A Prospective, Multicenter Clinical Trial of the VisAbility™ Micro Insert System for the Improvement of Near Visual Acuity in Presbyopic Subjects - Long Term Follow-up
Phase: NA
Conditions: Presbyopia
Sponsor: Refocus Group, Inc.

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 1 of 40 
 
 
 
 
 
 
 
 
VIS-2014-5YR 
 
NCT# 03811249 
 
A PROSPECTIVE, MULTICENTER CLINICAL TRIAL OF THE VISABILITY™ MICRO 
INSERT SYSTEM FOR THE IMPROVEMENT OF NEAR VISUAL ACUITY IN 
PRESBYOPIC SUBJECTS - LONG-TERM FOLLOW-UP 
 
 
Refocus Group, Inc. 
10210 North Central Expressway, Suite 400 
Dallas, TX 75231 
 
October 22, 2018 
 
 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 2 of 40 
 
Table of Contents 
PERSONNEL AND FACILITIES ...................................................................................................... 4 
LIST OF ABBREVIATIONS .............................................................................................................. 5 
1.0 
STUDY OUTLINE ................................................................................................................. 6 
1.1 
STUDY OBJECTIVE ................................................................................................. 6 
1.2 
INDICATIONS FOR USE .......................................................................................... 6 
1.3 
SUBJECT POPULATION .......................................................................................... 6 
1.4 
STUDY DESIGN ....................................................................................................... 6 
1.5 
SAMPLE SIZE .......................................................................................................... 7 
1.6 
DATA ANALYSES .................................................................................................... 7 
1.7 
CLINICAL PARAMETERS ........................................................................................ 7 
2.0 
INTRODUCTION & RATIONALE .......................................................................................... 9 
3.0 
SUBJECT POPULATION ................................................................................................... 10 
3.1 
INCLUSION CRITERIA ........................................................................................... 10 
3.2 
EXCLUSION CRITERIA .......................................................................................... 10 
4.0 
INVESTIGATIONAL PROCEDURES ................................................................................. 11 
4.1 
SUBJECT ENTRY .................................................................................................. 11 
4.1.1 
SUBJECT CONTACT ............................................................................................. 11 
4.1.2 
INFORMED CONSENT .......................................................................................... 11 
4.1.3 
SUBJECT REFUSAL, INABILITY TO PARTICIPATE, OR INABILITY TO CONTACT . 
 
 ............................................................................................................................... 11 
4.2 
EXAMINATION SCHEDULE ................................................................................... 11 
4.3 
CLINICAL PARAMETERS ...................................................................................... 12 
4.4 
DATA COLLECTION .............................................................................................. 12 
4.5 
STUDY COMPLETION PROCEDURES ................................................................. 12 
4.5.1 
SUBJECT COMPLETION ....................................................................................... 12 
4.5.2 
SUBJECT TERMINATION ...................................................................................... 12 
4.5.3 
SUBJECT EXIT ...................................................................................................... 13 
5.0 
STATISTICAL METHODS .................................................................................................. 14 
5.1 
SUBJECT ACCOUNTABILITY ................................................................................ 14 
5.2 
STATISTICAL ANALYSIS ....................................................................................... 14 
5.3 
ANALYSIS OF CLINICAL PARAMETERS .............................................................. 14 
6.0 
ADVERSE EVENT REPORTING ....................................................................................... 15 
6.1 
SERIOUS ADVERSE EVENTS (SAE) .................................................................... 15 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
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6.2 
UNANTICIPATED ADVERSE DEVICE EFFECTS (UADE) ..................................... 15 
6.3 
ADVERSE EVENT ASSESSMENT ......................................................................... 16 
6.4 
CLASSIFICATION OF ADVERSE EVENTS BY INTENSITY/SEVERITY ................ 17 
6.5 
CLASSIFICATION OF ADVERSE EVENTS BY EXPECTEDNESS/RELATEDNESS . 
 
 ............................................................................................................................... 17 
6.6 
ADVERSE EVENT OUTCOME ............................................................................... 18 
6.7 
TREATMENT OR ACTION TAKEN......................................................................... 18 
6.8 
POSSIBLE ADVERSE EVENTS ............................................................................. 18 
7.0 
MONITORING .................................................................................................................... 21 
8.0 
REFERENCES ................................................................................................................... 21 
 
APPENDIX 1: EXAMINATION METHODS ..................................................................................... 22 
APPENDIX 2:  ANTERIOR SEGMENT ISCHEMIA (ASI):  DETECTION, MITIGATION AND 
REPORTING .......................................................................................................... 29 
APPENDIX 3: DATA SAFETY MONITORING BOARD .................................................................. 34 
APPENDIX 4: SPONSOR COMMITMENTS .................................................................................. 35 
APPENDIX 5: INVESTIGATOR COMMITMENTS AND RESPONSIBILTIES ................................. 36 
APPENDIX 6: DECLARATION OF HELSINKI ................................................................................ 37 
 
 
 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 4 of 40 
 
VIS-2014-5YR 
 
A PROSPECTIVE, MULTICENTER CLINICAL TRIAL OF THE VISABILITY™ MICRO 
INSERT SYSTEM FOR THE IMPROVEMENT OF NEAR VISUAL ACUITY IN 
PRESBYOPIC SUBJECTS - LONG-TERM FOLLOW-UP 
 
 
PERSONNEL AND FACILITIES 
 
STUDY SPONSOR 
 
Refocus Group, Inc. 
 
 
 
 
10210 North Central Expressway 
Suite 400 
 
 
 
 
Dallas, TX 75231 
 
 
 
 
(214) 368-0200 
 
 
 
 
Fax: (214) 368-0332 
 
MEDICAL MONITOR  
Mark Packer, MD 
 
 
 
 
1400 Bluebell Ave. 
 
 
 
 
Boulder, CO 80302 
 
INVESTIGATORS 
 
All active sites that participated in the VIS-2014 study 
 
CLINICAL MONITOR  
Quality Data Services, Inc. 
 
 
 
 
1000 Continental Drive 
Suite 200 
 
 
 
 
King of Prussia, PA 19406 
 
 
 
 
(610) 354-0404 
 
 
 
 
Fax: (610) 354-0699 
 
 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 5 of 40 
 
LIST OF ABBREVIATIONS 
 
ACD 
Anterior Chamber Depth 
AE 
Adverse Event 
BCDVA 
Best Corrected Distance Visual Acuity 
CRO 
Clinical Research Organization 
CRF 
Case Report Form 
D 
Diopter 
DCNVA 
Distance Corrected Near Visual Acuity 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IOL 
Intraocular Lens 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
m 
Meter 
mm 
Millimeters 
mm Hg 
Millimeters of Mercury 
NAVQ 
Near Acuity Visual Questionnaire 
OD 
Right eye 
OS 
Left eye 
PI 
Principal Investigator 
PMMA 
Polymethylmethacrylate 
PRO 
Patient Reported Outcomes 
SAE 
Serious Adverse Event 
SPK 
Superficial Punctate Keratitis 
UADE 
Unanticipated Adverse Device Effect 
UCDVA 
Uncorrected Distance Visual Acuity 
UCIVA 
Uncorrected Intermediate Visual Acuity 
UCNVA 
Uncorrected Near Visual Acuity 
USA 
United States of America 
VMI 
VisAbility™ Micro Insert 
VMIS 
VisAbility™ Micro Insert System 
 
 
 
 
 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 6 of 40 
VIS-2014-5YR 
 
THREE YEAR ADDITIONAL FOLLOW-UP OF SUBJECTS PREVIOUSLY COMPLETING 
TWO YEAR PARTICIPATION IN PROTOCOL VIS-2014 
 
1.0 
STUDY OUTLINE 
 
1.1 
STUDY OBJECTIVE 
The objective of this study is to obtain an additional 36 months of safety and effectiveness data 
from all subjects who were implanted or explanted in Protocol VIS-2014, a prospective, multicenter 
clinical trial of the VisAbility™ Micro Insert System in presbyopic emmetropes.  
 
1.2 
INDICATIONS FOR USE 
The VisAbility Micro Insert is indicated for bilateral scleral implantation to improve unaided near 
vision in phakic, presbyopic patients between the ages of 45 and 60 years of age, who have a 
manifest spherical equivalent between -0.75 D and +0.50 D with less than or equal to 1.00 D of 
refractive cylinder in both eyes and require a minimum near correction of at least +1.25 D reading 
add. 
 
1.3 
SUBJECT POPULATION 
Subjects who were implanted or explanted with the VisAbility™ Micro Insert in Protocol VIS-2014 
will be invited to participate. 
 
Each subject will be contacted and asked to participate in this follow-up study.  Three documented 
attempts will be made by either regular mail, phone call, text, or email to contact each subject.   
 
Once contacted, study staff will explain the study purpose, procedures, and responsibilities to each 
potential participant.  Subjects who agree to participate must sign the informed consent, be able to 
understand the study requirements, be willing to follow study instructions, and agree to return for 
required follow-up visits. 
 
If all three attempts to contact the subject are unsuccessful, a certified letter will be sent to the last 
known address of the subject and a copy of the certified letter will be retained at the study site.  If 
there is no response from the subject over the course of the study, he/she will be deemed not 
enrolled at the close of the 60-month window.   
 
