Diabetes Endothelial Keratoplasty Study (DEKS): Impact of Diabetes on Corneal Transplant Success and Endothelial Cell Loss
Phase: NA
Conditions: Corneal Endothelial Decompensation, Fuchs' Endothelial Dystrophy
Sponsor: Case Western Reserve University

Diabetes Endothelial Keratoplasty Study (DEKS): 
Impact of Diabetes on Corneal Transplant Success and 
Endothelial Cell Loss 
Version Number: v.1.2 
26 January 2023 
Funded by: National Eye Institute 
 

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PROTOCOL VERSION HISTORY 
VERSION 
NUMBER 
AUTHOR(S) 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
1.0 
J. Lass 
M. Price 
L. Szczotka-Flynn 
C. Bauza 
J. Lass 
7/15/21 
Original protocol 
1.1 
J. Lass 
M. Price 
L. Szczotka-Flynn 
C. Bauza 
J. Lass 
10/21/21 
Edits to inclusion and exclusion 
criteria, enrollment of second eye, 
donor diabetes definitions, statistical 
analyses, and source documentation 
and 
congruence in adverse event 
definitions to align with the JCHR 
global adverse event application 
1.2 
J. Lass 
M. Price 
L. Szczotka-Flynn 
C. Bauza 
J. Lass 
2/3/23 
Clarified donor diabetes determination 
used for randomization and donor 
tissue selection is based on eye bank 
assessment, not reclassification 
determination after post-mortem 
HbA1c value is returned  
 
 
 
 
 
 
 
 
 
 
 

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KEY ROLES 
 
Name, degree 
Jonathan Lass, MD 
Title 
Protocol Chair 
Institution Name 
Case Western Reserve University (CWRU), University Hospitals Eye Institute 
(UHEI) 
 
Name, degree 
Marianne Price, Ph.D. 
Title 
Protocol Co-Chair 
Institution Name 
Cornea Research Foundation of America (CRFA) 
 
Name, degree 
Loretta Szczotka-Flynn, OD, Ph.D. 
Title 
Coordinating Center Director 
Institution Name 
CWRU 
 
Name, degree 
Colleen Bauza, Ph.D. 
Title 
Data Management and Analysis Center Director 
Institution Name 
Jaeb Center for Health Research (JCHR) 
 
Medical Monitor 
Jonathan Lass, MD 
Title 
Medical Monitor 
Institution Name 
CWRU, UHEI 
 

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TABLE OF CONTENTS 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 17
1.1 Introduction and Rationale ................................................................................................................ 17
1.2 Potential Risks and Benefits .............................................................................................................. 19
1.2.1 Known Potential Risks ................................................................................................................ 19
1.2.1.1 Known Potential Risks of DMEK ....................................................................................... 19
1.2.1.2 Known Potential Risks of Study Participation .................................................................... 20
1.2.2 Known Potential Benefits ............................................................................................................ 21
1.2.3 Risk Assessment .......................................................................................................................... 21
1.3 General Considerations...................................................................................................................... 21
CHAPTER 2: STUDY ENROLLMENT AND PARTICIPANT SCREENING ...................................................... 22
2.1 Participant Recruitment and Enrollment ........................................................................................... 22
2.1.1 Informed Consent and Authorization Procedures ....................................................................... 22
2.2 Participant Inclusion Criteria ............................................................................................................. 23
2.2.1 Study Participant-level Criteria ................................................................................................... 23
2.2.2 Study Eye Criteria ....................................................................................................................... 23
2.3 Participant Exclusion Criteria ............................................................................................................ 24
2.4 Screening/Pre-operative Procedures .................................................................................................. 25
2.4.1 Data Collection and Testing ........................................................................................................ 25
2.5 Screen Failures .................................................................................................................................. 26
CHAPTER 3: DONOR ELIGIBILITY AND CORNEA ASSIGNMENT, EYE BANKS ........................................ 27
3.1 Eye Bank Procedures ......................................................................................................................... 27
3.2 Donor Information, Procurement of Tissue and Other Samples ....................................................... 27
3.2.1 Donor Cornea Tissue Suitability ................................................................................................. 27
3.2.2 Determining Diabetic Status ........................................................................................................ 28
Defining Diabetic Status....................................................................................................................... 28
3.2.3 Eye Bank Procedures for Study Images ...................................................................................... 30
3.2.4 DMEK Lenticule Preparation ...................................................................................................... 30
3.3 Laboratory Testing ............................................................................................................................ 30
CHAPTER 4: TRANSPLANTATION AND FOLLOW-UP PROCEDURES AT CLINICAL SITES ....................... 31
4.1 DMEK Procedure .............................................................................................................................. 31
4.2 Post-Operative Management ............................................................................................................. 31
4.3 Study Visits ....................................................................................................................................... 31
4.3.1 Study Visits and Windows .......................................................................................................... 31
4.3.2 Procedures at Study Follow-up Visits ......................................................................................... 32

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4.4 Early Termination Visit ..................................................................................................................... 32
CHAPTER 5: CLINICAL PROCEDURES ...................................................................................................... 33
5.1 Corneal Assessment and Slit Lamp Examination .............................................................................. 33
5.1.1 Recipient Corneal Stroma Clarity ............................................................................................... 33
5.1.2 Graft Rejection Assessment ........................................................................................................ 33
5.1.3 Graft Attachment Assessment ..................................................................................................... 33
5.2 Graft Failure Assessment ................................................................................................................... 33
5.3 Intraocular Pressure ........................................................................................................................... 34
5.4 Pachymetry ........................................................................................................................................ 34
5.5 Specular Microscopy ......................................................................................................................... 34
5.6 Grading of Retinopathy ..................................................................................................................... 34
5.7 Additional Procedures after initial DMEK Surgery .......................................................................... 35
5.8 Laboratory Testing ............................................................................................................................ 35
CHAPTER 6: UNANTICIPATED PROBLEMS AND ADVERSE EVENT REPORTING ..................................... 36
6.1 Unanticipated Problems ..................................................................................................................... 36
6.2 Adverse Events .................................................................................................................................. 36
6.2.1 Definitions ................................................................................................................................... 36
6.2.2 Reportable Adverse Events ......................................................................................................... 37
6.2.2.1 Events Requiring Expedited Reporting ............................................................................... 37
6.2.2.2 Other Adverse Events ......................................................................................................... 37
6.2.2.3 Clinical Site AE Reporting Flow Chart .............................................................................. 38
6.2.3 Relationship of Adverse Event to Study Procedure .................................................................... 38
6.2.4 Severity (Intensity) of Adverse Events ........................................................................................ 39
6.2.5 Expectedness ............................................................................................................................... 39
6.2.6 Coding of Adverse Events ........................................................................................................... 39
6.2.7 Outcome of Adverse Events ........................................................................................................ 39
6.3 Timing of Event Reporting ................................................................................................................ 40
6.4 Safety Oversight ................................................................................................................................ 40
CHAPTER 7: MISCELLANEOUS CONSIDERATIONS ................................................................................... 41
7.1 Pregnancy Reporting ......................................................................................................................... 41
7.2 Participant Compensation .................................................................................................................. 41
7.3 Participant Withdrawal ...................................................................................................................... 41
7.4 Confidentiality ................................................................................................................................... 41
CHAPTER 8: STATISTICAL CONSIDERATIONS .......................................................................................... 42
8.1 Statistical and Analytical Plans ......................................................................................................... 42

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8.2 Statistical Hypotheses ........................................................................................................................ 42
8.3 Sample Size ....................................................................................................................................... 42
8.4 Outcome Measures ............................................................................................................................ 43
8.4.1 Primary Efficacy Endpoint .......................................................................................................... 43
8.4.2 Secondary Endpoint..................................................................................................................... 44
8.5 Analysis Dataset and Sensitivity Analyses ........................................................................................ 44
8.6 Analysis of the Primary Efficacy Endpoint ....................................................................................... 44
8.7 Analysis of the Secondary Endpoint.................................................................................................. 44
8.8 Safety Analyses ................................................................................................................................. 45
8.9 Protocol Adherence and Retention .................................................................................................... 45
8.10 Baseline Descriptive Statistics ......................................................................................................... 45
8.11 Planned Interim Analyses ................................................................................................................ 45
8.12 Sub-Group Analyses ........................................................................................................................ 45
8.13 Multiple Comparison/Multiplicity ................................................................................................... 46
8.14 Analysis of the Tertiary Exploratory Endpoint ............................................................................... 46
8.15 Additional Tabulations and Analyses .............................................................................................. 46
8.15.1 Additional Tabulations .............................................................................................................. 46
8.15.2 Additional Analyses .................................................................................................................. 46
CHAPTER 9: DATA COLLECTION AND MONITORING .............................................................................. 47
9.1 Case Report Forms and Other Data Collection ................................................................................. 47
9.2 Study Records Retention ................................................................................................................... 47
9.3 Quality Assurance and Monitoring .................................................................................................... 47
9.4 Protocol Deviations ........................................................................................................................... 48
CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 49
10.1 Ethical Standard ............................................................................................................................... 49
10.2 Institutional Review Boards ............................................................................................................ 49
10.3 Informed Consent Process ............................................................................................................... 49
10.3.1 Consent Procedures and Documentation ................................................................................... 49
10.3.2 Participant and Data Confidentiality ......................................................................................... 49
10.3.3 Future Use of Images and Data ................................................................................................. 50
CHAPTER 11: REFERENCES ....................................................................................................................... 51
 
 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
Adverse Event 
AGEs 
Advanced glycation endproducts 
ARDL 
Advanced Research and Diagnostics Laboratory 
BMI 
Body Mass Index 
CC 
Coordinating Center 
CCTS 
Collaborative Corneal Transplantation Studies  
CDC 
Centers for Disease Control and Prevention 
CDS 
Cornea Donor Study 
CFR 
Code of Federal Regulations 
CIARC 
Cornea Image Analysis Reading Center 
CRF 
Case Report Form 
CRFA 
Cornea Research Foundation of America 
CPTS 
Cornea Preservation Time Study 
CWRU 
Case Western Reserve University 
DEKS 
Diabetes Endothelial Keratoplasty Study 
DMAC 
Data Management and Analysis Center 
DMEK 
Descemet membrane endothelial keratoplasty 
DRAI 
Donor Risk Assessment Interview 
DRCR.net 
Diabetic Retinopathy Clinical Research Network 
DSAEK 
Descemet stripping automated endothelial keratoplasty 
DSMC 
Data Safety and Monitoring Committee 
EBAA 
Eye Bank Association of America 
ECD 
Endothelial cell density 
ECL 
Endothelial cell loss 
EK 
Endothelial keratoplasty 
FDA 
Food and Drug Administration 
FECD 
Fuchs endothelial corneal dystrophy 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
Hg 
Mercury 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council for Harmonisation 
IOL 
Intraocular lens 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 

