A Phase III, Multi-center Study to Evaluate the Safety and Efficacy of Epithelium-on Corneal Collagen Cross-linking in Eyes With Progressive Keratoconus
Phase: PHASE3
Conditions: Progressive Keratoconus
Sponsor: Glaukos Corporation

 
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A Phase III, Multi-center Study to Evaluate the Safety and Efficacy of 
Epithelium-on Corneal Collagen Cross-linking in Eyes with Progressive 
Keratoconus 
 
PROTOCOL NUMBER:    
 
ACP-KXL-308 
 
 
 
 
IND NUMBER: 
 
 
77,882 
VERSION: 
 
 
 
B  
SPONSOR:  
 
 
Avedro, Inc. 
 
 
 
201 Jones Road, 5th Floor West 
 
 
 
Waltham, MA 02451 
 
 
 
 
 
 
 
 
 
Phone: 781-768-3400 
 
 
 
Fax: 781-768-3401 
 
 
 
 
 
 
 
This protocol contains confidential, proprietary information which is the property of Avedro, Inc. 

 
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A Phase III, Multi-center Study to Evaluate the Safety and Efficacy of 
Epithelium-on Corneal Collagen Cross-linking in Eyes with Progressive 
Keratoconus 
 
SPONSOR CONTACTS 
 
Chief Medical Officer: 
 
 
 
    
Vice-President, Clinical Affairs: 
 
  
     
Medical Monitor: 
 
         
Medical Monitor: 
 
         
 
 

 
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group and 80 in the control group) provides approximately 80% power 
 
 
This 
  The sample size for this study is determined 
to be 275 eyes 
 
 

 
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TABLE OF CONTENTS 
SPONSOR CONTACTS .................................................................................................................................... 2 
PROTOCOL SYNOPSIS .................................................................................................................................... 3 
STUDY SCHEDULE .......................................................................................................................................... 8 
LIST OF ABBREVIATIONS ............................................................................................................................. 13 
1.0 
BACKGROUND AND RATIONALE ..................................................................................................... 14 
FIGURE 1:  MEAN CHANGE FROM BASELINE KMAX IN PATIENTS WITH PROGRESSIVE KERATOCONUS 
(UVX-001, UVX-002) ............................................................................................................................ 17 
2.0 
STUDY OBJECTIVES .......................................................................................................................... 19 
3.0 
OVERALL STUDY DESIGN ................................................................................................................. 19 
4.0 
STUDY POPULATION ....................................................................................................................... 20 
4.1 
NUMBER OF SUBJECTS ................................................................................................................ 20 
4.2 
STUDY POPULATION CHARACTERISTICS ..................................................................................... 20 
4.3 
INCLUSION CRITERIA ................................................................................................................... 21 
4.5 
WITHDRAWAL CRITERIA ............................................................................................................. 23 
5.0 
STUDY PARAMETERS ....................................................................................................................... 23 
5.1 
EFFICACY EVALUATIONS ............................................................................................................. 23 
5.1.1 
PRIMARY EFFICACY ENDPOINT ............................................................................................... 23 
5.1.2 
SECONDARY EFFICACY ENDPOINT .......................................................................................... 23 
5.2 
SAFETY EVALUATIONS ................................................................................................................. 23 
6.0 
INVESTIGATIONAL PRODUCT(S) ...................................................................................................... 24 
6.1 
 RIBOFLAVIN OPHTHALMIC SOLUTIONS (PARACEL 1 AND PARACEL 2 
[R0185])................................................................................................................................................... 24 
6.2 
0.0% RIBOFLAVIN OPHTHALMIC SOLUTION (PARACEL PLACEBO) .............................................. 25 
6.3 
UVA IRRADIATION SYSTEM (KXL HIGH POWER) ......................................................................... 25 
6.4 
OXYGEN DELIVERY SYSTEM ......................................................................................................... 25 
FIGURE 2:  
 (OXYGEN DELIVERY SYSTEM) ................................................................ 26 
6.5 
SUPPLY/LABELING/PACKAGING .................................................................................................. 26 
6.6 
STORAGE REQUIREMENTS .......................................................................................................... 26 
6.7 
ACCOUNTABILITY, RETURN, OR DISPOSAL OF TEST ARTICLE(S) ................................................. 27 
7.0 
RANDOMIZATION ............................................................................................................................ 27 
8.0 
STUDY PROCEDURES ....................................................................................................................... 28 

 
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8.1 
INFORMED CONSENT/HIPAA ...................................................................................................... 28 
8.2 
STUDY PROCEDURES ................................................................................................................... 29 
FIGURE 3: CXL TREATMENT FLOW ...................................................................................................... 32 
FIGURE 4: SHAM TREATMENT FLOW .................................................................................................. 34 
8.3 
SCHEDULE OF VISITS ................................................................................................................... 40 
8.4 
ADDITIONAL/UNSCHEDULED VISITS ........................................................................................... 42 
8.5 
STUDY TERMINATION ................................................................................................................. 42 
8.6 
SUBJECT STUDY DURATION ........................................................................................................ 42 
8.7 
MONITORING AND QUALITY ASSURANCE .................................................................................. 43 
9.0 
ADVERSE EVENTS ............................................................................................................................ 43 
9.1 
RELATIONSHIP OF TEST ARTICLE TO EACH ADVERSE EVENT ...................................................... 44 
9.2 
SEVERITY OF ADVERSE EVENT(S) ................................................................................................ 44 
9.3 
OUTCOME OF ADVERSE EVENT(S) .............................................................................................. 44 
9.4 
SERIOUS ADVERSE EVENTS AND SERIOUS UNEXPECTED SUSPECTED ADVERSE REACTIONS ..... 45 
9.5 
SERIOUS AND UNANTICIPATED ADVERSE DEVICE EFFECTS ........................................................ 46 
9.6 
NON-SERIOUS DRUG OR DEVICE OR ANTICIPATED DEVICE ADVERSE EVENTS .......................... 46 
9.7 
PROCEDURES FOR REPORTING ADVERSE EVENTS ...................................................................... 46 
9.8 
PROCEDURES FOR REPORTING A SERIOUS ADVERSE EVENT ...................................................... 47 
10.0 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .............................................................. 48 
10.1 
GENERAL METHODS .................................................................................................................... 48 
10.2 
STUDY POPULATIONS .................................................................................................................. 48 
10.3 
EFFICACY VARIABLES ................................................................................................................... 48 
10.4 
SAMPLE SIZE ................................................................................................................................ 49 
10.5 
PRIMARY EFFICACY ANALYSES .................................................................................................... 49 
10.6 
SECONDARY EFFICACY ANALYSES ............................................................................................... 50 
 
 
10.8 
SAFETY ANALYSIS ........................................................................................................................ 50 
10.9 
ADDITIONAL ANALYSIS ................................................................................................................ 51 
11.0 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL CONSIDERATIONS, AND 
ADMINISTRATIVE ISSUES ............................................................................................................................ 52 
11.1 
PROTECTION OF HUMAN SUBJECTS ........................................................................................... 52 
11.2 
RECORDING OF DATA ON SOURCE DOCUMENT AND ELECTRONIC CASE REPORT FORMS 
(ECRFS) .................................................................................................................................................... 54 

 
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11.3 
CHANGES IN THE CONDUCT OF THE STUDY ............................................................................... 54 
APPENDIX A: ASSESSMENT INSTRUCTIONS ................................................................................................ 55 
APPENDIX B: NATIONAL EYE INSITUTE VISUAL FUNCTIONING QUESTIONNAIRE 25 (VFQ-25) .................. 59 
REFERENCES ........................................................................................................................................ 69 
 