1.4 
STUDY DESIGN 
VIS-2014-5YR is a multicenter, observational study to evaluate the long-term safety of the VisAbility 
Micro Inserts in subjects who were implanted or explanted with the VisAbility™ Micro Insert in the 
VIS-2014 clinical trial.  Study subjects will be examined at 36-, 48-, and 60-months post-operatively 
(based on the anniversary of their first VisAbility™ surgery) with no planned interventions.  Subjects 
who opt to have all implant segments bilaterally removed (explanted) after enrollment in VIS-2014-
5YR will be followed for 2 years post removal, up to a maximum of 5 years follow-up.  Additional 
visits may include but are not limited to examination at day 1, week 1, month 1, and 2 annual visits, 
post removal. 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 7 of 40 
 
1.5 
SAMPLE SIZE 
All subjects who were implanted or explanted with the VisAbility Micro Insert will be invited to 
participate. Actual sample size will be determined at the completion of enrollment.   
 
1.6 
DATA ANALYSES 
Descriptive statistics and summaries will be provided for primary eyes and all eyes for the following: 
 
Primary safety outcomes:  
• 
Partial explantation (1–3 Micro inserts per eye) or complete explantation (4 Micro inserts per 
eye) and reason(s) 
• 
Anterior Segment Ischemia (Grades 2 – 4)   
• 
Segment exposure due to conjunctival and/or scleral erosion 
• 
Rate of serious adverse events (SAEs) 
 
Secondary safety outcomes: 
• 
Best Corrected Distance Visual Acuity (BCDVA)  
• 
IOP increase > 10 mm Hg over baseline or IOP > 30 mm Hg  
• 
Slit Lamp findings  
• 
Fundus exam findings  
• 
Rate of adverse events (AE’s) 
 
Secondary effectiveness outcome: 
• 
Change in uncorrected and distance corrected near visual acuity and letters correct in the 
primary eye of bilaterally implanted subjects (with all eight implants in place), as compared 
to baseline (VIS-2014). 
 
1.7 
CLINICAL PARAMETERS 
The following clinical parameters will be measured: 
• 
Near visual acuity (uncorrected, distance corrected) 
• 
Distance visual acuity (uncorrected and best corrected) 
• 
Intermediate visual acuity (uncorrected) 
• 
Patient Preferred Distance 
• 
Minimum add to 20/20 
• 
Dynamic pupillometry 
• 
Corneal Topography/Keratometry 
• 
Manifest refraction 
• 
IOP 
• 
Slit lamp biomicroscopy 
• 
Indirect Ophthalmoscopy 
• 
Cup/Disc Ratio 
 
A full description of the examination schedule and clinical parameters for the entire 5-year study 
can be found in Table 1. 
 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 8 of 40 
TABLE 1:  SCHEDULE OF VISITS AND MEASUREMENTS 
 
 
Initial 
VIS-2014 
Follow-up 
VIS-2014-5YR 
Follow-up 
Pre-
Op 
0    
Day 
1    
Day 
1     
Wk 
1    
Mo 
2   
Mo 
3   
Mo 
6   
Mo 
12  
Mo 
18 
Mo 
24 
Mo 
36 
Mo 
48 
Mo 
60 
Mo 
Slit Lamp 
Biomicroscopy  
OD, OS 
✓2 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Applanation Tonometry  
OD, OS 
✓2 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Gonioscopy  
OD, OS 
✓ 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
Scleral Thickness 
Measurement  
OD, OS 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Implant Assessment 
OD, OS 
 
 
 
 
✓ 
 
 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
Axial Length / ACD 
OD, OS 
✓ 
 
 
 
 
 
 
 
✓ 
 
✓ 
 
 
 
Corneal Topography/ 
Keratometry OD, OS 
✓ 
 
 
 
 
 
 
 
 
 
 
✓ 
✓ 
✓ 
Dynamic Pupillometry  
OD, OS 
✓2 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Posterior Pole exam with 
78 /90D lens 
OD, OS 
✓2 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
 
✓ 
✓ 
✓ 
Dilated Indirect 
Ophthalmoscopy 20/30D 
lens  
OD, OS 
✓ 
 
 
✓ 
 
 
 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
Visual Fields  
OD, OS 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cup/Disk Ratio OD, OS 
✓ 
 
 
 
 
 
 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
Cycloplegic Refraction 
w/ VA - OD, OS 
✓ 
 
 
 
 
 
 
 
✓ 
 
✓ 
 
 
 
Manifest Refraction  
OD, OS 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
BCDVA  
OD, OS, OU 
✓2 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
UCDVA 
OD, OS, OU 
✓ 
 
✓1 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
UCNVA @ 40 cm  
OD, OS, OU 
✓ 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
UCIVA @ 66 cm  
 OU 
✓ 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
DCNVA @ 40 cm  
OD, OS, OU 
✓ 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Patient Preferred 
Distance  
DCN - OD, OS, OU 
 
✓ 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Minimum add to 20/20 
✓ 
 
 
 
 
 
✓3 
✓3 
✓3 
✓3 
✓3 
✓ 
✓ 
✓ 
NAVQ (Validated PRO) & 
Subject Questionnaire 
✓ 
 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
 
 
 
Sub-Study Only 
Wavefront 
measurements³ 
✓ 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
Sub-Study Only 
Defocus Curve³ 
✓ 
 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
1Visual acuity will be measured using pinhole on day 1 
2Fellow Eye Safety Exam (when fellow eye surgery is 61-180 days after primary eye surgery) 
3Randomized Sub-study subjects only – control group subjects are examined through 6 months and the surgery group through 24 months. 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 9 of 40 
2.0 
INTRODUCTION & RATIONALE 
 
The VisAbility™ Micro Insert is a curved scleral implant that is injection molded from 
polymethylmethacrylate (PMMA), a material with an extensive history of use in permanent implants 
in the human eye, including intraocular lenses (IOLs).  Four VisAbility™ Micro Inserts are placed in 
a single presbyopic eye to improve near vision. 
 
Each VisAbility™ Micro Insert consists of 2 pieces, a main body segment with 2 legs and a locking 
segment. The locking segment has trans-longitudinal grooves on both sides that correspond to 2 
small “rails” on the interior edges of the legs of the main body segment (Figure 1). These features 
allow the locking segment to be smoothly snapped into place in the main body segment. The 
design of the VisAbility™ Micro Inserts include stabilization feet at each end intended to fixate 
at the entrance and exit sites of the scleral tunnel incision, thereby preventing displacement or 
migration of the implanted VisAbility™ Micro Insert. The VisAbility™ Micro Inserts are provided 
sterile in a Tyvek® peel pouch. 
 
 
Figure 1 
VisAbility™ Micro Insert Showing 2 Interlocking Pieces and Stabilization Feet 
 
Each VisAbility™ Micro Insert is implanted in a scleral tunnel approximately 4.0 mm posterior to 
the corneal limbus through scleral incisions centered at the 1:30, 4:30, 7:30, and 10:30 o’clock 
oblique quadrants.  Figure 2 shows a human eye model implanted with four VisAbility™ Micro 
Inserts. 
 
FIGURE 2 
PLACEMENT OF THE VISABILITY™ MICRO INSERTS 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 10 of 40 
3.0 
SUBJECT POPULATION  
Subjects who participated in the VIS-2014 clinical trial.  
 
3.1 
INCLUSION CRITERIA 
• 
Subjects must have been implanted or explanted with the VisAbility™ Micro Insert in the 
VIS-2014 clinical trial.  
• 
Subjects must be alert, mentally competent, and able to understand and comply with the 
requirements of the clinical trial and be personally motivated to abide by the 
requirements and restrictions of the clinical trial.   
• 
Subjects must provide written informed consent.  
 
3.2 
EXCLUSION CRITERIA 
• 
Subjects who do not wish to participate or do not provide written informed consent.   
 
 
 

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October 22, 2018 
 
 
 
 
 
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4.0 
INVESTIGATIONAL PROCEDURES 
 
4.1 
SUBJECT ENTRY 
4.1.1 SUBJECT CONTACT 
Each subject will be contacted and asked to participate in this follow-up study.  Three 
documented attempts will be made by either regular mail, phone call, text, or email to 
contact each subject.  
Once contacted, study staff will explain the study purpose, procedures, and responsibilities 
to each potential participant.  Subjects who agree to participate must sign the informed 
consent, be able to understand the study requirements, be willing to follow study 
instructions, and agree to return for required follow-up visits. 
If all three attempts to contact the subject are unsuccessful, a certified letter will be sent to 
the last known address of the subject and a copy of the certified letter will be retained at the 
study site.  If there is no response from the subject over the course of the study, he/she will 
be considered not enrolled at the close of the 60-month window. 
4.1.2 INFORMED CONSENT 
Written informed consent will be obtained for all subjects who agree to enroll in VIS-2014-
5YR.  Subjects may be consented and enrolled at any time between the opening of the 36-
month window and the close of the 60-month window.    
 
4.1.3 SUBJECT REFUSAL, INABILITY TO PARTICIPATE, OR INABILITY TO 
CONTACT 
If a subject refuses participation, or is unable to participate in the study, the reason for 
refusal or inability to participate will be documented. Documentation will also be retained for 
subjects who could not be contacted. 
 