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ABBREVIATION 
DEFINITION 
JCHR 
Jaeb Center for Health Research 
LASIK 
Laser assisted in situ keratomileusis 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIGS 
Minimally invasive glaucoma surgery 
NIH 
National Institutes of Health 
OARRS 
Online Adverse Reaction Reporting System 
QA 
Quality assurance 
QC 
Quality control 
RBM 
Risk-based monitoring 
Rho-kinase 
Rho-associated protein kinase inhibitor or ROCK inhibitor 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
UHEI 
University Hospitals Eye Institute 
US 
United States 
VEGF 
Vascular endothelial growth factor 
YAG  
Yttrium aluminum garnet 
 

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Signature Page 
Diabetes Endothelial Keratoplasty Study (DEKS): 
Impact of Diabetes on Corneal Transplant Success and 
Endothelial Cell Loss 
Protocol Identifying Number: DEKS 
Version Number: v.1.2 
26 January 2023 
 
Protocol Chair 
 
Name, Institution 
Jonathan Lass, M.D. / CWRU, UHEI 
Signature/Date 
 
 
Protocol Co-Chair 
 
Name, Institution 
Marianne Price, Ph.D. / CRFA 
Signature/Date 
 
 
Coordinating Center Director 
 
Name, Institution 
Loretta Szczotka-Flynn, O.D., Ph.D. / CWRU 
Signature/Date 
 
 




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Data Management and Analysis 
Center Director 
 
Name, Institution 
Colleen Bauza, Ph.D./JCHR 
Signature/Date 
 
 
Medical Monitor 
 
Name, Institution 
Jonathan Lass, M.D. / CWRU, UHEI 
Signature/Date 
 
 



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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
Protocol Title: Diabetes Endothelial Keratoplasty Study: Impact of Diabetes on Corneal 
Transplant Success and Endothelial Cell Loss 
Protocol Version/Date: 1.2/January 26, 2023 
I have read the protocol specified above. In my formal capacity as a Site Principal Investigator, 
my duties include ensuring the safety of the study participants enrolled under my supervision 
and providing the DEKS Coordinating Center at Case Western Reserve University, which serves 
as the Coordinating Center for the protocol, and the Jaeb Center for Health Research which 
serves as the Data Management and Analysis Center, with complete and timely information, as 
outlined in the protocol. It is understood that all information pertaining to the study will be held 
strictly confidential and that this confidentiality requirement applies to all study staff at this site. 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as 
required by the following (use applicable regulations depending on study location and sponsor 
requirements; examples follow): United States (US) Code of Federal Regulations (CFR) 
applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 
312, and/or 21 CFR Part 812). 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol 
will take place knowingly without prior agreement from the sponsor and documented approval 
from the Institutional Review Board (IRB), or other approved Ethics Committee, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Participants Protection Training and GCP Training. Further, I agree to ensure 
that all staff members involved in the conduct of this study are informed about their obligations 
in meeting the above commitments. 
Investigator’s Signature __________________________________ Date: _____ / _____ / _____ 
 
dd 
mmm 
yyyy 
Investigator’s Name: ____________________________________ 
Site Name/Number: _____________________________________ 
 

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PROTOCOL SUMMARY 
Title 
Diabetes Endothelial Keratoplasty Study: Impact of Diabetes on Corneal Transplant Success 
and Endothelial Cell Loss (DEKS) 
Précis 
The association of diabetes in the cornea donor with transplant success and loss of 
endothelial cells one year following Descemet membrane endothelial keratoplasty (DMEK) 
will be evaluated in a double-masked multi-center trial in which study eyes will be assigned 
to receive either a cornea from a donor without diabetes or a cornea from a donor with 
diabetes. 
Objectives 
· 
To determine if the 1-year graft success rate following DMEK performed with corneas 
from donors without diabetes is superior to the graft success rate with cornea donors 
with diabetes. 
· 
To determine if the 1-year central endothelial cell loss (ECL) following DMEK 
performed with corneas from donors without diabetes is superior to the central ECL 
when corneas from donors with diabetes are used.  
· 
To explore the relationship of severity of diabetes in the donor, as measured by eye 
bank-determined diabetes risk categorization scores, post-mortem hemoglobin A1c 
(HbA1c), and skin advanced glycation endproducts (AGE) and oxidation markers, with 
1-year graft outcomes (i.e., graft success and ECL) following DMEK in corneas from 
donors with diabetes. 
Study Design 
Prospective, randomized, double-masked (participant and clinical site) clinical trial 
Number of Sites 
~30 clinical sites and ~16 eye banks in the United States 
Endpoint  
Primary Efficacy Outcome: Graft failure within 1 year of surgery 
Key Secondary Efficacy Outcomes: Change in central endothelial cell density (ECD) at 
1 year after surgery 
Key Safety Outcomes: Endophthalmitis, microbial keratitis (bacterial, fungal, parasitic) 
within 3 months of DMEK, and other unexpected ocular serious adverse events (SAEs). 
Other Key Analyses: Develop separate models for predicting 1) risk of graft failure and 
2) ECL based on severity of diabetes in the donor as measured by eye bank-determined 
diabetes risk categorization scores, post-mortem HbA1c, and skin advanced glycation 
endproducts (AGE) and oxidation markers. 
Population 
Participant Inclusion Criteria: 
1) 
Age range 30- < 91 years with minimum life expectancy of at least 1 year 
2) 
Willingness to return to study site for follow up at 1 month and 1 year 
3) 
Fluent in English or Spanish 
4) 
Willingness to have fingerstick blood sample collected to determine HbA1c level 
at entry and at 1 year. The participant must agree to have their primary care 
provider contacted (or an appropriate referral provided) if they were not known to 
have diabetes and the HbA1c suggests they may have diabetes. Similarly, if 
already known to have diabetes and the HbA1c is high, the participant must agree 
to have their primary care provider contacted or an appropriate referral provided.  
Study Eye Eligibility Criteria 
Inclusion: 
1. 
At least one eye clinically recommended for DMEK that is able to be scheduled 
for DMEK between 5 to 90 days after enrollment 
2. 
If second eye is enrolled, must be scheduled for DMEK between 7 days and 6 
months after DMEK on the first eye.  
3. 
Presence of a condition related to endothelial dysfunction which will be treated by 
DMEK 
· 
Eligible indications for DMEK include: 
a. 
Presence of Fuchs endothelial corneal dystrophy (FECD) meeting at 
least one of the following: 

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u 
Phakic FECD with or without cataract 
· 
Triple procedure including DMEK for FECD, cataract 
extraction and posterior chamber intraocular lens implantation 
(IOL) is allowed  
u 
Pseudophakic FECD with posterior capsule supported, sulcus 
supported, or scleral-fixated posterior chamber IOL 
b. 
Pseudophakic corneal edema with posterior capsule supported, sulcus 
supported, or scleral-fixated posterior chamber IOL without FECD 
c. 
Failed Descemet stripping automated endothelial keratoplasty (DSAEK) 
or DMEK originally performed for the same indications above without 
current exclusionary criteria, as described below 
Exclusion Criteria: 
1. 
Pregnant or planning to become pregnant prior to the DMEK study surgery, based 
on verbal report. 
2. 
Lack cognitive capacity such that consent could not be provided. 
3. 
Presence of a condition that has a high probability for failure (e.g., failed 
penetrating keratoplasty, uncontrolled uveitis) 
4. 
Stromal vascularization that will impede assessment of recipient stroma clarity 
5. 
Other primary endothelial dysfunction conditions including posterior 
polymorphous corneal dystrophy and congenital hereditary corneal dystrophy. 
6. 
Indication for surgery that is not suitable for DMEK (e.g, keratoconus, stromal 
dystrophies and scars) 
7. 
Aphakic corneal edema with or without FECD 
8. 
Anterior chamber IOL in study eye prior to DMEK or planned placement of 
anterior chamber IOL during DMEK 
9. 
Presence of vitreous in the anterior chamber 
10. Planned IOL exchange of an anterior chamber IOL with a posterior chamber IOL 
in study eye at time of study DMEK 
11. Pre-operative central sub-epithelial or stromal scarring that could impact post-
operative recipient stromal clarity assessment 
12. Presence of anterior synechiae 
13. Peripheral anterior synechiae in the angle greater than a total of three clock hours 
14. Uncontrolled glaucoma with or without prior filtering surgery, tube shunt 
placement, or MIGS. Uncontrolled glaucoma is defined as intraocular pressure 
> 25mm Hg. 
15. Controlled glaucoma with prior tube shunt placement for glaucoma 
(controlled glaucoma with MIGS or trabeculectomy is allowed) 
16. Fellow eye visual acuity < 20/200 due to an ocular condition other than a cornea 
disease that would be a candidate for DMEK 
17. IOP <8 mmHg 
18. Topical Rho kinase inhibitor, including Rhopressa, used within 1 month prior to 
study entry and anticipated during the course of the study 
19. Fellow eye enrolled in the DEKS that has met study-criteria for graft failure. 
Sample Size 
Up to 1420 completed surgeries (~947 donors without diabetes and ~473 donors with 
diabetes) with a goal of 1278 completing the 1-year follow-up 
Treatment Groups 
Study eyes will be assigned to receive either a cornea from a donor without diabetes or a 
cornea from a donor with diabetes. Assignment selection will use a minimization procedure 
which will prioritize assignments in a 2:1 distribution of tissue from donors without known 
diabetes to tissue from donors with known diabetes as determined by the eye bank. 
Participants with 2 study eyes cannot receive a cornea from a donor with known diabetes in 
both eyes. The minimization procedure will attempt to achieve balance on several factors, 
including the surgeon and whether the recipient had diabetes versus not. 
Participant Duration 
12 months follow-up after DMEK  

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Protocol Overview/Synopsis 
Each of the ~ 30 clinical sites is expected to recruit 40-50 cases over 30 months. Eligibility 
is assessed during a routine examination by an investigator; there are no examination 
procedures required to assess participant eligibility other than those that are part of standard 
patient care. Eye eligibility is determined at the time DMEK is scheduled, meaning that the 
eligibility of the second eye will be assessed at the time surgery on the second eye is being 
scheduled. Surgery on the second eye must be performed between 7 days and 6 months (182 
days) after DMEK on the first eye. DMEK will be performed according to the investigator's 
usual routine. Aspects of the surgical technique and procedure will be tracked, but not 
standardized. Data to be collected will include incision size, insertion method, air or gas 
usage, other procedures, operative complications, and other key operative details. 
Donor diabetes classification will be made initially at the time of tissue assignment. 
Historical records will be the principal method to determine diabetes status. In parallel, 
postmortem donor HbA1c will be collected and analyzed at the Advanced Research and 
Diagnostics Laboratory (ARDL) at the University of Minnesota. There may be a small 
percentage of donors classified by the eye bank as non-diabetic who will be reclassified as 
diabetic due to an elevated HbA1c. Therefore, the final classification of donor diabetes status 
for analysis will include: 1) Diabetic Donor = known diabetes history or postmortem HbA1c 
≥ 6.5% or 2) Non-Diabetic Donor= no known history and postmortem HbA1c < 6.5% (or 
HbA1c is missing or unanalyzable). 
Surgeons and participants will be masked to the donor parameters, except the FDA-approved 
hypothermic (2-8 degrees C) storage solution being employed. Postoperative management 
will be at the discretion of the surgeon based on his/her usual practices. Key aspects of 
pharmacologic management will be collected on the data forms. 
Study eyes of participants will be examined at a baseline/enrollment visit, at the time of the 
scheduled DMEK procedure, and at post-operative study visits at 1 month and 12 months 
after surgery in addition to post-op visits according to the investigators’ usual routine. At the 
1-month visit all significant events during this first postoperative period will be recorded 
(e.g. rebubbling, repositioning, elevation of IOP > 25 mmHg). At the 12-month visit, all 
significant events from one month to one year will be recorded (e.g. secondary procedures, 
graft rejection episodes, elevation of IOP > 25 mmHg). Procedures at each visit will follow 
the surgeon’s standard of care including dilated fundus examinations to check and grade 
diabetic retinopathy (at baseline and 12 months), pachymetry (at 1 month and 12 months), 
and standardized measurements of recipient stroma clarity. Central endothelial cell imaging 
will be obtained at 1 month and 12 months. 
All participants, known diabetic and nondiabetic, will undergo a determination of diabetes 
status by having a fingerstick blood sample collection at baseline and at 12 months, with 
specimens sent to the ARDL of the University of Minnesota for HbA1c analysis. At baseline 
and the 12-month visit, a medical and ocular history will be obtained to track potential 
micro- and macrovascular complications related to diabetes. 
 