 
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1.0 
BACKGROUND AND RATIONALE 
Keratoconus is a naturally occurring ocular condition characterized by progressive thinning and steepening 
of the central cornea. As a result of this weakening, the cornea protrudes under the force of intraocular 
pressure and bows outward. This creates progressive steepening and thinning of the cornea, irregular 
astigmatism, and loss of uncorrected visual acuity (UCVA) and best spectacle-corrected visual acuity 
(BSCVA). Rigid contact lenses can be used to improve visual acuity in patients, but keratoconus can progress 
to the point that corneal transplantation is required to restore useful vision. 
Keratoconus is the most frequent, known indication for corneal transplantation, accounting for about 15% 
of the corneal transplants performed in the United States.1 Corneal transplantation has inherent risks that 
could result in permanent loss of vision and significantly impact the patient’s quality of life during the 
surgical recovery phase, with lost work time and often permanent changes in lifestyle. Any modality, such 
as corneal collagen cross-linking, that can delay or prevent corneal transplantation in patients with these 
conditions is of great benefit. 
Riboflavin 5’-phosphate sodium (Vitamin B2) is the precursor of two coenzymes, flavin adenine 
dinucleotide and flavin mononucleotide, which catalyze oxidation/reduction reactions involved in a 
number of metabolic pathways.  When used in conjunction with ultraviolet A light (UVA), riboflavin 5’-
phosphate acts as a photoenhancer and generates singlet oxygen which is responsible for cross-linking of 
collagen. 
The corneal collagen cross-linking procedure is intended to improve the biomechanical properties of the 
cornea by strengthening the corneal tissue in the anterior stroma. Corneal collagen cross-linking is 
performed by pretreating the cornea with riboflavin ophthalmic solution before UVA (365 nm) exposure. 
Exposure of the cornea to the UVA after topical administration of riboflavin has been shown to induce 
cross-linking of the corneal collagen fibrils with a resultant increase in tensile strength and diameter of the 
collagen fibrils. Clinically, cross-linking has been shown to stabilize the corneal curvature in eyes with 
keratoconus.  
Corneal collagen cross-linking using riboflavin and UVA was first used clinically in 1998 in Dresden, 
Germany. 2 Since then, corneal cross-linking has been studied and clinically used worldwide for the 
treatment of ectatic disorders, including keratoconus. 3-10   
The corneal cross-linking procedure using the riboflavin ophthalmic solutions PHOTREXA® VISCOUS and 
PHOTREXA® and the KXL® System was approved by the U.S Food and Drug Administration (FDA) in 2016 
for the treatment of progressive keratoconus and corneal ectasia following refractive surgery.  
The approved cross-linking procedure entails debridement of the epithelium (epithelium-off) to allow for 
penetration of the riboflavin into the stroma. The epithelial removal/debridement commonly produces 
pain, redness, light sensitivity, a temporary decrease in vision (caused by an irregularity in the corneal 
surface as the epithelium re-surfaces the cornea), and an increase in susceptibility to infection. 
This current study is being conducted to assess the safety and efficacy of corneal collagen cross-linking 
without epithelial debridement (epithelium-on) in eyes with progressive keratoconus. The epithelium-on 
procedure consists of a riboflavin formulation containing a permeability enhancer that allows riboflavin 

 
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diffusion to the corneal stroma without the need to remove the epithelium.  This is followed by UVA 
irradiation with supplemental oxygen. It is expected that the epithelium-on corneal cross-linking procedure 
will be efficacious in reducing or halting the progression of keratoconus without the risks associated with 
epithelial removal.  
Nonclinical Experience 
Nonclinical studies have been conducted to evaluate the safety of transepithelial riboflavin formulations 
containing benzalkonium chloride (BAC) as a permeability enhancer, as well to establish the safety of 
transepithelial corneal cross-linking in the presence of supplemental oxygen.   
GLP Rabbit Ocular Irritation Study 
An ocular irritation and safety study was performed under good laboratory practices, evaluating the ocular 
safety of riboflavin formulated with different concentrations 
 
 after acute 
topical ocular dosing in New Zealand White rabbits.  
 
 
 
 
 
 
 
 
No abnormal 
findings or gross lesions were observed upon necropsy and no adverse clinical observations were reported 
throughout the life of the study. 
Non-GLP Rabbit Study 
The objective of this non-GLP study was to evaluate the safety of corneal cross-linking procedure related 
to stromal haze and corneal swelling in normoxic and hyperoxic environments in the rabbit. This study 
consisted of 3 groups of 2 or 4 female New Zealand White rabbits. Animals underwent a single procedure 
on Day 0 in which the right eye was treated with VibeX Rapid™ 
 after 
epithelial debridement or ParaCel™ 
 and VibeX 
Xtra™ with or without oxygen therapy. All Groups received UV light administered 
 
 pulsed 1 second on, 1 second off, for a total of 8 minutes. A balanced salt solution (BSS) was 
applied during UV light administration every minute to keep the eye moist until the UVA illumination was 
complete. 
 
 
 
 
 
 
 

 
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 There was no evidence of endothelial loss in treated 
corneas in all animals in all 3 groups. 
Previous Human Experience 
FDA approved Avedro’s corneal collagen cross-linking products Photrexa Viscous, Photrexa and the KXL 
System for use in corneal collagen cross-linking in the treatment of progressive keratoconus and corneal 
ectasia following refractive surgery in 2016.  The approved cross-linking procedure entails debridement of 
the epithelium (epithelium-off) to allow for penetration of the riboflavin into the stroma.   
Approved Epithelium-off Corneal Cross-linking (5.4 J/cm2) 
The safety and effectiveness of riboflavin ophthalmic solution and UVA irradiation (365 nm; 3 mW/cm2) for 
performing corneal collagen cross-linking (with epithelial debridement) in eyes with progressive 
keratoconus were evaluated in two prospective, open-label, randomized, sham-controlled trials in the U.S. 
(Studies UVX-001 and UVX-002).  One eye of each subject was deemed the study eye and randomized to 
receive either the corneal cross-linking (CXL) procedure or the sham procedure.  Patients were followed 
for safety and efficacy for 12 months after the CXL procedure.  Patients who received the sham procedure 
were able to receive the CXL procedure in their study eyes 3 months after the sham procedure.  Study UVX-
001 enrolled 58 progressive keratoconus patients and 49 post refractive surgery corneal ectasia patients.  
Study UVX-002 enrolled only progressive keratoconus patients (147 patients).   
In Studies UVX-001 and UVX-002, the average age of keratoconus subjects was 33 years and the average 
baseline maximum corneal curvature (Kmax) was 61 diopters (D).  At Month 12 in study UVX-001, the CXL 
treated keratoconus eyes had an average Kmax reduction of 1.4 D compared to an average increase in Kmax 
of 0.5 D in the sham treated eyes for a difference of 1.9 D between the treatment groups.  In study UVX-
002 at Month 12, the CXL treated eyes had an average Kmax reduction of 1.7 D compared with an average 
increase in Kmax of 0.6 D in the sham treated eyes for a difference of 2.3 D between the treatment groups 
(see Figure 1).  

 
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Figure 1:  Mean Change from Baseline Kmax in Patients with Progressive Keratoconus (UVX-
001, UVX-002) 
Post-baseline missing data were imputed using last available Kmax value.  For the sham study eyes that 
received the cross-linking treatment after baseline, the last Kmax measurement recorded prior to receiving 
cross-linking treatment was used in the analysis at later time points.   
 
In progressive keratoconus subjects, the most common ocular adverse reactions in any CXL-treated 
eye were corneal opacity (haze), punctate keratitis, corneal striae, corneal epithelium defect, eye 
pain, reduced visual acuity, and blurred vision. These events are expected sequelae following 
epithelial corneal debridement and occurred at a higher incidence than observed in control (sham 
group) subjects, who did not undergo debridement or UV exposure.  The majority of adverse 
events reported resolved during the first month, while events such as corneal epithelium defect, 
corneal striae, punctate keratitis, photophobia, dry eye, and eye pain, and decreased visual acuity 
took up to 6 months to resolve.  Corneal opacity or haze took up to 12 months to resolve.  In 1-2% 
of subjects, corneal epithelium defect, corneal edema, corneal opacity and corneal scar continued 
to be observed at 12 months.  
 
US Clinical Studies of Epithelium-off Corneal Cross-linking 
 
Studies KXL-001 and KXL-002 were Phase 3, multi-center, randomized, placebo-controlled studies 
of the safety and efficacy of high power/accelerated corneal collagen cross-linking performed with 
UVA irradiation 
 and 
 riboflavin ophthalmic solution
 in 
eyes with keratoconus.  In these studies, the cross-linking was performed after removal of the 
epithelium (i.e., epithelium off) and the cornea irradiated 
 continuously for 4 minutes 
. These studies are completed and data analysis is in progress. 
 
 
 

 
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Dose Escalation, Safety Study of Epithelium-on Corneal Cross-linking 
 
 
A study being performed at the Singapore National Eye Centre in Singapore was designed to 
evaluate the safety of trans-epithelial corneal cross-linking. This Phase 1 study is being conducted 
in blind eyes with normal corneas. Cross-linking is performed with the epithelium intact, a two part 
trans-epithelium riboflavin formulation 
 
 a high-power UVA Irradiation System 
.  
Three sequential dose groups with 3 subjects in each group are planned. Dosing for each 
subsequent group will be initiated after all subjects in the preceding group have completed their 1 
week follow-up and no dose-limiting toxicities are observed.  
All subjects are being evaluated at screening, Days 0 (treatment day) and 1, week 1, and 1 and 3 
months after treatment. Study evaluations include slit lamp evaluations, corneal tomography, 
anterior segment OCT, specular microscopy and adverse event (AE) query.  
To date, five (5) subjects 
 have been enrolled and treated in this Phase 
1 study. Three (3) subjects were assigned to Dose Group 1 
 No serious AE has 
been reported. 
 
 
 
 
 
 
 
  
Two (2) subjects have been enrolled and treated in Dose Group 2 
 
 
 
  
Together, these clinical and nonclinical data support the investigation of epithelium-on corneal 
cross-linking as described in this clinical protocol for the treatment of progressive keratoconus.  
 

