Conditions: Myopia Refractive Errors
Keywords: Small incision lenticule extraction (SMILE) Femtosecond laser
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 114
Healthy volunteers: yes

Brief summary:
The purpose of this study is to validate the safety and effectiveness of treating myopia (short-sightedness) higher than -10D using small incision lenticule extraction (SMILE) with the VisuMax femtosecond laser.

Detailed description:
Laser refractive surgery (LASIK and PRK) has been established for 25 years to treat myopia (short-sightedness). Over this time, the technology has been significantly improved to enable safe treatment of myopia up to -15D. Improvements including changing the shape of the lens of corneal tissue removed to better match the natural shape, and increasing the diameter of the applied correction to cover larger pupil sizes, have greatly reduced side-effects such as night vision glare and halos. Similarly, safety has been improved by using a laser (femtosecond laser) to create the corneal flap rather than a blade (known as a microkeratome), meaning that the cornea is reliably left with more than the safe amount of tissue.

In 2006, a new method of laser refractive surgery was introduced, small incision lenticule extraction (SMILE), which provides a minimally invasive keyhole method as it avoids the need to create a flap. In SMILE, a single laser (femtosecond laser) is used to make two curved cuts inside the cornea (without breaching the outside) that separate the lens of tissue that needs removing to focus the vision. This lens of tissue is removed in once piece (rather than evaporated as in LASIK) through a small 2mm wide tunnel to the surface.

SMILE has been used to treat short-sightedness up to -10D for more than 200,000 procedures worldwide and has been shown to achieve similar results to LASIK. However, because no flap is needed, this upper part of the cornea can also contribute strength, meaning that the cornea is stronger after SMILE than after LASIK. It is also expected that the accuracy for higher corrections using SMILE would be better than LASIK because the potential inaccuracies associated with excimer lasers (used in LASIK) are eliminated. This study will investigate the results of SMILE for myopia above -10D.

Arms:
arm 1: Patients with high myopia will undergo a SMILE procedure to correct their refraction. Proxymetacaine 0.5% and Oxybuprocaine 0.4% will be used as anaesthetic during the procedure. Tobramycin and dexamethasone, and ofloxacin will be used four times a day for one week after the procedure.

Interventions: intervention 1: Small incision lenticule extraction intervention 2: Tobramycin and dexamethasone intervention 3: Ofloxacin intervention 4: Proxymetacaine 0.5% intervention 5: Oxybuprocaine 0.4%
Intervention descriptions: intervention 1: The VisuMax femtosecond laser is used to create two interfaces that define a refractive lenticule of stromal tissue and a 2mm wide tunnel to connect the upper layer to the corneal surface. The lenticule is manually dissected and removed through the small 2mm incision without the need to create a flap as in LASIK. intervention 2: Tobramycin and dexamethasone (Tobradex) eye drops will be used four times a day for 1 week after the procedure intervention 3: Ofloxacin (Exocin) eye drops will be used four times a day for 1 week after the procedure intervention 4: Proxymetacaine 0.5% eye drops will be used as an anaesthetic during the procedure intervention 5: Oxybuprocaine 0.4% eye drops will be used as an anaesthetic during the procedure

Protocol document:
Prot_SAP_000.pdf: 
CLINICAL STUDY 
CONFIDENTIAL MEDICAL DATA 
This document is the property of The London Vision Clinic 
138 Harley Street, London W1G 7LA, England 
This document should not be amended, used or communicated without the 
prior written permission of The London Vision Clinic  
CLINICAL STUDY 
VISUMAX™ FEMTOSECOND LASER SMALL 
INCISION LENTICULE EXTRACTION FOR THE 
CORRECTION OF HIGH MYOPIA 
STUDY NUMBER: LOVC-004 
clinicaltrials.gov: NCT02528123
Date: 01/02/2016


 
 
