Collagen Cross-Linking With Ultraviolet-A in Asymmetric Corneas
Phase: PHASE2
Conditions: Keratoconus, Corneal Diseases, Eye Diseases, Photosensitizing Agents
Sponsor: Cxlusa

CXLUSA, LLC. 
 
 
PAGE 1  
PROTOCOL CXL-005, REV. 04.3 
 
 05 MAY, 2017 
 
 
PROTOCOL NUMBER CXL-005 
Protocol Version:  Revision 04.3 
 
 
COLLAGEN CROSS-LINKING WITH ULTRAVIOLET-A 
IN ASYMMETRIC CORNEAS 
 
 
STUDY SPONSOR: 
CXLUSA, LLC 
CONTACT PERSON:  ROY RUBINFELD, M.D. 
11200 ROCKVILLE PIKE, SUITE 150 
ROCKVILLE, MD 20824 
PHONE:  (301) 908-8091 
 
 
STUDY PRINCIPAL INVESTIGATOR (PI): 
GREGG J. BERDY, M.D., F.A.C.S. 
ASSISTANT PROFESSOR OF CLINICAL OPHTHALMOLOGY 
WASHINGTON UNIVERSITY SCHOOL OF MEDICINE 
ST. LOUIS, MO 63110 
C/O OPHTHALMOLOGY ASSOCIATES 
12990 MANCHESTER ROAD, SUITE 200 
ST. LOUIS, MO 63131 
PHONE:  (314) 966-5000 
FAX:  (314) 909-6666 
 
 
The information in this document is confidential and will not be disclosed to others without 
written authorization from CXLUSA, LLC, except to the extent necessary to obtain informed 
consent from persons involved in the clinical study or their legal guardians, or for discussions 
with local regulatory authorities, institutional review boards (IRB), or persons participating in the 
conduct of the trial. 
 

CXLUSA, LLC. 
 
 
PAGE 2  
PROTOCOL CXL-005, REV. 04.3 
 
 05 MAY, 2017 
 
1.0 
PROTOCOL SUMMARY 
Protocol Number 
CXL-005, Revision 04.1 
Title 
Collagen Cross-Linking with Ultraviolet-A in Asymmetric 
Corneas 
Sponsor 
CXLUSA, LLC 
Regulatory Status 
Phase 2 investigational new drug study 
Objectives 
Assess changes in visual acuity and corneal symmetry after 
corneal collagen cross-linking (CXL) of asymmetric 
corneas. 
Study Design 
Prospective, randomized, controlled, open label, multicenter 
trial 
Study Population 
A total of 3,000 males and females >= 8 years old. 
Inclusion Criteria 
A diagnosis of at least one of the following conditions: 
1.  Keratoconus 
2.  Forme fruste keratoconus 
3.  Post-LASIK ectasia 
4.  Pellucid marginal degeneration 
5.  Forme fruste pellucid marginal degeneration 
6.  Diurnal fluctuation post-radial keratotomy 
7.  Terrien’s marginal degeneration 
 
Exclusion Criteria 
1.  Corneal thickness < 375 microns measured by  
     ultrasound or Pentacam. 
2.  Contraindications or hypersensitivities to any study  
     medications or their components. 
3.  Pregnancy or breastfeeding. 
4.  Any history of herpes simplex corneal disease in an eye to 
be treated. 
5.  Nystagmus or any other condition that would, in the 
     judgement of the investigator, prevent a steady gaze  
     during the treatment. 
6.  Inability to cooperate with diagnostic tests. 
7.  Enrollment in another ophthalmic clinical trial. 
Number of Centers 
21 
Investigational Product CXLO Corneal Strengthening Solution; ultraviolet-A 
illuminator. 
Study Procedures 
 
 
 
 
 
 
Pre-Procedure Screening 
Subjects will be instructed to remove contact lenses prior to 
screening – 2 weeks prior for rigid/gas permeable contact 
lenses and 3 days prior for soft or scleral lenses –  unless 
subject has no suitable vision correction option.  
Mandatory screening procedures include medical, prior 
ophthalmic surgery, and contact lens history, refractive 
assessments for manifest refraction, uncorrected visual 

CXLUSA, LLC. 
 
 
PAGE 3  
PROTOCOL CXL-005, REV. 04.3 
 
 05 MAY, 2017 
 
Study Procedures 
(cont’d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
acuity (UCVA), corrected distance visual acuity (CDVA), 
corneal thickness (ultrasound pachymetry or other 
scanning device such as Pentacam), Pentacam corneal 
tomography, intraocular pressure (IOP), slit lamp 
examination, and dilated fundus exam. 
 
Optional screening procedures include quality of life and/or 
comfort survey questions such as VFQ-25, ophthalmic 
assessments including corneal wavefront measurement, optical 
coherence tomography (OCT), Brillouin microscopy, iTrace 
wavefront aberrometry/topography, Orbscan corneal 
topography, tomography, contrast sensitivity testing, or other 
non-invasive diagnostic tools that may be available to an 
investigator, and previous ophthalmic history such as old 
eyeglass prescriptions and topographic maps. 
 
When eligibility has been established using the  
inclusion/exclusion criteria, the patient will be enrolled.  
 
Randomization 
Randomization will be stratified by indication and by 
investigational site among 3 UVA illumination groups 
consisting of: 
Group 1: 4 mW/cm2 cycled On/Off at 15 second intervals for 
20 minutes (total UVA corneal surface dose of 2.4 J/cm2), 
or 
Group 2: 6 mW/cm2 cycled On/Off at 15 second intervals for 
20 minutes (total UVA corneal surface dose of 3.6 J/cm2), 
or 
Group 3: 4 mW/cm2 cycled On/Off at 15 second intervals for 
30 minutes (total UVA corneal surface dose of 3.6 J/cm2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day of Cross-Linking Procedure 
One or both eligible eyes may be treated on the same day, or 
on different days. 
 
CXL Procedure 
A.   Instill anesthetic eye drops.  
B.   Insert lid speculum in each eye undergoing treatment. 
C.   Use a sterile ophthalmic sponge hydrated with saline or 
anesthetic drops to gently swab the surface of the cornea 
to remove mucus and any other debris and to enhance 
riboflavin penetration into the cornea. The epithelium is 
not to be removed, as treatment with an intact epithelium 
has the potential to halt progression of the disease while 
reducing post-procedure pain, complications related to  

CXLUSA, LLC. 
 
 
PAGE 4  
PROTOCOL CXL-005, REV. 04.3 
 
 05 MAY, 2017 
 
Study Procedures 
(cont’d) 
       epithelial debridement, and promoting faster vision 
recovery to baseline CDVA. 
D.   Apply a CXLO round loading sponge to the surface of the 
cornea to serve as a reservoir for CXLO Corneal 
Strengthening Solution. 
E.    Saturate the sponge with several drops of CXLO Corneal 
Strengthening Solution. Instill 1-2 drops of CXLO 
solution every 1-3 minutes for 10-90 minutes (this range is 
required as different corneas load at different rates and the 
surgeon will visually confirm sufficient stromal loading 
later in the procedure). Topical anesthetic drops may be 
used infrequently as needed (generally every 10 -15 
minutes) to maintain patient comfort. 
E.   After 10-20 minutes of saturation, remove the lid 
speculum.  Examine the eye using a slit lamp or a slit light 
to confirm uniform saturation of the cornea, referencing a 
“flip chart” of slit-lamp images, a copy of which is 
provided in Appendix 1.  If the cornea is not adequately 
saturated, repeat the CXLO solution application 
instructions above, and re-assess corneal saturation via 
slit-lamp or slit light examination every 5-10 minutes until 
adequate, uniform corneal saturation is confirmed.    
F.   After confirming adequate stromal saturation, irrigate the 
corneal epithelium with artificial tears for approximately 
30 seconds prior to UVA illumination to avoid the 
“sunscreen” effect of riboflavin in the epithelium. 
G.    Place the lid speculum(s) prior to UV light application. 
H.    Apply artificial tears every 30 to 60 seconds during UVA 
light application to avoid corneal drying. These artificial 
tear solutions may be stored overnight at room pressure 
under different atmospheric oxygen levels to test the 
effects of dissolved oxygen variations due to storage and 
altitude on cross-linking. 
I.    The total cumulative UVA dose will not exceed 3.6 
Joules/cm2. UV Irradiance will not exceed 6mW/cm2 and 
the UVA light will illuminate a 12 mm diameter area on 
one or both corneas for 10-30 minutes. The irradiance and 
duration of UV exposure will be recorded. 
J.   After completion of the procedure: 
1.   The lid speculum is removed. 
2.   PolytrimTM (or Floraquinolone or other appropriate 
broad spectrum antibiotic if the subject is hypersensitive) 
and anti-inflammatory drops are instilled. These may 
include Ciprofloxacin or Vigamox (or similar) and a 
nonsteroidal such as Voltaren, Acular or Xibrom. A 
topical steroid may also be instilled. 

