Cross-linking for Corneal Ulcers Treatment Trial
Phase: PHASE3
Conditions: Corneal Ulcer, Infectious Keratitis, Bacterial Ulcer, Fungal Ulcer
Sponsor: University of California, San Francisco

Cross-linking for Corneal Ulcers Treatment Trial (CLAIR)
NCT02570321
October 4, 2016

CLAIR MOP 
Version 1.8; Revised 4 October 2016 
 
 
 
 
 
 
 
Cross-Linking Assisted Infection Reduction 
CLAIR 
Manual of Operations and Procedures (MOP) 
 
 
Aravind Eye Hospital, Madurai, Coimbatore, and Pondicherry, India 
Francis I. Proctor Foundation, University of California San Francisco, USA 
 
 
 
Investigators: 
N. Venkatesh Prajna, DO DNB FICO1 
Dionna Fry, MPH2 
Tom Lietman, MD2 
Jeremy Keenan, MD MPH2 
Jennifer Rose-Nussbaumer, MD2 
Ariana Austin, MS2 
 
 
 
 
 
1Aravind Eye Hospital, Madurai, Pondicherry, and Coimbatore, India   
2 Francis I. Proctor Foundation, University of California, San Francisco, USA 

CLAIR MOP 
Version 1.8; Revised 4 October 2016 
 
 
 
 
 
CONTENTS 
1. 
INTRODUCTION AND BACKGROUND ......................................................................................................................... 1 
1.1 
Specific Aims:................................................................................................................................................................. 1 
1.2 
Study Outcomes: ........................................................................................................................................................... 2 
1.3 
Study Design: ................................................................................................................................................................. 2 
2. 
ORGANIZATION ......................................................................................................................................................... 2 
2.1 
Collaborating Institutions: ............................................................................................................................................. 3 
3. 
PATIENT FLOW ........................................................................................................................................................... 3 
3.1 
Study Timeline ............................................................................................................................................................... 3 
3.2 
Eligibility Requirements ................................................................................................................................................. 4 
3.3 
Randomization .............................................................................................................................................................. 4 
3.4 
Study visits..................................................................................................................................................................... 4 
3.5 
Study Schedule .............................................................................................................................................................. 6 
3.6 
Adverse Events (AEs) ..................................................................................................................................................... 6 
4. 
PROCEDURES ............................................................................................................................................................. 6 
4.1 
Masking ......................................................................................................................................................................... 6 
4.2 
Ulcer Classification .......................................................................................................... Error! Bookmark not defined. 
4.3 
Procedures ..................................................................................................................................................................... 7 
4.4 
Pentacam Protocol ........................................................................................................................................................ 7 
5. 
STUDY MEDICATIONS ................................................................................................................................................ 8 
5.1 
Medical management protocol & Treatment Schedule ................................................................................................ 8 
5.2 
Possible Side Effects of Study Medications .................................................................................................................... 9 
6. 
PROTECTION OF HUMAN SUBJECTS ........................................................................................................................... 8 
6.1 
Institutional Review Board Approval ............................................................................................................................. 8 
6.2 
Informed Consent .......................................................................................................................................................... 9 
6.3 
Risks to Study Participants .......................................................................................................................................... 10 
6.4 
Privacy, Confidentiality and Data Security .................................................................................................................. 10 
6.5 
Exclusion of Vulerable Populations ............................................................................................................................. 11 
6.6 
Compensation to Participants ..................................................................................................................................... 11 
7. 
DATA COLLECTION AND MANAGEMENT .................................................................................................................. 11 
7.1 
Data Collection and Entry............................................................................................................................................ 11 
7.2 
Data Consistency, Validity, and Monitoring ................................................................................................................ 11 
7.3 
Data Storage and Security........................................................................................................................................... 11 
8. 
STATISTICAL ANALYSIS PLAN ................................................................................................................................... 11 
9. 
References ............................................................................................................................................................... 12 
 