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SUMMARY 
5 
LIST OF ABBREVIATIONS AND DEFINITIONS 
6 
1 BACKGROUND INFORMATION 
7 
1.1 Investigational device 
7 
2.0 STUDY RATIONALE 
7 
3.0 STUDY OBJECTIVES 
10 
4.0 STUDY ENDPOINTS 
10 
4.1 Main Endpoint 
10 
4.2 Secondary Endpoints 
11 
5.0 STUDY DESIGN 
12 
6.0 STUDY population 
12 
6.1 INCLUSION CRITERIA 
12 
6.1.1 General inclusion criteria 
12 
6.1.2 Inclusion criteria specific to the protocol 
12 
6.2 EXCLUSION CRITERIA 
13 
6.2.1 General exclusion criteria 
13 
7.0 STUDY PROCEDURES 
15 
7.1 Pre-operative Assessment 
15 
7.2Operative Procedures 
15 
8.0  ADVERSE EVENT REPORTING 
16 
8.1 Surgical complications 
18 
8.2 Retreatment 
18 
9.0 STATISTICS 
18 
9.1 Statistical Methods 
18 
9.2Determination of sample size 
19 
10 DATA MANAGEMENT 
20 
11 
Monitoring 
20 
12 ETHICAL PRINCIPLES 
20 
12.1  Reference documents 
20 


 
 
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12.2 Provision of information to patients and consent 
20 
12.3 Respect of anonymity 
21 
13 ACCESS TO DATA AND ARCHIVING 
20 
13.1 Personnel participating in the Investigation 
21 
13.3 Archiving 
22 
14 REPORTS AND PUBLICATION 
22 
REFERENCES 
Error! Bookmark not defined. 
APPENDIX 1: ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS REPORTING 
23 
APPENDIX 2: NEXTECH EMR DATA MANAGEMENT 
23 
 


 
 
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SUMMARY 
Product name: VisuMax SMILE 
Name of investigator (surgeon) and location of site: 
Dan Reinstein, Glenn Carp, London, UK  
TITLE OF THE STUDY: VisuMax femtosecond laser small incision lenticule extraction (SMILE) for the 
correction of high myopia.  
DEVELOPMENT PHASE: Investigator Initiated Trial (IIT) 
METHODOLOGY: Prospective, single-center, non-randomized, including primary and secondary 
endpoints 
GENERAL OBJECTIVE:  
The objective of this clinical trial is to evaluate the safety and effectiveness of the Carl Zeiss Meditec 
VisuMax™ femtosecond laser small incision lenticule extraction (SMILE) procedure for the reduction 
or elimination of myopia for manifest refraction spherical equivalent (MRSE) up to -14.00 D with 
maximum 7.00 D cylinder (myopia with or without astigmatism).  
NUMBER OF PATIENTS: 187 eyes  
INVESTIGATIONAL DEVICE : VisuMax femtosecond laser 
DURATION OF TREATMENT: The overall treatment phase for all patients will be about 24 months  
DURATION OF FOLLOW-UP FOR EACH PATIENT: 1 year 
START OF STUDY: February  2016 
Interim Report:     February  2017 
FINAL REPORT: September 2019 
MAIN INCLUSION CRITERIA:  
 - Patients with high myopia with or without astigmatism for MRSE between -9.00 D and -14.00 D, who 
would like to undergo SMILE surgery with the VisuMax femtosecond laser system 
MAIN EXCLUSION CRITERIA:  
 - Patients, who are not medically suitable for laser refractive surgery 


 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS 
Astigmatism 
Refractive error, caused by an irregularly shaped cornea with one 
meridian being significantly more curved than the meridian 
perpendicular to it 
Cap 
Corneal tissue above the refractive lenticule that remains intact 
except for a small incision through which the refractive lenticule is 
removed 
CDVA 
Corrected Distance Visual Acuity 
CE 
Conformité Européenne 
CZM 
Carl Zeiss Meditec  
D 
Diopter 
eCRF 
electronic Case Report Form 
EMR 
Electronic Medical Record 
GCP 
Good Clinical Practice 
HOA 
Higher Order Aberrations 
LASIK 
Laser in situ Keratomileusis  
MPG 
Medizinproduktgesetz - Medical Devices Act 
Myopia 
Nearsighted or shortsighted 
MRSE 
Mean Refractive Spherical Equivalent (=sphere + cylinder/2) 
PRK 
Photorefractive Keratectomy 
RST 
Residual Stromal Thickness 
SAE 
SLT 
Serious Adverse Event 
Sub-lenticule Thickness 
SMILE 
Small Incision Lenticule Extraction 
Spherical Aberration 
Aberration, where parallel light rays do not have the same focus 
after they pass through an optical system 
In the Zernike Polynomial expansion the coefficient is: Z4
0  
TUST 
Total Uncut Stromal Thickness 
UDVA 
Uncorrected Distance Visual Acuity 
 