CXLUSA, LLC. 
 
 
PAGE 5  
PROTOCOL CXL-005, REV. 04.3 
 
 05 MAY, 2017 
 
Clinical Parameters 
The following clinical parameters will be evaluated: 
 
1.   Corrected distance visual acuity  
2.   Uncorrected distance visual acuity 
3.   Slit lamp assessment 
4.   Corneal topography/tomography 
5.   Manifest refraction 
6.   Pachymetry 
7.  Intraocular pressure (IOP) 
8.  Maximum corneal curvature (Kmax) 
 
A schedule of assessment procedures is provided in Appendix 
2. 
Efficacy Endpoints 
Primary:  Change in corrected distance visual acuity (CDVA) 
at 6 months, compared to baseline. 
 
Secondary:  Change at 6 months as compared to baseline in: 
1.   Uncorrected distance visual acuity 
2.   KMax 
 
Statistical Methods 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Change from baseline will be calculated as follow-up visit – 
baseline. The baseline visit will be defined as Visit 1 (Pre-
procedure visit).  In general, continuous variables will be 
analyzed with two-sample t-tests for changes from baseline in 
normally distributed variables.  For non-parametric data sets, 
Wilcoxon Signed Rank tests will be utilized.  Patient 
demographics will be summarized using descriptive statistics 
(means, medians, standard deviations, etc.). 
 
Subject demographic characteristics and background variables 
will be summarized.  Treatment differences with respect to 
baseline characteristics will be discussed in the final study 
report and assessed.  
 
All subjects enrolled in the study will be included as part of the 
safety analysis.  All eyes treated (single or both eyes of an 
individual subject) will be included in the analysis of safety 
and efficacy. 
 
To determine efficacy, standard statistical methods such as p 
value analyses of continuous variables will be used along with 
newer artificial intelligence algorithms such as Logitboost or 
Random Forest to detect groupings and correlations of various 
outcome variables 1. Large data sets will be analyzed and in 
these analyses stratification by UVA irradiance and total dose, 
age, diagnosis, severity of disease, gender, tomography, 

CXLUSA, LLC. 
 
 
PAGE 6  
PROTOCOL CXL-005, REV. 04.3 
 
 05 MAY, 2017 
 
Statistical Methods 
(cont’d) 
topography metrics and other such criteria will be used to 
answer key questions related to the science and effects of 
treatments. 
 
Reference:  1Statistical Learning for Biomedical Data JD 
Malley, KG Malley, S Pajevic Cambridge University Press, 
2011) 
 

CXLUSA, LLC. 
 
 
PAGE 8 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
TABLE OF CONTENTS 
 
1.0 
PROTOCOL SUMMARY ....................................................................................... 2 
2.0 
BACKGROUND AND INTRODUCTION .......................................................... 10 
2.1 
DESCRIPTION OF INDICATION FOR USE ...................................................... 10 
2.2 
CURRENT TREATMENT AND LIMITATIONS ................................................. 11 
3.0 
STUDY DESIGN .................................................................................................. 11 
3.1 
OBJECTIVE .................................................................................................. 11 
3.2 
DESCRIPTION OF THE STUDY ...................................................................... 11 
3.3 
OUTCOME MEASURES ................................................................................ 11 
3.4 
STUDY POPULATION ................................................................................... 12 
4.0 
STUDY TREATMENTS ....................................................................................... 13 
4.1 
INVESTIGATIONAL TREATMENT .................................................................. 13 
5.0 
STUDY PROCEDURES ....................................................................................... 15 
5.1 
INFORMED CONSENT .................................................................................. 15 
5.2 
ASSIGNMENT OF SUBJECT IDENTIFICATION ................................................ 16 
5.3 
CONCOMITANT AND EXCLUDED THERAPIES ............................................... 16 
5.4 
TIMING OF STUDY ASSESSMENTS ............................................................... 16 
5.5 
WITHDRAWAL CRITERIA ............................................................................ 20 
5.6 
FOLLOW UP OF WITHDRAWN OR TERMINATED SUBJECTS .......................... 20 
6.0 
SAFETY PARAMETERS ..................................................................................... 20 
6.1 
DEFINITIONS OF ADVERSE EVENTS ............................................................. 20 
6.2 
ADVERSE EVENT ASSESSMENT AND DOCUMENTATION .............................. 21 
6.3 
ANTICIPATED ADVERSE EVENTS ................................................................ 24 
6.4 
SERIOUS ADVERSE EVENT AND UNANTICIPATED ADVERSE DEVICE EFFECT 
REPORTING ................................................................................................. 26 
7.0 
STUDY DISCONTINUATION ............................................................................ 27 
8.0 
 STATISTICAL PLAN .......................................................................................... 27 
8.1 
EFFICACY ENDPOINTS ................................................................................ 28 
8.2 
SAMPLE SIZE JUSTIFICATION ...................................................................... 28 
8.3 
SAFETY ....................................................................................................... 28 
9.0 
RECORD RETENTION ........................................................................................ 29 
10.0 
 STUDY MONITORING REQUIREMENTS ....................................................... 29 
11.0 
 PROTOCOL DEVIATIONS/AMENDMENTS ................................................... 29 

CXLUSA, LLC. 
 
 
PAGE 9 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
12.0 
 REFERENCES ..................................................................................................... 30 
APPENDIX 1:  FLIP CHART OF RIBOFLAVIN CORNEAL LOADING ..................................... 33 
APPENDIX 2: SCHEDULE OF ASSESSMENTS ..................................................................... 62 
APPENDIX 3:  UVA LIGHT CALIBRATION, CENTERING, AND APPLICATION INSTRUCTIONS63 
 

CXLUSA, LLC. 
 
 
PAGE 10 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
2.0 
BACKGROUND AND INTRODUCTION 
Asymmetric corneas involved in this study are those caused by a number of “orphan” diseases 
that markedly impair vision due to progressive corneal thinning, steepening, and/or irregular 
astigmatism.  These diseases include keratoconus, forme fruste keratoconus, post-LASIK ectasia, 
pellucid marginal degeneration, forme fruste pellucid marginal degeneration, diurnal fluctuation 
post-radial keratotomy, and Terrien’s marginal degeneration. 
Current non-surgical treatment alternatives include soft or rigid contact lenses or spectacles.  
However, as the disease progresses, these treatment modalities may not provide functional 
vision.  Implantable intracorneal ring segments have been shown to improve visual acuity, but 
they do not affect the underlying disease and are associated with several possible complications.  
As a result, a significant number of these patients have had no treatment alternatives other than 
corneal transplantation. 
Corneal collagen cross-linking has been shown to halt the progression of keratoconus (Raiskup-
Wolf et. al., 2008;  Wittig-Silva  et. al., 2008; Coskunseven et. al., 2009, Grewel et. al., 2009; 
Vinciguerra et. al., 2009, Agrawal 2009, Kymionis et. al., 2009; Caporossi et. al., 2010; 
Greenstein et. al., 2011; Mazzotta et. al., 2012; Pinelli and Marzouky 2009; Stojanovic et. al., 
2012; Rubinfeld et. al., 2013), as well as post-LASIK ectasia (Kymionis et. al., 2009, Greenstein 
et. al., 2011, Hovakimyan et. al., 2012), pellucid marginal degeneration (Spadea 2010), diurnal 
fluctuation post-radial keratotomy (Elbaz et.al 2014), and Terrien’s marginal degeneration 
(Hafezi 2014). 
The recent approval of the Avedro, Inc. system for corneal collagen cross-linking provides a 
method of stiffening the cornea to prevent progression of ectatic disease.  This procedure, 
however, requires the surgical debridement of the corneal epithelium, saturation of the cornea 
with riboflavin ophthalmic solution, and illumination with ultra-violet A (365 nm) radiation.  
Side effects of surgical epithelial debridement include prolonged pain, epithelial healing, and 
vision recovery.  In contrast, the procedure described in this application will not require 
epithelial debridement, and has the potential to halt progression of the disease while reducing 
post-procedure pain, and promoting faster vision recovery to baseline CDVA. 
2.1 
DESCRIPTION OF INDICATION FOR USE 
The indications for use during this study will be the treatment of asymmetric corneas diagnosed 
with one of the following conditions:  keratoconus, forme fruste keratoconus, post-LASIK 
ectasia, pellucid marginal degeneration, forme fruste pellucid marginal degeneration, diurnal 
fluctuation post-radial keratotomy, or Terrien’s marginal degeneration. 

CXLUSA, LLC. 
 
 
PAGE 11 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
2.2 
CURRENT TREATMENT AND LIMITATIONS 
There is currently no medical therapy in the United States that preserves the corneal epithelium 
for the treatment of corneal ectasia associated with keratoconus, forme fruste keratoconus, post-
LASIK ectasia, pellucid marginal degeneration, forme fruste pellucid marginal degeneration, 
diurnal fluctuation post-radial keratotomy, or Terrien’s marginal degeneration.  As a result, 
subjects who progress to severe disease must have more invasive procedures involving surgical 
removal of the epithelium, implantation of corneal rings, or penetrating keratoplasty.  
 