CLAIR MOP 
Version 1.6; Revised 3 May 2016 
 
1 | P a g e  
 
1. INTRODUCTION AND BACKGROUND  
Cross-linking (CXL), a process by which collagen fibrils form covalent bonds with adjacent molecules, was 
first discovered in the corneas of diabetic patients who cross-link through glycosylation and have a 
decreased incidence of keratoconus.1 It is currently used as a treatment for corneal ectatic disorders such as 
keratoconus and post-LASIK ectasia. CXL involves applying riboflavin to the cornea and photo-chemically 
activating it with UV light. This has been shown to strengthen the cornea and allow it to retain its normal shape.1-4 
There has been recent interest in corneal CXL as an adjuvant therapy for infectious keratitis.5 There are two 
mechanisms by which CXL may benefit patients with infectious corneal ulcers; antimicrobial effects, and increased 
resistance of corneal tissue to enzymatic degradation.  
In vitro efficacy of UV-A + riboflavin against the most common bacterial ocular pathogens, such as 
Pseudomonas aeruginosa and Streptococcus pneumonia has been demonstrated.6 In addition to these in vitro 
data, multiple case reports have suggested potential benefits of collagen CXL for treatment of bacterial and fungal 
keratitis, such as symptomatic improvement, resolution of resistant infection, and halting of progressive melting.7-
10 One small study treated a series of patients with bacterial keratitis exclusively with photo-chemically activated 
riboflavin, which resolved infection in all patients.11 Interestingly, only 2 of the 16 study participants required 
topical antibiotic treatment. Thus, riboflavin + UV-A could potentially decrease antibiotic resistance and ocular 
surface toxicity that can complicate the current management of bacterial keratitis. 
Filamentous fungal corneal ulcers continue to have a poor prognosis and further investigation into their 
treatment is warranted. Unfortunately, in vitro collagen CXL alone has failed to demonstrate fungal pathogen 
inactivation.6,12 However, one study showed improved inhibition of fungus in vitro with amphotericin plus 
riboflavin+UV-A compared with amphotericin alone.6 The authors suggest that CXL may improve diffusion of 
antifungal medications or inhibit fungal proliferation through more complex mechanisms. Although the evidence 
for cross-linking as a treatment for fungal keratitis is less robust, clinicians have already begun using UV-A + 
riboflavin in conjunction with antifungals in hopes that there will be some benefit in this challenging disease. Thus, 
scientific investigation into this treatment approach is necessary.   
Research Question: Is collagen cross-linking a useful adjuvant in the treatment of infectious corneal ulcers? 
1.1 Specific Aims: 
1. To determine if patients with culture positive bacterial and fungal keratitis clear their repeat cultures 
more quickly with the addition of collagen cross-linking. 
 
We hypothesize that there will be an increased rate of negative cultures immediately post procedure in the 
CXL group compared with sham CXL. 
2. To determine if CXL can decrease enzymatic degradation and prevent corneal thinning and perforation.  
 
Hypothesis 2A) There will be a decreased rate of perforation among study participants treated with CXL.  
 
Hypothesis 2b) There will be less corneal thinning as measured by optical coherence tomography in the 
CXL group at 3 months. 
 
3. To determine what effect CXL has on visual acuity, corneal astigmatism, and 3-month infiltrate/scar size.  

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 
Hypothesis 3A) There will be improved visual acuity with reduced 3-month infiltrate/scar size among 
study participants treated with CXL. 
 
Hypothesis 3B) There will be no difference in irregular astigmatism (as measured by topography) 
between participants in the CXL group versus antibiotics alone. 
 