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SCHEMATIC OF STUDY DESIGN 
 
 
Notes: HbA1c assessment at baseline may be obtained between enrollment and 1 month visits 
(inclusive); a minimization procedure is used for ‘randomization’.

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SCHEDULE OF STUDY VISITS AND PROCEDURES 
Table 1. Schedule of Study Visits and Procedures 
 
Visit (V) 
 
V 
V 
V 
Comment 
 
Screen/Enroll 
 
 
Eligibility Assessment 
SC 
X 
 
 
Medication History  
SC 
X 
X1 
X2 
Slit lamp examination 
SC 
X 
X 
X 
FECD grading 
SC 
X 
 
 
Assessment of other corneal 
dystrophies 
SC 
X 
 
 
Recipient corneal stroma 
clarity 
SC 
 
X1 
X2 
Evidence of graft rejection 
SC 
 
X1 
X2 
Presence of corneal vessels 
SC 
X 
 
 
Presence of corneal opacities 
SC 
X 
 
 
Donor positioning1 
SC 
 
X1 
 
Graft attachment 
SC 
 
X1 
 
Graft failure assessment3 
SC 
 
X1 
X2 
Intraocular pressure1,2 
SC 
X 
X1 
X2 
Pachymetry 
SC 
 
X 
X 
Endothelial imaging 
R 
 
X 
X 
HbA1c sample collection 
(sent to central lab) 
R 
X4 
 
X 
Record additional procedures 
after initial DMEK  
SC 
 
X1 
X2 
Grading of diabetic retinopathy 
SC 
X 
 
X 
Review post-op complications 
and other untoward events 
SC 
 
X1 
X2 
1Record findings from surgery to 1-month visit 
2Record findings from 1-month visit to 12-month visit 
3Additionally submit graft failure form any time graft failure definition has been met 
4Sample collection can span up to 1-month visit 
 
 

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Chapter 1: Background Information 
1.1 Introduction and Rationale 
Based on the increase in diabetes in the United States (US) over the past decade,1,2 there has 
been a comparable increase in the percentage of corneas from donors with diabetes that meet 
the Eye Bank Association of America (EBAA) guidelines suitable for corneal transplantation. 
The EBAA, however, does not specifically report this at the national level. 18% of the donors 
in the Cornea Donor Study (CDS) obtained between 2000 and 2002 were diabetic.3 Data from 
Midwire from 2016 and 2017 (total of 16,139 donor eyes) (Michael Titus, personal 
communication) showed that 27% of their transplanted tissue was from donors with diabetes, 
while Lions VisionGift (Ryan Williams, personal communication) was 34% of 4,260 donors 
during this same period, a 67% increase in the percentage of donors with diabetes used for 
transplantation over the past 15 years compared to the CDS data. And this in fact may be an 
underreporting of donors with diabetes, since many eye banks still have no specific field for 
the history for diabetes and data is retrieved from a write-in field, along with the problem of 
undiagnosed diabetes in the population which is reported as high as 21% (7.3 million) of the 
US population by the CDC in 2020.4 The type of diabetes, duration, and treatment is also not 
captured. In the Cornea Preservation Time Study (CPTS) with data from 2012-14, a similar 18% 
of the donors as in the CDS were classified as diabetic.5 Since then some eye banks in the CPTS 
with a more rigorous effort now track the presence of diabetes in the donor. Like the recent 
Eversight and Lions VisionGift data, they report on a monthly basis that their diabetic donors 
determined historically run as high as 40%. Thus, the epidemic continues unabated. 
The literature has noted that the diabetic endothelium shows functional and morphometric 
differences as well as cell damage compared to non-diabetic endothelium that could compromise 
short term and long-term success of the keratoplasty.6-26 Thus, some consider the use of donor 
corneas from individuals with diabetes to decrease graft success and endothelial cell density 
(ECD) following keratoplasty and the acceptance of these donors, when offered by the eye bank, 
has been at the discretion of the surgeon. 
Additionally, the general consensus within internal medicine and endocrinology is that there may 
be increased rates and types of infections in patients with diabetes. However, the literature is not 
as firm. A recent case series reported risk for Corynebacterium-related ocular infections in 
patients with poor immunity including those with diabetes.27 The association of diabetes with the 
rare and devastating rhino-orbito-cerebral involvement with mucormycosis is well known.28 
In case-control studies, patients with diabetes are 1.3-9.4 fold more likely than controls to 
develop microbial keratitis,29,30 and type II diabetes mellitus has been significantly associated 
with chronic endophthalmitis following cataract surgery.31 There is also good evidence that 
diabetes predisposes hosts to infection, especially (of relevance to the eye) in wounds, skin and 
mucous membranes.32 Innate immunity may be altered in diabetes32; if the remaining immune 
cells in the donor tissue remain active once transplanted, their compromised immunity may 
predispose recipients to infection. Therefore, there is scientific rationale to suspect that diabetes 
in the donor and/or recipient may increase the risk of ocular infection after keratoplasty 
procedures although there is no evidence of such in the corneal transplant literature. 

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The CDS, the largest prospective study examining the effect of donor age on graft success and 
cell loss following penetrating keratoplasty for endothelial dysfunction conditions, did track the 
presence of diabetes in both the donor and recipient with limited historical information, and did 
not find an effect on either graft success or cell loss compared to donors without diabetes.3 
One major limitation of this study was that the presence of diabetes in donors was defined 
simply by presence or absence of diabetes. Vislisel et al for Descemet stripping endothelial 
keratoplasty (DSAEK) donors33 and Price et al for Descemet membrane endothelial keratoplasty 
(DMEK) donors34 found a similar lack of donor diabetes effect on graft failure, while both series 
had similar limitations on donor diabetes determination by historical grounds only. However, our 
group now has suggestive data on the negative impact of donor diabetes on endothelial 
keratoplasty (EK) outcomes from a secondary analysis of a large prospective multi-center 
clinical trial, the CPTS. In the CPTS, corneal tissue from donors with diabetes had a significantly 
greater risk of primary or early graft failure,35 greater long term endothelial cell loss (ECL),36 
and increased risk of graft dislocation37 following EK compared to corneas from donors without 
diabetes. 
Since about 1/3 of the nationwide donor pool now includes tissue from donors with diabetes, and 
there are now conflicting results among studies that were not designed to assess the question of 
diabetic donor status directly, our group is interested in determining whether corneal tissue from 
donors without diabetes is indeed superior for EK outcomes, and if severity of donor diabetes 
correlates with graft success using novel biomarkers of glycemic burden. Finally, the most recent 
Online Adverse Reaction Reporting System (OARRS) data from the EBAA reported at the 
Medical Advisory Board meeting in November 2020 showed an unexplained increasing rate of 
primary and early failures associated with DMEK. The EBAA will be looking at increasing use 
of pre-loaded lenticules as one source of the issue, but admittedly there is an underreporting issue 
from surgeons and thus there is no comprehensive database of all the factors that could be 
contributing to this increasing rate of DMEK primary and early failures. 
Building upon the strengths of the successfully completed CPTS structure,5 the Diabetes 
Endothelial Keratoplasty Study (DEKS) will address these concerns through a prospective, 
masked, multi-center clinical trial in which the donor corneas are assigned by diabetes status 
in the same distribution pattern (2:1 distribution of tissue from donors without diabetes to tissue 
from donors with diabetes) as is recognized nationally. The DEKS will assess graft success 
and ECD through 1 year following DMEK to determine whether the surgical success rate with 
corneas from donors with well characterized diabetes (including post-mortem hemoglobin A1c 
(HbA1c)38 and advanced glycation endproducts (AGE) testing)39-42 is truly inferior to the rate 
with donors without diabetes. We hypothesize that the majority of donor corneas from 
individuals with diabetes will be suitable, but that a portion of donors with a higher diabetes 
severity scale,43 and/or poorer control based on HbA1c will have a greater risk for graft failure 
and ECL. We will also examine from collected skin biopsies whether high levels of AGE 
biomarkers in donor skin tissue – which quantifies disease severity over many years39-42 (and 
possibly coupled with elevated HbA1c levels) - will be associated with greater risk for graft 
failure and cell loss. This novel approach to characterization of donor tissue can provide a 
paradigm shift in the risk assessment of transplanted corneas from diabetic donors. The effect of 
recipient diabetes on keratoplasty success and cell loss will also be studied in a rigorous manner 
to determine the potential combined effect of donor and recipient diabetes status. 