4.2 
EXAMINATION SCHEDULE 
Visit windows are calculated based on a 30-day month. The visit windows are based on the 
anniversary of the first VisAbility surgery. The examination schedule is as follows: 
• 
Month 36 (+/- 60 days postoperative) 
• 
Month 48 (+/- 60 days postoperative) 
• 
Month 60 (+/- 60 days postoperative) 
 
Subjects may be consented and enrolled at any time between the opening of the 36-month window 
and the close of the 60-month window.  Visit data for subjects examined between visit windows for 
the 36, 48, and 60 month exam will be considered out-of-window.   
 
Subjects who opt to have all implant segments bilaterally removed (explanted) after enrollment will 
be followed for 2 years post removal, up to a maximum of 5 years follow-up.  Additional visits may 
include but are not limited to examination at day 1, week 1, month 1, and 2 annual visits, post 
removal. 
 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 12 of 40 
4.3 
CLINICAL PARAMETERS   
The following clinical parameters will be measured: 
• 
Near visual acuity (uncorrected, distance corrected) 
• 
Distance visual acuity (uncorrected and best corrected) 
• 
Intermediate visual acuity (uncorrected) 
• 
Patient Preferred Distance 
• 
Minimum add to 20/20 
• 
Dynamic pupillometry 
• 
Corneal Topography/Keratometry 
• 
Manifest refraction 
• 
IOP 
• 
Slit lamp biomicroscopy 
• 
Indirect Ophthalmoscopy 
• 
Cup/Disc Ratio 
 
A full description of the examination schedule and clinical parameters are referenced in Table 1. 
4.4 
DATA COLLECTION 
Sample paper source documents will be provided by the Sponsor, Refocus Group, Inc. (Refocus) 
for each subject enrolled in the study and may be completed by the Investigator or Sub-Investigator 
at the time of the subject examination.  The source documents should be completed in a clear and 
legible manner in black or blue ink and then signed and dated by the Investigator as indicated on 
the form.  Any corrections will be made by drawing a single line through the incorrect entry, adding 
the correct entry, and then initialing and dating the corrected entry. 
 
The information recorded on the source documents will then be entered into the electronic case 
report form (eCRF) in the Electronic Data Capture (EDC) System by the Investigator, Sub-
Investigator, or designee. The validated database will be equivalent to that used for the VIS-2014 
trial. Study data will be maintained on a secure computer with appropriate data security provisions. 
The original dated and signed source document will be kept in the subject’s study file at the 
Investigator’s site.  Instructions for the entry of data into the EDC will be provided to the clinical 
sites. 
 
4.5 
STUDY COMPLETION PROCEDURES 
4.5.1 SUBJECT COMPLETION 
Subjects are considered to have completed the study if they have completed the 60-month 
exam, or the 60-month visit window has closed.  
 
4.5.2 SUBJECT TERMINATION 
Subjects may be terminated from the study if the Investigator believes that continued 
participation in the study may jeopardize the subject’s health or welfare.  Subjects may also 
elect to withdraw from the study at their discretion.  Every effort will be made to encourage 
the subject to maintain compliance with the protocol and to continue in the study.  
Furthermore, every effort will be made in all instances to conduct examinations as 
determined by the Investigator to ensure the safety of the subject.  The Sponsor shall be 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 13 of 40 
notified promptly by the Investigator/study staff upon the termination or withdrawal of a 
subject by completion of the Study Exit form. Subjects who opt to have all implant segments 
bilaterally removed (explanted), after enrollment in VIS-2014-5YR, will be followed for 2 
years post removal, up to a maximum of 5 years follow-up.  Additional visits may include but 
are not limited to examination at day 1, week 1, month 1, and 2 annual visits, post removal. 
 
4.5.3 SUBJECT EXIT 
A subject exit form must be completed for all subjects who either complete, discontinue, are 
lost to follow-up, or are terminated from the study. 

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October 22, 2018 
 
 
 
 
 
Page 14 of 40 
5.0 
STATISTICAL METHODS 
 
5.1 
SUBJECT ACCOUNTABILITY 
The following terms and definitions will be used for the accountability of the study population and are 
based on the definitions found in ANSI Z80.29, Revision 018, Section B.5.3, as modified and explained 
below:  
• 
Enrolled – the total number of subjects enrolled (consented) in the study. 
 
• 
Discontinued – Subjects (eyes) that have discontinued treatment prior to the visit window 
associated with the form, as a result of death, or any other reason except lost to follow-up.  
 
• 
Lost to Follow-up – Subjects that have withdrawn from the study after enrollment, or subjects 
that have missed the visit window associated with the form and all subsequent scheduled 
visits despite documented efforts by the Investigator to schedule the subject for follow-up.  
 
• 
Missed Visit – Data for subjects (primary eyes) that is not available for a follow-up visit within 
the specified visit window associated with the form, but data is available for a subsequent 
follow-up visit for such subject.   
 
5.2 
STATISTICAL ANALYSIS  
Due to the observational, non-comparative nature of this study, the statistical analysis will be based 
on descriptive statistics. Summary statistics will be provided for all primary and secondary 
outcomes (listed above in Section 1.6) for primary and all eyes. 
 
All subjects enrolled will be included in the data analyses. Visit data for subjects examined between 
visit windows for the 36, 48, or 60 month exam will be considered out-of-window. Missing data will 
only be imputed for observations that occur after enrollment into the study.  In the absence of 
observed data between 36 months and including 60 months, the missing data will be imputed using 
trends seen in subjects with available data using data recorded between and including the 36-
month visit up to the 60-month visit (including out of window).  Scientific evidence and rational for 
those trends and imputation methodology will be provided in the report of the final analysis.  
Imputation may include but is not limited to; best/worst case analysis, multiple imputation or tipping 
point analysis (for binary outcomes). 
 
Analysis will contain primary implanted eyes (dominant eye), fellow implanted eyes, and bilateral 
(OU) data where appropriate. Analysis will include all implanted and explanted eyes (OD, OS).  
 
5.3 
ANALYSIS OF CLINICAL PARAMETERS 
Means, standard deviations, and ranges (min/max) will be derived from the continuous 
measurements.  Frequencies, rates (cumulative incidence), and proportions will be used for 
summarizing the categorical and ordinal outcomes. 
 
 

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October 22, 2018 
 
 
 
 
 
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6.0 
ADVERSE EVENT REPORTING 
 
An Adverse Event (AE) is any untoward sign, symptom or disease observed during the study 
regardless of the suspected cause.  Conditions or diseases that are pre-existing or chronic but 
stable are not Adverse Events.  Changes in pre-existing or chronic conditions or diseases that are 
consistent with natural disease progression are not Adverse Events. 
 
6.1 
SERIOUS ADVERSE EVENTS (SAE) 
An Adverse Event should be classified as a Serious Adverse Event (SAE) and reported as such, if it 
meets one or more of the following criteria: 
 
• 
It results in death (i.e., the Adverse Event causes or leads to death). 
• 
It is life threatening (i.e., the Adverse Event places the subject at immediate risk of death). 
• 
It is considered sight-threatening and requires intervention to prevent permanent impairment 
or damage. 
• 
It requires or prolongs inpatient hospitalization.  Hospitalization or prolonged hospitalization 
for diagnostic or elective surgical procedures for preexisting conditions are not SAEs. 
• 
It results in persistent or significant disability/incapacity (i.e., the Adverse Event results in 
substantial disruption of the subject’s ability to conduct normal life functions) or impairment 
of a body function or damage to body structures. 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to the investigational product. 
• 
It does not meet any of the above serious criteria but may jeopardize the subject or may 
require medical or 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 Adverse 
Event, 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). 
 
Investigators must notify Refocus of any SAE within 24 hours of observing or learning of the 
event.  For initial SAE reports, Investigators should record all case details that can be gathered 
within 48 hours on the SAE Form and fax immediately upon completion to Refocus. 
 
6.2 
UNANTICIPATED ADVERSE DEVICE EFFECTS (UADE) 
An unanticipated adverse device effect (UADE) is any serious adverse effect on health or safety or 
any life-threatening or sight-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. 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.  
 
 
 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
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Investigators must notify Refocus of any serious adverse effect on health or safety within 24 hours of 
observing or learning of the event.  The sponsor will monitor and evaluate all study AEs to ensure 
the collective nature, severity, and degree of incidence is measured.  Refocus will be responsible 
for informing the appropriate Regulatory Authorities, IRBs, and Investigators participating in the 
study of the UADE. 
 
6.3 
ADVERSE EVENT ASSESSMENT  
All study subjects will be evaluated for Adverse Events as defined in this protocol. All adverse 
events, regardless of severity, and whether or not they are ascribed to the study treatment, will be 
recorded in the source documents using standard medical terminology. Pre-existing conditions or 
diseases present at the 36-month exam that remain stable or change in a manner consistent with 
natural disease progression are not considered Adverse Events. 
 
All Adverse Events will be evaluated beginning at the time of onset, and evaluation will continue 
until resolution 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 source document.  
 