 


 
 
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1 BACKGROUND INFORMATION  
1.1 INVESTIGATIONAL DEVICE 
The following devices and software options have to be used during the clinical investigation: 
VisuMax femtosecond laser (device) for therapeutic and refractive applications of 
corneal surgery.1 
The VisuMax has CE approval for treating myopia and myopia with astigmatism up to -10D 
sphere and 5D cylinder.2 
The focus of this Investigator Initiated Trial is on the treatment option SMILE for high myopia 
and high myopia with astigmatism up to -14D spherical equivalent and 7D cylinder. 
SMILE treatment option (software-license) 
 
2.0 
STUDY RATIONALE 
Laser refractive surgery has been established for more than 25 years3, 4 for the treatment of 
low to high myopia. While PRK was defined as a first generation of laser refractive surgery, 
LASIK was the second generation. In the 1990s many studies were published reporting PRK 
and LASIK correction of very high myopia (up to -32.00 D in some cases),5-10 however, these 
early treatments were associated with low predictability, significant regression of the 
refractive correction, and induced night vision disturbances.11-13 During this period, it was 
found that these issues were for the most part due to the use of small optical zones and 
minimal transition zones,14, 15 as well as the non-aspheric nature of the Munnerlyn ablation 
profiles that were resulting in high induction of spherical aberration16 and producing serious 
changes in night vision (glare and halos) and loss of contrast sensitivity. The introduction of 
aspheric profiles in the early 2000s resulted in significant reduction of the induction of 
spherical aberration along with improved safety in contrast sensitivity.17, 18 At around the 
same time, many studies investigated the influence of the optical zone diameter, and 
demonstrated that small optical zones were one of the major risk factors for night vision 
complaints.19-21 It was also shown that larger optical zones significantly reduced the amount 
of aberrations post-operatively and provided better outcomes and greater stability. Recent 
studies have shown that treatment of high myopia (<-10 D) using larger optical zones and 
aspheric profiles is safe and effective. 3, 4, 22-25 


 
 
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A further concern of treating high level of myopia was the increased risk of keratectasia. 
Keratectasia can be induced either by excessive tissue removal or by tissue removal in an 
already ectatic cornea such as a keratoconic cornea. It has now been established and is 
accepted in the community of refractive surgeons that the residual stromal thickness of uncut 
stroma under a LASIK flap should be no thinner than 250 µm and the total uncut stromal 
thickness for a postop PRK treatment should be no thinner than 300 µm. The major 
contributor to the risk of excessive keratectomy is the variation in flap thickness.26-28 
Improvements in microkeratome design and the introduction of femtosecond lasers for flap 
creation have significantly reduced the variation in flap thickness.29-32 Femtosecond lasers 
also add the ability to create very thin flaps (down to 80 µm using the VisuMax33), which has 
further reduced the risk of leaving less than 250 µm of residual stromal thickness. 
There have also been significant improvements in diagnostic techniques, and a lot of effort 
has been directed towards improving methods of screening for keratoconus preoperatively.34-
38  
The combination of knowledge of safety limits, improved safety calculations and improved 
keratoconus screening has dramatically reduced the risk of ectasia.  
SMILE, as the third generation of refractive laser surgery, performed using the VisuMax 
femtosecond laser system, is established for treatments of myopia and myopia with 
astigmatism with CE approval for sphere up to -10.00 D and cylinder up to 5.00 D.2 
Refractive predictability, safety and patient satisfaction after SMILE have been reported to be 
high and comparable to results in previous studies of femtosecond LASIK for moderate to 
high myopia.39, 40 
SMILE involves passing a dissector through a small 2–3 mm incision to separate the 
lenticular interfaces created by the femtosecond laser and allow the lenticule to be removed,  
thus eliminating the need to create a flap. This means that less anterior corneal lamellae are 
severed in SMILE, which has two main advantages. First, it is known that vertical cuts (e.g. 
flap sidecut) have more biomechanical impact than horizontal cuts. Recently, Knox 
Cartwright et al41 performed a study on human cadaver eyes that compared the corneal 
strain produced by a LASIK flap, a sidecut only, and a delamination cut only. The authors 
demonstrated that the increase in strain was equivalent between a LASIK flap cut and a 
sidecut alone. In contrast, the increase in strain after a delamination cut only was lower than 
after a LASIK flap or sidecut only. Applying this finding to SMILE, since no anterior corneal 
sidecut is created, there will be a reduced impact on corneal strain in SMILE compared to 
thin flap LASIK. Second, it is known that that the cohesive tensile strength (i.e., how strongly 