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In summary, this study is designed to determine if non-diabetic donor corneas are superior to 
diabetic donor corneas in terms of both graft success and ECD outcomes, with an additional 
specific aim to determine whether donors with a higher diabetes severity scale,43 and/or poorer 
control based on HbA1c are driving the effect. We will also determine whether a high AGE/A1c 
metric is also associated with the potential superiority finding and establish a novel composite 
score (severity score, HbA1c and AGE/A1c) based on these metrics that can be used to identify 
high versus low risk diabetic donors. This distinction may enable eye banks to potentially utilize 
the majority of donors with diabetes for EK surgery, while excluding the severely affected 
donors with diabetes. 
With the growth of DMEK in the past 5 years,44 including at our proposed clinical 
sites/surgeons, DMEK will be the only EK procedure to be utilized to test the study’s diabetes 
question and its impact on the transplanted endothelium. Additionally, with the concerning rise 
in DMEK primary and early failures nationally reported in November 2020 from the EBAA 
OARRS data, the need for the DEKS is even greater. As the CPTS utilized DSAEK only as its 
procedure to test the impact of preservation time on graft success and cell loss which streamlined 
the analyses, having one procedure, DMEK, for the DEKS will similarly assist in the analyses of 
best practices surrounding DMEK. 
The DEKS could have a major impact on the targeted use of corneas from diabetic donors 
whose tissues are more and more widely utilized for keratoplasty purpose in the US today. Use 
of biomarkers of disease severity new to the corneal transplant and eye banking field could lead 
to the development of novel technologies for rapid assessment of glycemic burden and tissue 
damage in diabetic donors. Finally, the DEKS may be able to sort out other donor, recipient, 
operative and postoperative factors that impact DMEK outcomes, including primary and early 
failures. 
1.2 Potential Risks and Benefits 
1.2.1 Known Potential Risks 
1.2.1.1 Known Potential Risks of DMEK 
The risks and discomforts for patients undergoing DMEK are the same regardless of study 
participation. Potential risks of DMEK include: 
· mild pain for approximately one week after surgery 
· temporary discomfort from the eye examination or eye drops, which may include 
stinging, itching, or redness 
· serious infection or bleeding in 1 in 1,000 patients and serious problems related to 
anesthesia in 1 in 10,000 
· in rare instances topical drops used during standard of care exams can cause an allergic 
reaction, seizures, and an irregular heartbeat 
· development of a rapid rise in the eye pressure 
· development of glaucoma 

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· additional surgery required due to healing problems or movement out of position of the 
donor cornea 
· retinal swelling or detachment 
· loss of vision 
· rejection reactions occur approximately in about 2-3% of eyes within 5 years of 
surgery,45 but are usually reversible if treated promptly with topical corticosteroids, 
but sometimes it leads to failure of the transplant 
· endophthalmitis: a serious intraocular infection that requires prompt treatment and 
may cause permanent loss of vision or in severe circumstances loss of the eye 
· corneal infection: a serious microbial infection of the cornea that requires immediate 
treatment and may result in permanent scarring and possible permanent loss of vision 
requiring a repeat of the corneal transplant 
· rare chance of dissemination of a communicable disease from the donor tissue 
· corneal scarring: permanent haze or cloudiness in the cornea that may result in 
permanent loss of vision and/or requiring a repeat of the corneal transplant 
· corneal neovascularization: blood vessel growth into the cornea that could subject the 
transplant to a higher risk for rejection and/or permanent loss of vision, requiring a repeat 
of the corneal transplant 
· corneal swelling: thickening of the cornea that may result in loss of vision which may or 
may not be reversible. If not reversible, another corneal transplant may be required to 
restore the vision 
· wrinkling of the corneal layers: wrinkling of the donor cornea as it heals may result in 
blurred vision and require another corneal transplant 
1.2.1.2 Known Potential Risks of Study Participation 
The following are risks of procedures that are not necessarily part of routine care but are being 
performed for the purposes of this study: 
· Fingerstick blood collection: Transient mild discomfort common. In about 1 in 10 times a 
small amount of bleeding under the skin will produce a bruise. A small scar may persist 
for several weeks. The risk of an infection is less than 1 in 1000. 
· Subjects will be informed of their HbA1C results. Some who have not been previously 
diagnosed with diabetes might be uncomfortable to learn that their HbA1C level suggests 
that they may have diabetes. Similarly, those that already know they have diabetes might 
be uncomfortable to learn that their HbA1C level suggests their diabetes is not under 
good control. 
· There are no known risks to the imaging procedures. 

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1.2.2 Known Potential Benefits 
Study participants may not benefit directly from participation in this study. If the study identifies 
certain donor corneas as being associated with worse outcomes, eye banking practice could 
formally change to discourage use of potentially inferior tissue. In the future, if a study 
participant requires another DMEK in either the same eye or their other eye, the information 
obtained from this study might benefit them. 
1.2.3 Risk Assessment 
The risks for events noted in Section 1.2.1.1 are no greater when participating in the study 
compared with standard care. The likelihood of receiving a cornea from a donor with diabetes in 
this study will be the same or less compared to the manner in which corneal tissue is distributed 
nationally (see section 1:1).  Other than the study procedures of allocation and distribution of 
donor tissue in a masked manner, finger stick blood collection and non-contact corneal 
photographs, the study procedures include collection of data from standard of care office visits, 
surgical techniques and post-operative care and evaluations. 
1.3 General Considerations 
The study is being conducted in compliance with the policies described in the study policies 
document, with the ethical principles that have their origin in the Declaration of Helsinki, 
with the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
When feasible, data will be directly collected in electronic case report forms, which will be 
considered the source data. 
 

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Chapter 2: Study Enrollment and Participant Screening 
2.1 Participant Recruitment and Enrollment 
Note: throughout this document the term randomization may be used in reference to the study’s 
assignment of donor tissue. However, the process is actually a minimization procedure as 
explained in Section 3.2.2 rather than traditional randomization; nonetheless for simplicity we 
retain the term randomization for descriptive purposes.  
The goal is to randomize 1420 study eyes with at least 1278 study eyes followed with complete 
outcome assessments. Participants who have signed consent and started the screening process 
may be permitted to continue into the trial, if eligible, even if the randomization goal has been 
reached. Up to 2000 individuals may be enrolled (i.e., sign informed consent) to enable 
randomization of the 1420 study eyes.  
Study participants will be enrolled at ~30 clinical centers in the US. All eligible participants will 
be included without regard to gender, race, or ethnicity. There is a restriction of a maximum of 
20% of the number of eyes (284 eyes) to be randomized by a single surgeon toward the overall 
recruitment goal. 
2.1.1 Informed Consent and Authorization Procedures 
Potential eligibility may be assessed as part of a routine-care examination. Before completing 
any procedures or collecting any data that are not part of usual care, informed consent will be 
obtained. The informed consent process is described in Section 10.3. 
The study will be discussed with the potential study participant by study staff. If the potential 
participant lacks the capacity to consent, then they should not be approached to consent for the 
study. The sites’ policies and procedures shall be followed to determine capacity, and in general, 
if the person was able to consent for the transplant themselves, then they can consent for the 
study themselves. If they require a legally authorized representative to consent to the transplant 
on their behalf, then they should not be approached to participate in the study.  
The potential study participant will be provided with the Informed Consent Form to read in a 
language understandable to the participant (in English or Spanish as applicable) and will be 
given the opportunity to ask questions. Potential study participants will be encouraged to discuss 
the study with family members and their personal physicians(s) before deciding whether to 
participate in the study. If the potential study participant is interested in the study, the paper 
Informed Consent Form will be signed by both the participant and an authorized study designee.  
The subject will be given a signed copy by the study team for their records. 
As part of the informed consent process, each participant will be asked to sign an authorization 
for release of personal information, which may be within the consent form or a separate form. 
The investigator, or his or her designee, will review with the potential participant the study-
specific information that will be collected and to whom that information will be disclosed. After 
speaking with the participant, questions will be answered about the details regarding 
authorization. 
A participant is considered enrolled when the informed consent form has been fully executed and 
HIPAA authorization has been provided. 

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2.2 Participant Inclusion Criteria 
Individuals must meet all of the following participant-level inclusion criteria and have at least 
one eye meeting the study eye inclusion criteria in order to be eligible to participate in the study. 
2.2.1 Study Participant-level Criteria 
1. Age range 30-<91 years with minimum life expectancy of at least 1 year. 
2. Willingness to return to study site for follow up at 1 month and 1 year. 
3. Fluent in English or Spanish. 
4. Willingness to have fingerstick blood sample collected to determine HbA1c level at 
entry and 1 year.  
a. The participant must agree to have their primary care provider contacted (or an 
appropriate referral provided) if they were not known to have diabetes and the 
HbA1c suggests they may have diabetes. Similarly, if already known to have 
diabetes and the HbA1c is high, the participant must agree to have their primary 
care provider contacted or an appropriate referral provided. 
2.2.2 Study Eye Criteria 
1. At least one eye clinically recommended for DMEK that is able to be scheduled for 
DMEK between 5 and 90 days after enrollment. 
 
2. If second eye is enrolled, must be scheduled for DMEK between 7 days and 6 months 
after DMEK on the first eye.  
 
3. Presence of a condition related to endothelial dysfunction which will be treated by 
DMEK. 
Eligible indications for DMEK include: 
a. Presence of FECD meeting at least one of the following: 
i. 
Phakic FECD with or without cataract 
1. Triple procedure including DMEK for FECD, cataract extraction and 
posterior chamber intraocular lens implantation (IOL) is allowed 
ii. 
Pseudophakic FECD with posterior capsule supported, sulcus supported, 
or scleral-fixated posterior chamber IOL 
b. Pseudophakic corneal edema with posterior capsule supported, sulcus supported, 
or scleral-fixated posterior chamber IOL without FECD 
c. Failed DSAEK or DMEK originally performed for the same indications above 
without current exclusion criteria below, as described below. 
NOTES: 
· Stromal vascularization is acceptable, as long as not visually significant (by 
investigator’s judgement) 

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· Penetrating keratoplasty and DSAEK will not be included procedures; only DMEK 
2.3 Participant Exclusion Criteria 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from 
study participation. 
1. Pregnant or planning to become pregnant prior to the DMEK study surgery, based on 
verbal report.  
2. Lack cognitive capacity such that consent could not be provided. Such individuals are 
excluded because they are at greater risk for post-operative complications if they do not 
follow proper instructions (use of drops, ocular protection, physical positioning) and 
therefore can confound study outcomes.   
3. Presence of a condition that has a high probability for failure (e.g., failed penetrating 
keratoplasty, uncontrolled uveitis) 
4. Stromal vascularization that will impede assessment of recipient stroma clarity 
5. Other primary endothelial dysfunction conditions including posterior polymorphous 
corneal dystrophy and congenital hereditary corneal dystrophy 
6. Indication for surgery that is not suitable for DMEK (e.g, keratoconus, stromal 
dystrophies and scars) 
7. Aphakic corneal edema with or without FECD  
8. Anterior chamber IOL in study eye prior to DMEK or planned placement of anterior 
chamber IOL during DMEK 
9. Presence of vitreous in the anterior chamber   
10. Planned IOL exchange of an anterior chamber IOL with a posterior chamber IOL in 
study eye at time of study DMEK 
11. Pre-operative central sub-epithelial or stromal scarring that could impact post-operative 
recipient stromal clarity assessment 
12. Presence of anterior synechiae  
13. Peripheral anterior synechiae in the angle greater than a total of three clock hours  
14. Uncontrolled glaucoma with or without prior filtering surgery, tube shunt placement, 
or MIGS. Uncontrolled glaucoma is defined as intraocular pressure > 25mm Hg. 
15. Controlled glaucoma with prior tube shunt placement for glaucoma (controlled glaucoma 
with MIGS or trabeculectomy is allowed) 
16. Fellow eye visual acuity < 20/200 due to an ocular condition other than cornea disease 
that would be a candidate for DMEK 
17. IOP <8 mmHg 
18. Topical Rho kinase inhibitor, including Rhopressa, used within 1 month prior to study 
entry and anticipated during the course of the study 
19. Fellow eye enrolled in the DEKS that has met study criteria for graft failure. 