 
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Post-procedure, eyes will be assessed at Day 1, Day 3, Week 1, Months 1, 3, 6, and 12. Additional 
clinical visits may be scheduled at the discretion of the Investigator. Pentacam measurements, 
manifest refraction, Uncorrected Visual Acuity (UCVA), Best Spectacle Corrected Visual Acuity 
(BSCVA), specular microscopy, dilated fundus examination, Optical Coherence Tomography (OCT) 
(in a subset of study eyes), and intraocular pressure (IOP) will be obtained at baseline and at the 
specified times after the treatment.  Safety monitoring throughout the study will include 
observations at appropriate times for AEs, new findings on ophthalmic examination, dilated 
fundus examination, and slit lamp examination.  Quality of vision will be evaluated pre-treatment 
and post-treatment with a vision related quality of life questionnaire. 
Post-procedure follow-up visits and assessments will be contingent on the type of study 
treatment: 
CXL Treatment Group: Post-procedure, study eyes in the CXL Treatment group will be 
assessed at Day 1, Day 3, Week 1, Months 1, 3, 6, and 12.  Additional clinical visits may 
be scheduled at the discretion of the Investigator.  
Sham Treatment/Control Group: Post-procedure, study eyes in the Sham 
Treatment/Control group will be followed through Month 6 with assessments at Day 1, 
Day 3, Week 1, Months 1, 3, and 6.  
 
 
   
 
 
  
 
 
 
 
   
 
4.0 
STUDY POPULATION 
4.1 
Number of Subjects 
Up to 275 study eyes with progressive keratoconus will be enrolled to provide at least 240 (160 in 
the CXL treatment group and 80 in the control group) evaluable eyes for the primary efficacy 
endpoint. Each Investigator is expected to contribute at least 5 evaluable study eyes and no 
Investigator should treat more than 60 study eyes. 
4.2 
Study Population Characteristics 
This study is a multicenter study that will be conducted at up to 20 investigational sites in the 
United States in approximately 275 eyes with progressive keratoconus.   

 
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4.3 
Inclusion Criteria 
Subjects must meet all of the following criteria in order to be enrolled into the trial.  Both eyes 
must be evaluated for inclusion criteria specific to ocular conditions:  
1. Be between 12 and 55 years of age, male or female, of any race; 
2. Provide written informed consent and sign a HIPAA form. Subjects who are under the 
age of 18 (or have not yet reached the age of majority per local regulations) will need to 
sign an assent form as well as having a parent or legal guardian sign an informed 
consent; 
3. Ability to read English or Spanish to complete the NEI-VFQ 25 questionnaire; 
4. Willingness and ability to follow all instructions and comply with schedule for follow-up 
visits; 
5. For females capable of becoming pregnant, agree to have urine pregnancy testing 
performed prior to randomization of each study eye 
; must not be lactating, and must agree to use a medically acceptable form of 
birth control for at least one week prior to the randomization visit, 
 
and continue to use the method for one month 
following 
 treatment. Acceptable forms for birth control are spermicide with 
barrier, oral contraceptive, injectable or implantable method of contraception, 
transdermal contraceptive, intrauterine device, or surgical sterilization of partner. For 
non-sexually active females, abstinence will be considered an acceptable form of birth 
control. Women considered capable of becoming pregnant include all females who have 
experienced menarche and have not experienced menopause (as defined by 
amenorrhea for greater than 12 consecutive months) or have not undergone successful 
surgical sterilization (e.g. hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy); 
6. Having topographic and clinical evidence of keratoconus defined as the following: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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4.4 
Exclusion Criteria 
Subjects must not meet any of the following criteria in order to be enrolled into the trial.  Both 
eyes must be evaluated for exclusion criteria specific to ocular conditions: 
1. Contraindications, sensitivity or known allergy to the use of the test article(s) or their 
components; 
2. If female, be pregnant, nursing or planning a pregnancy or have a positive urine pregnancy 
test prior to the randomization or treatment of either eye or during the course of the 
study; 
3. 
 
; 
4. 
 
 
 
 
 
 
7. Previous ocular condition (other than refractive error) in the eye to be treated that may 
predispose the eye for future complications.
 
 
 
 
 
 
8. A history of delayed epithelial healing in the eye to be treated or a current condition that 
may interfere with or prolong epithelial healing; 
 
10. A history of previous corneal cross-linking treatment in the eye to be treated; 
11. Have used an investigational drug or device within 30 days of screening or be concurrently 
enrolled in another investigational drug or device trial within 30 days of the study. 

 
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In addition, the Investigator may exclude or discontinue any subject for any sound medical 
reason.  
4.5 
Withdrawal Criteria 
Subjects will be advised that they are free to withdraw from the study at any time.  Subjects 
experiencing adverse safety events will be followed until the event resolves or stabilizes, or until 
the subject completes the study, whichever is first.  The Investigator may discontinue a subject if a 
Serious Adverse Event (SAE) occurs and it is in the subject's best interest not to continue in the 
study. When a subject withdraws early from the study, a final examination will be performed at 
the time of withdrawal, if possible. Subjects withdrawn from the study will not be replaced. 
 
5.0 
STUDY PARAMETERS 
5.1 
Efficacy Evaluations 
The following parameters will be assessed as measures of efficacy of the cross-linking treatment: 
• 
 
 
 
 
 
 
 
 
5.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean change from baseline in maximum corneal curvature 
(Kmax between the CXL treatment group and the Sham treatment/control group at Month 6. 
 
5.1.2 Secondary Efficacy Endpoint 
The secondary efficacy endpoint is the mean change from baseline in maximum corneal curvature 
(Kmax between the CXL treatment group and the Sham treatment/control group at Month 12. 
 
 
 
5.2 
Safety Evaluations 
The following safety parameters will be assessed: 
• 
Incidence of treatment emergent ocular AEs reported during the study 
• 
Percentage of eyes with loss in BSCVA of 3 lines or more from pre-treatment baseline 

 
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6.6.3 
Study Materials 
All test article(s) and unused 
 must be stored in a locked area with access 
limited to the Investigator and designated personnel. The temperature of test article storage room 
should be recorded on a weekly basis. All investigational materials will be returned to the secure 
area with access limited to the Investigator and designated personnel. Used 
 
will be stored in the subject’s source binder.   
6.7 
Accountability, Return, or Disposal of Test Article(s)   
The Investigator must keep accurate accounts of the receipt, usage, return/disposal of all 
investigational products.  Additionally, the Investigator must document details of the treatment 
procedure and the amounts of riboflavin ophthalmic solutions used during the procedure, 
including lot numbers, for each study eye.   
7.0 
RANDOMIZATION 
7.1.1 
 
 
 
  
 
  
• 
 
o 
 
 
 
• 
 
o 
 
 
 
 
• 
 
o 
 
 
 
7.1.2 Allocation of Study Treatment 
Subjects will be considered enrolled in the study once they have signed the informed consent form 
and been randomized. Study eyes of subjects that meet all the inclusion criteria and none of the 
exclusion criteria will be randomized to either the CXL Treatment group or the Sham 
Treatment/Control Group in a 2:1 allocation ratio. 
 
 
 
 
 

 
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Randomization will occur immediately prior to cross-linking or sham treatment per Section 8.2.2.   
Subjects with bilateral keratoconus in which both eyes qualify for the study may have both eyes 
designated as study eyes by the Investigator; each eligible eye will be randomized independently. 
One eye will undergo the study procedure first.  The second eye can be randomized to undergo 
the study procedure between the Week 1 and Month 3 visits for the first eye.   
Subjects may be re-screened if they are not randomized within 45 days of screening examinations, 
or if they have a history of progressive keratoconus but do not meet the progression criteria (as 
outlined in inclusion criterion # 7) at the time of initial screening.  Subjects who fail to meet any of 
the other eligibility criteria (do not meet any other inclusion criteria or meet any exclusion criteria) 
cannot be re-screened and will be documented as screen failures.   Subjects who are re-screened 
will retain their assigned subject number. 
A 
 randomization scheme 
 
 
 
 will not be revealed to the 
participating Investigators or study site personnel.  
7.1.3 CXL Treatment Group 
Study eyes randomized to the CXL treatment group will undergo cross-linking treatment as 
described in Section 8.2.2.2.1, within 45 days of the completion of the screening measurements.  
Cross-linking must be performed on the same day as randomization, which will be considered Day 
0.  
7.1.4 Sham Treatment/Control Group 
Eyes randomized to the control group will undergo a sham treatment, as described in Section 
8.2.2.2.2, within 45 days of the completion of the screening measurements. Sham treatment must 
be performed on the same day as randomization, which will be considered Day 0.  
 