 
 
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the stromal lamellae are held together) of the stroma decreases from anterior to posterior 
within the central corneal region, with the anterior 40% stromal lamellae being the strongest 
region of the cornea, whereas the posterior 60% of the stroma are at least 50% weaker.42, 43 
In addition to cohesive tensile strength, tangential tensile strength (i.e., stiffness along the 
stromal lamellae) and shear strength (i.e., resistance to torsional forces) have both been 
found to vary with depth in the stroma. Kohlhaas et al.44 and Scarcelli et al.43  found that the 
tangential tensile strength was greater for the anterior stroma than posterior stroma, each 
using different methodology. Applying this knowledge to SMILE, since the anterior stroma 
remains uncut, the strongest part of the stroma continues to contribute to the strength of the 
cornea postoperatively, in contrast to both photorefractive keratectomy (PRK) and LASIK 
where the strongest anterior stroma is affected. 
In order to model these differences in corneal tensile strength between LASIK and SMILE, 
we recently developed a mathematical model based directly on the Randleman42 depth 
dependent tensile strength data to compare the postoperative tensile strength between PRK, 
LASIK and SMILE.45 The total tensile strength after PRK, LASIK and SMILE was calculated 
as the area under the regression line for the depths of the stroma that remain uncut in each 
type of procedure. The model demonstrated that the postoperative tensile strength would be 
greater after SMILE than after both PRK and LASIK.  
In summary, considering the safety of subtractive corneal refractive surgical procedures in 
terms of tensile strength represents a paradigm shift away from classical residual stromal 
thickness limits. Ideally, a parameter such as total tensile strength, which takes the 
nonlinearity of the strength of the stroma into account, seems more appropriate than residual 
stromal thickness as the limiting factor for corneal refractive surgery. At least, a simpler and 
more conservative way of modelling the total postoperative tensile strength is to calculate the 
Total Uncut Stromal Thickness (TUST). In SMILE, the TUST is the addition of the uncut 
stromal thickness in the cap and the Sub-Lenticule Thickness (SLT) defined as the remaining 
stromal thickness below the lenticule. This is different to LASIK, where only the RST is taken 
into account as all lamellae in the anterior stroma are cut as a result of the flap.  
Knowing that a RST of 250 µm is safe for LASIK, the minimum total uncut stromal thickness 
(TUST) was conservatively set to 300 µm for the present study, with a minimum sub-lenticule 
thickness of 220 µm.  
As described earlier, the results of SMILE up to -10.00 D have been shown to be similar to 
those achieved by LASIK. However, there is reason to expect the results of SMILE to be 
superior to LASIK for very high myopia because all of the potential errors associated with 


 
 
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excimer laser ablation are avoided, such as stromal hydration,46 laser fluence projection and 
reflection losses,47, 48 and other environmental factors.49 In SMILE, the tissue removal is 
defined only by the accuracy of the femtosecond laser, which is not affected by any changes 
in environmental conditions. Therefore, the accuracy of the lenticule interfaces will be 
independent of the overall thickness of the lenticule (i.e. the amount of correction), meaning 
that the potential error due to the surgery will be the same for low and high myopia. 
These factors should also reduce the induction of higher order aberrations, particularly 
spherical aberration, compared to LASIK as has been shown for moderate myopia.50, 51 The 
induction of spherical aberration should be reduced both by the increased contribution of the 
anterior stroma thereby reducing the peripheral stromal expansion postoperatively,52, 53 as 
well as the elimination of the laser fluence projection and reflection losses that degrade the 
peripheral ablation.47, 48 
Therefore, the introduction of SMILE has the potential to improve the outcomes of corneal 
refractive surgery for very high myopia in terms of accuracy, safety, and quality of vision 
(induction of aberrations). This study will investigate safety and effectiveness for high myopia 
with sphere -10.00 D or higher treated by SMILE with the VisuMax femtosecond laser 
system. 
 