3.0 
STUDY DESIGN 
3.1 
OBJECTIVE 
The objective of this study is to assess changes in visual acuity after corneal collagen cross-
linking of asymmetric corneas. 
3.2 
DESCRIPTION OF THE STUDY 
Approximately 3,000 eligible subjects presenting with asymmetric corneas will be enrolled at  
21 clinical sites. 
The primary effectiveness analysis will be based on 6-month post-procedure assessments.  
Subjects will be assessed post-procedure day 1, at 3 months and at 6 months.  Visual acuity 
measurements and full ocular assessments (manifest refraction with CDVA, UCVA, slit lamp 
biomicroscopy including a rating of corneal haze, pachymetry, Pentacam corneal tomography, 
IOP) will be performed during that period.  
Optional 1 week, 1-2 month, 12-month, 24-month, and 36-month assessments will also be 
performed, at the discretion of the physician.  The 1-2 month visit may occur if the subject 
experiences changes in refractive error, and requires a new prescription for spectacles or contact 
lenses. 
Optional assessments including corneal wavefront measurement, optical coherence tomography 
(OCT), Brillouin microscopy, iTrace wavefront aberrometry/topography, Orbscan corneal 
topography, or other non-invasive diagnostic tests that may be available to an investigator, as 
well as quality of life and/or comfort survey questions may be performed during the study 
period. 
3.3 
OUTCOME MEASURES 
Effectiveness Outcome Measures 
The following will be evaluated 6 months after the cross-linking procedure: 
 
Primary effectiveness measure: 
Change in CDVA 
 

CXLUSA, LLC. 
 
 
PAGE 12 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
Secondary effectiveness measures:  
Change in UCVA 
Change in Kmax 
 
Safety Outcome Measures 
Safety will be evaluated by assessing the following: 
 
Adverse events (AEs) 
Serious adverse events (SAEs) 
3.4 
STUDY POPULATION 
Up to 3,000 subjects with asymmetric corneas will be enrolled.  After providing informed 
consent and documenting it in writing, subjects with keratoconus, forme fruste keratoconus, 
post-LASIK ectasia, pellucid marginal degeneration, forme fruste pellucid marginal 
degeneration, diurnal fluctuation after RK, or Terrien’s marginal degeneration will be screened 
for participation in the study. Screening evaluations may be performed at any time within 3 
months preceding or on Day 0, and subjects must fulfill the following criteria: 
Inclusion Criteria: 
1. Diagnosis of keratoconus, forme fruste keratoconus, post-LASIK ectasia, pellucid 
marginal degeneration, forme fruste pellucid marginal degeneration,  history of radial 
keratotomy with fluctuating vision, or Terrien’s marginal degeneration. 
2. Must have provided informed consent, documented it in writing, and have been given a 
copy of the signed informed consent form. 
3. Must be willing and able to return for scheduled treatment and follow-up examinations 
for the duration of the study. 
4. Must be at least 8 years of age. 
 
Exclusion Criteria: 
1. 
Corneal thickness < 375 microns measured by ultrasound or Pentacam. 
2. 
Contraindications or sensitivities to any study medications or their components. 
3. 
Pregnancy or breastfeeding. 
4. 
Any history of herpes simplex corneal disease in an eye to be treated. 
5. 
Nystagmus or any other condition that would, in the judgement of the investigator, prevent a 
steady gaze during the treatment. 
6. 
Inability to cooperate with diagnostic tests. 
7. 
Enrollment in another ophthalmic clinical trial. 
 
 

CXLUSA, LLC. 
 
 
PAGE 13 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
Randomization: 
Randomization will be stratified by indication and by investigational site, with study subjects 
randomly assigned to one of three treatment groups.  The three treatment groups consist of 
CXLO Corneal Strengthening Solution combined with one of 3 different UVA exposure 
parameters.  The UVA treatment parameters will consist of: 
• Group 1: 4 mW/cm2 cycled On/Off automatically at 15 second intervals for 20 minutes 
(total UVA corneal surface dose of 2.4 J/cm2), 
• Group 2: 6 mW/cm2 cycled On/Off automatically at 15 second intervals for 20 minutes 
(total UVA corneal surface dose of 3.6 J/cm2), and 
• Group 3: 4 mW/cm2 cycled On/Off automatically at 15 second intervals for 30 minutes 
(total UVA corneal surface dose of 3.6 J/cm2). 
 
4.0 
STUDY TREATMENTS 
4.1 
INVESTIGATIONAL TREATMENT  
One or both eligible eyes may be enrolled and procedure performed on the same day or on 
different days. Subjects eligible for enrollment will be instructed to instill Polytrim (or 
Floraquinolone or other appropriate broad spectrum antibiotic if the subject is hypersensitive) 4 
times daily into the eligible eye(s) one day prior to treatment 
 
A. Instill anesthetic eye drops.   
B. Place a lid speculum in each eye undergoing treatment.  
C.  Use a sterile ophthalmic sponge hydrated with saline or anesthetic drops to gently swab the 
surface of the cornea to remove mucus and any other debris and to enhance riboflavin 
penetration into the cornea. The epithelium is not to be removed, as treatment with an intact 
epithelium has the potential to halt progression of the disease while reducing post-procedure 
pain, complications related to epithelial debridement, and promoting faster vision recovery to 
baseline CDVA. 
D. Apply a sterile corneal sponge protector to the surface of the cornea to serve as a reservoir 
for CXLO Corneal Strengthening Solution.   
E. Saturate the sponge protector with several drops of CXLO Corneal Strengthening Solution.  
Thereafter, to assure for continuous application of CXLO solution to the surface of the 
cornea, keep the sponge moistened by applying 1-2 drops of CXLO solution every 1-3 
minutes for 10-90 minutes (this range is required as different corneas load at different rates 
and the surgeon will visually confirm sufficient stromal loading later in the procedure).  
F. After 10-20 minutes of saturation, remove the lid speculum.  Examine the eye using a slit 
lamp or slit light to confirm adequate saturation of the cornea, referencing the “flip-chart” of 
slit-lamp images, a copy of which is provided in Appendix 1.  If the cornea is not adequately 
saturated, repeat the CXLO Corneal Strengthening Solution application instructions above, 

CXLUSA, LLC. 
 
 
PAGE 14 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
and re-assess corneal saturation via slit-lamp or slit light examination every 5-10 minutes 
until adequate corneal stromal saturation is confirmed.  
G. After confirming adequate stromal saturation, irrigate the corneal epithelium with artificial 
tears for approximately 30 seconds prior to UVA illumination to avoid the “sunscreen” effect 
of riboflavin in the epithelium. 
H. Place the lid speculum(s) prior to UVA light application. 
I. Perform UVA illuminator calibration, centering of the beam, and application instructions in 
accordance with Appendix 3, which will result in a 12 mm diameter UVA spot size on the 
cornea. 
J. Perform UVA illumination in accordance with the UVA irradiance, dose, and 15 second 
on/off interval to which the subject has been randomized.  Magnetic treatment cards are 
provided, each of which are labeled with the respective randomization UVA treatment 
parameters specified in Section 3.4 above.  The 15-second UVA on/off interval is controlled 
automatically by the UVA illumination device.  To initiate the randomized UVA treatment 
cycle, swipe the respective magnetic treatment card through the magnetic card reader on the 
UVA illumination device.  Record the irradiance and duration of UVA exposure.  
K. Riboflavin solution is not to be instilled during UVA light application, due to the sunscreen 
effect of the riboflavin which would diminish UVA irradiance required for stromal cross-
linking.  Apply artificial tears/gels and/or other moistening solutions every 30-60 seconds 
during the UVA light application to avoid corneal drying.  These artificial tear solutions may 
be stored overnight at room pressure under different atmospheric oxygen levels to test the 
effects of dissolved oxygen variations due to storage and altitude on cross-linking. 
L. After completion of the procedure: 
1. The lid speculum is removed. 
2. PolytrimTM (or Floraquinolone or other appropriate broad spectrum antibiotic if subject is 
hypersensitive), and anti-inflammatory drops are instilled. These may include 
Ciprofloxacin or Vigamox (or similar) and a nonsteroidal such as Voltaren, Acular or 
Xibrom. A topical steroid may also be instilled. 
3. Post-procedure the surgeon may prescribe: 
i. 
Brand or generic PolytrimTM or other antibiotic qid (i.e. Ciprofloxicin or Vigamox). 
These drops may be continued for up to a week if surgical judgment suggests this 
might benefit the patient. 
ii. 
Topical nonsteroidal anti-inflammatory (i.e. Acular, Acuvail, Voltaren Xibrom) up 
to qid for up to 6 days postop.  
iii. 
Topical Steroid (FML, Pred Forte, Flarex, etc.) qid 4 days postoperatively,, 
although steroids can be used longer if corneal haze develops. 