8.0 
STUDY PROCEDURES 
8.1 
Informed Consent/HIPAA 
In accordance with the provision of 21 CFR Part 50, prior to a subject’s participation in the study, 
the study will be discussed with each subject and subjects wishing to participate will sign a HIPAA 
authorization form and give written informed consent using an informed consent form. In addition, 
subjects who are under the age of 18 (or have not yet reached the age of majority per local 
regulations) will need to sign an assent form as well as having a parent or legal guardian sign an 
informed consent form. The informed consent and assent forms must be the most recent versions 
that have received approval by an Institutional Review Board (IRB). 

 
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The study will be explained to the prospective subject by the Investigator or designee.  The subject 
will be informed that he/she is free to terminate participation in the study for any reason.  The 
original signed consent form will be retained in the study chart. Once the informed consent has 
been signed, a subject number will be assigned which will consist of a 2 digit site number (e.g. 01) 
and a sequential 3 digit number (e.g. 001).  
8.1.1 
Enrollment 
Subjects will be considered enrolled in the study if they have signed the informed consent and 
meet all eligibility criteria. Enrollment of the subject may occur up to 45 days prior to Treatment 
or on the day of Treatment.   
If the subject is a woman of childbearing potential, she must not be pregnant or lactating, and must 
have a negative urine pregnancy test at the time of enrollment. Women considered capable of 
becoming pregnant include all females who have experienced menarche and have not experienced 
menopause (as defined by amenorrhea for greater than 12 consecutive months) or have not 
undergone successful surgical sterilization (e.g. hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy). 
 
8.2 
Study Procedures 
8.2.1 
Visit 1 (Day -45 to -1): Screening Visit  
All screening examination procedures will be performed by the Investigator or trained personnel 
working under the Investigator’s direct supervision. Subjects will sign a consent form before any 
clinical protocol procedures or tests specific to the study protocol are performed, including for 
females of childbearing potential, the requirement to use a medically acceptable method of birth 
control one week prior to treatment and continue to use the method for one month following 
 
treatment. Contact lens wearers must remove contact lenses for a 1 week period prior to the 
screening refraction. 
Potential cross-linking candidates will undergo a complete eye examination to determine their 
eligibility for study participation. A complete ocular history, medical history and medication history 
will be obtained. The complete eye examination and ocular history will include:  
• 
Confirmation that the study informed consent form has been signed 
• 
History of contact lens wear  
• 
UCVA (ETDRS)  
• 
BSCVA (ETDRS)  
• 
Manifest refraction  
• 
Pentacam measurements, including  
o Pachymetry  
o Keratometry  
o Topography  
• 
IOP (by Goldmann applanation tonometry)  

 
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• 
Slit lamp biomicroscopy  
• 
Dilated fundus examination 
• 
Specular microscopy for ECC 
• 
Anterior segment and macular OCT (in a subset of study eyes) 
• 
National Eye Institute Visual Function Questionnaire (NEI-VFQ 25)  
Manifest refractions will be recorded on the source documents in the Investigator’s usual notation 
(plus or minus cylinder format). All manifest refractions will be recorded on the electronic case 
report forms (eCRFs) for the study using negative cylinder format. Additional instructions for these 
test procedures are provided in Appendix A.  
8.2.2 
Visit 2 (Day 0): Treatment 
All baseline measurements are to be completed and all eligibility requirements confirmed prior to 
randomization (Visit 2/Day 0).   
The following will be performed at Visit 2 prior to Treatment: 
• 
Updates to subject’s medical and ocular history, medication, and ocular status 
• 
Negative urine pregnancy test in females of childbearing potential 
• 
Slit lamp biomicroscopy 
Once it has been confirmed that the subject and study eye are eligible for the study, the study eye 
will be randomized. Sites will use the EDC system to randomize the subject’s eye to either the CXL 
or Sham Treatment. 
 
 
 
The EDC 
system will record the subject and site number,
 and the randomized 
assignment (either CXL Treatment or Sham Treatment). The Investigator or designee should print 
a copy of this information from the EDC system and maintain it in the subject’s source document. 
The following will be performed at Visit 2 during and/or after Treatment: 
• 
Ultrasound pachymetry 
o Performed following the completion of Riboflavin or Placebo drop instillation 
 
• 
Slit lamp biomicroscopy 
o 
 
• 
AE collection (post-randomization) 
8.2.2.1 Pre-Treatment Medications  
Pre-treatment medications should be prescribed using the Investigator’s standard of care. All pre-
treatment medications will be recorded in the subject's chart.    

 
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Figure 3: CXL Treatment Flow 
 
 

 
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8.2.2.2.2 
Sham Treatment 
The corneal epithelium will not be removed. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
he UVA system should be turned on 
 
  
 
 
Lastly, slit lamp examination will be performed following the end of the treatment and removal of 
the speculum. Reference flow chart below for the Sham Treatment flow (Figure 4). 
 
 
 

 
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8.2.2.3 Post-Treatment Medications 
Prescriptions for post-treatment medications and post-treatment instructions will be given to each 
CXL treated subject and reviewed prior to discharge. 
 
 
 
 
 
 
 
 
 
 
   
 
  
8.2.3 
Visit 3 (Day 1 to 2): Day 1 
The following will be performed at Visit 3: 
• 
Documentation of interim medical, medication, and ocular status 
• 
 
• 
UCVA (ETDRS) 
• 
Slit lamp biomicroscopy 
• 
Documentation of any AEs 
 
8.2.4 
Visit 4 (Day 3 to 4): Day 3 
The following will be performed at Visit 4: 
• 
Documentation of interim medical, medication, and ocular status 
• 
 
• 
UCVA (ETDRS) 
• 
Slit lamp biomicroscopy 
• 
Documentation of any AEs 
 
8.2.5 
Visit 5 (Day 5 to 14): Week 1 
The following will be performed at Visit 5: 
• 
Documentation of interim medical, medication, and ocular status 
• 
 
• 
UCVA (ETDRS) 
• 
Slit lamp biomicroscopy 
• 
Documentation of any AEs 

 
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For subjects that have both eyes that are eligible to participate in the study, the second eye may 
be randomized and receive study treatment at this visit after completion of the protocol required 
examinations for the first study eye. The treatment must be performed as required in Section 
8.2.2.2. 
 
 The subject will be required to return for examination during the visit windows for 
the 1 day, 3 day, 1 week, 1 month, 3 months, 6 months, and 12 months post-procedure visits. 
NOTE: If the subject is a female of childbearing potential, a urine pregnancy test is required to be 
performed prior to the second eye treatment. 
8.2.6 
Visit 6 (Day 21 to 42): Month 1 
An examiner who is masked to treatment assignment will be used to measure the UCVA, BSCVA, 
and manifest refraction at the 1-month examination. The masked examiner is a qualified study 
team member whom the Investigator has designated the responsibility of conducting this protocol 
requirement.  The masked examiner will not be aware of the subject’s treatment assignment. The 
masked examiner should not have access to the subject’s medical and/or study records, which 
would unmask them to the subject’s treatment assignment, and should not discuss the treatment 
with the subject. The masked examiner should not conduct any study examinations on that subject 
beyond the visual measurements indicated on the Schedule of Visits 
The following will be performed at Visit 6: 
• 
Documentation of interim medical, medication, and ocular status 
• 
UCVA (ETDRS) (conducted by a masked examiner) 
• 
BSCVA (ETDRS) (conducted by a masked examiner) 
• 
Manifest refraction (conducted by a masked examiner) 
• 
Pentacam measurements, including  
o Pachymetry  
o Keratometry  
o Topography  
• 
IOP (by Goldmann applanation tonometry)  
• 
Slit lamp biomicroscopy  
• 
Only Anterior segment OCT 
 
• 
NEI-VFQ 25 
• 
Documentation of any AEs 
For subjects that have both eyes that are eligible to participate in the study, the second eye may 
be randomized and receive study treatment at this visit after completion of the protocol required 
examinations for the first study eye. The treatment must be performed as required in Section 
8.2.2.2. 
 
The subject will be required to return for examination during the visit windows for 
the 1 day, 3 day, 1 week, 1 month, 3 months, 6 months, and 12 months post-procedure visits. 
NOTE: If the subject is a female of childbearing potential, a urine pregnancy test is required to be 
performed prior to the second eye treatment. 

 
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8.2.7 
Visit 7 (Day 84 to 98): Month 3 
 
An examiner who is masked to treatment assignment will be used to measure the UCVA, BSCVA, 
and manifest refraction at the 3-month examination. 
 
The following will be performed at Visit 7: 
• 
Documentation of interim medical, medication, and ocular status 
• 
UCVA (ETDRS) (conducted by a masked examiner) 
• 
BSCVA (ETDRS) (conducted by a masked examiner) 
• 
Manifest refraction (conducted by a masked examiner) 
• 
Pentacam measurements, including  
o Pachymetry  
o Keratometry  
o Topography  
• 
IOP (by Goldmann applanation tonometry)  
• 
Slit lamp biomicroscopy  
• 
Specular microscopy for ECC 
• 
Anterior segment and macular OCT 
 
• 
Dilated fundus examination 
• 
NEI-VFQ 25 
• 
Documentation of any AEs 
 
For subjects that have both eyes that are eligible to participate in the study, the second eye may 
be randomized and receive study treatment at this visit after completion of the protocol required 
examinations for the first study eye. The treatment must be performed as required in Section 
8.2.2.2. 
 