3.0 
STUDY OBJECTIVES  
The primary objective of this study is to evaluate the safety and efficacy of the Carl Zeiss 
Meditec VisuMax™ femtosecond laser SMILE procedure for the reduction or elimination of 
myopia with spherical equivalent from -9.00 D to -14.00 D with a maximum cylinder of 7.00 D 
(high myopia with or without astigmatism). The secondary objective of the study is to 
establish appropriate safety parameters for SMILE surgery given that they have been set to 
be the same as LASIK.  
 
4.0 
STUDY ENDPOINTS 
4.1 
MAIN ENDPOINT 
1. Standard deviation of SEpostop-SEtarget at each follow-up time point (represent the 
scatter of the refractive outcome) 
2. Difference in keratometry between the 3 months and 12 months’ time points to be the 
same as for group of matched LASIK eyes.  


 
 
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4.2 
SECONDARY ENDPOINTS 
The secondary, descriptive endpoints will include:  
3. Cumulative UDVA distribution at each time point compared to pre-operative CDVA 
(efficacy diagram A54).  
4. Distribution of lines difference between post-operative UDVA and pre-operative 
CDVA in order to normalize the improvement in visual acuity between eyes (efficacy 
diagram B54). 
5. Change in CDVA as a loss-of-line distribution at each time point (safety diagram C54) 
including the percentage of eyes with CDVA unchanged or lines gained, and the 
percentage of eyes with a loss of 2 or more lines. 
6. Cumulative distribution of CDVA at each time point. 
7. Stability of spherical equivalent refraction (SE) (diagram F54):  
The mean and standard deviation at each time point will be calculated, as well as the 
percentage of eyes with a change of 0.5 D and 1.0 D between 1-month- and  
3-months follow-up, and between 3-months and 12-months follow-up. 
8. Predictability of spherical equivalent including linear regression analysis of achieved 
SE depending on attempted SE (diagram D54). 
9. Spherical equivalent refractive accuracy (diagram E54):  
Distribution of SEpostop-SEtarget at each follow-up time point. 
10. Refractive astigmatism as a distribution of pre- and post-operative astigmatism at 
each follow-up time point (diagram G54). 
11. Side effects and complications at each time point (numbers and percentages) 
according appendix 1. 
12. Standard analysis of corneal aberrations with focus on spherical aberration with 
ATLAS pre- versus post-operative and stability of corneal aberrations post-operative 
for all follow-up visits with an ATLAS. 
13. Cylinder vector analysis  according to the Alpins method55 including predictability of 
the target induced astigmatism vector relative to the surgically induced astigmatism 
vector, and the distribution of the angle of error (angle between the target induced 
astigmatism vector and surgically induced astigmatism vector) (diagrams H and I54). 
 


 
 
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5.0 
STUDY DESIGN  
This is a prospective single-center clinical trial in which a maximum of 187 eyes will be 
consented, enrolled, and treated with the VisuMax™ femtosecond laser.   
Study subjects will be followed for 12 months. Subjects will be screened for eligibility, and 
informed consent will be obtained from those who meet screening criteria and are interested 
in participating in the study. Eligible subjects will be examined preoperatively to obtain a 
medical history and to establish a baseline ocular condition. Baseline and postoperative 
measurements will include manifest refraction, cycloplegic refraction, distance visual acuity 
(best corrected and uncorrected using ETDRS charts), slit-lamp examination, fundus 
examination, corneal topography and wavefront, corneal tomography (front and back corneal 
surface), central corneal pachymetry, dynamic pupillometry (dark, scotopic, and mesopic), 
whole-eye wavefront analysis, mesopic contrast sensitivity, and intraocular pressure (IOP). 
All baseline and postoperative measurements will be done in accordance to the daily routine 
procedure of the clinic for standard SMILE treatments.  
Retreatments of the study eye will not be allowed during the course of the study.  
 
6.0 
STUDY POPULATION 
6.1 
INCLUSION CRITERIA 
6.1.1 General inclusion criteria 
Only patients who are medically suitable for corneal refractive surgery can be included in the 
study.  
As general inclusion criteria the following aspects are defined: 
 
Subjects should be 21 years of age or older 
 
Contact lens wearers must stop wearing their contact lenses at least four weeks per 
decade of wear before baseline measurements in case of hard contact lenses and 
one week before baseline measurements in case of soft contact lenses. 
 
6.1.2 Inclusion criteria specific to the protocol  
 
Eyes with high myopia spherical equivalent between -9.00 D up to -14.00 D, with 
cylinder up to 7.00 D will be included. 