CXLUSA, LLC. 
 
 
PAGE 15 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
iv. 
Topical anesthetic (e.g. Proparacaine 0.5% every 6 hours as needed for up to 24 
hours post-procedure). 
v. 
Over the counter oral analgesics such as ibuprofen, acetaminophen, or even 
narcotics may be taken for discomfort.  Prescription pain meds such as 
acetaminophen with an opiate and/or a gabapentin modulator such as Lyrica may 
also be prescribed short term for patient comfort.  Application of cold or ice packs 
may be recommended for improved comfort. 
M. Punctal plugs can be placed at the surgeon’s discretion if needed to improve the tear film. 
Treating both eyes on the same day: 
 
2 options: 
 
1. Sequential epithelium preparation, sequential UVA light administration:  Prepare 
epithelium in one eye, load the cornea with CXLO Corneal Strengthening Solution, then 
prepare the epithelium in the second eye prior to initiating the UV light source.  While 
one eye is receiving UVA light therapy, the other eye is receiving the loading dose of 
topical CXLO solution. 
2. Bilateral epithelium preparation, simultaneous UV light treatment:  Prepare epithelium in 
both eyes, and initiate CXLO solution drops in both eyes.  After 10-90 minutes of loading 
both eyes with riboflavin, the eyes will be checked with a slit lamp or slit beam check.  
UV light treatment in both eyes will then be performed.  
 
Post-Procedure Treatment Regimen Details: 
Topical corticosteroids and antibiotics as per standard surgeon regimen following other UV 
procedures such as PRK may be used.  Topical nonsteroidal medications and dilute anesthetic 
drops may be used as needed for early postop discomfort, but should be discontinued by post-
procedure day 6. 
 
5.0 
STUDY PROCEDURES 
5.1 
INFORMED CONSENT 
Prior to recruitment of any subjects into the study, written approval of the protocol, and informed 
consent and assent forms, must be obtained from the Institutional Review Board (IRB) for each 
participating clinical site. 
 
Informed consent and assent forms, the assent form being applicable to subjects less than 18 
years old, must be obtained and documented in writing prior to the initiation of any study 
procedures.  The subject (or the subject's legally authorized representative) and the minor (when 
applicable) must be allowed sufficient time to thoroughly read (or have explained) the respective 
consent/assent form, which will be written at a level that can be understood by someone with 
minimal education. 

CXLUSA, LLC. 
 
 
PAGE 16 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 
The Investigator or his/her designee should answer any questions that the subject/representative 
might have.  If the adult subject/parent/guardian and the minor, when applicable, agree to 
participate in the study, i.e., provides informed consent and assent, the subject/representative 
must sign both copies of the informed consent/assent forms.  The witness and the Investigator 
must also sign both copies of these forms.  One copy of these forms will be given to the 
subject/representative.  If applicable, it will be provided in a certified translation of the local 
language. 
 
Subjects who provide informed consent (and assent, if applicable) and document this in writing 
will be screened for eligibility.  Screened subjects will be recorded on site-specific screening 
logs and once they are determined as being eligible, they will be enrolled into the study. 
5.2 
ASSIGNMENT OF SUBJECT IDENTIFICATION 
A subject identification number (ID) will be assigned at screening.  This ID should be used on all 
study-related documents.  To maintain confidentiality, the subject’s name should not be recorded 
on any study document other than the informed consent form. 
5.3 
CONCOMITANT AND EXCLUDED THERAPIES  
Concomitant medications are any prescription drugs used by a subject during the study, until 
conclusion of study participation (Month 6-9) or early termination. The CRF will record 
administration of these medications. 
 
No other experimental or investigational treatments are allowed during this study, including 
ocular experimental and investigational treatments in either eye. 
5.4 
TIMING OF STUDY ASSESSMENTS 
All procedures will be performed according to the following schedule unless otherwise specified.  
When assessments are scheduled, subjects will be instructed to remove contact lenses prior to 
screening – 2 weeks prior for rigid/gas permeable contact lenses and 3 days prior for soft or 
scleral lenses –  unless subject has no suitable vision correction option.   
 
Pre-Procedure: 
Assessments: 
• UCVA 
• Manifest refraction 
• CDVA 
• Pentacam corneal tomography 
• Pachymetry by ultrasound or other scanning device such as Pentacam 
• Slit lamp examination 
• Intraocular pressure (IOP) 

CXLUSA, LLC. 
 
 
PAGE 17 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
• Dilated fundus exam (or documented dilated fundus exam by another provider within 1 
year) 
• Medial history 
• Contact lens history 
• History of previous eye surgeries 
Optional Assessments: 
• Quality of life and/or comfort survey questions such as VFQ-25. 
• Optional assessments including corneal wavefront, optical coherence tomography (OCT), 
Brillouin microscopy, iTrace wavefront aberrometry/topography, Orbscan corneal 
topography, tomography, contrast sensitivity testing, or other non-invasive diagnostic 
tools that may be available to an investigator. 
• Previous ophthalmic history such as:  
o Previous old eyeglass prescriptions & topographic maps may be requested and 
documented. 
o UCVA within the past 3 months (if evaluation was performed at the same clinic 
as that involved in this study); 
o CDVA within the past 3 months (if evaluation was performed at the same clinic 
as that involved in this study); 
o Manifest refraction within the past 3 months (if evaluation was performed at the 
same clinic as that involved in this study). 
 
Day 1 Post-Procedure:  
Assessments: 
• UCVA 
• Slit lamp examination 
 
Optional Assessments:   
• CDVA 
• Manifest Refraction  
• IOP  
• Pachymetry  
• Optional assessments including Pentacam corneal tomography, corneal wavefront, optical 
coherence tomography (OCT), Brillouin microscopy, iTrace wavefront 
aberrometry/topography, Orbscan corneal topography, tomography, contrast sensitivity 
testing, or other non-invasive diagnostic tools that may be available to an investigator. 
 
Optional Visit Days 2-10 (If Post-Procedure Day 1 shows incomplete epithelium healing): 
Assessments: 
• UCVA 
• Slit lamp exam 
• IOP 
 
 
 

CXLUSA, LLC. 
 
 
PAGE 18 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
Optional Assessments: 
• Manifest refraction and CDVA 
• Pachymetry  
• Optional assessments including Pentacam corneal tomography, corneal wavefront, optical 
coherence tomography (OCT), Brillouin microscopy, iTrace wavefront 
aberrometry/topography, Orbscan corneal topography, tomography, contrast sensitivity 
testing, or other non-invasive diagnostic tools that may be available to an investigator. 
 
Interim visits may also be suggested in which similar safe non-invasive measurements may be 
obtained.  Manifest refraction and non-contact corneal biomechanical and/or non-invasive 
biometry measurements may be obtained.  These non-invasive measurements can be performed 
as frequently as the surgeon believes would be useful, especially in circumstances where the 
patient’s vision and refraction can be expected to be changing rapidly. 
 
Optional 1-2 month visit: 
Some patients may experience significant changes in their refractive error, and may benefit from 
an optional visit at 1-2 months to get a new prescription for glasses or contact lenses.   
 
Assessments:   
• UCVA 
• Slit lamp exam  
• Pachymetry (ultrasound and/or Pentacam)  
• Pentacam corneal tomography  
• IOP 
 
Optional Assessments: 
• Optional assessments including corneal wavefront, optical coherence tomography 
(OCT), Brillouin microscopy, iTrace wavefront aberrometry/topography, Orbscan 
corneal topography, tomography, contrast sensitivity testing, or other non-invasive 
diagnostic tools that may be available to an investigator. 
• Manifest refraction  
• CDVA 
• Medical and contact lens history will be recorded  
 
Month 3 (60-120 days):  
Assessments:   
• UCVA 
• Manifest refraction with CDVA  
• Slit lamp exam (including rating of corneal haze if present from 0 (none) to 4)  
• Pachymetry (ultrasound and/or Pentacam) 
• Pentacam corneal tomography 
• Medical and contact lens history will be recorded.  
• IOP will be measured.  
 

CXLUSA, LLC. 
 
 
PAGE 19 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
Optional Assessments:   
• Quality of life and/or comfort survey questions. 
• Optional assessments including corneal wavefront, optical coherence tomography (OCT), 
Brillouin microscopy, iTrace wavefront aberrometry/topography, Orbscan corneal 
topography, tomography, contrast sensitivity testing, or other non-invasive diagnostic 
tools that may be available to an investigator. 
 
Month 6 (150-210 days): 
Assessments:   
• UCVA 
• Manifest refraction with CDVA  
• Slit lamp exam (including rating of corneal haze if present from 0 (none) to 4)  
• Pachymetry (ultrasound and/or Pentacam) 
• Pentacam corneal tomography 
• Medical and contact lens history will be recorded.  
• IOP will be measured.  
 