 The subject will be required to return for examination during the visit windows for 
the 1 day, 3 day, 1 week, 1 month, 3 months, 6 months, and 12 months post-procedure visits. 
NOTE: If the subject is a female of childbearing potential, a urine pregnancy test is required to be 
performed prior to the second eye treatment. 
8.2.8 
Visit 8 (Day 180 to 210): Month 6 
 
An examiner who is masked to treatment type will be used to measure the UCVA, BSCVA, and 
manifest refraction at the 6-month examination. 

 
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The following will be performed at Visit 8: 
• 
Documentation of interim medical, medication, and ocular status 
• 
UCVA (ETDRS) (conducted by a masked examiner) 
• 
BSCVA (ETDRS) (conducted by a masked examiner) 
• 
Manifest refraction (conducted by a masked examiner) 
• 
Pentacam measurements, including  
o Pachymetry  
o Keratometry  
o Topography  
• 
IOP (by Goldmann applanation tonometry)  
• 
Slit lamp biomicroscopy  
• 
Specular microscopy for ECC 
• 
Anterior segment and macular OCT 
  
• 
Dilated fundus examination 
• 
NEI-VFQ 25 
• 
Documentation of any AEs 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.9 
Visit 9 (Day 360 to 390): Month 12 
 
An examiner who is masked to treatment assignment will be used to measure the UCVA, BSCVA, 
and manifest refraction at the 12 month examination. 
 

 
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The following will be performed at Visit 9: 
• 
Documentation of interim medical, medication, and ocular status 
• 
UCVA (ETDRS) (conducted by a masked examiner) 
• 
BSCVA (ETDRS) (conducted by a masked examiner) 
• 
Manifest refraction (conducted by a masked examiner) 
• 
Pentacam measurements, including  
o Pachymetry  
o Keratometry  
o Topography  
• 
IOP (by Goldmann applanation tonometry)  
• 
Slit lamp biomicroscopy  
• 
Specular microscopy for ECC 
• 
Anterior segment and macular OCT 
• 
Dilated fundus examination 
• 
NEI-VFQ 25 
• 
Documentation of any AEs 
  
Additional instructions for these test procedures are provided in Appendix A: ASSESSMENT 
INSTRUCTIONS.  

 
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8.4 
Additional/Unscheduled Visits 
The Investigator may schedule subjects for additional clinic visit(s) at his/her discretion to ensure 
subject safety, such as subjects who have any AEs, including, but not limited to, ocular events.  
8.4.1 
Missed Visit 
If a subject does not attend their scheduled visit, every attempt will be made to reschedule the 
visit within the visit window.    
8.4.2 
Exit Visit 
An Exit visit will be scheduled for any subject that is discontinued from the study. Procedures 
conducted at an Exit visit are the same as those listed for the Month 12 visit in the Schedule of 
Visits.  If early removal from the study is necessary, every effort will be made to perform an Exit 
examination before the subject is discontinued from the study.  
8.5 
Study Termination 
The study may be stopped at any time by the Sponsor with appropriate notification. 
8.6 
Subject Study Duration 
The expected study duration for each subject following treatment is approximately 12 months 
when only one eye receives the study treatment. For subjects that receive study treatment in both 
eyes, the study duration may be approximately 15 months. 
8.6.1 
Completed Subjects 
A completed subject is one who has not been discontinued from the study and has completed all 
the required visits listed in the Schedule of Visits for all treated eyes.  
8.6.2 
Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• 
Adverse event 
• 
Death 
• 
Protocol deviation 
• 
Subject withdrew consent 
• 
Subject became lost to follow-up 
• 
Sponsor termination of study 
• 
Other 
 
Note:  Any subject may be discontinued for any sound medical reason. Notification of a subject 
discontinuation and the reason for discontinuation will be made available to the Sponsor and will 
be clearly documented on the subject’s chart and CRF. 
 

 
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8.7 
Monitoring and Quality Assurance 
8.7.1 
Monitoring  
A monitor will be designated by the Sponsor to oversee the progress of the investigation.  The 
monitor will be an employee of the Sponsor or a consultant to the Sponsor.  
Sponsor will monitor all clinical studies in a manner consistent with any applicable health authority 
regulations including Good Clinical Practices (GCPs).  Study monitoring involves the following 
elements: 
Sponsor personnel will assess Investigators prior to the initiation of the study in order to review 
the adequacy of the patient population, facilities, and equipment with respect to the needs of the 
study, and to familiarize the Investigator with the study protocol. 
Sponsor personnel may meet 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. 
Sponsor personnel may visit the clinical site at any time during the course of the study to ensure 
that the treatment procedures described in the protocol are being followed. Sponsor personnel 
may also observe examination techniques used by study personnel to ensure that the procedures 
being utilized are the procedures described in Appendix A to this protocol. Sponsor personnel will 
visit the clinical site to review and verify the accuracy of the eCRFs.  
Remote monitoring may also be utilized between site monitoring visits. Sponsor personnel may 
require copies of source documents to be made available for off-site (remote monitoring). Subject 
data should be de-identified prior to transmission to Sponsor’s personnel not at the Site. 
Additionally, sites will be contacted as necessary during the course of the study to ensure the 
proper progress and documentation of the study findings.  
8.7.2 
Institutional Review Board 
This protocol and the informed consent form will be approved initially and reviewed by an IRB per 
the IRB’s requirements constituted according to FDA regulations. Progress reports will be 
submitted at the completion of the study or at least once yearly, whichever comes first, to the IRB.  
SAEs will be reported to the IRB and the FDA in accordance with FDA regulations and IRB 
requirements.  
9.0 
ADVERSE EVENTS 
An Adverse Event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An AE (also referred to as an adverse experience) 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug and does not imply any judgment 
about causality.  

 
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AEs that are observed by the Investigator or reported by the subject will be recorded on the study 
source documents and eCRFs.  For all AEs, a description of the event, severity of the event, 
relationship to the test article, location of the event, date first observed, any action taken, its 
resolution and outcome will be recorded. 
When completing the appropriate CRFs for reporting AEs, the Investigator will be asked to assess 
the AE for relationship, severity, and outcome as described below.  
9.1 
Relationship of Test Article to Each Adverse Event 
Not Related: Based upon available information regarding subject history, disease process, 
relationship of AE to dosing and drug pharmacology, there is no reasonable relationship between 
the test and AE. 
Possibly related:  Relationship exists when the AE follows a reasonable sequence from the time of 
the test article administration but could also have been produced by the subject’s clinical state or 
by other drugs administered to the subject. 
Probably related: Relationship exists when the AE follows a reasonable sequence from the time of 
the test article administration, follows a known response pattern of the drug class, is confirmed by 
improvement on stopping the test article and the suspect test article is the most likely of all causes. 
Definitely related: Relationship exists when the AE follows a reasonable sequence from the time of 
the test article administration, follows a known response pattern of the drug class, is confirmed by 
improvement on stopping the test article and no other reasonable cause exists. 
9.2 
Severity of Adverse Event(s) 
Additionally, the severity of each AE will be assessed. Severity of an AE is defined as a qualitative 
assessment of the degree of intensity of an AE as determined by the Investigator or reported to 
him/her by the subject. The assessment of severity is made irrespective of test article relationship 
or seriousness of the event and should be evaluated according of the following scale: 
Mild: Event is noticeable to the subject but is easily tolerated and does not interfere with the 
subject’s daily activities. 
Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with the 
subject’s daily activities. 
Severe: Event is intolerable, necessitates additional therapy, or alteration of therapy and interferes 
with the subject’s daily activities. 
9.3 
Outcome of Adverse Event(s) 
Not Recovered/Not Resolved: One of the possible results of an AE outcome that indicates that the 
event has not improved or recuperated. 
Recovered/Resolved: One of the possible results of an AE outcome that indicates that the event 
has improved or recuperated. 

 
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Recovered/Resolved with Sequelae: One of the possible results of an AE outcome where the subject 
recuperated but retained pathological conditions resulting from the prior disease or injury. 
Recovering/Resolving: One of the possible results of an AE outcome that indicates that the event 
is improving. 
Unknown: Not known, not observed, not recorded, or refused.  
Fatal: The termination of life as a result of an AE 
9.4 
Serious Adverse Events and Serious Unexpected Suspected Adverse Reactions 
9.4.1 
Definitions 
The Sponsor and Investigator must comply with the applicable sections of 21CFR 312.32 and 21CFR 
312.64(b) for IND safety reports. In accordance with these regulations, the following definitions 
apply: 
 
• 
ADVERSE REACTION: Any AE caused by a drug. Adverse reactions are a subset of all suspected 
adverse reactions where there is reason to conclude that the drug caused the event. 
 