 
 
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 
Calculated sub-lenticule thickness (SLT) ≥220 µm 
 
Calculated total uncut stromal thickness (TUST) ≥300 µm 
 
The corrected distance visual acuity will be 20/40 or better in each eye pre-
operatively. 
 
Patient will be able to understand the patient information and willing to sign an 
informed consent. 
 
Patient will be willing to comply with all follow-up visits and the respective 
examinations as specified in the flow-chart. 
6.2 
EXCLUSION CRITERIA 
6.2.1 General exclusion criteria 
 
Previous intraocular or corneal surgery of any kind on the eye being treated 
 
Patient not being able to lie flat in a horizontal position 
 
Patient not being able to tolerate local or topical anesthesia 
 
Autoimmune diseases  
 
Sicca syndrome, dry eye  
 
Herpes viral (herpes simplex) infections  
 
Herpes zoster  
 
Diabetes  
 
Pregnant or nursing women (or who are planning pregnancy during the study) 
 
Patients with a weight of > 135 kg 
 
Any residual, recurrent or acute ocular disease or abnormality of the eye, e.g. 
– Cataract 
– Suspected glaucoma  
– Corneal disease 
– Corneal thinning disorder, e.g. keratoconus, 
– Pellucid marginal corneal degeneration 
– Dystrophy of the basal membrane 
– Corneal oedema 
– Exudative macular degeneration 
– Infection 
 
Any residual, recurrent, or active abnormality of the cornea to be treated, e.g. 
– Existing corneal implant 
– Corneal lesion 


 
 
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– Unstable refraction 
– Connective tissue disease 
– Dry eye 
 
The complete list of contraindications is included in the Surgical Information Package 
provided to the patient by the London Vision Clinic before surgery. Furthermore, the 
contraindications related to a SMILE treatment correspond to those reported in the medical 
literature for laser refractive surgery. 
 


 
 
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7.0 
STUDY PROCEDURES 
7.1 
PRE-OPERATIVE ASSESSMENT  
Note: As soon as the first screening for each patient is done and the patient is enrolled in the 
study, patient data will be pseudonymized. Only the investigator and monitor will be able to 
identify the patient name if necessary. 
Informed consent and permission to use data for analysis and publication have to be 
obtained from each patient prior to the pre-operative assessment.  
A full ophthalmologic examination will be performed on all patients prior to surgery as 
described in the schedule of assessments (chapter 8.2).  
7.2 
OPERATIVE PROCEDURES 
The treatment protocol will provide information as described in the schedule of assessments 
and as usually done in daily practice for SMILE.  
Schedule of Assessments  
Examination  
Days to treatment  
preOP 
-60 to -1 
OP 
1d 
1 to 2 
1m 
21 to 42 
3m 
75 to 110 
12m 
305 to 440 
Patient Demographics, medical history 
x 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
Pupil diameter (Procyon) 
x 
 
 
 
 
 
Intraocular pressure (IOP) (Goldmann) 
x 
 
 
 
 
x 
Fundus examination  
x 
 
 
 
 
x 
Cycloplegic refraction 
x 
 
 
 
 
 
Subjective refraction 
x 
 
x 
x 
x 
x 
Contrast sensitivity  
x 
 
 
 
x 
x 
Slitlamp examination 
x 
x 
x 
x 
x 
x 
Corneal topography and wavefront (ATLAS) 
x 
 
x 
x 
x 
x 
Corneal tomography (Pentacam) 
x 
 
 
 
x 
x 
Wavefront (WASCA) 
x 
 
 
 
x 
x 
Optical quality (HD Analyzer) 
x 
 
 
 
x 
x 
Corneal & epithelial thickness (RTVue OCT) 
x 
 
 
 
x 
x 
Ocular Response Analyzer 
x 
 
 
 
 
x 
Severe side effects / complications 
 
x 
x 
x 
x 
x 
UDVA  
x 
 
x 
x 
x 
x 
CDVA   
x 
 
 
x 
x 
x 
Patient questionnaire for night vision 
disturbances 
x 
 
 
 
x 
x 
Light Disturbance Analysis (LDA) 
x 
 
 
 
x 
x 
Treatment protocol and videos  
 
x 
 
 
 
 
Laser settings  
 
x 
 
 
 
 
Note: All described examinations are usually done in daily routine practice. 