All AEs will be characterized by the following criteria: 
• 
Event term, 
• 
Intensity or severity, 
• 
Expectedness, 
• 
Relationship to study treatment, 
• 
Outcome, and 
• 
Treatment or action taken. 
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 known at the time of reporting, a diagnosis (i.e., disease or syndrome) should be recorded on the 
source document rather than individual signs and symptoms (e.g., record congestive heart failure 
rather than dyspnea, rales, and cyanosis). If a constellation of signs and/or symptoms cannot be 
characterized with a single medical diagnosis or syndrome, and they are considered unrelated to an 
encountered syndrome or disease at the time of reporting, these individual events should be 
recorded as separate AEs (e.g., if congestive heart failure and severe headache are observed at 
the same time, each event should each be recorded as an individual AE). If a diagnosis was not 
initially reported and is subsequently established, it should be reported as follow-up information and 
the original AE documents updated accordingly. 
 
 

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October 22, 2018 
 
 
 
 
 
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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  ⇒ fainting and fall to floor ⇒ head trauma ⇒ neck pain 
The primary event is orthostatic hypotension and the sequelae are head trauma and neck pain. 
 
6.4 
CLASSIFICATION OF ADVERSE EVENTS BY INTENSITY/SEVERITY 
All Adverse Events should be graded on a four-point scale (mild, moderate, marked, severe) for 
intensity/severity. These definitions are as follows: 
Mild: Transient discomfort; no medical intervention/therapy required and does not interfere 
with daily activities. 
Moderate: Low level of discomfort or concern with mild to moderate limitation in daily 
activities; some assistance may be needed; minimal or no medical intervention/therapy 
required. 
Marked: Considerable discomfort with limitation in daily activities, some assistance usually 
required; medical intervention/therapy usually required. 
Severe: Extreme discomfort and limitation in daily activities, significant assistance required; 
significant medical intervention/therapy required. 
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. 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. 
 
6.5 
CLASSIFICATION OF ADVERSE EVENTS BY EXPECTEDNESS/RELATEDNESS 
All AEs will be evaluated as to whether they are expected or unexpected.  The sponsor will monitor 
and evaluate all study AEs to confirm the appropriate assignment of classification based on the 
collective nature, severity, and degree of incidence.  
Expected (anticipated): An Adverse Event is expected when the nature, severity, or degree 
of incidence was previously described.   
Unexpected (unanticipated): An Adverse Event is unexpected when the nature, severity, 
or degree of incidence was not previously described.  
All AEs will be evaluated as to whether they are related to the device, as defined below: 
Not Related: Strong evidence exists that the Adverse Event has a cause other than the 
investigational device (e.g. pre-existing condition or underlying disease, concurrent illness, 
or concomitant medication). 
Possibly Related: There is a temporal association with the investigational device and it 
cannot be excluded as a cause, but other etiologies could possibly be the cause based upon 
available information. 
 

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October 22, 2018 
 
 
 
 
 
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Probably Related: There is a temporal association with the investigational device which 
makes a causal relationship probable where other etiologies are possible but unlikely to be 
the cause, based upon available information. 
Definitely Related: Strong evidence exists that the investigational device definitely caused 
the Adverse Event.  There is a temporal relationship between the event onset and the 
investigational device and the subject’s clinical state and concomitant therapies have been 
ruled out as a cause, based upon available information. 
6.6 
ADVERSE EVENT OUTCOME 
The clinical outcome of an Adverse Event will be recorded and characterized as follows: 
• 
Resolved, i.e., all signs and symptoms of the adverse event have resolved without sequelae 
and all medications or treatment have been discontinued. 
• 
Resolved with Continuing Treatment, i.e., all signs and symptoms of the adverse event have 
resolved, although treatment may be ongoing at the time of study discontinuation. 
• 
Resolved with sequelae (specify), i.e., at least one sign and/or symptom referable to the 
adverse event is still present at the time of study discontinuation. 
• 
Ongoing, i.e. the adverse event is ongoing at the time of study discontinuation. 
• 
Death. 
 
6.7 
TREATMENT OR ACTION TAKEN 
The clinical treatment of an Adverse Event will be documented and characterized as follows: 
• 
None, 
• 
Medical Intervention, 
• 
Surgical Intervention, and/or 
• 
Other 
6.8 
POSSIBLE ADVERSE EVENTS 
Possible Adverse Events that might reasonably be expected to occur in this study are listed below. 
The time periods refer to the exam visit that occurs corresponding to the post-operative follow-up 
visit schedule (i.e., 36 months means the 36-month postoperative visit).   
 
These specific examples of possible Adverse Events for VIS-2014-5YR include, but are not limited 
to: 
Lids and Lashes 
• 
Ptosis 
• 
Hordeolum 
• 
Chalazion 
• 
Onset of or worsening to severe clinically significant lid margin disease 
 
(e.g., blepharoconjunctivitis, blepharitis, meibomitis, meibomian gland dysfunction, 
etc.)  
Cornea 
• 
Corneal dellen  
• 
Corneal abrasion > 2mm  
• 
Dry eye signs (moderate or severe) of corneal and/or conjunctival staining, etc., 
 
requiring prescription medication  
• 
Corneal edema (moderate or severe)  
• 
Corneal infiltrate or ulcer 

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October 22, 2018 
 
 
 
 
 
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Conjunctiva/Sclera 
• 
Conjunctival cyst 
• 
Conjunctival erosion 
• 
Moderate or severe conjunctival injection  
• 
Subconjunctival hemorrhage (not associated with an explant or concomitant 
procedure) 
• 
Conjunctivitis (allergic, bacterial, viral) 
• 
Scleral erosion 
• 
Scleritis 
  
 
Anterior Segment, Iris, Lens 
• 
Persistent pupil abnormalities 
• 
Posterior Synechiae 
• 
Rubeosis Irides  
• 
Anterior segment ischemia (Grades 2 – 4) 
 
Grade 2: Decreased pupil reactivity (%CH < 25%)  
 
Grade 3: Decreased pupil reactivity plus anterior chamber reaction (Grade 2 with 
cell and/or flare) 
 
Grade 4: Corneal edema, anterior chamber reaction and decreased pupillary 
reactivity (Grade 3 with striate keratopathy) 
• 
Anterior chamber cells or flare  
• 
Intraocular Inflammation other than anterior chamber cells and flare (e.g. Vitritis) 
• 
Two grade change in lens opacity as compared to preoperative baseline 
 
Implants 
• 
Displaced, extruded, or missing implant segments 
Intraocular Pressure 
• 
Glaucoma 
• 
Hypotony (IOP < 6 mm Hg)  
• 
Increase in IOP of > 10 mm Hg over baseline or IOP > 30 mm Hg at two 
 
consecutive visits  
 
BCDVA Loss 
• 
Decrease in BCDVA of greater than or equal to 2 lines (≥ 10 letters ETDRS) 
 
 
Fundus 
• 
Choroidal effusion 
• 
Retinal detachment 
• 
Retinal or vitreous hemorrhage 
• 
Retinal hole 
• 
Posterior vitreous detachment 
 
 
 
 

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October 22, 2018 
 
 
 
 
 
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Secondary Surgical Intervention 
• 
Implant segment removal 
• 
Exposed implant segments or conjunctival retraction requiring conjunctival re-
approximation   
• 
Cataract extraction 
• 
Any other secondary surgical intervention 
 
Other 
• 
Eye pain requiring oral prescription pain medication  
• 
Allergic reactions to medications, devices, sutures or anesthesia 
• 
Other findings indicating a worsening of two grades (i.e. grade +3 or +4), as 
compared to the initial VIS-2014 5YR baseline 
 

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October 22, 2018 
 
 
 
 
 
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7.0 
MONITORING 
 
Sponsor or CRA personnel will monitor all clinical studies in a manner consistent with FDA 
guidelines.   Study monitoring will involve the following elements: 
• 
Sponsor or CRO personnel will meet with Investigators prior to the initiation of the VIS-2014-
5YR study in order to review the adequacy of the facility, equipment, and clinical personnel, with 
respect to the needs of the study and to familiarize the Investigator and clinic staff with the 
protocol. 
 
• 
Sponsor or CRO personnel will meet with Investigators and clinic staff at initiation of the time of 
study to ensure that subjects are being properly consented, the protocol examination methods 
are being complied with, and that study data is being properly recorded. 
 
• 
Sponsor or CRO personnel will meet with the Investigator and clinic staff at any time during the 
study regarding study conduct to ensure ongoing compliance with the protocol and data 
recording requirements.  
 
• 
Sponsor or CRO personnel will maintain ongoing email and telephone communication with the 
Investigator and clinic staff regarding study conduct. 
 
• 
The CRO shall select, train and manage qualified contract personnel to visit each Investigational 
site to review and monitor source documents and electronic data in accordance with FDA 
guidance.  
 