Optional Assessments:   
• Quality of life and/or comfort survey questions. 
• Optional assessments including corneal wavefront, optical coherence tomography (OCT), 
Brillouin microscopy, iTrace wavefront aberrometry/topography, Orbscan corneal 
topography, tomography, contrast sensitivity testing, or other non-invasive diagnostic 
tools that may be available to an investigator. 
 
Optional 1, 2, and 3 Year Post-Procedure Visits: 
Patients may elect to return for 1, 2, and 3 year post-procedure visits as well as interim visits as 
per surgeon judgment. 
 
Assessments: 
• UCVA  
• Manifest refraction with CDVA  
• Slit lamp examination (including rating of corneal haze if present from 0 (none) to 4)  
• Pachymetry (ultrasound and/or Pentacam) 
• Pentacam corneal tomography 
• Medical and contact lens history will be recorded.  
• IOP will be measured.  
 
Optional Assessments: 
• Patient may be asked to answer quality of life and/or comfort survey questions.  
• Optional assessments including corneal wavefront, optical coherence tomography (OCT), 
Brillouin microscopy, iTrace wavefront aberrometry/topography, Orbscan corneal 
topography, tomography, contrast sensitivity testing, or other non-invasive diagnostic 
tools that may be available to an investigator. 
 

CXLUSA, LLC. 
 
 
PAGE 20 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
Option for additional simultaneous or sequential treatments: 
 
• Patients may undergo a repeat CXL procedure following their 6-month visit.  Patients 
will exit the study on that visit, and then will be re-enrolled as a new patient, and must 
meet all of the inclusion and exclusion criteria, and investigators must follow the same 
protocol as outlined above. 
 
Unscheduled Visits 
 
Interim visits may also be suggested in which similar, safe, non-invasive measurements may be 
obtained.  Manifest refraction and non-contact corneal biomechanical and/or non-invasive 
biometry measurements may be obtained.  These non-invasive, measurements can be performed 
as frequently as the surgeon feels would be useful, especially in circumstances where the 
patient’s vision and refraction can be expected to be changing rapidly.  Only unscheduled visits 
related to adverse event follow up will be recorded in the CRFs. 
 
The timing of each scheduled assessment is summarized in Appendix 2. 
5.5 
WITHDRAWAL CRITERIA 
Subjects have the right to withdraw from the study at any time, for any reason, without 
jeopardizing their medical care. 
5.6 
FOLLOW UP OF WITHDRAWN OR TERMINATED SUBJECTS 
Subjects who withdraw from the study will be followed for safety where possible and 
encouraged to return for follow-up visits for any unresolved safety events. 
 
Subjects who withdraw from the study will be asked to complete procedures outlined in the 6-9 
month visit (if withdrawn prior to that visit).  Subjects who are terminated due to adverse events 
will be followed, if possible, at least until resolution or stabilization of the adverse event. 
 
6.0 
SAFETY PARAMETERS 
Safety assessments include adverse events/serious adverse events, visual acuity loss, slit lamp 
findings, and intraocular pressure.  The reporting time period is from the day cross-linking is 
performed through the last through the last study visit. 
6.1 
DEFINITIONS OF ADVERSE EVENTS 
An adverse event is any untoward and unintended sign, symptom or disease temporally 
associated with the use of an investigational drug or device, or other protocol-imposed 
intervention, regardless of the suspected cause.  Conditions or diseases that are chronic but stable 
should not be recorded on AE pages of the CRF.  Changes in a chronic condition of disease that 
are consistent with natural disease progression are NOT adverse events and also should not be 
recorded on the AE pages of the CRF.   
 

CXLUSA, LLC. 
 
 
PAGE 21 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 
6.1.1 Serious Adverse Events (SAE) 
An AE should be classified as an SAE and reported as such, if it meets one or more of the 
following criteria: 
• It results in death (i.e., the AE actually causes or leads to death) 
• It is life threatening (i.e., the AE places the subject at immediate risk of death) 
• It requires or prolongs inpatient hospitalization 
• It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions) 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product 
• It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical 
intervention to prevent one of the outcomes listed above) 
 
If a subject is hospitalized to undergo a medical or surgical procedure as a result of an 
AE, the event responsible for the procedure, not the procedure itself, should be recorded 
as the event. For example, if a subject is hospitalized to undergo coronary bypass surgery, 
record the heart condition that necessitated the bypass. 
 
Hospitalizations for the following reasons will not be recorded as SAEs: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for pre-existing conditions. 
• Hospitalization or prolonged hospitalization required to allow outcome measurement 
for the study. 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
 
6.1.2 Unanticipated Adverse Device Effects (UADE) 
An unanticipated adverse device effect (UADE) is any serious adverse effect on health or 
safety or any life-threatening problem or death caused by or associated with a drug or 
device, if that effect, problem, or death was not previously identified in nature, severity or 
degree of incidence.  Anticipated adverse events are identified in Section 6.3.  UADEs 
also include any unanticipated sight-threatening events and any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.  
6.2 
ADVERSE EVENT ASSESSMENT AND DOCUMENTATION 
All subjects who have been exposed to the study treatment will be evaluated for adverse events.  
All adverse events, regardless of severity and whether or not they are ascribed to the study 
treatment, will be recorded in the source documents and CRF using standard medical 
terminology.  

CXLUSA, LLC. 
 
 
PAGE 22 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 
All adverse events will be evaluated beginning with onset, and evaluation will continue until 
resolution is noted, or until the investigator determines that the subject’s condition is stable.  The 
investigator will take appropriate and necessary therapeutic measures required for resolution of 
the adverse event.  Any medication necessary for the treatment of an adverse event must be 
recorded on the concomitant medication case report form.  
 
All AEs will be characterized by the following criteria: 
• Date of onset 
• Event diagnosis 
• Intensity or severity 
• Expectedness 
• Relatedness to study treatment 
• Treatment or action taken. 
• Outcome 
 
Whenever possible, recognized medical terms should be used when recording AEs. Colloquialisms 
and/or abbreviations should not be used. Only one medical concept, preferably a diagnosis instead 
of individual symptoms, should be recorded as the event. 
 
If more than one distinct adverse event occurs, each event should be recorded separately. 
However, if known at the time of reporting, a diagnosis (i.e., disease or syndrome) should be 
recorded on the CRF rather than individual signs and symptoms.  However, if a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as a separate AE. A diagnosis 
that is subsequently established should be reported as follow-up information. However, signs and 
symptoms that are considered unrelated to an encountered syndrome or disease should be 
recorded as individual AEs. 
 
Adverse events occurring secondary to other events (e.g., sequelae) should be identified by the 
primary cause; a "primary" event, if clearly identifiable, should represent the most accurate 
clinical term to record as the AE event term.  For example: 
 
Orthostatic hypotension  Þfainting and fall to floor Þhead trauma Þneck pain 
 
The primary event is orthostatic hypotension and the sequelae are head trauma and neck pain. 
 
6.2.1 Classification of Adverse Events by Intensity/Severity 
All adverse events should be graded on a three-point scale (mild, moderate, severe) for 
intensity/severity, defined as a qualitative assessment of the level of discomfort of an adverse 
event as is determined by the Investigator or reported to him/her by the subject.  The assessment 

CXLUSA, LLC. 
 
 
PAGE 23 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
of intensity is made irrespective of study procedure relationship or seriousness of the event and 
should be evaluated according to the following scale:  
 
Mild:  
Awareness of sign or symptom, but easily tolerated. 
Moderate:  
Discomfort enough to cause interference with usual activity. 
Severe:  
Incapacitating with inability to work or do usual activity. 
 
There is a distinction between the severity and the seriousness of an adverse event. Severity is a 
measurement of intensity; thus, a severe reaction is not necessarily a serious adverse event 
(SAE). For example, a headache may be severe in intensity, but would not be serious unless it 
met one of the criteria for serious adverse events listed in Section 7.1.1. 
 
6.2.2 Expectedness 
All AEs will be evaluated as to whether they are expected or unexpected. 
  
Expected (anticipated): 
An adverse event is expected when the nature, severity, 
or degree of incidence was previously described.  
Expected adverse events are listed in 7.3. 
Unexpected (unanticipated): 
An adverse event is unexpected when the nature, 
severity, or degree of incidence was not previously 
described.  
 
6.2.3 Relatedness 
The study investigator will evaluate if the AE is related to the corneal cross-linking procedure.  
Relationship is defined in the following manner: 
  
Not related: The event is clearly related to other factors such as subject’s clinical state, 
therapeutic interventions, concomitant disease or therapy administered to the subject, and 
does not follow a known response pattern to the procedure. 
  
Related: The event follows a reasonable, temporal sequence from the time of 
procedure and/or follows a known response pattern to the study procedure and 
cannot be reasonably explained by other factors such as subject’s clinical state, 
therapeutic interventions, or concomitant therapy administered to the subject. 
 
6.2.4 Treatment or Action Taken 
Action taken in response to an adverse event will be recorded as: 
• None 
• OTC or Rx drug added 
• Non-drug treatment/procedure 
• Hospitalization or ER visit 
 
 
 

CXLUSA, LLC. 
 