1.2 Study Outcomes: 
Primary Outcome: 
 
Microbiological cure on repeat culture 
o CLAIR I. Bacterial ulcers – Culture at 4 hours  
o CLAIR II Fungal ulcers – Culture at 24 hours  
Secondary Outcomes: 
 
BSCVA at 3 months 
 
Scar size/depth, as measured by clinical exam, slit lamp photographs and OCT  
 
Adverse events including rate of perforation/need for TPK 
 
Thinning as measured by pachymetry and OCT  
 
Topography and corneal higher-order aberrations  
 
Change in IND-VFQ from baseline to 3 months.  
1.3 Study Design: 
Cross-Linking Assisted Infection Reduction (CLAIR) I for bacterial ulcers and CLAIR II for fungal ulcers is a series 
of randomized, masked, clinical trials. The purpose of these studies is to determine differences in microbiological 
cure for 1-day repeat cultures between different medical antimicrobial treatments alone versus antimicrobial 
treatment plus collagen cross-linking. There will be 1:1 randomization to each of these treatment groups: 
CLAIR I. Bacterial Ulcers: 
1) Topical 0.5% Moxifloxacin alone  
2) Topical 0.5% Moxifloxacin plus cross-linking  
CLAIR II. Fungal Ulcers: 
1) Topical 5% natamycin alone  
2) Topical 5% natamycin plus cross-linking  
3) Topical 0.15% amphotericin alone 
4) Topical 0.15% amphotericin plus cross-linking 
2. ORGANIZATION 
Aravind Eye Hospital, Madurai along with the University of California San Francisco (UCSF) will jointly execute 
these clinical trials. Aravind Eye Hospital will mainly be responsible for recruitment and enrollment, intervention 
implementation, and follow-up visits. UCSF will take the lead on all data analysis, writing of study-related 
materials, and writing journal publications. 
 
 

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2.1 Collaborating Institutions: 
Aravind Eye Hospital, India  
Dr. N. Venkatesh Prajna will be the lead investigator at Aravind Eye Hospital. All recruitment, 
treatment/intervention, and follow-up visits will be done at the Aravind Eye Hospitals. All study personnel 
assisting with the research will be adequately informed about the protocol, the research procedures, and their 
duties and functions through ongoing communication between the 2 sites.   
 
Aurolab at Aravind Eye Hospital in Madurai will be responsible for preparing and distributing study medications. 
The microbiology lab in Madurai will perform the cultures and serve as a bank for all specimens collected. Madurai 
microbiology lab will serve as a reference lab that will assist with any difficult microbiological identification. 
Francis I. Proctor Foundation, University of California, San Francisco, USA 
 
The Proctor Foundation is an organized research unit at the University of California, San Francisco. The 
Foundation has a 56-year history of research in ocular infectious and inflammatory disease and runs one of the 
leading corneal fellowship training programs in the United States.  Proctor Foundation faculty have been involved 
in prevention of blindness research in developing countries since the Foundation’s inception. The impetus for 
establishing the Foundation in 1947 was to eradicate trachoma in the American Southwest and other parts of the 
world. 
 
UCSF will perform the data analysis. UCSF will not consent any participants, perform surgeries, or collect study 
data. UCSF will have the most current protocol, consent documents and HIPAA authorization for reference. UCSF 
has received IRB approval for this study (IRB number: 14-14918). All modifications to either IRB of record will be 
communicated between sites. UCSF will ensure protection of all study-related data by using de-identified 
information over a secure server. All non-compliance with the study protocol or applicable requirements will be 
reported in accordance with local policy. There will be ongoing communication of problems, interim results, and 
study closure between both sites. 
 
 
Jennifer Rose-Nussbaumer, MD is the co-PI at UCSF for this study. Dr. Rose-Nussbaumer is a Cornea fellowship 
trained Ophthalmologist at F. I. Proctor Foundation. In addition to her clinical work in cataract and corneal 
transplant surgery, she is an NIH funded clinical researcher. She is studying corneal ulcer treatment in India and 
Nepal and corneal transplant outcomes in Ethiopia. She is the principle investigator on the Corneal Preservation 
Time Study (CPTS) and Descemets Endothelial Thickness Comparison Trial (DETECT) at UCSF. Her previous vision 
research in Ophthalmology includes work with the World Health Organization on Trachoma, as well as 
investigating the ocular manifestations of HIV disease. Dr. Rose-Nussbaumer’s role in this study will be to perform 
data analysis, to collaborate with surgery site and eye bank regarding study design and protocols. 
 