• 
SUSPECTED ADVERSE REACTION: Any AE for which there is a reasonable possibility that the 
drug caused the AE.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the AE. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction. 
 
• 
SERIOUS ADVERSE EVENT (SAE)/SERIOUS SUSPECTED ADVERSE REACTION: An AE or 
suspected adverse reaction is considered “serious” if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes:  
o 
Death;  
o 
Life-threatening (an AE or Suspected Adverse Reaction that if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject or subject at 
immediate risk of death.  It does not include an AE or suspected adverse reaction that, 
had it occurred in a more severe form, might have caused death);  
o 
In-patient hospitalization or prolongation of existing hospitalization; 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
o A congenital anomaly/birth defect; or 
o A sight-threatening event.   
 
An AE or suspected adverse reaction is considered "sight-threatening" if, in 
the view of either the Investigator or Sponsor its occurrence places the subject 
or subject at immediate risk of loss of sight. It does not include an AE or 
suspected adverse reaction that, had it occurred in a more severe form, might 
have caused loss of sight.  

 
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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in patient hospitalization, or the 
development of drug dependency or drug abuse.  
• 
UNEXPECTED ADVERSE EVENT: An AE or Suspected Adverse Reaction is considered 
“unexpected” if it is not consistent with the risk information described in the Paracel 1 and 
Paracel 2 Investigators Brochure, the KXL System operator’s manual, or is not listed at the 
specificity or severity that has been observed.   
9.5 
Serious and Unanticipated Adverse Device Effects 
An unanticipated adverse device effect is defined as “any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan, or any other unanticipated serious problem associated with a device that 
relates to the rights, safety or welfare of patients.” Since CDER has primary jurisdiction for the 
regulation of this combination product, serious and unanticipated adverse device effects will be 
reported to FDA and the IRB in accordance with the reporting requirements described in Section 
9.8.  
9.6 
Non-serious Drug or Device or Anticipated Device Adverse Events 
Non-serious drug or device AEs or anticipated device AEs and complications should be documented 
on the eCRFs and tabulated for reporting in the periodic safety reports to FDA. 
9.7 
Procedures for Reporting Adverse Events           
Any AE should be reported to Sponsor and the IRB as required by the IRB, federal, state or local 
regulations and governing health authorities and recorded on the appropriate CRF along with the 
outcome. For all AEs, the reporting period begins post treatment and continues until the subject 
completes study participation (e.g. early termination or final study visit). 
 
All AEs where a causal relationship between test article and the AE is at least a reasonable 
possibility (Suspected Adverse Reaction) and that are not expected (i.e. not listed in the 
Investigators Brochure or the Operator’s Manual) are to be reported to Sponsor and the IRB as 
required by the IRB, federal, state or local regulations and governing health authorities. Preliminary 
determination of classification of an AE or adverse drug reaction as unexpected is the responsibility 
of the Investigator subject to the Sponsor’s final determination.     

 
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9.8 
Procedures for Reporting a Serious Adverse Event 
The Investigator must immediately report SAEs that occur or are observed during the course of the 
study to Sponsor.  In the event of an SAE, the site must complete a 
 
form 
 within 
24 hours of notification, observation, or occurrence of the SAE, whether or not complete 
information is available within this period.  In case of incomplete information, the Investigator 
must provide follow-up information as soon as possible, again using the “Serious Adverse Event 
Report Form”. 
SAEs must be reported to the IRB according to the IRB requirements. 
Important:  The Investigator must report any SAE occurring at his/her site to Sponsor regardless 
of causality.  
The Investigator is obligated to pursue and obtain information (e.g., medical records, discharge 
summaries) requested by Sponsor in addition to that information reported on the eCRF.  All 
subjects experiencing an SAE must be followed until the subject completes the study or until the 
SAE resolves, whichever is first.  All suspected adverse reactions that are both serious and 
unexpected are subject to expedited reporting.  
SAE reports will be evaluated by the Sponsor.  The IRB(s) and Investigators at other study sites will 
be informed as required.  
Any adverse reaction that is both serious and unexpected shall be reported by the Sponsor to FDA 
and to all participating Investigators as soon as possible and in no event later than 15 calendar days 
after the Sponsor’s initial receipt of the information. Each written notification may be submitted 
on FDA Form 3500A or in a narrative format. Each written notification to FDA shall be transmitted 
to the FDA new drug review division in the Center for Drug Evaluation and Research that has 
responsibility for review of the IND/NDA. If FDA determines that additional data are needed, the 
agency may require further data to be submitted.  
The Sponsor shall also notify FDA by means of rapid communication (telephone, facsimile 
transmission, or by e-mail) of any unexpected fatal or life-threatening adverse reaction as soon as 
possible but in no event later than 7 calendar days after the Sponsor's initial receipt of the 
information. Each telephone call or facsimile transmission to FDA shall be transmitted to the FDA 
new drug review division in the Center for Drug Evaluation and Research that has responsibility for 
review of the IND. 
In addition to notifying FDA, the Sponsor will also notify each Investigator in an IND safety report 
of potentially serious risks as soon as possible and no later than 15 calendar days of any serious 
and unexpected, fatal, or life-threatening adverse reactions. The Investigators will promptly report 
these experiences to the IRB. If the IRB has different or specific reporting deadlines, reports should 
be made to the IRB in accordance with the IRB’s requirements. 

 
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10.0 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 
General Methods 
A detailed statistical analysis plan (SAP) will be developed and finalized prior to locking the 
database for this study.  Required analyses and target endpoints that will be included in this SAP 
are summarized below.  The methods by which each of these analyses is performed will be 
described in detail in the SAP.  The required analyses and target endpoints include but are not 
limited to those listed below.  
All statistical analyses will be performed using SAS Version 9.4 or higher for Windows. 
Descriptive statistics for continuous variables will include the mean, standard deviation, median, 
minimum and maximum; 2-sided 95% confidence intervals (CI) or 2-sided p-values will also be 
presented for efficacy endpoints.  Descriptive statistics for categorical variables will include 
number and percentage of subjects or eyes, as appropriate.  All testing and confidence intervals 
for endpoints will use a two-sided significance level of 5% unless otherwise specified. 
10.2 
Study Populations 
10.2.1 Intent-to-Treat Population 
The intent-to-treat (ITT) population includes all randomized study eyes that had at least one post-
treatment follow-up efficacy assessment.  The ITT population is designated as the primary 
population for all efficacy analyses.  
10.2.2 Safety Population  
The safety population is comprised of all study eyes that received the study treatments 
 
. The safety population will be used for the analysis of the safety 
endpoints. 
10.2.3 Per Protocol Population 
The per protocol (PP) population is a subset of the ITT population and is comprised of study eyes 
that complete the study without any major protocol deviations and that have non-missing data 
available for the primary endpoint. The SAP will provide a definition of major protocol violations. 
The PP population will be used to provide supportive efficacy analyses. 
10.3 
Efficacy Variables 
The primary efficacy variable for this study is the change from pretreatment baseline in Kmax at 
each post-treatment follow-up time point.  
  
 
 

 
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• 
 
 
 
10.4 
Sample Size 
The sample size for this study is based on unequal group sizes with the number of eyes in the 
crosslinked group being 2 times greater than in the control group (2:1 randomization).  Two 
hundred forty (240) eyes (160 in the cross-linking treatment group and 80 in the control group) 
provides approximately 80% power 
 to detect a difference in the mean 
change in Kmax from baseline 
 between the cross-linking treatment group and the 
control group. 
  The sample size for this study is 
determined to be 275 eyes 
 
10.5 
Primary Efficacy Analyses 
10.5.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the month 6 change-from-baseline in Kmax. The primary efficacy 
null hypothesis is that there is no difference in the mean month 6 change-from-baseline in Kmax 
between the CXL Treatment group and the Sham Treatment/control group. The alternative 
hypothesis is that there is a difference. 
The null (H0) and alternative (Ha) statistical hypotheses for the primary efficacy endpoint, to be 
tested are: 
H0: μT - μC = 0 
Ha: μT - μC ≠ 0. 
Where: 
• μT is the mean Kmax change-from-baseline to 6 months for the CXL treatment group  
• μC is the mean Kmax change-from-baseline to 6 months for the Sham treatment/control 
group 
 
 
 
The primary efficacy endpoint criterion is 
 Month 6 Kmax 
change-from-baseline between the CXL Treatment group and the Sham Treatment/control group. 

 
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10.6 
Secondary Efficacy Analyses 
10.6.1 Secondary Efficacy Endpoint 
The secondary efficacy endpoint is the month 12 change-from-baseline in Kmax. The secondary 
efficacy null hypothesis is that there is no difference in the mean month 12 change-from-baseline 
in Kmax between the CXL Treatment group and the Sham Treatment/control group. The alternative 
hypothesis is that there is a difference. 
 