 
PAGE 24 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
Action taken with study procedure will be recorded as: 
• None 
• Study procedure interrupted 
• Study procedure discontinued 
 
6.2.5 Outcome 
The clinical outcome of an AE will be characterized as follows: 
• 
Resolved without sequelae 
• 
Resolved with sequelae (specify) 
• 
Ongoing (i.e. continuing at time of study discontinuation) 
• 
Death 
• 
Unknown. 
6.3 
ANTICIPATED ADVERSE EVENTS 
Epithelial Defect – A breach in the corneal epithelium that does not heal within 24 hours. 
Persistent Epithelial Defect - A breach in the corneal epithelium that does not heal within 2 
weeks. 
Significant Decrease in Visual Acuity – loss of >2 lines CDVA 
Sterile Infiltrates – Gray-white lesions caused by acute immune response to corneal damage. 
Central Stromal Scars – New, significant corneal opacity in the central stromal region. 
Corneal Haze – Cloudy or opaque appearance of the cornea.  Grade Scale:  0 = clear cornea;  
1 = focal areas of minimal stromal clouding or reticulation; 2 = diffuse mild stromal clouding or 
reticulation; 3 = Diffuse stromal clouding or reticulation somewhat obscuring the iris details;  
4 = focal or diffuse areas of dense stromal haze obscuring iris detail. 
Infectious Keratitis – Microbial infection of the epithelium or stroma.  
Corneal Melt – A progressive, rapidly expanding, erosive, non-infectious, corneal ulcer. 
Non-Infectious Keratitis – Inflammation of the cornea not associated with an infection. 
Eye Pain – Eye pain lasting for >5 days. 
Conjectiva Hyperemia – Eye redness. 
Foreign Body Sensation – Patient reports a feeling of a foreign body (e.g. gravel or sand) in the 
eye lasting >24 hours. 
Corneal Hydrops – Acute corneal edema caused by a break in Descement membrane. 
Herpes Simplex Virus (HSV) Reactivation – Epithelial keratitis, stromal keratitis, or disciform 
edema proven or clinically diagnoses as being caused by HSV. 

CXLUSA, LLC. 
 
 
PAGE 25 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
Disease progression – Increase of >4D Kmax as assessed by topography or tomography or loss of 
> 2 lines of CDVA. 
Photophobia – Sensitivity to light lasting >24 hours. 
Elevated Intraocular Pressure (IOP) – IOP ≥30 mmHg or an increase in IOP of ≥10 mm from 
baseline recorded on two separate occasions or an increase in IOP that requires intervention. 
Dry Eye Syndrome (DES) – Irritation of corneal surface due to inadequate production of tears 
that is consistently worse than the patient’s pre-procedure state longer than 3 months after the 
cross-linking procedure. 
Endophthalmitis – Diffuse intraocular inflammation predominantly involving the vitreous 
cavity but also involving the anterior chamber, implying a suspected underlying infectious cause. 
Iritis – Presence of inflammatory cells in the anterior chamber.  The presence of aqueous flare 
alone is not considered to constitute iritis. 
Iridocyclitis – Presence of inflammatory cells in both the aqueous and vitreous. 
 
 

CXLUSA, LLC. 
 
 
PAGE 26 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
6.4 
SERIOUS ADVERSE EVENT AND UNANTICIPATED ADVERSE DEVICE EFFECT REPORTING 
Serious Adverse Events (SAE) and unanticipated adverse device effects (UADE) must be 
reported to the study sponsor (CXLUSA, LLC) and study Principal Investigator (PI) as soon as 
possible and no later than 24 hours after the investigator first learns of the event.   
 
For initial reports, investigators should record all case details that can be gathered within the 
reporting timeframe.  The contact information for CXLUSA and the PI is below: 
 
Study Sponsor: 
CXLUSA, LLC 
CONTACT PERSON:  ROY RUBINFELD, M.D. 
11200 ROCKVILLE PIKE, SUITE 150 
ROCKVILLE, MD 20824 
PHONE:  (301) 908-8091 
 
Study Principal Investigator: 
GREGG J. BERDY, M.D., F.A.C.S. 
ASSISTANT PROFESSOR OF CLINICAL OPHTHALMOLOGY 
WASHINGTON UNIVERSITY SCHOOL OF MEDICINE 
ST. LOUIS, MO 63110 
C/O OPHTHALMOLOGY ASSOCIATES 
12990 MANCHESTER ROAD, SUITE 200 
ST. LOUIS, MO 63131 
PHONE:  (314) 966-5000 
FAX:  (314) 909-6666 
 
Relevant follow-up information should be submitted to the sponsor as soon as it becomes 
available and/or upon request.  For some events, the sponsor or his designee may follow up with 
the site by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case 
details deemed necessary to appropriately evaluate the event (e.g., hospital discharge summary, 
consultant report, or autopsy report).  Reports relating to the subject’s subsequent medical course 
must be submitted to the study sponsor until the event has subsided or, in case of permanent 
impairment, until the event stabilizes and the overall clinical outcome has been ascertained. 
 
 

CXLUSA, LLC. 
 
 
PAGE 27 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
7.0 
STUDY DISCONTINUATION 
The study sponsor has the right to terminate participation of an investigator, or this study, at any 
time. Reasons for termination may include, but are not limited to, the following: 
• The incidence or severity of adverse events in this or other studies indicates a potential health 
hazard to subjects 
• Subject enrollment is unsatisfactory 
• Data recording is inaccurate or incomplete. 
• Study has reached maximal enrollment.  
 
8.0  
STATISTICAL PLAN 
Change from baseline will be calculated as follow-up visit – baseline.  The baseline visit will be 
defined as Visit 1 (Pre-procedure visit).  The required analyses and target endpoints include, but 
are not limited to those listed below.  In general, continuous variables will be analyzed with two-
sample t-tests for changes from baseline in normally distributed variables.  For non-parametric 
data sets, Wilcoxon Signed Rank tests will be utilized.  Patient demographics will be 
summarized using descriptive statistics (means, medians, standard deviations, etc.). 
 
Subject demographic characteristics and background variables will be summarized. Treatment 
differences with respect to baseline characteristics will be discussed in the final study report and 
assessed. 
 
All subjects enrolled in the study will be included as part of the safety analysis.  All eyes treated 
(single or both eyes of an individual subject) will be included in the analysis of safety and 
efficacy.  
 
To determine efficacy, standard statistical methods such as p value analyses of continuous 
variables will be used along with newer artificial intelligence algorithms such as Logitboost or 
Random Forest to detect groupings and correlations of various outcome variables.1 Large data 
sets will be analyzed and in these analyses stratification by age, diagnosis, severity of disease, 
gender, tomography, topography metrics and other such criteria will be used to answer key 
questions related to the science and effects of treatments. 
 
Reference:  1Statistical Learning for Biomedical Data JD Malley, KG Malley, S Pajevic 
Cambridge University Press, 2011). 
 
 

CXLUSA, LLC. 
 
 
PAGE 28 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
8.1 
EFFICACY ENDPOINTS 
The primary efficacy endpoint of this trial is change in corrected distance visual acuity (CDVA) 
at the last required study visit (6 months post-op), compared to baseline.  CDVA will be 
evaluated by an observer who is masked to the treatment protocol to which study subjects have 
been assigned. All eyes treated (single or both eyes of an individual subject) will be included in 
the analysis of efficacy. 
 
The Secondary Endpoints will be: 
1. Change in UCVA at 6 months, compared to baseline. 
2. Change in Kmax, compared to baseline. 
 
Additional analyses will be performed in subgroups of patients using standard statistical 
stratification methods, including patients over the age of 35, patients under the age of 18, disease 
severity, and patients with and without pre-procedure corneal scars.  Results in male vs. female 
patients and post LASIK ectasia vs. primary keratoconus will also be evaluated. 
8.2 
SAMPLE SIZE JUSTIFICATION 
Three thousand subjects will be enrolled in this open-label, prospective multicenter trial.   One or 
both eyes of each patient may be enrolled and evaluated, based on whether treatment is unilateral 
or bilateral, based on clinical indications.  All eyes treated (single or both eyes of an individual 
subject) will be included in the analysis of safety and efficacy.   
A substantial number of eyes will need to be treated and evaluated in this study in order to obtain 
sufficient data to facilitate the analysis of potential differences between and among patient 
groups for each study indication.  For example, it is expected that presenting disease severity, 
prior treatment (e.g. Intacs), subject age, and corneal thickness will impact the magnitude of 
effect of procedure efficacy for the treatment of keratoconus, forme fruste keratoconus, post-
LASIK ectasia, pellucid marginal degeneration, and forme fruste pellucid marginal degeneration.  
Accordingly, in order to perform analyses with adequate study power, a large sample size is 
required. 
A large sample size for a study involving fewer but similar indications is not unprecedented, as 
FDA clearance was previously granted for the conduct of a clinical study involving only 
keratoconus and post-LASIK ectasia (ref: http://clinicaltrials.gov/ct2/show/NCT01459679).  
Although that study was a Phase 3 clinical trial, it is expected that the study power needed to 
support analyses and conclusions of this proposed CXXLUSA study will be similar and further 
justifies the proposed sample size. 
8.3 
SAFETY 
AEs, SAEs, and other findings will be summarized by presenting the percentages of subjects 
with each event. Continuous endpoints will be summarized using summary statistics such as 
means, medians, standard deviations, minima, maxima, and relevant percentiles. 
 