3. PATIENT FLOW 
3.1 Study Timeline 
When the patient presents to clinic with infectious keratitis and undergoes corneal scraping by the treating 
ophthalmologist, a specimen will be submitted for microbiological testing (KOH and Gram stain bacterial or 
fungal). This is a routine practice already in place at the hospital. If the patient has a positive KOH or Gram stain, 
the patient will be approached by study personnel to be enrolled in study.   

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If enrolled, study subjects will follow the procedures below - if bacteria positive on Gram stain, the subject will 
undergo procedures outlined for CLAIR I. Bacterial ulcers; if positive for fungus on KOH, subject will undergo 
procedures outlined for CLAIR II. Fungal ulcers. 
Study participants will be required to have 4 follow-up visits, one for the cross-linking procedure and re-scraping, 
one at 3 days for re-scraping, one at 3 weeks  (2.5 – 5 weeks) and one at 3 months (visit window: 2.5 -3.5 months). 
Additional visits may be needed and will be determined by the physician/investigator.  
 
3.2 Eligibility Requirements 
Only those who meet all of the inclusion criteria and none of the exclusion criteria will be enrolled in this study.  
Inclusion criteria: 
 
Corneal ulcer that is smear positive for either bacteria, filamentous fungus  
 
Pinhole visual acuity worse than 6/21 (20/70) in the affected eye  
 
Age over 18 years 
 
Basic understanding of the study as determined by the physician 
 
Commitment to be hospitalized for 3 days 
 
Commitment to return for follow up visits 
 
Exclusion criteria: 
 
No evidence of concomitant infection on exam or gram stain (i.e. herpes, both bacteria and acanthameoba 
on gram stain) 
 
Impending or frank perforation at recruitment 
 
Involvement of sclera at presentation 
 
Non-infectious or autoimmune keratitis 
 
History of corneal transplantation or recent intraocular surgery 
 
No light perception in the affected eye 
 
Pinhole visual acuity worse than 20/200 in the unaffected eye  
 
Participants who are decisionally and/or cognitively impaired 
 
Involvement of posterior 1/3 of stroma at presentation for fungal patients 
3.3 Randomization 
Each study eye will be randomly assigned to the treatment group. Block randomization will be performed using a 
computer program (Statistical package R; Version 2.12; R Foundation for Statistical Computing, Vienna, Austria) by 
the coordinating site.  
 
Once an eye is enrolled in the study, the study coordinator will assign the study participant’s eye an ID (alpha-
numeric code) and organize the procedure in the operating room within 3 hours for bacterial ulcers, and within 24 
hours for fungal ulcers. Once the study participant has been assigned a study participant ID and randomized to 
treatment group, they will be included in the intention to treat analysis.  
 
3.4 Study visits 
3.3.1 Baseline Visit. During this visit, eligible patients will be enrolled in the study and will give consent. The 
baseline patient form will be completed and baseline topography will be obtained. 