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Study eye eligibility is determined at the time DMEK surgery is scheduled. A participant 
can contribute two study eyes if both eyes are eligible. The eligibility of the second eye, 
if applicable, will be assessed at the time surgery on the second eye is scheduled; second eye 
surgery as part of the study can be performed between 7 days and 6 months (182 days) after 
DMEK on the first eye. If participant agrees to second eye study participation, he/she will not 
receive a cornea from a donor with known diabetes in both study eyes.  Specifically, if the first 
eye received a cornea from a donor with known diabetes, after thorough medical record review 
as part of standard eye banking practices (see Section 3.2.2), the second eye will receive a cornea 
from a donor without known diabetes. (Study surgery could thus potentially be cancelled if a 
donor cornea without known diabetes is not available). If the first eye received a cornea from a 
donor without known diabetes, the second eye will proceed through the minimization algorithm 
for assignment of donor tissue. Note, because of the reclassification process based on HbA1c 
testing at the central laboratory, this means that donors not known to have diabetes after 
thorough eye bank staff medical record review, may still have diabetes that was not known at the 
time of the keratoplasty procedure. This testing is not standard practice and could delay 
proceeding with the keratoplasty if the cornea could not be placed until the result (HbA1c value 
< or >= 6.5%) was returned. Therefore, there is a possibility that a participant who agreed to both 
eyes participating in the study can in both eyes receive a cornea from a donor classified as 
having diabetes based upon post-mortem study-specific HbA1c laboratory values (>=6.5%) that 
are not acquired in standard practice.  
2.4 Screening/Pre-operative Procedures 
After informed consent has been signed, a potential participant will be evaluated for study 
eligibility through the elicitation of a medical history and a routine examination including 
a dilated eye examination. There are no examination procedures required to assess patient 
eligibility other than those that are part of standard patient care. Historical data (which may 
predate the date of informed consent) may be obtained from the medical record after informed 
consent has been signed to acquire baseline data described below.  
2.4.1 Data Collection and Testing 
The following procedures/data will be performed/documented for each study eye, unless 
otherwise specified: 
· Inclusion and exclusion criteria assessed 
· Demographics (date of birth, sex, race and ethnicity) 
· Contact information (site enters into limited access study database) 
· Medical history (including history and complications of diabetes, last HbA1c, and any 
ocular treatments for diabetes) 
· Current diabetic and selected systemic and topical ocular medications 
· Slit lamp examination (including FECD grading, assessment of other corneal dystrophies, 
presence of corneal vessels, presence of corneal opacities, anterior synechiae and lens 
status) 
· Intraocular pressure 

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· Dilated fundus exam for grading of diabetic retinopathy 
Once participant eligibility has been confirmed and informed consent has been obtained, a 
fingerstick blood sample will be collected for HbA1c determination prior to or within about 1 
month of surgery. A fingerstick blood sample for HbA1c determination will be collected at the 
12-month follow-up visit as well to monitor diabetes control and also to detect new diabetes in 
the original non-diabetic group. 
Screening procedures will last approximately 1 hour. 
· Those participants that were unaware they had diabetes will be reclassified as diabetic for 
study purposes based on this measurement. See Clinical Site Manual of Procedures for 
details regarding dissemination of participant HbA1c results.   
2.5 Screen Failures 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
date per investigator discretion. 
 

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Chapter 3: Donor Eligibility and Cornea Assignment, Eye Banks 
3.1 Eye Bank Procedures 
Eye bank procedures will mimic standard procedures as closely as possible to minimize 
disruption to their normal routine, with the exception of procedures related to donor assignment 
including classification of donor diabetes status and specular microscopy (including calibration, 
technician certification, and procedure for obtaining specular images). Eye banks will be able to 
use any FDA-approved hypothermic (2-8oC) storage solution for intermediate term storage. 
3.2 Donor Information, Procurement of Tissue and Other Samples 
1. Donor information will be obtained by the eye bank’s usual routine. 
The eye banks must have authorization for research use in order to obtain a blood 
sample and skin tissue biopsy for the study. The eye banks may need to add a statement to 
their usual authorization forms referencing the DEKS to assure that they have proper 
authorization to take blood and skin biopsy samples for the purpose of the study. The 
Coordinating Center (CC) will work with each eye bank and provide templates for 
authorization for research. 
2. Eye banks will follow their usual routine for procurement of tissue. 
In addition to the usual cornea tissue procurement, the eye banks will also need to 
draw/obtain a whole blood sample from the potential donor for cadaveric HbA1c testing. 
If there is proper authorization for skin biopsies referred to above, the eye bank should 
also obtain a skin tissue sample for AGE testing at the time of recovery. See specific 
DEKS Eye Bank Procedures Manual, Advanced Research and Diagnostics Laboratory 
(ARDL)) Eye Bank Central Laboratory Manual of Procedures, and the AGE Testing 
Program and Procedure Manual for details. 
3.2.1 Donor Cornea Tissue Suitability 
1. All eye banks will follow their procedural routine for procurement of cornea tissue and 
determination of suitability for DMEK in accordance with the Medical Standards 
and Procedure Manual of the EBAA. This includes standard serologic testing, 
specular microscopy, and slit lamp examination. 
2. The following eligibility criteria will apply to all donor cornea tissue assigned to study 
eyes. 
· Must meet current EBAA standards for human corneal transplantation 
· Age of donor at time of death 50–75 years 
· If the donor body was refrigerated or eyes on ice within 12 hours of death, the body 
or eye may stay refrigerated up to 24 hrs; if no refrigeration then the death to 
preservation time should be <12 hrs 
· Preservation time ≤ 11 days 
· Eye bank determined minimum ECD (at screening) of ≥ 2300 cells/mm2 
· Pleomorphism/Polymegethism: At eye bank and medical director discretion 

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· Guttae: no true guttae present 
· No evidence of central endothelial cell damage/trauma or dystrophy, such as FECD, 
by slit lamp examination 
3.2.2 Determining Diabetic Status 
Eye Banks should review various data collection documents and consult with treating physicians 
to help collect information to confirm diabetes status. If there are conflicting data found within 
the various data collection documents, continue to request additional primary care records, 
consults, and other sources of electronic health records as available. Examples include, as 
available: 
· DRAI – Donor Risk Assessment Interview46 – the current uniform DRAI for tissue 
banks has the following question: Did he/she EVER have diabetes?  If yes a) for 
how many years? b) Was it treated? If yes How? The eye banks should add this 
question to the “eye only” DRAI to obtain diabetes information in addition to medical 
information. Eye Banks should also obtain the name of the treating physician in order 
to perform a follow up consult.  
· Hospital medical record 
· Physician consults  
· Primary Care/Internist Medical Records 
Defining Diabetic Status 
For the purpose of tissue assignment for the minimization procedure, the eye bank will define the 
donor as having diabetes using ICD-10 codes and medical records with respect to diagnoses and 
treatments.  Refer to the Eye Bank Manual of Procedures for detailed definitions.  
Only donors definitely diabetic or definitely not diabetic by above approach will be eligible for 
the study. Those indeterminant may be used for keratoplasty, but not eligible for the study. 
Diabetes Risk Categorization 
Once diabetes status determination is complete, if found to have diabetes, additional information 
will be obtained to determine diabetes risk categorization on a 1 to 5 scale. 
Specifically, the following aspects will be determined to calculate the diabetes risk 
categorization score: 
· Any history of diabetes mellitus [1 point] 
· Body mass index > 30kg/m2 [1 point] 
· Hypertension [1 point] 
Additionally, 2 points are added to the score for any of the following, regardless of how 
many are chosen: 
· Diabetes mellitus history of at least 10 years 
· Insulin dependent outpatient 

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· Possible comorbidities 
o peripheral nerve damage/neuropathy 
o renal failure and/or dialysis, chronic kidney disease 
o stroke 
o myocardial infarction 
o leg ulcers or amputations 
o peripheral vascular disease 
o diabetic retinopathy with proliferative disease including vitreous hemorrhage 
o diabetic retinopathy with history of retinal laser  
o diabetic retinopathy with history of vitrectomy  
o diabetic retinopathy with history of intravitreal anti-VEGF therapy 
 
Once diabetes status and severity are determined a computer program will be able to run a 
minimization procedure to select a donor cornea for a given participant DMEK surgery. For the 
first eye of each participant, if only one donor cornea is available, then this cornea is selected. 
Otherwise, if all available donor corneas are the same donor diabetes classification, then a cornea 
is randomly selected from all available. Otherwise, if at least one donor cornea is from each 
donor diabetes classification, a minimization procedure will select based on achieving balance on 
several factors, including the surgeon, and the donor diabetes risk categorization score. 
For participants with two study eyes, if the first eye received a cornea from a known diabetic 
donor, then the second eye will receive a cornea from a donor the eye bank determined as non-
diabetic, if available. If a cornea from a donor the eye bank determined as non-diabetic is not 
available, then surgery must be postponed or performed outside of the study. If the first eye 
received a cornea from a donor the eye bank determined as non-diabetic, then the minimization 
procedure will run and the second eye could receive a cornea from a known diabetic or 
nondiabetic donor.  
The most important aspect of the protocol for the eye banks is maintaining masking of the 
surgeon and surgeon staff from any direct or indirect knowledge of the diabetic status of the 
donor tissue assigned to study participants. 
The surgeon will be masked to all other donor parameters except storage solution. NO eye 
bank’s standard reports and labels (including donor tissue report, donor cornea container label, 
recipient information form, package insert form and adverse reaction report) can be sent to the 
surgeon. Study-specific documentation will be used in lieu of these reports. See the Eye Bank 
Manual of Procedures for a summary of the EBAA waivers and other references, and examples 
of the DEKS Donor Tissue Label, DEKS Donor Tissue Report, DEKS Adverse Reaction Report, 
and DEKS Shipping Label. 

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3.2.3 Eye Bank Procedures for Study Images 
Detailed procedures for study images will be provided in the DEKS-Cornea Image Analysis 
Center (CIARC) Eye Bank Imaging Manual. In screening images for eye bank prepared DMEK 
tissue, a minimum of central ECD of ≥ 2300 cells/mm2 determined by the eye bank at screening 
will be required along with fulfilling all medical director determined criteria for quality post 
prep, including assessment of cell damage within the anticipated donor diameter. 
3.2.4 DMEK Lenticule Preparation 
Detailed procedures are found in the DEKS Eye Bank Procedures Manual. Each DEKS eye 
bank will perform their DMEK lenticule preparation following their usual technique while 
documenting technique, and observations as to any problems during the stripping. Most 
importantly, each eye bank will ensure that the technician performing the prep will be masked 
as to the diabetes status of the donor. 
For both the eye bank- and surgeon- prepared DMEK preps, the extent of endothelial cell 
damage post prep utilizing trypan blue will be assessed by the masked technician (or surgeon). 
The masked technician (or surgeon) will also perform an assessment of scroll tightness modified 
from earlier description whenever possible48. Whether eye-bank or surgeon-prepared, the 
preferred time from DMEK donor preparation to surgery will be at the discretion of the surgeon, 
but tracked. Also, if corneal tissue is pre-loaded by the eye bank, the eye bank will follow its 
normal loading procedure according to their standard operating procedures. The loading system 
will be recorded (i.e., injector, storage container) and the preferred time from loading to surgery 
will be at the discretion of the surgeon and tracked. 
 
