, Price FW Jr, Kruse FE, Bachmann BO, Tourtas T. Randomized comparison 
of topical prednisolone acetate 1% versus fluorometholone 0.1% in the first year 
after descemet membrane endothelial keratoplasty. Cornea 2014;33:880-6.