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CLAIR I. Bacterial Ulcers: 
Study participants will be randomized to one of two possible treatment arms: 1) topical 0.5% moxifloxacin alone 
2) topical 0.5% moxifloxacin plus CXL.  Those randomized to CXL will undergo the procedure in the operating 
theatre within 4 hours. Both arms will undergo repeat scraping at 4 hours post enrollment. Thereafter, all study 
participants will start 0.5% moxifloxacin every hour. All patients will be admitted to the inpatient setting until the 
3rd day. 
CLAIR II. Fungal Ulcers: 
They will be randomized to one of four possible treatment arms 1) topical 5% natamycin alone, 2) topical 5% 
natamycin plus CXL, 3) topical 0.15% amphotericin alone or 4) topical 0.15% amphotericin plus CXL. All study 
participants will begin medical therapy immediately (either natamycin or amphotericin) every hour and those 
randomized to CXL will undergo the procedure in the operating theatre within 24 hours. All study participants will 
undergo repeat scrapping at 24 hours from enrollment. All patients will be admitted to the inpatient setting until 
the 3rd day.  
3.3.2 Procedure visit. All study participants randomized to CXL will have the procedure in the operating theater. 
This will occur within 4 hours for bacterial ulcers and within 24 hours of the baseline visit for fungal ulcers. Once a 
study participant has been randomized to treatment, he will have the treatment even if there is a delay in the 
operating theatre that results in delayed treatment, however re-scraping will occur at 4 hours for bacterial ulcers 
and 24 hours for fungal ulcers even if they have not yet had cross-linking.  If the cross-linking occurs after repeat 
scrapping, a third smear and culture should be performed.  
3.3.3 Day 3 visit. During this visit, study participants will have BSCVA recorded, IND-VFQ, slit lamp examination and 
undergo repeat scraping and culture of the corneal ulcer. Thereafter, all additional treatments including but not 
limited to topical antimicrobials, or oral antimicrobials, will be at the clinician’s discretion.  At this point patients 
may be discharged from the inpatient setting.  
3.3.4 3 week visit. During this visit study participants will have BSCVA recorded, slit lamp examination, and they 
will have digital photography. 
3.3.5 Final Visit. At the 3- Month visit study participants will have their BSCVA and slit lamp examination recorded, 
in addition to repeat topography and be administered the IND-VFQ.  
 
 
 
 
 

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3.5 Study Schedule 
Visit 1 
Baseline Exam 
Visit 2 
Procedure & Repeat 
Culture 
Visit 3 
3-Day Repeat 
Culture 
Visit 4 
3 week Follow-up 
Visit 5 
Month 3 Final 
Forms 
 
 
 
 
 
Consent and Authorization form  
X 
 
 
 
 
Baseline form  
X 
 
 
NEI-VFQ 
 
 
X 
 
X 
Follow-up form  
 
 
X 
X 
X 
Final form 
 
 
 
 
X 
Procedures 
 
 
 
 
 
 
Cross-linking 
X 
 
Tests 
 
 
 
 
 
IOP 
X 
 
X 
X 
X 
Pachymetry U/S 
X 
 
X 
X 
X 
Pentacam Topography 
X 
 
 
 
X 
Slit Lamp Photography* 
X 
 
 
X 
X 
BSCVA/ETDRS/MRx 
 
X 
 
X 
X 
Total visit time 
2 hours 
2 hours 
2 hours 
1 hour 
1 hour 
 
 
* Slit lamp photography also taken upon an adverse event 
 
 
3.6 Adverse Events (AEs) 
During each study visit, the subject will be questioned about AEs in a non-leading manner. All AEs, whether 
observed by the Investigator, elicited by the Investigator, or spontaneously reported by the subject, will be 
documented in the subject's chart and the adverse event form. Slit lamp photography will also be completed after 
any adverse event takes place.  
 
All AEs should be followed until they are resolved or until a stable clinical endpoint is reached. Each AE is to be 
classified by the Investigator as SERIOUS (SAE) or NONSERIOUS (NSAE). 
 
If a SAE occurs, the investigator at Aravind Eye Hospital, Madurai must fill out the serious adverse event form and 
email it to Stephen Mcleod at UCSF within 24 hours of the occurrence of the SAE. The investigator must provide 
written follow-up reports until the SAE or clinically significant AE has resolved or until a stable clinical endpoint is 
reached. Notification of an SAE or clinically significant AE must also be submitted to the Institutional Review Board 
(IRB)/Ethics Committee (EC) in accordance with its requirements. All AEs must be reported from the time that the 
subject provides informed consent through the last study visit.  
4. PROCEDURES 
4.1 Masking 
Due to the nature of the intervention, the study participant, surgeon and technician performing cross-linking will 
not be masked, however, the physician performing repeat scraping as well as the microbiologist will be masked to 
treatment arm. The refractionist performing the BSCVA will also be masked. UCSF study personnel will not be 
given any identifying information.  