8.0 
REFERENCES 
1. Buckhurst, P.J., et al., Development of a questionnaire to assess the relative subjective benefits 
of presbyopia correction. J Cataract Refract Surg, 2012. 38(1): p. 74-9. 
2. Kass MA. Standardizing the measurement of intraocular pressure for clinical research. 
Guidelines from the Eye Care Technology Forum. Ophthalmology. 1996 Jan;103 (1):183-5]. 
3. ANSI Z80.29-2015 - Ophthalmics - Accommodative Intraocular Lenses 
 
 
 

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
Page 22 of 40 
APPENDIX 1: EXAMINATION METHODS 
Refractions and acuity measurements shall be obtained by an ophthalmologist, optometrist or 
trained technician (who is supervised directly by the ophthalmologist or optometrist).  Sites should 
maintain dim room illumination throughout the testing sequence and during manifest refraction and 
FVA/OPTEC acuity testing, and care should be taken to avoid light shining on the lenses of the 
FVA/OPTEC or on the subject’s face. All distance-corrected acuities (BCDVA, DCNVA) will be 
tested using a trial frame and subjects shall be visually observed and verbally reminded not to 
squint during all distance and near acuity measurements.   
 
Manifest Refraction 
Manifest refraction will be performed using Lombart CVSI21 computerized acuity systems and all 
recorded visual acuities will be measured via the Functional Vision Analyzer (FVA)/OPTEC 6500.. 
All systems will employ actual or equivalent optical distances of at least 20 feet and ambient lighting 
will be adjusted to be dimmer than the chart.  Chart luminance will fall within the ANSI required 
range of 80-160 cd/m2 and chart contrast will be a minimum of 85%.  The final manifest refraction 
will be confirmed in a trial frame, after testing in the phoropter.  
 
Instruments for Measuring Visual Acuities 
Manifest refraction will be determined using the Lombart CVSI21 computerized acuity system and 
all recorded visual acuities will be measured via the Functional Vision Analyzer (FVA)/OPTEC 6500 
(Stereo Optical, 8623 W. Bryn Mawr Ave., Suite 502, Chicago, IL, 60631, USA, 1.773.867.0380 or 
1.800.344.9500).  This FVA/Optec 6500 system utilizes a lens system to simulate various test 
distances for distance, intermediate, and near.  The FVA/Optec 6500 has a microprocessor 
controlled internal illumination system that results in constant luminance of 85 cd/m2; therefore, dim 
ambient lighting will be used.  The manufacturer’s instructions for use will be provided to each 
Investigational site.  
 
Distance Visual Acuity 
Distance visual acuity will be measured at a simulated (optical) distance of 6 m (~20 ft.). 
 
Intermediate Visual Acuity 
Intermediate visual acuity will be measured at a simulated (optical) distance of 66 cm 
(~26 in.). 
 
Near Visual Acuity  
Near visual acuity will be measured at a simulated (optical) distance of 40 cm (~15.75 in.).   

PROTOCOL VIS-2014-5YR 
 
 
October 22, 2018 
 
 
 
 
 
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Patient Preferred Distance  
Patient preferred distance will be measured monocularly and binocularly (OD, OS, OU) thru the 
manifest refraction.  The Cal light meter, a tape measure, and an ETDRS VA flip chart are required. 
• 
Place the patient’s manifest refraction into a trial frame. 
• 
Have the subject hold an ETDRS VA flip chart at 40 cm from the spectacle plane of the trial 
frame. 
• 
Hold the Cal light meter at the plane of the ETDRS VA flip chart to ensure that the 
illumination falls between 250-284 lux. 
• 
Identify the visual acuity line that corresponds with the threshold DCNVA obtained with the 
Optec/FVA instrument.  
• 
Have the subject cover one eye with an occluder and ensure the subject can read the line. 
• 
Then, have the subject adjust the reading distance of the flip chart via a “tromboning” motion 
until they determine the distance at which the VA line appears clearest to them.  Remind the 
subject that it may be closer or further away than the initial starting point (40 cm). 
• 
When the subject has determined the clearest distance, measure the distance from the 
spectacle plane in cm, using a tape measure and round to the nearest whole number. 
• 
Repeat the entire above process for the contralateral eye and then with both eyes together 
(OU). 
• 
Record all three distances on the source document. 
 
Determination of Minimum Add to 20/20 
Minimum add will be measured at a simulated distance of 40cm and will be determined by adding 
plus lenses monocularly until 20/20 is achieved. 
 
Dynamic Pupillometry 
Measurement of the pupillary reflex in both eyes will be conducted with the NeurOptics Pupillometer 
(Neuroptics, Inc., Irvine, CA) at each postoperative visit.  
Prior to testing, stimulus intensity should be set to 180µW (microwatts) and stimulus duration should 
be set to 802msec (milliseconds).  To get maximum pupil size, be sure to dark adapt the subject in 
a completely dark room for at least 3 minutes (as described on Page 16 of the Neuroptics 
Pupillometer Instruction Manual).   Before the scans are initiated, a flexible, contoured cup is used 
to reduce the possibility of stray light entering the eye.  During the initial phase of the scan, the 
maximum pupil size is measured without visible light (0µW) using only infrared lighting thereby 
maintaining the dark adapted (0µW) lighting conditions.  During the next phase of the scan, the 
pupillometer captures and analyzes a rapid sequence of digital images then stimulates the eye with 
a flash of light at an intensity of 180µW to measure minimum pupil size.  At the end of the 
measurement sequence, the following scan results will display (as described on Page 21 of the 
NeurOptics Pupillometer Instruction Manual):  
• 
The intensity (180µW) and duration (802msec) of the light stimulus  

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October 22, 2018 
 
 
 
 
 
Page 24 of 40 
• 
MAX (maximum pupil size) which represents the diameter of the pupil just before 
constriction  
• 
MIN (minimum pupil size) which represents the diameter of the pupil at the peak of 
constriction 
• 
LAT (latency) which represents the time of the onset of constriction 
• 
CON (percent constriction) is the percent of the constriction based on the following formula: 
 
 
{[MAX pupil diameter – MIN pupil diameter]/[MAX pupil diameter]} x 100 
Pupil shape:  The pupil shape of both eyes will be assessed at each and every visit as part of the 
slit lamp examination as follows: 
o 1 = round 
o 2 = elliptical 
o 3 = irregular 
 
Topography/Keratometry 
All topography/keratometry measurements will be taken using an automated, commercial grade 
topographer.  All systems will have the capability to map the surface curvature of the cornea, using 
non-invasive imaging.  Central keratometry will be measured and the K values will be recorded.  
Topography will be captured to rule out corneal irregularities.     
Slit Lamp Evaluation – Grading 
Lids/Lashes 
Blepharitis (using the Efron Grading scale and reference drawings): 
o 0 = none 
o 1 = trace (1+) 
o 2 = mild (2+) 
o 3 = moderate (3+) 
o 4 = marked/severe (4) 
 
Meibomian Gland Dysfunction (using the Efron Grading scale and reference drawings): 
o 0 = none 
o 1 = trace (1+) 
o 2 = mild (2+) 
o 3 = moderate (3+) 
o 4 = marked/severe (4) 
Cornea 
Superficial punctate keratitis (using the Efron Grading scale and reference drawings): 
o None 
o Trace 
o Mild 
o Moderate 
o Marked or Severe 
 

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October 22, 2018 
 
 
 
 
 
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Corneal abrasion: 
o None 
o Tiny 
o 1-2 mm 
o 2-3 mm 
o > 3 mm 
 
Corneal edema (using the Efron Grading scale and reference drawings): 
o 0 = no evidence of corneal edema 
o 1 = trace corneal edema (edema involves 0% to 5% of the cornea) 
o 2 = mild corneal edema (edema involves 6% to 25% of the cornea) 
o 3 = moderate corneal edema (edema involves 26% to 50% of the cornea) 
o 4 = marked/severe corneal edema (edema involves > 50% of the cornea) 
 
Corneal endothelial guttata: 
o 0 = no corneal guttata 
o 1 = rare corneal guttata 
o 2 = few corneal guttata 
o 3 = many corneal guttata 
o 4 = marked/severe corneal guttata with stromal edema and bullous lesions 
Other abnormal corneal findings (specify) 
Conjunctiva 
Conjunctiva injection (using the Efron Grading scale and reference drawings): 
o 0 = none 
o 1 = trace (1+) 
o 2 = mild (2+) 
o 3 = moderate (3+) 
o 4 = marked/severe (4) 
 
Subconjunctival hemorrhage: 
o 0 = none 
o 1 = less than or equal to 1 quadrant 
o 2 = 2 quadrants 
o 3 = 3-4 quadrants 
 
Conjunctiva edema: 
o 0 = none 
o 1 = trace 
o 2 = mild 
o 3 = moderate 
o 4 = marked/severe 
 
 

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October 22, 2018 
 
 
 
 
 
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Conjunctival erosion: 
o Absent 
o Present 
Scleral erosion: 
o Absent 
o Present 
Crystalline Lens 
Crystalline lens pathology using the LOCSII scale (with reference photos as published 
in Archives of Ophthalmology July 1989) as follows: 
o Normal 
o Lens Opacity 
o Other Abnormal Findings (specify) 
If lens opacity, please complete the following: 
o Nuclear/Color Opalescence:   □ N0     □ N1    □ N2    □ N3  
o Cortical:           
 