 
The secondary efficacy endpoint criterion is 
 in Month 12 Kmax 
change-from-baseline between the CXL Treatment group and the Sham Treatment/control group. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.8 
Safety Analysis 
The primary safety endpoints for this study are: 
• 
Incidence of treatment emergent ocular AEs  
• 
Loss in BSCVA 

 
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The incidence of treatment emergent AEs will be tabulated presented descriptively.   
Additional safety analysis will be performed on the following data: 
• 
Slit lamp biomicroscopy  
• 
Pentacam Pachymetry 
• 
IOP (applanation tonometry) 
• 
Manifest refraction 
• 
Dilated fundus examination 
• 
Endothelial cell count 
• 
Macular OCT 
 
 
 
 
  
 
 
 
 
 
10.8.1 Overall Incidence of Adverse Events 
The incidence of subjects reporting any treatment-emergent AE during the study will be 
presented. Incidence will be tabulated by MedDRA System Organ Class and preferred term within 
each system organ class.  The number and percentage of subjects reporting ocular and non-
ocular AEs will be tabulated by body system and preferred term.  The number of subjects 
reporting AEs will also be summarized by relationship to the test article as well as severity of AEs.  
SAEs will be summarized in a similar fashion. 
 
 
 
 
 
 

 
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11.0 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL CONSIDERATIONS, AND 
ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with GCPs, including International Harmonization (ICH) 
Guidelines, and in general, consistent with the 1996 version of the Declaration of Helsinki. In 
addition, all applicable local, state and federal requirements relevant to the use of investigational 
agents in the countries involved will be adhered to. This study will be conducted in accordance 
with FDA’s GCP regulations. 
11.1 
Protection of Human Subjects 
11.1.1  Compliance with Informed Consent Regulations  
Refer to 21 CFR Part 50 for requirements related to informed consent. 
Written informed consent must be obtained from each subject (or subject’s legal representative, 
if applicable) prior to participation in the study.  In seeking informed consent, the following 
information shall be provided, at minimum, to each subject.  
• 
A statement that the study involves research, an explanation of the purpose of the 
research and the expected duration of the subject’s participation, a description of the 
procedures to be followed, and identification of any procedures which are experimental.  
• 
A description of any reasonably foreseeable risks or discomforts to the subject.  
• 
A description of any benefits to the subject or to others which may reasonably be expected 
from the research. 
• 
A disclosure of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the subject.  
• 
A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and that notes the possibility that the U.S. Food and Drug 
Administration may inspect records.  
• 
For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if 
injury occurs and, if so, what they consist of, or where further information may be 
obtained.  

 
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• 
An explanation of whom to contact for answers to pertinent questions about the research 
and research subject’s rights, and whom to contact in the event of a research-related 
injury.  
• 
A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled.  
• 
Notification that study results will be posted in the ClinicalTrials.gov website, when 
applicable: 
"A 
description 
of 
this 
clinical 
trial 
will 
be 
available 
on 
http://www.clinicaltrials.gov, as required by U.S. law. This web site will not include 
information that can identify you. At most, the web site will include a summary of the 
results. You can search this web site at any time.” 
11.1.2 Compliance with Institutional Review Board Regulations 
The Investigator will not deviate from the protocol without prior approval from the IRB and/or the 
Sponsor, unless such deviation is necessary to manage a medical emergency. The Investigator will 
notify the IRB and the Sponsor of any protocol deviation to protect the life or physical well-being 
of a subject in an emergency.  Such notice shall be given as soon as possible, but in no event, any 
later than 5 working days after the emergency occurred.  All other revisions and/or amendments 
to the protocol that affect subject treatment, study outcome, or subject safety will be submitted 
in writing to the IRB and the Sponsor for approval prior to implementation if the changes or 
deviations to the protocol affect the scientific validity of the study or the rights, safety, or welfare 
of human subjects.  In this case, the change will not be implemented until IRB approval is obtained.  
The Investigator will maintain a record of all protocol deviations showing the dates of, and the 
reason for, each protocol deviation. 
Changes that affect the scientific validity of the study or the rights, safety, or welfare of human 
subjects may also require FDA and IRB approval prior to implementation.  The Sponsor and 
Investigator will obtain such approvals, if required. Refer to 21 CFR Part 312.60 regarding other 
Investigator responsibilities. 
11.1.3 Compliance with the Declaration of Helsinki 
Refer to Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects. 
11.1.4 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study should be 
maintained by the Investigator and his/her staff with adequate precautions as to ensure the 
confidentiality of the data in accordance with local, state, and federal laws and regulations.  

 
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Monitors, auditors, and other authorized representative of Sponsor, the IRB approving this study,  
FDA, the DHHS, other domestic government agencies, and other foreign regulatory agencies will 
be granted direct access to the study subject’s original medical and study records for verification 
of the data and/or clinical trial procedures. Access to this information will be permitted to 
representatives of the aforementioned organizations to the extent permitted by law.  
11.1.5  Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, the 
Investigator’s study subject files as well as the results of diagnostic tests.  The Investigator’s copy 
of the eCRFs serves as the Investigator’s record of a subject’s study-related data. All data related 
to the study will be recorded on eCRFs to be provided by Sponsor via an EDC system. The 
Investigator is responsible for verifying that all data entries in the eCRFs are accurate and correct. 
The Investigator must sign the completed eCRFs before its submission to Sponsor.  
The EDC system will be designed and used per 21 CFR Part 11 and the “Computerized Systems Used 
in Clinical Trials Guidance for Industry.” 
11.1.6   Retention of Documentation 
All study related correspondence, subject records, consent forms, record of the distribution and 
use of the test article and copies of eCRFs should be maintained on file for the duration specified 
in each site’s Clinical Trial Agreement and per the requirements of 21 CFR Part 312, “E6 Good 
Clinical Practice Guidance for Industry” part 5.5 and any local requirements.  
11.2 
Recording of Data on Source Document and Electronic Case Report Forms (eCRFs) 
Adequate records will be maintained for the study including subject medical and surgical records, 
test reports, work sheets, nursing notes, signed informed consent forms, drug and device use 
records, adverse experience reports and information regarding subject discontinuation and 
reasons for discontinuation.  All original source documentation will remain at the investigative site. 
Study data that are stored at the Investigator site in any electronic medical records system, that is 
not 21 CFR Part 11 compliant (e.g., Pentacam, OCT), should be printed and retained in the study 
files. 
Sponsor personnel may require copies of source documents to be made available for off-site 
(remote) monitoring. Subject data should be de-identified prior to transmission to Sponsor’s 
personnel not at the site. 
All study data will be recorded onto eCRFs designed for the study. 
11.3 
Changes in the Conduct of the Study  
Changes that affect the scientific soundness of the study or the rights, safety, or welfare of human 
subjects may also require FDA and IRB approval prior to implementation.  The Sponsor and 
Investigator will obtain such approvals, if required. 
 
 
 

 
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Appendix A: ASSESSMENT INSTRUCTIONS   
 
VISUAL ACUITY TESTING  
Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Chart: Modified Bailey-Lovie, 
Distance12  
Illumination of the ETDRS Visual Acuity Charts and Room Illumination: 
The standard ETDRS chart light box is used at the four- and one-meter test distances. The bulbs 
in the ETDRS chart light box are to be two 20 watt Daylight fluorescent tubes. Room illumination 
should be 50 to 100 foot-candles as measured with a photometer four meters and one meter 
from the ETDRS chart held four feet from the floor and directed toward the ceiling.  ETDRS Charts 
will be changed as needed to maintain high contrast letters on a white background.  
Uncorrected distance visual acuity (UCVA) must be assessed, followed by the determination of 
best spectacle-corrected distance visual acuity (BCVA).   
Uncorrected Visual Acuity (UCVA): 
Distance UCVA must be performed using calibrated Original Series ETDRS eye charts. Chart R will 
be used for UCVA testing. The total number of letters read correctly will be recorded.  
Each of the two eyes is tested separately.  The 4M ETDRS chart is presented and the subject is 
asked to proceed with reading the letters at the top of the chart. The subject should continue to 
read as many letters as possible in each subsequent row on the chart until he/she can no longer 
identify at least one letter correctly on a given line. At this point, the subject is asked to stop 
reading letters. The examiner tallies how many total letters the subject has correctly identified 
during the testing process and records this number. If the subject has correctly identified 20 or 
more total letters, visual acuity testing for the eye is complete.  
If the subject has identified fewer than 20 letters correctly, place a +0.75 D spherical lens in front 
of the eye being tested and move the chart to a test distance of 1.0 meters. Once again, ask the 
subject to read the letters from the top of the chart. The subject should continue to read as many 
letters as possible in each subsequent row on the chart until he/she can no longer identify at least 
one letter correctly on a given line. At this point, the subject is asked to stop reading letters. The 
examiner tallies how many total letters the subject has correctly identified while looking through 
the +0.75 D spherical lens and records this number. UCVA testing for the eye is now complete. 
Best-Spectacle Corrected Visual Acuity (BSCVA) 
Distance BSCVA must be performed using calibrated Original Series ETDRS eye charts. Chart 1 is 
used for BSCVA testing of the right eye and Chart 2 is used for the left eye.  The total number of 
letters read correctly will be recorded in the eCRF.  
The distance from the subject’s eyes to the ETDRS Visual Acuity Chart should be four meters. With 
the lens correction obtained by subjective refraction in the trial frame, the subject is asked to read 