 

CXLUSA, LLC. 
 
 
PAGE 29 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
9.0 
RECORD RETENTION 
The investigator shall maintain all subject records for a period of two years after the 
investigation is discontinued and FDA is notified. 
The investigator must maintain accurate records of the receipt of all investigational material 
shipped by the sponsor, including the date and lot numbers received. In addition, accurate 
records must be kept on the amount and date that the investigational material, by lot number, was 
used and for each subject.  
The investigator must assure that study supplies are used only in conjunction with subjects 
enrolled in the study and under the direct supervision of the investigator or co-investigators. 
 
10.0 
 STUDY MONITORING REQUIREMENTS 
CXLUSA, LLC, or designee, will monitor this study. Study monitoring involves the following 
elements: 
CXLUSA personnel, or designee, may meet in person or via teleconference with investigators 
prior to the initiation of the study in order to review the adequacy of the subject population, 
facilities, and equipment with respect to the needs of the study, and to familiarize the investigator 
and support staff with the study protocol. 
CXLUSA personnel, or designee, may meet in person or via teleconference with the investigators 
at the time enrollment is initiated in order to ensure that subjects are being properly selected, that 
the methods described in the study protocol are thoroughly understood by the investigator, and 
that study data are being correctly recorded. 
CXLUSA personnel, or designee, may visit in person or communicate via teleconference with the 
clinical site at any time during the course of the study to review and/or collect completed case 
report forms. Additionally, telephone consultation will occur as necessary during the course of 
the study to ensure the proper progress and documentation of the study findings. 
 
11.0 
PROTOCOL DEVIATIONS/AMENDMENTS 
An investigator may deviate from the protocol to protect the life or physical well-being of a 
subject in an emergency, and must notify the sponsor and the reviewing IRB within 5 working 
days after the emergency occurred.  Except in such an emergency, an investigator may not 
deviate from the protocol unless he/she obtains the prior approval of CXLUSA.  FDA and 
IRB/EC approval is also required in accordance with 812.35(a). 
 
 

CXLUSA, LLC. 
 
 
PAGE 30 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
12.0 
REFERENCES 
Agrawal VB. Corneal collagen cross-linking with riboflavin and ultraviolet - a light for 
keratoconus: results in Indian eyes. Indian journal of ophthalmology 2009;57(2):111–4. 
 
Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. Long-term results of riboflavin ultraviolet a 
corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. American 
journal of ophthalmology 2010;149(4):585-93.  
 
Coskunseven E, Jankov MR, Hafezi F. Contralateral eye study of corneal collagen cross-linking 
with riboflavin and UVA irradiation in patients with keratoconus. Journal of refractive surgery 
2009;25(4):371–6. 
 
Elbaz U, Yeung S, Ziai S, Lichtinger A, Zauberman N, Goldich Y, Slomovic A, Rootman D. 
Collagen Crosslinking After Radial Keratotomy,  Cornea 2014;33:131-136. 
 
Greenstein SA, Fry KL, Hersh PS. Corneal topography indices after corneal collagen 
crosslinking for keratoconus and corneal ectasia: one-year results. Journal of cataract and 
refractive surgery 2011;37(7):1282–90.  
 
Grewal DS, Brar GS, Jain R, Sood V. Singla M., Grewal SP. Corneal collagen crosslinking using 
riboflavin and ultraviolet-A light for keratoconus: one-year analysis using Scheimpflug imaging. 
Journal of cataract and refractive surgery 2009;35(3):425–32.  
 
Hafezi F, Gatzioufas Z, Seiler TG, Seiler T.  Corneal Collagen Cross-Linking for Terrien 
Marginal Degeneration.  J Refract Surg. 2014;30(7):498-500. 
 
Hovakimyan R, Guthoff R, Stachs O. Collagen cross-linking: current status and future directions. 
Journal of Ophthalmology 2012:1-12. 
 
Kymionis GD, Diakonis VF, Kalyvianaki M, Portaliou D. Siganos C. Kozobolis VP, Pallikaris 
Al. One-year follow-up of corneal confocal microscopy after corneal cross-linking in patients 
with post laser in situ keratosmileusis ectasia and keratoconus. American journal of 
ophthalmology 2009;147(5):774–8, 778. 
 
Mazzotta C, Caporossi T, Denaro R, Bovone C, Sparano C, Paradiso A, Baioccho S, Caporossi 
A. Morphological and functional correlations in riboflavin UV A corneal collagen cross-linking 
for keratoconus. Acta ophthalmologica 2012;90(3):259–65.  
 
Pinelli R and Marzouky M E-SH. Tensioactive-mediated Transepithelial Corneal Cross-linking – 
First Laboratory Report. Touch Briefings 2009:67–70. 
 
Raiskup-Wolf  F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and 
ultraviolet-A light in keratoconus: long-term results. Journal of cataract and refractive surgery 
2008;34(5):796–801.  
 

CXLUSA, LLC. 
 
 
PAGE 31 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
Rubinfeld R, Trattler T, Mrochen M, et al. Retrospective Evaluation of Epithelial-On Cross-
Linking (CXL) With Two Formulations of Riboflavin in Advanced Keratoconus.  Presented at 
the Annual Congress of the American Academy of Ophthalmology, November, 2013.  
 
Spadea L, Mencucci R. Transepithelial Corneal Collagen Cross-Linking in Ultrathin Keratoconic 
Corneas. Clinical Ophthalmology 2012;6:1785-92. 
 
Stojanovic A, Chen X, Jin N, Zhang T, Stojanovic F, Raeder S. Ultheim TP. Safety and efficacy 
of epithelium-on corneal collagen cross-linking using a multifactorial approach to achieve proper 
stromal riboflavin saturation. Journal of ophthalmology 2012;2012:498435.  
 
Vinciguerra P, Albè E, Trazza S, Rosetta P, Vinciguerra R, Seiler T, Epstein D. Refractive, 
topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal 
cross-linking. Ophthalmology 2009;116(3):369–78.  
 
Wittig-Silva C, Whiting M, Lamoureux E, et al. A Randomized Controlled Trial of Corneal 
Collagen Cross-linking in Progressive Keratoconus: Preliminary Results. J Refract Surg 
2008;24:S720–S725. 
 
 

CXLUSA, LLC. 
 
 
PAGE 32 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 
Revision History: 
 
Revision Effective Date 
Description of Changes 
00 
3 September, 2014 
Initial Release 
01 
2 October, 2014 
Study design modified to randomized controlled to 3 UVA 
treatment parameters.  
02 
13 April 2015 
Increased minimal corneal thickness to 375 microns ; added 
that CXLUSA will convene a DSMB to review safety 
information after 250 subjects are treated; modified 
performance of certain diagnostic procedures from “may be” to 
“will be” performed; clarified that “epi-off” is not one of the 
procedures to be performed. 
03 
9 November, 2015 
Pentacam tomography mandatory instead of optional pre-op 
and in mandatory follow up visits; added 3-year optional 
follow up; changed post riboflavin instillation wash with 
artificial tears from 3-5 minutes to approx. 30 seconds; added 
requirement to record “Date of Onset” of any adverse events; 
upgraded instructions for UVA light calibration, centering, and 
application (Appendix 3), other minor clarifications of existing 
requirements. 
04 
14 October, 2016 
Additional exclusion criteria added (nystagmus or any 
condition investigator believes would prevent steady gaze 
during treatment, inability to cooperate with diagnostic tests, 
enrollment in another ophthalmic trial); changed last required 
study visit from 8 months to 6 months post-op; changed 
mandatory assessment from 4 months to 3 months post-op; 
secondary endpoints changed from UCVA, Kmax, and manifest 
refraction spherical equivalent (MRSE) to UCVA and Kmax; 
deleted DSMB assessment after 250 subjects treated; CDVA to 
be assessed by masked evaluator; clarified that all eyes treated 
(single or both eyes of individual subject) will be included in 
analysis of safety and efficacy; clarified Sect. 4.1 that 
epithelium is not to be removed; other minor changes. 
04.1 
27 October, 2016 
Deleted “Official Correspondent: Geoffrey Hervey, JD” from 
cover page to avoid confusion as to parties to contact; clarified 
study population age in 1.0 Protocol Summary from > 8 years 
old to >= 8 years old; Sect. 4.1, corrected information related 
to same-day treatment options from “3 options” to “2 options”. 
04.2 
14 November, 2016 In response to IRB comments, changed exclusion criteria of 
“Active herpes simplex corneal disease” to “Any history of 
herpes simplex corneal disease in an eye to be treated” and 
changed post-op topical anesthetic from “Tetracaine 0.5% to 
0.05% PRN eye pain for up to 3 days” to “Proparacaine 0.5% 
every 6 hours as needed for up to 24 hours post-procedure”. 
 