□  C0     □ C1     □ C2     □ C3      □ C4  
o Posterior Subcapsular:    
□ P0        □ P1     □ P2     □ P3  
o Anterior Subcapsular:     
□ A0        □ A1     □ A2     □ A3 
Implant Assessment 
o Missing Segments = segment is not present 
o Shallow segments = segment is closer to the surface and the contour of the implant 
is easily seen 
o Deep segments = segment is barely visible and little to no contour of the implant is 
seen 
o Non-tangential = segment is not equidistant from the limbus 
o Tilted segments = one end of the segment is higher than the other 
o Too close = segments < 3mm from the limbus 
o Too far = segments > 4mm from the limbus 
o Exposed Segments = overlying conjunctiva is not present 
o Extruded Segments = segment is protruding from the scleral tunnel 
 
 

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October 22, 2018 
 
 
 
 
 
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Anterior Chamber 
Cell and flare will be graded according to the SUN grading scheme (using a 1x1 mm slit 
lamp beam): 
SUN Grading for AC Cells 
GRADE 
CELLS IN 1x1mm Field 
0 
0 
(None) 
0.5+ 
1-5 
(Faint) 
1+ 
6-15 
(Mild) 
2+ 
16-25 (Moderate) 
3+ 
26-50 (Marked) 
4+ 
50+ 
(Severe) 
 
SUN Grading for AC Flare 
GRADE 
Description 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris/lens details clear) 
3+ 
Marked (iris/lens details hazy) 
4+ 
Intense (fibrin/plastic aqueous) 
 
Iris appearance 
o 1 = Normal 
o 2 = Diffuse atrophy 
o 3 = Segmental atrophy 
o 4 = Sectoral contraction 
o Other abnormal iris findings 
 
Assessment of Anterior Segment Ischemia 
o Grade 2: Decreased pupil reactivity (%CH < 25%)  
o Grade 3: Decreased pupil reactivity plus anterior chamber reaction (Grade 2 with 
cell and/or flare) 
o Grade 4: Corneal edema, anterior chamber reaction and decreased pupillary 
reactivity (Grade 3 with striate keratopathy) 
 

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October 22, 2018 
 
 
 
 
 
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Intraocular Pressure 
Intraocular pressure will be measured using Goldmann applanation tonometry.  Measurements will 
be taken according to the published guidelines set forth by Michael A. Kass [Kass MA. 
Standardizing the measurement of intraocular pressure for clinical research. Guidelines from the 
Eye Care Technology Forum. Ophthalmology. 1996 Jan;103 (1):183-5]. Copies of this guideline will 
be provided to all sites. 
 
Posterior Segment Examination 
Posterior segment examination should include a full dilated fundus examination and will be assessed 
using a 20D condensing lens.  Abnormalities of any of the structures in any location of the fundus 
should be noted.  Examination may include but is not limited to: vitreous body, optic disc, vasculature, 
macula, and periphery.   
Peripheral Fundus Examination 
o Normal 
o Abnormal (if abnormal, please describe) 
 
Cup to Disc Ratio will be assessed by means of a fundus exam using condensing lenses 
(78 D/90 D) and the slit lamp biomicroscope.  
Other Observations: 
Photographs, drawings and/or standard descriptive ophthalmic terms may be used as needed to 
describe any other ocular findings. 
 

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October 22, 2018 
 
 
 
 
 
 
 
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APPENDIX 2:  ANTERIOR SEGMENT ISCHEMIA (ASI):  DETECTION, MITIGATION AND 
REPORTING 
Anterior Segment Ischemia (ASI) is a potentially serious but most often self-limited response to 
decreased perfusion that even in severe cases generally resolves without sequelae or detrimental 
effects on vision.  The rich collateral blood supply of the anterior segment likely explains its 
relatively benign common clinical course. 
Decreased constriction of the pupil in response to light is the earliest physiological indicator of ASI 
and serves as a bellwether indicating diminished perfusion.  Recovery of perfusion, when it occurs 
at this mild stage, avoids potential sequelae such as persistent pupillary abnormalities.  Monitoring 
the pupillary reflex in the immediate postoperative period helps prevent progression by allowing 
prompt intervention to restore perfusion while the condition remains completely reversible. 
In this clinical study of the VisAbility Micro Insert, Refocus has adopted digital infrared dynamic 
pupillometry as a sensitive indicator of neuromuscular disturbance secondary to decreased iris 
vascular perfusion in the immediate postoperative period.  Pupillometry serves the primary purpose 
of evaluating the impact of surgery on perfusion and allowing for prompt removal of scleral implants 
from eyes that demonstrate compromised perfusion, thus reversing impaired pupillary function and 
preventing progressive damage from ischemia. 
Clinical Syndrome, Natural History and Severity Grading 
ASI represents an acute, generally self-limited response of the anterior segment of the eye to 
decreased vascular perfusion.  While mild cases most often resolve without sequelae, more severe 
cases may develop persistent pupillary abnormalities and iris atrophy.  Though rare, cataract and 
hypotony have been reported in a few isolated, very severe cases.  
The clinical syndrome of ASI was first described in 1954 and has become recognized as an 
uncommon complication of surgery involving the extraocular muscles.1  Risk factors for the 
development of ASI include advanced age, previous extraocular surgery, blood dyscrasias, 
hypercoagulable states, atherosclerosis, carotid artery disease and thyroid related immune 
orbitopathy.  In the setting of strabismus surgery, these risk factors play a larger role in determining 
susceptibility to ASI than the number or combination of muscles operated.2 
Anatomical studies have demonstrated that the anterior ciliary arteries are the source of 70 to 80% 
of the circulation of the anterior segment, including the iris and ciliary body.  The long posterior 
ciliary arteries provide the remainder, along with some contribution from the conjunctiva.3  The 
anterior ciliary arteries run along the rectus muscles, dividing into multiple branches and forming 
three levels of collateral anastomoses near the muscles’ scleral insertion points.  This rich collateral 
circulation likely explains the rarity and generally self-limited nature of postoperative ASI. 
 
1  Wilson WA, Irvine SR.  Pathologic changes following disruption of blood supply to iris and ciliary body. Trans Am Acad 
Ophthalmol Otolaryngol. 1955 Jul-Aug;59(4):501-2. 
 
2  Hiatt RL. Production of anterior segment ischemia.  Trans Am Ophthalmol Soc. 1977;75:87-102. 
 
3  Wilcox LM, Keough EM, Connolly RJ, Hotte CE. The contribution of blood flow by the anterior ciliary arteries to the 
anterior segment in the primate eye. Exp Eye Res. 1980 Feb;30(2):167-74. 

PROTOCOL VIS-2014-5YR 
 
 
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Delayed perfusion of the iris as demonstrated by angiography is recognized as Grade 1 ASI.4  
However, iris fluorescein angiography is not a useful tool in predicting which patients are likely to 
progress to higher grades of ASI or develop long-term sequelae postoperatively.9   Acutely 
decreased pupil reactivity represents Grade 2 ASI.  Anterior chamber reaction in addition to 
decreased pupil reactivity constitutes Grade 3.  Striate keratopathy, which is similar to the type of 
corneal edema typically seen following cataract surgery, in addition to anterior chamber reaction 
and decreased pupil reactivity represents the highest level of severity, Grade 4. 
Patients with Grade 4 ASI typically experience pain and reduced visual acuity beginning one or two 
days after surgery.  Without any surgical re-intervention, a period of gradual clinical improvement 
follows, with return of preoperative visual acuity in nine weeks or less.9  It is not known whether 
medical treatment with topical or systemic anti-inflammatory agents has any effect on the natural 
history of ASI.  Patients with severe iris ischemia may develop iris atrophy, decreased pupil 
reactivity and an oval or irregular pupil. 
Case reports and series in the literature reveal the natural history typical of ASI.  For example, 
Forbes reported on a case of Grade 4 ASI occurring after a four muscle operation.  Striate 
keratopathy initially reduced the visual acuity to 20/200.  Over two months the vision improved to 
20/30. Iris atrophy and an irregular pupil were the only sequelae.5 Keech et al described a case of 
Grade 4 ASI following a transposition procedure in a 74 year old woman with hypertension. On 
postoperative day 1, visual acuity was reduced to 20/100.  Slit lamp exam revealed an oval pupil 
with an atonic sphincter, anterior chamber reaction and striate keratopathy.  By 6 weeks all clinical 
signs had resolved except for a sluggishly reactive, oval pupil.6  
 
4  Olver JM, Lee JP. The effects of strabismus surgery on anterior segment circulation. Eye (Lond). 1989;3 ( Pt 3):318-
26. 
 
5   Forbes SB. Muscle Transplantation for External Rectus Paralysis : Report of Case with 
 
Unusual Complications. Am. J. Ophth. 48:248-251 (Aug.) 1959. 
 
6   Keech RV, Morris RJ, Ruben JB, Scott WE. Anterior segment ischernia following vertical muscle transpositionand 
botulinum toxin injection (letter) . Arch Ophthalmol 108:176, 1990. 
 