 
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ETDRS Visual Acuity Chart 1 from the top with the right eye. It is emphasized to the subject that 
each answer will be scored so that adequate time should be allowed for each letter in order to 
achieve the best identification. 
When the subject cannot read a letter, he/she is encouraged to guess if necessary. If the subject 
states that a letter is one of two letters, he/she is asked to choose only one letter. Only one 
reading is allowed for each letter. When a subject attempts to read the chart and comes to a line 
at which he/she cannot even guess, the examiner may stop the test. 
If the number of letters read correctly at four meters is less than twenty, the test is repeated at 
one meter and both the four- and one-meter totals are recorded. Both eyes must be tested at 
four meters before the subject is moved up to the one-meter test distance. Prior to actual testing 
at one-meter, +0.75 spheres should be added to the correction already in the trial frame to 
compensate for the new distance. The subject may stand or sit for the visual acuity test at four 
meters, but must sit for the one-meter distance. 
The same procedure for obtaining visual acuity for the right eye is used for the left eye, except 
that ETDRS Visual Acuity Chart 2 is used. 
 
MANIFEST REFRACTION 
Manifest refractions will be recorded on the source documents in the Investigator’s usual notation 
(plus or minus cylinder format). All manifest refractions will be recorded on the CRFs for the study 
using minus cylinder format.  Once the manifest refraction has been performed on both eyes, the 
BCVA should be performed. The ETDRS Refraction Chart R or any other visual acuity chart except 
Original Series ETDRS Visual Acuity Chart 1 or 2 may be used to determine the best distance lens 
correction, for each eye. 
 
SLIT LAMP EXAMS 
The slit lamp exam conducted by the Investigator should include a complete survey of the anterior 
segment including orbit/lids, lashes, pupil, conjunctiva, cornea, anterior chamber, iris, and lens. A 
grading of normal or abnormal will be noted at each visit. The following areas of the cornea should 
be examined – Epithelium, Descemet’s membrane/endothelium, cornea-other. The grading of 
any abnormalities in any of the above mentioned areas should be recorded using the following 
scale: 
 
0+ = 
 
1+ =
 
2+ = 
 
3+ = 
 
4+ = 
 

 
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In addition, the corneal clarity should be examined in detail with specific recordings and grading 
of any abnormalities using the following scale:   
 
 
0+ = 
 
 
1+ = 
 
2+ = 
 
 
3+ = 
 
 
4+ =
  
 
  
 
 
PENTACAM TOPOGRAPHY 
 
  The median Kmax 
value is to be reported in the eCRF. 
 
 
 
 
  
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 

 
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• 
 
   
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
SPECULAR MICROSCOPY 
The methods used for the collection and analysis of specular microscopy data are critically 
important to minimizing the variability associated with these measurements. Common sources of 
variability in specular microscopy are: 
• 
difficulty in returning to same location on the cornea at each visit; 
• 
poor image quality (less than 100 countable cells); 
• 
technician error 
 
 
   
An acceptable image has: 
• 
distinct cells; 
• 
at least 100 identifiable (countable) cells as a minimum, 150 cells preferred; and 
• 
cells that can be grouped in a uniform area. 
 

 
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To capture a good image: 
• 
make sure the subject is comfortable; 
• 
instruct the subject to blink; 
• 
instruct subject not to move and to open eyes wide; 
• 
instruct subject to focus straight ahead or on the green light; 
• 
be patient; and 
• 
if necessary, use the manual setting. (Note that the use of the manual setting may 
require additional training). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX B: 
 
 

 
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Sponsor:  Avedro, Inc. 
Protocol:  ACP-KXL-308 
Subject Number __ __ __ __ __          Subject Initials __ __ __   
Date (mm/dd/yyyy)          __ __ /__ __ /2  0  
 __ 
 
  SCREEN 
1 MONTH 
3 MONTH 
6 MONTH 
12 MONTH 
VISIT: 
_____________________________________________________________________________________________________________________ 
This questionnaire has been modified to remove the appendix of optional additional questions (A1-A13) that 
appeared on the original questionnaire and to add a clinical study specific header to each page of the questionnaire. 
The following is a survey with statements about problems which involve your vision or feelings that you have about 
your vision condition. After each question please choose the response that best describes your situation.  
Please answer all the questions as if you were wearing your glasses or contact lenses (if any).  
Please take as much time as you need to answer each question. All your answers are confidential. In order for this 
survey to improve our knowledge about vision problems and how they affect your quality of life, your answers must 
be as accurate as possible. Remember, if you wear glasses or contact lenses, please answer all of the following 
questions as though you were wearing them.  
INSTRUCTIONS:  
1 
In general we would like to have people try to complete these forms on their own. If you find that you need 
assistance, please feel free to ask the project staff and they will assist you.  
2 
Please answer every question (unless you are asked to skip questions because they don’t apply to you).  
3 
Answer the questions by circling the appropriate number.  
4 
If you are unsure of how to answer a question, please give the best answer you can and make a comment in 
the left margin.  
5 
Please complete the questionnaire before leaving the center and give it to a member of the project staff. Do 
not take it home.  
6 
If you have any questions, please feel free to ask a member of the project staff, and they will be glad to help 
you.  
 
STATEMENT OF CONFIDENTIALITY:  
All information that would permit identification of any person who completed this questionnaire will be regarded as 
strictly confidential. Such information will be used only for the purposes of this study and will not be disclosed or 
released for any other purposes without prior consent, except as required by law.  
Version date:  28-Nov-2017 
 
Page 1 of 69 
 
 
 

 
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Sponsor:  Avedro, Inc. 
Protocol:  ACP-KXL-308 
Subject Number __ __ __ __ __          Subject Initials __ __ __   
Date (mm/dd/yyyy)          __ __ /__ __ /2  0  
 __ 
 
  SCREEN 
1 MONTH 
3 MONTH 
6 MONTH 
12 MONTH 
VISIT: 
________________________________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version date:  28-Nov-2017                                              
  
 
 
                   Page 9 of 69 
                                                                                              
 
 

 
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REFERENCES 
 
 Eye Bank Association of America Statistical Report, 2015. 
2 Wollensak G, Spoerl E, Seiler T. Riboflavin/Ultraviolet-A-induced collagen cross-linking for the 
treatment of keratoconus. Am J Ophthalmol. 2003; 135:620-627.  
3 Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Parasurgical therapy for keratoconus by 
riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen: preliminary refractive results 
in an Italian study. J Cataract Refract Surg. 2006; 32(5):837-45.  
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. Am J Ophthalmol. 2010 
Apr;149(4):585-93.  
5 Vinciguerra P, Albe E, Trazza S, Seiler T, Epstein D. Intraoperative and postoperative effects of corneal 
collagen cross-linking on progressive keratoconus. Arch Ophthalmol. 209 Oct;127(10):1258-65.  
6 Coskunseven E, Jankov MR 2nd, Hafezi F. Contralateral eye study of corneal collagen cross-linking with 
riboflavin and UVA irradiation in patients with keratoconus. J Refract Surg. 2009 Apr;25(4):371-6.  
7 Grewal DS, Brar GS, Jain R, Sood V, Singla M, Grewal SP. Corneal collagen crosslinking using riboflavin 
and ultraviolet-A light or keratoconus: one year analysis using Scheimpflug imaging. J Cataract Refract 
Surg. 2009 Mar;35(3):425-32.  
8 Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A 
light in keratoconus:long-term results. J Cataract Refract Surg. 2008 May;34(5):796-801.  
9 Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen crosslinking with riboflavin and ultraviolet-A light in 
keratoconus: long-term results. J Cataract Refract Surg. 2008;34(5):796-801. doi: 
10.1016/j.jcrs.2007.12.039. 
10 Wittig-Silva C, Chan E, et al. A randomized, controlled trial of corneal collagen cross-linking in 
progressive keratoconus. Ophthalmology 2014;121:812-821. 
 
 
12 Beck RW, Moke PS, Turpin AH, et al.  A Computerized Method of Visual Acuity Testing: Adaptation of 
the Early Treatment of Diabetic Retinopathy Study Testing Protocol. Am J Ophthalmol 2003; 135: 194-
205.