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4.2 Procedures  
4.2.1 
Corneal Gram Stain and Culture  
After patient history and slit lamp examination at the enrollment visit (Day 0), corneal scraping is performed to determine 
the eligibility of the patient (positive fungal stain and negative bacterial stain). Corneal scraping is recommended as 
standard of care for all corneal ulcer patients at the Aravind Eye Hospitals. There is a small risk to patients of inducing a 
perforation, worsening an epithelial defect, or contaminating an ulcer, and patients are duly informed of these risks prior 
to the taking of the corneal scrape.  
 
Corneal scraping will be obtained as follows:  
 
A drop of topical anesthetic (0.5% tetracaine or 4% lidocaine) is administered to the eye to be examined.  
 
Aseptic technique is used to obtain each corneal scrape. A flame-sterilized Kimura spatula is used, with the aid of 
slit lamp magnification, to obtain a scrape from the leading edge and base of the corneal ulcer. The Kimura 
spatula is again flame sterilized between the takings of each sample.  
 
Two scrapings are smeared directly on to two separate glass microbiology slides for Gram stain and for KOH wet 
mount (if necessary, Giemsa or Gram Stain can be used to identify fungal elements as well). 
 
Three further scrapings are taken and directly inoculated on to sheep’s blood agar, chocolate agar, potato dextrose 
agar or Sabouraud’s agar for bacterial and fungal culture. 
 
 
4.2.2 
Collagen Cross-Linking 
All study participants randomized to collagen cross-linking will have cross-linking within 4 hours for bacterial 
ulcers and within 24 hours for fungal ulcers. They will be taken to the operating theatre and the procedure will 
be performed under sterile conditions.  
Cross-linking will be performed as follows: 
 
A drop of topical anesthetic (0.5% tetracaine or 4% lidocaine) is administered to the eye.  
 
A 30-minute loading dose of 0.1% topical riboflavin and 20% dextran T500 drops will be administered 
every 2 minutes. 
 
The cornea will be exposed to UV-A light at a wavelength of 365nm with irradiance of 3mW/cm2 for a 
total of 30 minutes. 
 
Throughout the UV-A treatment the study participant will continue to receive topical riboflavin Q5 min 
intervals during treatment. 
 
The study participant will be transferred back to the microbiology laboratory for repeat scraping and 
culture (see section 4.4.1). 
4.3 Pentacam Protocol 
Cornea densitometry and topography will be documented using the Pentacam HR (high resolution) 
Scheimpflug camera at baseline and 3 months.  The images will be captured using standardized protocols by 
study certified ophthalmic technicians. The data will then be shared with UCSF via Dropbox. 
 
In order to obtain the highest quality Pentacam HR Scheimpflug camera examination, the technician will scan 
the appropriate eye according to the Pentacam HR instruction manual.  
 

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4.3.1 
Imaging Procedures 
Corneal densitometry and topography measurement 
 
The examination will be performed in a designated diagnostic room with a uniform ambient light level.
 
To begin the corneal densitometry measurement, the technician will select the examination scan for 
cornea densitometry measurement, per the Pentacam HR manual.  
 
The cornea densitometry measurement will consist of a measurement protocol of 25 images under the 
examination mode of 3D scan.  
4.3.2 
Check Scan Quality 
 
If Quality Specifications (“QS”) field reads “OK,” then the measurement is correct and reproducible.  
 
If the “QS” field is highlighted YELLOW, the examination will be repeated until an “OK,” reading is
obtained.  
 