PROTOCOL VIS-2014-5YR 
 
 
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Saunders et al reported on a series of cases involving surgery on three extraocular muscles.7  Five 
adult patients developed acute ASI, including 3 with pupil signs and anterior chamber reaction 
(Grade 3) and 2 with striate keratopathy (Grade 4).  Treatment consisted of topical and systemic 
steroids.  With the exception of corectopia, there was complete resolution of all signs within 9 
weeks postoperatively. No patient suffered permanent visual loss.  Olver and Lee reported a series 
including 17 eyes with Grade 1, 11 eyes with Grade 2 and 5 eyes with Grade 3 ASI.15  Recovery of 
the iris circulation in most patients occurred within 4 weeks of surgery.  Only 2 eyes in the entire 
series demonstrated long-term pupil changes; the remaining eyes had no sequelae.  
To further elucidate the natural history of ASI, Bagheri et al investigated ASI in a rabbit model, 
chosen for its anatomic similarity to the human, including the significant contribution of the 
vasculature of the 4 rectus muscles to nourishment of the anterior segment.8  Performing various 
combinations of surgery involving from 1 to 4 muscles, they found that 51 eyes (30.4%) developed 
signs of ASI, but in most cases inflammation and corneal edema resolved spontaneously and 
histopathology revealed no major permanent ischemic changes.  Long-term complications included 
pupil irregularity and decreased response to light in 12 eyes and cataract in 4 eyes. A single case in 
the 4-muscle group showed neovascularization of the cornea and iris.  These findings support the 
clinically recognized natural history of ASI, which involves complete resolution without sequelae in 
most cases. 
Digital Pupillometry  
Because pupillary dysfunction constitutes the earliest functional sign of ASI, sensitive and precise 
measurement of the pupillary response to light in the immediate postoperative period represents a 
useful indicator of the risk of disease progression.  Other methods of detecting changes in anterior 
segment perfusion, including iris angiography and laser Doppler flowmetry, have not been proven 
as useful.  Iris angiography is not a useful tool for predicting which patients may develop clinical 
signs of decreased perfusion; therefore, iris angiography has not been standardized as a means of 
assessing postoperative iris perfusion, nor has it been utilized to assess the risk of sequelae.9  In 
addition, iris angiography does not reveal filling of intrastromal vessels in eyes with highly 
pigmented irides.  Further, the dye pattern is different in each individual, with a wide range of 
normal filling times and patterns. Additionally, validated commercial instruments designed 
specifically for iris angiography are not currently available, so iris angiography requires modification 
of existing equipment.10  Lastly, iris angiography adds risk due to potential reactions to intravenous 
fluorescein dye and may also prove difficult due to the status of the ocular surface and subjects’ 
reduced ability to comply with the procedure in the immediate postoperative period due to fatigue 
and residual effects of intraoperative sedation. 
 
7   Saunders RA, Phillips MS. Anterior segment ischemia after three rectus muscle surgery. Ophthalmology. 1988 
Apr;95(4):533-7. 
 
8   Bagheri A, Tavakoli M, Torbati P, Mirdehghan M, Yaseri M, Safarian O, Yazdani S, Silbert D.  Natural course of 
anterior segment ischemia after disinsertion of extraocular rectus muscles in an animal model. J AAPOS. 2013 
Aug;17(4):395-401. 
 
9  Saunders RA, Bluestein EC, Wilson ME, Berland JE. Anterior segment ischemia after strabismus surgery.  Surv 
Ophthalmol. 1994 Mar-Apr;38(5):456-66. 
 
10  Brancato R, Bandello F, Lattanzio R.  Iris fluorescein angiography in clinical practice. Surv Ophthalmol. 1997 Jul-
Aug;42(1):41-70. 
 

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While laser Doppler flowmetry has found utility in the study of the retinal and optic nerve head 
circulation, it has had only limited investigational use for the purpose of measuring the blood flow of 
the iris in humans.11,12,13  This technique requires adaptation of a laser delivery system, 
photodetector and target fixation device to a slit lamp, and while it has been used to investigate the 
effects of increased intraocular pressure and increased arterial pressure on perfusion, it has not to 
date been used to investigate the impact of reduced blood flow in the anterior ciliary arteries.14 
Therefore, digital infrared dynamic pupillometry is the optimal indicator of iris neuromuscular 
function relative to iris vascular perfusion.  Measurement of the dynamic response of the pupil to 
standardized illumination is the most sensitive means to assess the eye’s recovery from surgery 
because pupillary abnormalities represent the earliest functional sign of anterior segment ischemia 
(ASI).15  The purpose of pupillometry in the immediate postoperative period in this study is to allow 
for timely removal of scleral implants and prevent the development of potential sequelae. 
Infrared digital pupillometry consists of an integrated intense light source for pupil stimulation; an 
image capture system with an infrared digital camera capable of obtaining pupil measurements 
throughout the entire examination process (pupil diameter at rest, during light stimulation, and at the 
end of the stimulus), without interfering with pupil response because it provides no visible light; and 
a data processor to perform calculations.16  Using this type of device, i.e., the NeurOptics NPi™-
200 Pupillometer (Neuroptics, Inc., Irvine, CA)], the mean percent pupil constriction in a population 
of healthy adults has been determined to be 34% according to the formula %CH ={[dilated pupil 
diameter – constricted pupil diameter]/[dilated pupil diameter]} x 100.17  The authors of this study 
noted that, “in only one of 2432 measurements was the percentage of reduction below 10%.”17  
Therefore, digital infrared pupillometry offers a non-invasive method of obtaining a precise, 
numerical clinical measurement that serves as an early indicator of risk for progressive ASI and 
provides a clear threshold criterion value, allowing for timely intervention. Of note, an enrollment 
criterion for this study excludes any subject in whom the baseline mean percent pupil constriction is 
less than 30% in either eye, so that any impact of surgery on pupillary function can be readily 
discerned. 
 
11  Chamot SR, Movaffaghy AM, Petrig BL, Riva CE. Blood flow in the human iris measured by laser Doppler flowmetry. 
Microvasc Res. 1999 Mar;57(2):153-61. 
 
12  Chamot SR, Movaffaghy A, Petrig BL, Riva CE. Iris blood flow response to acute decreases in ocular perfusion 
pressure: a laser Doppler flowmetry study in humans.  Exp Eye Res. 2000 Jan;70(1):107-12. 
 
13  Michelson G, Groh M, Gründler A. Regulation of ocular blood flow during increases of arterial blood pressure. Br J 
Ophthalmol. 1994 Jun;78(6):461-5. 
 
14  Riva CE, Geiser M, Petrig BL; Beijing 100193, PR China. Ocular Blood Flow Research Association. Ocular blood flow 
assessment using continuous laser Doppler flowmetry. Acta Ophthalmol. 2010 Sep;88(6):622-9.  
 
15  Olver JM, Lee JP.   Recovery of anterior segment circulation after strabismus surgery in adult patients.  
Ophthalmology. 1992 Mar;99(3):305-15. 
 
16  Martínez-Ricarte F, Castro A, Poca MA, Sahuquillo J, Expósito L, Arribas M, Aparicio J. Infrared pupillometry. Basic 
principles and their application in the non-invasive monitoring of neurocritical patients. Neurologia. 2013 Jan-
Feb;28(1):41-51.  
 
17 Taylor WR, Chen JW, Meltzer H, Gennarelli TA, Kelbch C, Knowlton S, Richardson J, Lutch MJ, Farin A, Hults KN, 
Marshall LF. Quantitative pupillometry, a new technology: normative data and preliminary observations in patients with 
acute head injury. Technical note. J Neurosurg. 2003 Jan;98(1):205-13. 
 

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In this protocol we have adopted the following instrumentation and standard operating procedures: 
Measurement of the pupillary reflex in both eyes will be conducted with the NeurOptics Pupillometer 
(Neuroptics, Inc., Irvine, CA) at each postoperative visit.  
Prior to testing, stimulus intensity should be set to 180µW (microwatts) and stimulus duration should 
be set to 802msec (milliseconds).  To get maximum pupil size, be sure to dark adapt the subject in 
a completely dark room for at least 3 minutes (as described on Page 16 of the Neuroptics 
Pupillometer Instruction Manual).   Before the scans are initiated, a flexible, contoured cup is used 
to reduce the possibility of stray light entering the eye.  During the initial phase of the scan, the 
maximum pupil size is measured without visible light (0µW) using only infrared lighting thereby 
maintaining the dark adapted (0µW) lighting conditions.  During the next phase of the scan, the 
pupillometer captures and analyzes a rapid sequence of digital images then stimulates the eye with 
a flash of light at an intensity of 180µW to measure minimum pupil size.  At the end of the 
measurement sequence, the following scan results will display (as described on Page 21 of the 
NeurOptics Pupillometer Instruction Manual):  
• 
The intensity (180µW) and duration (802msec) of the light stimulus  
• 
MAX (maximum pupil size) which represents the diameter of the pupil just before 
constriction  
• 
MIN (minimum pupil size) which represents the diameter of the pupil at the peak of 
constriction 
• 
LAT (latency) which represents the time of the onset of constriction 
• 
CON (percent constriction) is the percent of the constriction based on the following formula: 
 
 
{[MAX pupil diameter – MIN pupil diameter]/[MAX pupil diameter]} x 100 
 
Pupil shape:  The pupil shape of both eyes will be assessed at each and every visit as part of the 
slit lamp examination as follows: 
o 1 = round 
o 2 = elliptical 
o 3 = irregular 
 
Adverse Event Reporting 
The constellation of findings of Grade 4 ASI, i.e., corneal edema, anterior chamber reaction and 
decreased pupillary reactivity, should be reported as follows: 
• 
Anterior segment ischemia (Grades 2 – 4) 
 
Grade 2: Decreased pupil reactivity (%CH < 25%)  
 
Grade 3: Decreased pupil reactivity plus anterior chamber reaction (Grade 2 with cell 
and/or flare) 
 
Grade 4: Corneal edema, anterior chamber reaction and decreased pupillary reactivity 
(Grade 3 with striate keratopathy) 
 

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APPENDIX 3: DATA SAFETY MONITORING BOARD  
 
Per the 01March2006 FDA Guidance document “The Establishment and Operation of Clinical Trial 
Data Monitoring Committees for Clinical Trial Sponsors”, the Data Safety Monitoring Board (the 
“DSMB”) established by Refocus for the VIS-2014 Clinical Trial will not need to be continued for the 
three years’ additional follow-up of subjects in protocol VIS-2014-5YR.   
 