3.3 Laboratory Testing 
1. HbA1c 
· De-identified whole blood samples will be sent to the central laboratory (ADRL at 
the University of Minnesota) for sample analysis.53 
· De-identified skin biopsy samples for AGE testing will be sent to Dr. Vincent 
Monnier’s laboratory at CWRU for sample analysis.  
 

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Chapter 4: Transplantation and Follow-up Procedures 
at Clinical Sites 
4.1 DMEK Procedure 
DMEK will be performed according to the investigator’s usual routine. Aspects of the surgical 
technique and procedure will be tracked, but not standardized. Data to be collected will include 
but are not limited to incision size, insertion method, air or gas usage, other procedures (e.g. 
cataract surgery), and operative complications (e.g., difficult donor preparation, difficult 
placement). 
The surgeon will be masked to donor parameters (e.g. donor age, donor ECD), except the FDA-
approved hypothermic (2-8oC) storage solution being employed. 
4.2 Post-Operative Management 
Postoperative management will be at the discretion of the surgeon based on his/her usual 
practices. Key aspects of pharmacologic management (e.g. topical corticosteroid usage, 
glaucoma medications) will be collected on the data forms. 
4.3 Study Visits 
Protocol-specified post-operative follow-up visits (and visit windows) for the first eye, 
established to conform to the usual practice and timed from surgery date, will be scheduled as 
outlined in Section 4.3.1 below. 
4.3.1 Study Visits and Windows 
Protocol-specified post-operative follow-up visits (and visit windows) for the first eye, 
established to conform to the usual practice and timed from surgery date, will be scheduled 
as outlined as below. 
Table 2. Study Visits and Windows 
1 Month (Day 30) 
+/- 10 days 
*note an out of window but not missed visit will be allowed up to 100 days 
and baseline HbA1c assessment is allowable within this time period as well   
12 Months (Day 364)  
-30 / +100 days 
Additional contacts or visits may occur as needed. Additional visits are expected to be performed 
per standard of care at the discretion of the investigator. A data form will be completed for each 
protocol visit (1 month and 12 months) capturing data from that visit plus selected data from the 
medical record from prior standard of care visits. If graft failure is determined and/or a regraft is 
required on a non-protocol visit, a graft failure form should be completed if and when this 
occurs. 

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4.3.2 Procedures at Study Follow-up Visits 
The following data will be collected and procedures will be performed at each protocol-specified 
post-operative follow-up visit, unless otherwise specified: 
· Medication history 
· Slit lamp examination: 
¿ 
Recipient corneal stroma clarity  
¿ 
Evidence of graft rejection 
¿ 
Donor positioning (1 month) 
¿ 
Graft attachment (1 month) 
¿ 
Other abnormalities of interest 
· Graft failure assessment 
· Intraocular pressure 
· Pachymetry 
· Endothelial imaging 
· HbA1c sample collection (may be performed up to 1 month visit after surgery for 
baseline measurement and then at 1 year) 
· Record additional procedures after initial DMEK surgery 
· Grading of diabetic retinopathy (1 year)  
· Post-operative complications and other untoward events 
4.4 Early Termination Visit 
Participants will be asked to come for an end of study visit in the event of withdrawal or early 
termination for another reason. If graft failure occurs in the absence of re-graft, follow-up is 
not terminated prematurely. However, if the graft is replaced, follow-up will be discontinued. 
 

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Chapter 5: Clinical Procedures 
5.1 Corneal Assessment and Slit Lamp Examination 
The slit lamp examination should be performed per the investigator’s usual routine. 
Specific details of the data collected from the slit lamp examination are found in the site 
procedures manual. Any corneal images obtained for standard of care and therefore part of the 
medical record may be considered study data.  
5.1.1 Recipient Corneal Stroma Clarity 
The recipient corneal stroma clarity will be assessed by slit lamp examination using the 
following validated 3-level classification5  
· clear central recipient stroma 
· equivocally cloudy central recipient stroma 
· clouded central recipient stroma. 
Specific details regarding the grading of recipient corneal stroma clarity for DMEK are found in 
the Site Procedures Manual. Investigators will be provided a high resolution color standard scale 
and will be trained and certified on this classification scheme prior to enrolling participants. 
5.1.2 Graft Rejection Assessment 
Graft rejection will be assessed during the slit lamp examination using a modification of the 
Collaborative Corneal Transplantation Studies (CCTS) classification and as used in the CPTS.5,49 
Graft rejection will be classified as definite, probable/ possible, or not present. Details of the 
assessment of graft rejection are found in the Site Procedures Manual. 
The management of suspected graft rejection episodes will be according to the investigator’s 
clinical discretion. 
5.1.3 Graft Attachment Assessment 
Graft attachment and position will be assessed by the investigator’s routine. If the donor button is 
detached, the percentage of detachment will be documented. The investigator’s management of 
the detachment and/or repositioning will be standard of care and tracked for study purposes. 
5.2 Graft Failure Assessment 
Graft failure will be assessed and defined as the occurrence of one of the following: 
· Cornea which requires regrafting for any reason 
· Cornea which remains cloudy without clearing, according to the following: 
(1) cloudy cornea which does not clear in the first postoperative week and stays cloudy 
through 8 weeks post-operatively 
OR 
(2) cloudy cornea which was initially clear in the first postoperative week but becomes 
and remains cloudy for 3 months without clearing. 

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¿ 
A study participant whose cornea becomes cloudy (clouded recipient central stroma, 
based on the DEKS grading scale) will be treated by the investigator’s usual routine. 
For eyes meeting the definition of graft failure above, the principal cause of graft failure will be 
classified as one of the following: 
· Early failure (cloudy cornea in the first postoperative week which does not clear or 
requires a regraft within 8 weeks), associated with surgical complications   
· Primary donor failure (cloudy cornea in the first postoperative week which does not 
clear or requires a regraft within 8 weeks), in the absence of surgical complications 
· Graft rejection (defined as a clouded recipient central stroma following an allograft 
reaction); 
· Non-rejection graft failure (defined as a graft that initially had a clear central recipient 
stroma and becomes cloudy due to causes other than an immune event. These include: 
surface failure, infection, glaucoma/hypotony, endothelial decompensation, interface 
irregularity or opacity, pre-existing stromal scarring, blunt or penetrating trauma, and 
other causes); 
· Refractive/visual graft failure (defined as a graft that requires regrafting due to 
inadequate vision while the recipient central stroma remains clear). 
5.3 Intraocular Pressure 
Intraocular pressure will be measured using the investigator’s usual routine. 
5.4 Pachymetry 
Corneal thickness will be measured using the investigator’s usual routine. If there is a 
choice, slit scanning topography (i.e. Pentacam) corneal thickness maps are preferred. If no 
measurement can be obtained (e.g. if the cornea is too thick), this will be noted on the data form. 
5.5 Specular Microscopy 
At the 1 month and 12 month visits, specular microscopy of the central endothelium will be 
obtained on all participants that have not experienced graft failure.5,50,51 Detailed procedures 
for obtaining best image quality and image transmission will be provided in the DEKS-CIARC 
Clinical Site Imaging Manual. 
5.6 Grading of Retinopathy 
Fundus exams will be performed on all enrolled participants at the initial visit and the 12 month 
visit to grade the presence or absence of diabetic retinopathy; if present, the degree will be 
grading according to the DRCR.net grading scales.52 Specifics are found in the Clinical Site 
Procedures Manual. 

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5.7 Additional Procedures after initial DMEK Surgery 
Data on additional procedures performed on the study eye after the initial DMEK surgery will be 
collected, including, but not limited to: 
· air bubbling/repositioning in the first month 
· cataract surgery and placement of intraocular lens (anterior chamber, posterior chamber) 
· YAG capsulotomy  
· refractive procedure (e.g. limbal relaxing incision, LASIK)  
· glaucoma surgery (e.g. trabeculectomy, laser trabeculoplasty, tube shunt, mini shunt, 
other) 
5.8 Laboratory Testing 
2. HbA1c 
· De-identified capillary whole blood samples obtained around the Baseline and 12-
month visits will be sent to the central laboratory (ADRL at the University of 
Minnesota) for sample analysis.53 

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Chapter 6: Unanticipated Problems and Adverse Event Reporting 
6.1 Unanticipated Problems 
Site investigators will promptly report to the CC all unanticipated problems meeting the criteria 
below and the JCHR IRB must be notified within seven calendar days of recognition. For this 
protocol, an unanticipated problem is an incident, experience, or outcome that meets all of the 
following criteria: 
· Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied 
· Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research) 
· Suggests that the research places participants or others at a greater risk of harm than was 
previously known or recognized (including physical, psychological, economic, or social 
harm) 
The CC also will report to the IRB all unanticipated problems not directly involving a specific 
site such as unanticipated problems that occur at the CC or at another participating entity such as 
a laboratory. These instances must be reported to the JCHR IRB within seven calendar days of 
recognition. The Director of the Human Research Protection Program will report to the 
appropriate regulatory authorities if the IRB determines that the event indeed meets the criteria 
of an Unanticipated Problem requiring additional reporting. 
6.2 Adverse Events 
6.2.1 Definitions 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
relationship between the adverse event and the device(s) under investigation. 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
· Results in death. 
· Is life-threatening; (a non-life-threatening event which, had it been more severe, might 
have become life-threatening, is not necessarily considered a serious adverse event). 
· Requires inpatient hospitalization or prolongation of existing hospitalization. 
· Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions (sight threatening). 
· Is a congenital anomaly or birth defect. 
· Is considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
prevent one of the outcomes listed above). 

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6.2.2 Reportable Adverse Events 
Related and unrelated ocular adverse events will be reported only in the study eye as there is no 
plausible reason to believe that the DMEK procedure could affect a non-study eye. Since the 
DEKS does not involve investigational drugs or devices and participants in this study would 
have undergone DMEK regardless of study participation, related adverse events are those limited 
to events that are related or possibly related to randomization of donor tissue or study procedures 
of blood sample collection and specular microscopy. Eye banks will follow their standard 
procedures for reporting of AEs related to the donor cornea as required to the FDA and the 
EBAA. 
6.2.2.1 Events Requiring Expedited Reporting 
The following events will require expedited reporting to the CC (see 6.3). 
· Endophthalmitis 
· Microbial keratitis (bacterial, fungal, parasitic) within 3 months of DMEK 
6.2.2.2 Other Adverse Events 
All deaths will be reported, with cause of death if known; other systemic events will not be 
reported unless determined to be related to study participation.  
The following events will be reported on a separate online AE form: 
· non-serious events related to study procedure of blood sample collection that requires 
some form of medical intervention (note: expected events such as pain, bruising, 
irritation at site of fingerstick do not require reporting) 
· non-serious events related to study procedure of specular microscopy that requires 
medical intervention 
The following ocular adverse events of interest, even if serious, will be reported on electronic 
study visit case report forms and not on separate AE Forms: 
· Surgical complications  
· Dislocated donor 
· Donor detachment 
· Clouded recipient corneal stroma  
· Wound leak 
· Donor wrinkles/folds/curls 
· Anterior chamber abnormalities  
· New onset glaucoma 
· Graft rejection 
· Other serious ocular abnormalities (ex. trauma, retinal detachment, suprachoroidal 
hemorrhage) 

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6.2.2.3 Clinical Site AE Reporting Flow Chart 
The following flow chart outlines the required AE reporting procedures described above: 
 
6.2.3 Relationship of Adverse Event to Study Procedure 
The study investigator will assess the relationship of any adverse event requiring reporting on an 
AE form to be related or unrelated by determining if there is a reasonable possibility that the 
adverse event may have been caused by a study procedure (in the DEKS study procedures 
include randomization of donor tissue by donor diabetes status, blood sample collection and 
specular microscopy).  
To ensure consistency of adverse event causality assessments, investigators should apply the 
following general guideline when determining whether an adverse event is related: 
Yes 
There is a plausible temporal relationship between the onset of the adverse event and the study 
procedure, and the adverse event cannot be readily explained by the participant’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern 
of response to the study procedure; and/or the adverse event abates or resolves upon 
discontinuation of the study procedure and, if applicable, reappears upon re-challenge. 
No 
Evidence exists that the adverse event has an etiology other than the study procedure 
(e.g., preexisting medical condition, underlying disease, concurrent illness, or concomitant 
medication); and/or the adverse event has no plausible temporal relationship to study device, 
drug or procedure. 
 