If the “QS” field is RED, then the examination must be repeated.  
 
If an “OK” reading is not obtainable, then the best of 3 examinations will be saved.  
4.3.3 
Saving Image 
 
Download data to excel or save to USB drive  
 
De-identify data 
o Patient names or any other identifying information such as birthday should not appear within 
any of the image files.  
 
Rename data 
o The image files will be designated with: 1) the eye ID number, 2) the timing of visit  ‘3m’, ‘6m’, or
‘12m’ respectively for the 3, 6, and 12-month follow-up visits, and 3) image number of the series. 
An image renamed to C101_3m_1.jpg will be the first image for eye number C101’s 3 month 
follow-up visit.  An image renamed to C222_12m_3.jpg will be the third image for eye 222’s 12 
month follow-up visit.  
 
Batch upload images to Dropbox. Procedures for uploading images to Dropbox:  
o Nagivate to Dropbox  eye’s folder  relevant study visit 
o Upload images to the eye’s relevant study visit folder 
 
5. STUDY MEDICATIONS 
5.1 Medical management protocol & Treatment Schedule  
All study participants will receive the same medical management in the initial 3 day study period. Table 2 outlines 
the dosing schedule for medications for CLAIR I and CLAIR II. Study participants will be randomized to medical 
management plus CXL versus medical management alone. This study requires 5 visits over 3 months including 
baseline visit, procedure visit, 3-day follow-up, 1 and 3-month follow-up. After the 3-day repeat culture visit 
additional treatments may be added per clinician preference including but not limited to topical and oral 
antimicrobials. 
 
 
 

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Table 2: Dosing schedule for Medications in the first 3 days. 
 
CLAIR I 
CLAIR II 
Moxifloxacin 0.5%  
Q 1 hours x 3 days 
 
Natamycin 5%  
 
Q 1 hour x 3 days*  
Amphotericin 0.15% 
 
Q 1 hour x 3 days* 
Homatropine 
TID x 3 days  
TID x 3 days 
*50% randomized to Natamycin 5% and 50% randomized to Amphotericin 0.15% 
 
5.2 Possible Side Effects of Study Medications 
 
Amphotericin: eye irritation, swelling, pain and/or redness, discharge 
 
Homatropine: eye irritation, swelling, pain, or redness; Eye dilation may result in temporary blurred vision, light 
sensitivity, and increased heart rate.  
 
Moxifloxacin: eye irritation, swelling, pain, or redness 
 
Natamycin: eye irritation, swelling, pain and/or redness, discharge 
 
6. PROTECTION OF HUMAN SUBJECTS 
6.1 Institutional Review Board Approval 
6.1.1 Aravind Eye Hospital, Ethics Review Committee The Ethics Committee with review the study protocol annually 
for ethical approval. 
 
6.1.2 University of California, San Francisco Committee on Human Research (CHR)  The UCSF CHR will review the 
study protocol annually for ethical approval. 
 
6.2 Informed Consent   
Aravind personnel will obtain full written consent from each patient. The primary surgeon will screen participants 
and determine their eligibility. He/she will clearly explain the process and risks involved and will also ask the 
patient to sign any necessary consent documents. The study participant will have 4 visits total per eye included in 
the study over 3 months; visits include hospitalization for the first 3 days and a procedure visit. The patient has the 

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ability to withdraw at any time and will not be forced into anything with which he/she is not comfortable.  Consent 
documents have been uploaded to the IRB application. 
 