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APPENDIX 4: SPONSOR COMMITMENTS 
 
Refocus is committed to: 
 
1. 
Complying with the Declaration of Helsinki, and all applicable health authority regulations 
governing the conduct of clinical research studies. 
2. 
Protecting the rights, health, safety, and welfare of study subjects. 
3. 
Informing the clinical investigators of any new information about the study which may affect 
the health, safety, or welfare of the subjects, or may influence their decision to continue 
participation in the study. 
4. 
Providing the clinical investigators with the study protocol and a full set of Case Report 
Forms on which to document the study evaluation variables for each subject entered into the 
study. 
5. 
Providing the statistical analysis and study report writing resources necessary to complete 
reporting of the study results. 
6. 
Ensuring equity of consideration among all investigators in multicenter studies in all matters 
of publications, meeting presentations, etc. 
7. 
Certifying that IRB approval of the protocol and Investigator’s Clinical Agreement will be 
completed prior to initiation of study at an investigational site. 
 

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APPENDIX 5: INVESTIGATOR COMMITMENTS AND RESPONSIBILTIES 
 
Each Investigator must be a licensed physician who has completed a residency in ophthalmology 
and had been trained in the VisAbility™ Micro Insert Surgical Procedure. The investigators have the 
following responsibilities: 
 
1. Subject Selection 
The investigator is responsible for assuring that all subjects enrolled and determined eligible for the 
study meet all inclusion and exclusion criteria stated in this protocol. 
 
2. Informed Consent 
The investigator is responsible for fully reviewing the nature of the study, the possible risks, and 
alternative treatments with prospective subjects prior to their enrollment in the study. The 
investigator is responsible for obtaining written Study Informed Consent in compliance with 21 CFR 
50 for each subject, prior to performing surgery on a subject. The original signed Informed Consent 
Form will be maintained in the subject's medical record, and a redacted copy of the signed Informed 
Consent Form will become an integral part of each Case Report file provided to the Sponsor. 
 
3. Institutional Review Board (IRB) Approval 
The investigator will obtain or verify approval for his/her participation in this study from the IRB for 
the institution at which the procedure will be performed, prior to enrolling any subjects in the study. 
The Informed Consent document to be used must also be approved by the IRB prior to initiation of 
the study. 
 
4. Subject Evaluations and Data Reporting 
The investigator is responsible for performing the subject evaluations as described in the study 
protocol. All information generated by the subject evaluation will be recorded on the subject source 
document or case report forms. The investigator will sign and date each form as indicated on the 
form upon its completion. Originals of all case report forms will be retained in the investigator’s 
office to be available for monitoring by the Sponsor or authorized regulatory bodies. The 
investigator will not deviate from the study protocol without prior approval from the Sponsor unless 
protection of the health, safety, or welfare of study subjects requires prompt action. 
 
5. Record Retention 
The investigator shall maintain all subject records for whichever of the following periods is shortest: 
• 
A period of two years after the date on which the FDA approves the marketing of the device for 
the purpose that was the subject of the study. 
• 
A period of five years after the date on which the results of the study are submitted to the FDA 
in support of the marketing of the device for the purpose that was the subject of the study. 
 

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APPENDIX 6: DECLARATION OF HELSINKI 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964,  
amended by the 29th World Medical Assembly, Tokyo, Japan, October 1975,  
and the 35th World Medical Assembly, Venice, Italy, October 1983 
 
INTRODUCTION 
It is the mission of the physician to safeguard the health of the people. His or her knowledge and 
conscience are dedicated to the fulfillment of this mission.  
The Declaration of Geneva of the World Medical Association binds the physician with the words, 
"The health of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, "A physician shall act only in the patient's interest when providing medical 
care which might have the effect of weakening the physical and mental condition of the patient.”  
The purpose of biomedical research involving human subjects must be to improve diagnostic, 
therapeutic and prophylactic procedures and the understanding of the etiology and pathogenesis 
of disease.  
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve 
hazards. This applies especially to biomedical research.  
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects.  
In the field of biomedical research, a fundamental distinction must be recognized between medical 
research in which the aim is essentially diagnostic or therapeutic for a patient, and medical 
research, the essential object of which is purely scientific and without implying direct diagnostic or 
therapeutic value to the person subjected to the research.  
Special caution must be exercised in the conduct of research which may affect the environment, 
and the welfare of animals used for research must be respected.  
Because it is essential that the results of laboratory experiments be applied to human beings to 
further scientific knowledge and to help suffering humanity, the World Medical Association has 
prepared the following recommendations as a guide to every physician in biomedical research 
involving human subjects. They should be kept under review in the future. It must be stressed that 
the standards as drafted are only a guide to physicians all over the world. Physicians are not 
relieved from criminal, civil and ethical responsibilities under the laws of their own countries.  
 
 

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I. 
BASIC PRINCIPLES 
1. 
Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and animal 
experimentation and on a thorough knowledge of the scientific literature.  
2. 
The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol which should be transmitted to a 
specially appointed independent committee for consideration, comment and guidance.  
3. 
Biomedical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. The 
responsibility for the human subject must always rest with a medically qualified person and 
never rest on the subject of the research, even though the subject has given his or her 
consent.  
4. 
Biomedical research involving human subjects cannot legitimately be carried out unless 
the importance of the objective is in proportion to the inherent risk to the subject.  
5. 
Every biomedical research project involving human subjects should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
subject or to others. Concern for the interests of the subject must always prevail over the 
interests of science and society.  
6. 
The right of the research subject to safeguard his or her integrity must always be 
respected. Every precaution should be taken to respect the privacy of the subject and to 
minimize the impact of the study on the subject's physical and mental integrity and on the 
personality of the subject.  
7. 
Physicians should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable. 
Physicians should cease any investigation if the hazards are found to outweigh the 
potential benefits.  
8. 
In publication of the results of his or her research, the physician is obliged to preserve the 
accuracy of the results. Reports of experimentation not in accordance with the principles 
laid down in this Declaration should not be accepted for publication.  
9. 
In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail. He or she should be informed that he or she is at liberty to abstain 
from participation in the study and that he or she is free to withdraw his or her consent to 
participation at any time. The physician should then obtain the subject's freely-given 
informed consent, preferably in writing.  
10. 
When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress. In that case the informed consent should be obtained by a 
physician who is not engaged in the investigation and who is completely independent of 
this official relationship.  

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11. 
In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation. Where physical or mental incapacity 
makes it impossible to obtain informed consent, or when the subject is a minor, permission 
from the responsible relative replaces that of the subject in accordance with national 
legislation.  
Whenever the minor child is in fact able to give a consent, the minor's consent must be 
obtained in addition to the consent of the minor's legal guardian.  
12. 
The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration are 
complied with.  
 
II. 
MEDICIAL RESEARCH COMBINED WITH PROFESSIONAL CARE 
(Clinical Research)  
1. 
In the treatment of the sick person, the physician must be free to use a new diagnostic and 
therapeutic measure, if in his or her judgement it offers hope of saving life, reestablishing 
health or alleviating suffering.  
2. 
The potential benefits, hazards and discomfort of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods.  
3. 
In any medical study, every patient - including those of a control group, if any - should be 
assured of the best proven diagnostic and therapeutic method.  
4. 
The refusal of the patient to participate in a study must never interfere with the physician 
patient relationship.  
5. 
If the physician considers it essential not to obtain informed consent, the specific reasons 
for this proposal should be stated in the experimental protocol for transmission to the 
independent committee (I, 2).  
6. 
The physician can combine medical research with professional care, the objective being 
the acquisition of new medical knowledge, only to the extent that medical research is 
justified by its potential diagnostic or therapeutic value for the patient.  
 
 

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III. 
NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN 
SUBJECTS 
 (Non-clinical biomedical research)  
1. 
In the purely scientific application of medical research carried out on a human being, it is 
the duty of the physician to remain the protector of the life and health of that person on 
whom biomedical research is being carried out.  
2. 
The subjects should be volunteers - either healthy persons or patients for whom the 
experimental design is not related to the patient's illness.  
3. 
The investigator or the investigating team should discontinue the research if in his/her or 
their judgement it may, if continued, be harmful to the individual.  
4. 
In research on man, the interest of science and society should never take precedence 
over considerations related to the wellbeing of the subject.