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6.2.4 Severity (Intensity) of Adverse Events 
The severity (intensity) of an adverse event requiring reporting on an AE form will be rated on a 
three-point scale: (1) mild, (2) moderate, or (3) severe. A severity assessment is a clinical 
determination of the intensity of an event. Thus, a severe adverse event is not necessarily serious. 
For example, itching for several days may be rated as severe, but may not be clinically serious. 
· MILD: Usually transient, requires no special treatment, and does not interfere with the 
participant’s daily activities. 
· MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the 
participant and may interfere with daily activities, but is usually ameliorated by simple 
therapeutic measures and participant is able to continue in study. 
· SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may 
cause discontinuation of study device, and generally requires systemic drug therapy or 
other treatment. 
6.2.5 Expectedness 
For a serious adverse event that is considered possibly related to a study procedure as 
noted in 6.2.1, the Medical Monitor will classify the event as unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information. 
6.2.6 Coding of Adverse Events 
Each AE form is reviewed by the Medical Monitor to assess safety and to verify the coding and 
the reporting that is required. 
Adverse events will be coded using the MedDRA dictionary. To facilitate coding, the site will 
enter a preliminary MedDRA code that describes the type of event, which the Medical Monitor 
may accept or change (the Medical Monitor’s MedDRA coding will be used for all reporting). 
The Medical Monitor will review the investigator’s assessment of causality and may agree 
or disagree. Both the investigator’s and Medical Monitor’s assessments will be recorded. 
The Medical Monitor will have the final say in determining the causality as well as whether an 
event is classified as a serious adverse event. 
6.2.7 Outcome of Adverse Events 
The outcome of each reportable adverse event (requiring completion of an AE form) will be 
classified by the investigator as follows: 
· RECOVERED/RESOLVED (COMPLETE RECOVERY) – The participant recovered 
from the AE/SAE without sequelae. Record the AE/SAE stop date. 
· RECOVERED/RESOLVED WITH SEQUELAE – AE/SAE where the subject 
recuperated but retained pathological conditions resulting from the prior disease or injury. 
Record the AE/SAE stop date. 
· FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event 
that was the cause of death should be reported as fatal. AEs/SAEs that were ongoing at 
the time of death; however, were not the cause of death, will be recorded as “resolved” 
at the time of death. 

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· ONGOING NOT RECOVERED/NOT RESOLVED  – An ongoing AE/SAE is defined 
as an ongoing event with an undetermined outcome. 
¿ 
An ongoing outcome will require follow-up by the site in order to determine the final 
outcome of the AE/SAE. 
¿ 
The outcome of an ongoing event at the time of death that was not the cause of death, 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
date. 
· ONGOING (MEDICALLY STABLE) – AE/SAE is ongoing, but medically stable. For 
example, a chronic condition where no further change is expected. 
If any reportable adverse events are ongoing when a participant completes the study 
(or withdraws), data collection will continue until the specific adverse event is resolved. 
Note: participants should continue to receive appropriate medical care for all adverse events 
after their participation in the study ends, even if they are not reportable adverse events. 
6.3 Timing of Event Reporting 
The events noted in 6.2.2.1 and any SAEs possibly related to study participation must be 
reported to the CC within 24 hours of the site becoming aware of the event. This can occur via 
phone or email, or by completion of the online serious adverse event form. If the form is not 
initially completed, it should be completed as soon as possible after there is sufficient 
information to evaluate the event. The site will be responsible for reporting the event to the 
JCHR IRB within 7 days. 
All other reportable AEs (as defined in 6.2.2.2) should be submitted by completion on the online 
form within 7 days of the site becoming aware of the event. 
The CC will notify all participating investigators of any adverse event that is serious, related, and 
unexpected. Notification will be made within 10 working days after the CC becomes aware of 
the event. 
Each principal investigator is responsible for reporting serious study-related adverse events to 
the JCHR IRB as the overseeing IRB. Sites must report all serious, related adverse events within 
seven calendar days to the IRB. 
6.4 Safety Oversight 
The study Medical Monitor will review all adverse events that are reported during the study. 
Additionally, the Medical Monitor will review compiled safety data at periodic intervals 
(generally timed to the review of compiled safety data by the DSMC). 
The DSMC will review compiled safety data at periodic intervals. The DSMC can recommend 
modifications to the study protocol or suspension or outright stoppage of the study if deemed 
necessary based on the totality of safety data available. Details regarding DSMC review will 
be documented in a separate DSMC document. 

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Chapter 7: Miscellaneous Considerations 
7.1 Pregnancy Reporting 
If pregnancy occurs, the participant will remain in the study since the study intervention will 
have been completed and remaining in the study consists of only low risk follow-up procedures. 
The occurrence of pregnancy will be reported to the CC.  
7.2 Participant Compensation 
Participant compensation will be specified in the informed consent form. 
7.3 Participant Withdrawal 
Participation in the study is voluntary, and a participant may withdraw at any time. 
For participants who withdraw, their data will be used up until the time of withdrawal. 
7.4 Confidentiality 
For security and confidentiality purposes, both the donor and the human subject participants will 
be assigned identifiers that will be used instead of their names for study purposes. However, 
protected health information, such as name and social security number, will need to be shared 
with the specific eye bank processing the participant’s donor tissue (eye banks require additional 
unique patient identifiers) as part of the EBAA standard requirements of transplant processing 
and notification; this information will be shared directly between the clinical site and their 
respective eye bank as per standard practices and therefore will not be stored in the study 
database. Alternatively, participant name and contact information will be shared by the sites 
through the study database and will be accessible (limited access) to members in the CWRU 
Coordinating Center for purposes of contacting participants that may be lost to follow-up. De-
identified or coded participant information may also be provided to research sites involved in the 
study. The samples sent to the laboratories will be coded for HbA1c and AGE testing, and the 
labs will not receive any identifying information other than date of collection. Similarly, the 
images sent to CIARC will be coded and are not identifiable other than date of collection. 
 

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Chapter 8: Statistical Considerations 
8.1 Statistical and Analytical Plans 
The approach to sample size and statistical analyses are summarized below. 
8.2 Statistical Hypotheses 
The primary outcome for this study is graft failure by 12 months. The null/alternative hypotheses 
are: 
a. Null Hypothesis: There is no difference in the probability of graft failure by 12 months 
between the diabetic group and the non-diabetic group. 
b. Alternative Hypothesis: The probability of graft failure by 12 months is different for the 
diabetic and non-diabetic groups. 
8.3 Sample Size 
The sample size is calculated based on a superiority (2-sided test) design with the goal to 
determine that the graft failure rate of the recipients of tissue from donors with diabetes is 
different than the graft failure rate of recipients of tissue from donors without diabetes. 
Numbers in table are total sample size for both donor groups combined (lost to follow up not 
accounted for), assuming different distributions of tissue from persons without:with diabetes. 
 
For the final sample size, the following has been assumed:  
· Type I error of 5% 
· 90% power 
· Non-diabetic 1-year failure rate (PND) of 4% 
· 5% difference between PND and PD 
¿ 
CPTS results 
· Failure rate for donors with diabetes: 9% 
· Failure rate for donors without diabetes: 4% 
· 2:1 distribution of tissue from donors without diabetes to tissue from donors with 
diabetes 
¿ 
Recent distribution estimates from eye banks showing regional differences 
· Midwire 2015 data (N=11,834 donors): 36% had diabetes 
· Midwire 2016-2017 data (N=16,139 donors): 27% had diabetes 

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· Eversight 2018 data (N=10,672 donors): 24% had diabetes 
· Lions Visiongift 2015-2018 data (N=4,260 donors): 34% had diabetes 
This requires a total of 1278 study eyes before adjusting for lost to follow-up. Increasing the 
calculated sample size by 10% to account for loss to follow-up gives a total of 1420 study eyes 
(~947 donors without diabetes and ~473 donors with diabetes). 
· A participant can enroll both eyes into the study, if both are eligible. It is anticipated that 
about 30% of participants will have two study eyes, based on the CPTS data54, data from 
single site study of Price et al for DMEK55, and a participating surgeon survey, indicating 
more common bilateral cases associated with DMEK, the endothelial keratoplasty 
procedure in the DEKS, compared to DSAEK which was the procedure in the CPTS. 
This would mean it is expected that approximately 1092 participants would need to be 
enrolled in order to enroll 1420 study eyes. 
Although both eyes of a study participant can be enrolled, and/or both eyes of the donor may be 
provided for the study, the sample size calculation does not adjust for these correlations, for the 
reasons noted below. 
· If participants with two study eyes receive a cornea from a donor with known diabetes for 
the first eye, the second eye will receive a cornea from a donor without known diabetes. 
If the first study eye received a cornea from a donor without known diabetes, then there is 
a 1/3 chance that the second study eye will receive a cornea from a donor with known 
diabetes. Note, the primary analyses will adjust for these correlations. Those classified as 
having known diabetes are participants with a diabetes diagnosis prior to tissue donation 
or reclassified as diabetic based on post-mortem HbA1c values. 
 
Regarding donors, CPTS found there were no cases of graft failures occurring from the cornea 
mates of the same donor because of the low graft failure rate and low number of cornea mates in 
the study;35 a similar trend is expected in the DEKS and sample size will not be adjusted for this. 
If there are cases of graft failures occurring from cornea mates both assigned in the study, 
sensitivity analysis will account for the correlation in the models. 
8.4 Outcome Measures 
8.4.1 Primary Efficacy Endpoint 
· Graft failure within 1 year of surgery as defined in the SAP 
Graft failure will be assessed and defined as the occurrence of one of the following: 
· Cornea which requires regrafting for any reason 
· Recipient cornea remains cloudy after surgery without clearing for 8 weeks or longer 
For eyes meeting the definition of graft failure above, the principal cause of graft failure will be 
classified and described in the SAP. Further, the date of graft failure will also be described in the 
SAP. 