6.3 Risks to Study Participants 
Blindness from infectious corneal ulcers is a worldwide public health problem. If our hypothesis is correct, and 
corneal crosslinking provides an additive benefit to topical antimicrobials in the treatment of corneal infections, 
there could potentially be a profound societal benefit. The process of corneal cross-linking is painless. Adverse 
events associated with corneal cross-linking appear to be exceedingly rare. A recent publication of 3-year follow-up 
of 100 keratoconus eyes, found two adverse events: one instance of corneal infection and one case of corneal 
edema, which resolved within one week.13 In a series of 16 patients with bacterial ulcers and presenting average 
visual acuity of approximately 20/100 (including one patient with 20/20 vision) no complications or side effects of 
treatment were observed.11 Additionally, a meta-analysis of the literature concerning cross-linking for infectious 
keratitis concluded that the available evidence supports the use of cross-linking for the treatment of infectious 
keratitis.5 All procedures will be performed by ophthalmologists board certified in the study country who are well 
versed in all planned treatment procedures. 
We anticipate minimal risk for study patients. This fact, coupled with the potential benefit the data provided by the 
study could provide in terms of guiding future therapies for corneal infections, makes the minimal risks posed to 
the patient entirely reasonable. 
 
There may be some discomfort during follow-up testing (BSCVA, IOP, slit lamp, Pachymeter, Topography, and photo 
imaging of the eye), but this will be kept to a minimum. The participant will be asked to tell the doctor if any of this 
testing feels painful. There may be a medication reaction such as eye irritation, swelling, pain, redness, or discharge. 
If this occurs the risks of stopping the medication must be weighed against the severity of infection and other 
treatment options.  
6.4 Privacy, Confidentiality and Data Security  
All data will be stored and transferred using a secure server with de-identified information. 
 
We will take steps to keep the participant’s personal information confidential. Health information will be kept 
secure and separate from information which identifies participants.  Upon enrollment, participants will be 
assigned a code that will be used instead of their name, medical record number or other personally identifying 
information. Electronic files for data analysis will contain only the participant code. The code will be stored at 
Aravind on a secure server and will only be accessed by study personnel – the PI, study coordinator, or other 
member of the study team). Access to study-related patient information will be limited only to members of the 
study team. 
 
Only a small number of researchers related to this study will have direct access to the participant’s medical 
information. Paper files will be stored in locked filing cabinets in restricted access offices at Aravind. Access to 
data/specimens is restricted to study personnel. 
 
Information may be released to others outside of Aravind who are involved in coordinating or overseeing research, 
but information which identifies the participant will be kept secure. To ensure the success of this study, Aravind 
has partnered with University of California, San Francisco (UCSF)’s   F.I. Proctor Foundation, which is a center that 
specializes in ophthalmology research. The coordinating center at UCSF will have access to de-identified 
information using a code number. UCSF’s role is to support Aravind on the data analysis portion of this study and 
assisting with the development of consent and study-related materials. UCSF has obtained IRB approval to take 
part in this study (IRB number: #14-14918). 

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6.5 Exclusion of Vulnerable Populations 
The following populations will not be enrolled in this study: children (18 years and under), pregnant women, 
decisionally impaired adults, and prisoners. 
6.6 Compensation to Participants 
There is no additional cost or compensation for the study participant.  
7. DATA COLLECTION AND MANAGEMENT 
7.1 Data Collection and Entry 
All data will be collected using hardcopy patient forms at Aravind during baseline and follow-up visits. De-
identified data will be uploaded to a Box account in order to share the data with the UCSF study coordinator. De-
identified data will be input into a database using double data entry at UCSF.  
7.2 Data Consistency, Validity, and Monitoring 
Data monitoring reports will be prepared using STATA and Excel. If the forms are not filled out completely, 
the UCSF study coordinator will contact the person responsible for completing the form to provide the missing 
data, or clarify any inconsistent data. The Aravind study coordinator is the only person who is authorized to add 
missing data or make any changes to the study forms.  All changes should be made with a red ink pen, and then 
signed and dated. 
7.3 Data Storage and Security 
De-identified data will then be input into a database using double data entry at UCSF. Data will be stored at UCSF 
for about 10 years. 
8. STATISTICAL ANALYSIS PLAN 
Please see the Statistical Analysis Plan (SAP) for details on the statistical analysis. 
 
 

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