 

CXLUSA, LLC. 
 
 
PAGE 33 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 
 
 
 
 
APPENDIX 1:  FLIP CHART OF RIBOFLAVIN CORNEAL LOADING 
 
 
 

CXLUSA, LLC. 
 
 
PAGE 34 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 35 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 36 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 37 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 38 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 39 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 40 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 41 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 42 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 43 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 44 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 45 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 46 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 47 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 48 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 49 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 50 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 51 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 52 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 53 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 54 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 55 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 56 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 57 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 58 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 59 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 60 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

CXLUSA, LLC. 
 
 
PAGE 61 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
 
 

 
CXLUSA, LLC. 
 
 
 
PAGE 62 
PROTOCOL CXL-005, REV. 04.3 
 
05 MAY, 2017 
1OR DOCUMENTED DILATED FUNDUS EXAM BY ANOTHER PROVIDER 
2BY ULTRASOUND OR OTHER SCANNING DEVICE SUCH AS PENTACAM 
3OPTIONAL ASSESSMENT PROCEDURES 
4OTHER ASSESSMENTS INCLUDE CORNEAL WAVEFRONT, OPTICAL COHERENCE TOMOGRAPHY (OCT), BRILLOUIN MICROSCOPY, ITRACE WAVEFRONT 
ABERROMETRY/TOPOGRAPHY, ORBSCAN CORNEAL TOPOGRAPHY, TOMOGRAPHY, CONTRAST SENSITIVITY TESTING, OR OTHER NON-INVASIVE DIAGNOSTIC 
TOOLS THAT MAY BE AVAILABLE TO AN INVESTIGATOR. 
 
 
APPENDIX 2: SCHEDULE OF ASSESSMENTS 
 
Pre-Procedure 
 
Post-Op Day 1 
  Optional Post-Op 
Days 2-10  
  Optional Post-Op 
Month 1-2 
Post-Op          
Month 3  
(60-120 Days) 
Post-Op  
Month 6 
(150-180 Days) 
Optional Post-Op 
1 Year 
 Optional Post-Op 
2 Year 
 Optional Post-Op 
3 Year 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History/Concomitant Medications 
X 
 
 
X3 
X 
X 
X 
X 
X 
Contact Lens History 
X 
 
 
X3 
X 
X 
X 
X 
X 
History of Prior Eye Surgery 
X 
 
 
 
 
 
 
 
 
Slit Lamp Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fundus Exam 
X1 
 
 
 
 
 
 
 
 
Intraocular Pressure (IOP) 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
Uncorrected Visual Acuity (UCVA) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corrected Distance Visual Acuity (CDVA) 
X 
X3 
X3 
X3 
X 
X 
X 
X 
X 
Manifest Refraction 
X 
X3 
X3 
X3 
X 
X 
X 
X 
X 
Pachymetry 
X2 
X3 
X3 
X 
X2 
X 
X 
X 
X 
Pentacam Corneal Topography/Tomography 
X 
X3 
X3 
X 
X 
X 
X 
X 
X 
Quality of Life Survey 
X3 
 
 
 
X3 
X3 
X3 
X3 
X3 
Prior Eyeglass Prescriptions, UCVA, CDVA, 
and Topographic Maps 
X3 
 
 
 
 
 
 
 
 
Other Optional Assessments 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 

CXLUSA, LLC. 
 
PAGE 63 
PROTOCOL CXL-005, REV. 04.3 
05 MAY, 2017 
 
 
 
 
 
 
APPENDIX 3:  UVA LIGHT CALIBRATION, CENTERING, AND APPLICATION INSTRUCTIONS 
 

CXLUSA, LLC. 
 
PAGE 64 
PROTOCOL CXL-005, REV. 04.3 
05 MAY, 2017 
 
 
UVA Light Calibration, Centering, and Application 
Instructions to Ensure Safe UVA Treatment 
 
NOTE: Please read the CXLUSA UVA Illumination System User’s Manual 
prior to initiating clinical use.  No patient is to be treated with UVA unless 
adequate corneal stromal riboflavin loading has been confirmed by slit lamp 
examination using the grading system defined in the Study Flip Chart.  
The UVA study device has a fixed, non-adjustable aperture. To achieve consistent 12 mm 
diameter circular UVA beam (for either 4 or 6 mW/cm2 treatment) the following steps must be 
performed prior to every cross-linking procedure.  
1. Put on a pair of safety glasses supplied with the UVA Illumination System. 
2. Turn ON the UVA Illumination Source, and allow 10 minutes for warm-up prior to 
calibration. 
3. Draw a 12 mm diameter circle on a white piece of paper. 
4. Place the external radiometer on a solid surface (cart, counter-top, etc.). 
5. Place the white piece of paper on top of the external radiometer. 
6. Set the Shutter Select Switch on the front of the UVA illumination source to “Open”. 
7. Set the selector on the front of the Power Control Box mounted on the pole with caster base 
to “Single,” to limit UVA output to the left emission aperture only. 
8. Swipe a “Calibration” magnetic card through the card reader to activate UVA illumination 
and confirm that the UVA light is on by observing a bright white spot on the white piece of 
paper.  
9. Adjust the distance from the left emission aperture optic to the paper until the beam spot 
size is the same as that of the 12 mm diameter circle, and record this distance. 
10. Remove the paper from the top of the radiometer, and by moving the radiometer from side-
to-side, verify that the 12 mm beam encompasses the entire area of the 9 mm diameter 
radiometer sensor. This assures that the radiometer will accurately measure UVA irradiance 
and that the UVA device will be properly calibrated. 
 
       
 
                           Incorrect                             Correct
9 mm diameter 
radiometer sensor 
covered by 12 mm 
diameter UVA beam 
¬ 

CXLUSA, LLC. 
 
PAGE 65 
PROTOCOL CXL-005, REV. 04.3 
05 MAY, 2017 
 
11. Turn the knob on the Intensity Adjustment box mounted on the pole with caster base 
clockwise/counterclockwise to adjust the UVA output to the desired irradiance (e.g. 4 
or 6 mW/cm2). 
12. If simultaneous, bilateral corneal cross-linking will be performed, turn the selector 
switch on the front of the Power Control Box to “Dual”.  Note that the LED on top of 
the control box is illuminated. 
13. Repeat calibration steps above to calibrate the right UVA emission aperture. 
14. After completion of calibration procedures, re-swipe the Calibration card to close the 
illumination source shutter. 
15. Ensure the patient is lying down in a comfortable position. Provide a pillow for their 
back or neck if needed to ensure comfort and reduce movement during the treatment.  
Instruct the patient to remain in this position without moving their head and, when 
necessary, repeat these instructions to avoid movement during the procedure. 
16. For treatment, position the UVA optic at the distance from the cornea that was 
previously measured to create a 12 mm diameter circle. This consistently provides a 
12 mm UVA beam spot size.  
17. Swipe a Treatment card labeled with the Randomization Group to which the patient 
has been randomized. 
18. Center the beam on the cornea.  This is easily performed since the UVA beam spot 
size is easily delineated by bright fluorescence of the riboflavin-loaded cornea, 
assuring for easy and consistent beam centration.  Use this fluorescence and easy 
visibility of the beam to confirm accurate positioning at the initiation UVA 
illumination, and throughout the Treatment procedure.  
If the patient moves, you will see the beam is off center. The image below shows a 
decentered beam that can be seen to not sufficiently cover the cornea (right yellow 
arrow) and to be decentered onto the eyelid (left yellow arrow).  During the UV 
procedure, the centration is monitored in this fashion in each eye. In this image, no 
speculum has been placed. In the current study, speculae will be placed which will 
also assist in centration and placement of the UVA beam making these even more 
accurate and safer. 
 
 
 
             Beam Properly Centered 
            Beam Off Center 

CXLUSA, LLC. 
 
PAGE 66 
PROTOCOL CXL-005, REV. 04.3 
05 MAY, 2017 
 
 
19. Monitor the patient’s cooperation and eye position during the dark cycle of treatment 
i.e. when the UVA light has been turned off by the illumination source shutter. If the 
patient tends to look away from the optic, this is obvious and the patient should be 
instructed to look straight ahead again.  
 
20. Be aware also of the cadence of UVA light turning on and off at consistent 15-second 
intervals. This is easily monitored by observation of the light turning on and off and 
by the audible sound of the illumination source shutter opening and closing.  
 
21. To ensure optimum accuracy and precision in calibration, radiometers should be 
replaced 12 months after receipt.