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8.4.2 Secondary Endpoint 
Endothelial cell density at 1 year is considered a secondary endpoint. 
8.5 Analysis Dataset and Sensitivity Analyses 
The primary analysis will follow the intent-to-treat principle, with the following exceptions: 
it will exclude eyes that did not have DMEK surgery, received a non-study donor cornea tissue, 
had an anterior chamber IOL implanted during surgery, or experienced a suprachoroidal 
hemorrhage. It is highly unlikely that any of these events could be related to diabetes status of 
the donor. 
Safety outcomes will be reported for all enrolled study eyes that have DMEK surgery, 
irrespective of whether the participant completed the study. 
Sensitivity analyses for the primary and secondary outcomes, such as adjusting for significant 
operative complications and/or recipient diabetes, will be described in the SAP. 
8.6 Analysis of the Primary Efficacy Endpoint 
Summary statistics (Kaplan-Meier estimates of 1-year graft failure with 95% confidence 
intervals) will be reported by donor diabetes status groups (with versus without diabetes). 
Further, point estimates and 95% confidence intervals for donor diabetes status group differences 
will be presented. 
One-year graft failure between donor diabetes status groups will be compared using a 
proportional hazards model while adjusting for corneal diagnosis and accounting for participants 
who have two study eyes included in the study using a frailty model. The proportional hazards 
assumption will be tested. If this assumption is violated, then hazard ratios will be presented 
separately over time. There will be no imputation of missing data in the primary analysis. 
8.7 Analysis of the Secondary Endpoint 
For ECD, only participants with a gradable 1-year image who have not experienced graft failure 
1-year after DMEK will be included in the analysis. There will be no imputation of missing data. 
Summary statistics (mean ± SD or median (IQR)) appropriate to the distribution will be tabulated 
by donor diabetes status group and at baseline, 1-year and for the changes from baseline to 1-
year. 
Repeated measures regression models with unstructured covariance including data from baseline, 
1 month, and 1 year will be used to compare donor diabetes status effects while adjusting for 
baseline ECD, corneal diagnosis, and recipient study eyes (random effect. A point estimate, 95% 
confidence interval, and two-sided p-value will be reported for the donor diabetes status effect 
based on the linear regression model. Residual values will be examined for an approximate 
normal distribution. If residual values from the regression model have a skewed distribution then 
an appropriate transformation, truncation, or a nonparametric analysis based on ranks will be 
performed. Descriptive analyses (e.g., boxplots) stratified by donor diabetes status group will be 
given at baseline, 1 month, and 1 year. 

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8.8 Safety Analyses 
The safety analysis will include events occurring on or after the day of surgery until and 
including the 12-month visit, or Day 464, whichever occurs first. 
All reportable adverse events, operative complications and procedures, post-operative 
complications and procedures (e.g., dislocation of donor, graft detachment, air injection), 
and abnormalities noted on ocular exam will be tabulated by donor diabetes status group. 
These will include but not be limited to: 
· Endophthalmitis 
· Microbial keratitis 
· IOP>25 mmHg  
· Corneal Thickness >750 microns  
· Definite signs of graft rejection 
· Recipient stromal clarity = cloudy 
8.9 Protocol Adherence and Retention 
The following tabulations and analyses will be performed by donor diabetes status group: 
· Protocol and procedural deviations 
· Flow chart accounting for all enrolled participants 
· Participants who dropped and reasons 
8.10 Baseline Descriptive Statistics 
Baseline demographic and clinical characteristics will be tabulated overall, and by donor 
diabetes status group. Additionally, baseline characteristics will be tabulated for cases with graft 
failure, cases with incomplete follow-up without graft failure, and cases with complete follow-up 
without graft failure. 
Donor characteristics will also be tabulated. 
8.11 Planned Interim Analyses 
No formal interim efficacy analyses are planned for this study. Compiled safety data reports will 
be reviewed by the DSMC semi-annually. 
8.12 Sub-Group Analyses 
Subgroup analyses/assessments of effect modification (interaction) will be conducted separately 
for the graft failure within the first year after surgery and ECD at one-year. These analyses will 
be considered exploratory. Additionally, interpretation of the analyses will depend on whether 
the overall analysis demonstrates a significant treatment group difference; in the absence of such 
an overall difference, subgroup analyses will be interpreted with caution. The general approach 
for these exploratory analyses will be to add an interaction term for the subgroup factor, which 
will be noted in the SAP, by diabetes group into the models used for the primary analyses. For 

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continuous variables, results will be displayed in subgroups based on cutpoints although the 
analysis will utilize the variable as continuous. If there is insufficient sample size in a given 
subgroup, the cutpoints for continuous measures may be adjusted per the observed distribution of 
values. Cutpoint selection for display purposes will be made masked to the outcome data. 
8.13 Multiple Comparison/Multiplicity 
There will be no adjustment for primary and secondary analyses. 
For comparison of all exploratory analyses, Benjamini-Hochberg false discovery rate adjusted 
p-values will be calculated within several subcategories. 
8.14 Analysis of the Tertiary Exploratory Endpoint 
Exploratory analyses will evaluate the effect of donor diabetes status on 1-year graft failure rate 
with donor diabetes severity defined in the alternative ways as measured by eye bank-determined 
diabetes risk categorization scores, post-mortem HbA1c, and skin AGEs and oxidation markers. 
Additionally, the effect of donor diabetes status on 1-year ECD with alternative definitions for 
donor diabetes severity will be examined. The alternative definitions will be detailed in the SAP. 
Potential confounders or interaction terms determined in the analyses of graft failure and ECD 
will be explored in adjusted models mirroring the primary analyses. 
8.15 Additional Tabulations and Analyses 
8.15.1 Additional Tabulations 
The following tabulations will be performed by donor diabetes status group: 
· Additional post-operative study eye procedures 
· Immunizations or vaccinations vs signs of graft rejection 
· Ocular and systemic diabetic complications 
8.15.2 Additional Analyses 
The association of donor, recipient, and operative factors potentially related to graft failure 
within 1-year following DMEK will be evaluated and detailed in the SAP. 
 

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Chapter 9: Data Collection and Monitoring 
9.1 Case Report Forms and Other Data Collection 
Since data are captured retrospectively, direct data entry onto electronic case report forms 
(CRFs) is not feasible. Thus, paper worksheets will be provided to capture relevant post-
operative data for transcription later, which is the preferred method of data capture.  When 
utilized, these will be considered source documentation and must be maintained in the study 
records. If data is transcribed from the medical record onto electronic forms, the medical record 
is considered the source document. The source documents must be readily verifiable against the 
values entered into eCRF, and if paper worksheets are utilized they may be compared to 
concurrent medical records as well.   
9.2 Study Records Retention 
Each participating site will maintain appropriate medical and research records for this trial, 
in compliance with ICH E6 and regulatory and institutional requirements for the protection of 
confidentiality of participants. 
Study documents should be retained for a minimum of 3 years after completion of final grant 
reporting. These documents should be retained for a longer period, however, if required by local 
regulations. No records will be destroyed without the written consent of the CWRU CC, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these documents 
no longer need to be retained. 
9.3 Quality Assurance and Monitoring 
Designated personnel from the CWRU CC and the JCHR Data Management and Analysis Center 
will be responsible for maintaining quality assurance (QA) and quality control (QC) systems to 
ensure that the clinical portion of the trial is conducted and data are generated, documented and 
reported in compliance with the protocol, Good Clinical Practice (GCP) and the applicable 
regulatory requirements, as well as to ensure that the rights and wellbeing of trial participants are 
protected and that the reported trial data are accurate, complete, and verifiable. 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
Investigations — A Risk-Based Approach to Monitoring” (August 2013).56 
For the DEKS, data of most importance for monitoring at the site are informed consent, proper 
characterization of donor and recipient diabetes status, and outcome assessments (graft failure). 
Therefore, the RBM plan will focus on these areas. All monitoring will be performed remotely. 
Elements of the RBM plan may include: 
· Qualification assessment, training, and certification for sites and site personnel 
· Oversight of Institutional Review Board (IRB) coverage and informed consent 
procedures 
· Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
review of entered data and edits, statistical monitoring, study closeout 
· Remotely monitored source data verification, site visit reports 

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· Tissue accountability 
· Communications with site staff 
· Patient retention and visit completion 
· Quality control reports 
· Management of noncompliance 
· Documenting monitoring activities 
· Adverse event reporting and monitoring 
CC representatives or their designees may remotely “visit” the study facilities (eye banks as well 
as clinical sites) at any time in order to maintain current and personal knowledge of the study 
through review of records, comparison with source documents, observation and discussion of the 
conduct and progress of the study. The investigational site will provide access to all source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. 
9.4 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. 
Further details about the handling of protocol deviations will be included in the Site Manual of 
Procedures. 
 

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Chapter 10: Ethics/Protection of Human Participants 
10.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56, and/or the ICH E6. 
10.2 Institutional Review Boards 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. 
All changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented. 
10.3 Informed Consent Process 
10.3.1 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families. 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
paper document. The investigator or their designee will initially explain the research study to the 
participant and answer any questions that may arise. All participants will receive a verbal 
explanation in terms suited to their comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants. Participants will have the 
opportunity to carefully review the consent form and ask questions prior to signing.  
The participants should have the opportunity to discuss the study with their surrogates or 
think about it prior to agreeing to participate. The participant will sign the informed consent 
document prior to any procedures being done specifically for the study. They may need to 
complete execution of the informed consent form remotely using the process outlined in the 
clinical site Manual of Procedures.  
The participants may withdraw consent at any time throughout the course of the trial. A copy of 
the informed consent document will be given to the participants for their records. The rights and 
welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
10.3.2 Participant and Data Confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor. 

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The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
or regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study and will be uploaded to a limited access database accessible to 
the CC at CWRU. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, institutional policies, or CWRU 
requirements. 
Limited participant identifiable information (name and unique patient identifier) will be provided 
by the clinical sites to the eye banks per usual practices to satisfy EBAA regulations. 
Additionally, study participant research data, which is for purposes of statistical analysis and 
scientific reporting, will be transmitted to and stored at the JCHR. Individual participants and 
their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites, eye banks and by JCHR research 
staff will be secured and password protected with access provided to the CC at CWRU, the 
Study Chairs and the CIARC as required. At the end of the study, all study databases will be 
fully de-identified and archived at the JCHR or the CWRU CIARC. 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
obtained from the NIH. This certificate protects identifiable research information from forced 
disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
researchers and institutions from being compelled to disclose information that would identify 
research participants, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to participants. 
10.3.3 Future Use of Images and Data 
Data collected for this study will be analyzed and stored at the JCHR. After the study is 
completed, the de-identified, archived data will be made publicly available. Further, some data 
and images may be requested and shared with other researchers under a Data Use Agreement as 
a limited data set, since other than date of collection, there are no other identifiable elements. No 
additional identifying information shall be provided in a manner that would make the human 
subjects readily identifiable.  
 

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