 
 
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8.0  
AVERSE EVENT REPORTING 
 
DEFINTION OF AN ADVERSE EVENT (AE) 
An AE is any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical treatment or procedure. 
REPORTING OF AES 
Patients will be instructed by the investigator to report the occurrence of any AE. The 
investigator assesses and records all AEs observed during the AE reporting period which is 
defined as postoperative until  the end of the study. Any event considered as related to the 
procedure will be reported regardless of timing. 
DEFINITION OF SERIOUS ADVERSE EVENT (SAE) SAES DURING STUDY 
PERIOD 
A SAE includes any of the events listed in Table 1 below and occurring between registration 
and until completion of the study.  


 
 
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Table 1 
SAE Definitions 
 
Comments 
Fatal 
All events resulting in death 
Life-threatening 
The patient was at immediate risk of death from the event as it occurred. 
It does not include an event that, had it occurred in a more serious form, 
might have caused death 
Requires inpatient 
hospitalization 
(> 24 hours) 
Events not considered to be SAE are hospitalizations > 24 hours and 
occurring under the following circumstances:  
- elective surgery (planned before entry into the trial) 
- part of the normal treatment or monitoring of the trial treatment 
- hospitalization for social reasons (e.g. in rehabilitation home) 
- progressive disease 
Prolongs 
hospitalization 
Prolongation of an existing hospitalization 
Disabling 
Includes persistent or relevant disability or incapacity  
Secondary 
malignancy 
Any new malignancy other than a relapse of the current tumour 
Congenital anomaly Birth defect of offspring  
Other medically 
significant condition 
Important AEs that are not immediately life-threatening or do not result 
in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed above 
 
SAEs after End of Trial Treatment 
During the follow-up phase, the following events have to be reported as SAE: 
o fatal, life-threatening and other medically significant events possibly, probably or 
definitely related to late effects of trial treatment 
o disabling events possibly, probably or definitely related to late effects of trial 
treatment 
o secondary malignancy 
o congenital anomaly 
 


 
 
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DEFINITION OF SERIOUS ADVERSE DRUG REACTIONS (SADRS) 
SADRs are all SAEs considered to be related (possibly, probably, definitely) to the trial 
treatment. 
RECORDING OF SAES 
Any SAE must be recorded by completion of an SAE form within 24 hours of becoming 
aware of the SAE. 
 
REPORTING OF SAES TO THE REGULATORY AUTHORITIES 
The London Vision Clinic will report all SAEs to the regulatory authorities as required by local 
and national guidelines.   
An overview of expected adverse events and serious adverse events is shown in appendix 1.  
 
8.1 SURGICAL COMPLICATIONS 
If any surgical complication occurs, the surgeon will finish the treatment of the patient as 
usually done in daily routine practice for SMILE. This patient might be excluded from the 
efficacy analysis if the surgical problem can be defined as a reason for low predictability or 
loss of lines of CDVA. However, the patient will be still included in the safety investigation 
and will be reported in the intermediate and final report. If necessary, single patients will be 
described in detail as case reports. 
An overview of intraoperative surgical complications, is shown in appendix 1.  
 
8.2 
RETREATMENT  
To avoid any permanent risk of under- or overcorrection for the patient, a retreatment will be 
performed if necessary as done in daily routine practice. However, retreatments will not be 
performed earlier than the 12-month time point in order to collect the study data.  
 
9.0 
STATISTICS  
9.1 
STATISTICAL METHODS 
The main criterion and secondary criteria represent the standard analysis of refractive and 
visual outcomes and will be analyzed according to the Standard Graphs for Reporting 
Refractive Surgery, as recommended by the Journal of Refractive Surgery.54 


 
 
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9.2 
DETERMINATION OF SAMPLE SIZE 
The main criterion for the study is to evaluate the standard deviation of the SEpostop-SEtarget, 
which represents the scatter of the refractive outcome. This metric was chosen in place of 
the predictability of the refractive correction as a mean under or overcorrection can be 
adjusted for simply using a nomogram, so the scatter is an indicator of the best possible 
refractive predictability. 
To calculate the sample size for this study, the standard deviation of the refractive outcome 
will be compared to that reported for LASIK for an equivalent range of myopia. In a previous 
study of 480 eyes using the MEL80 excimer laser for myopia between -8.00 and -14.00 D, 
we found the standard deviation of the spherical equivalent refraction 1 year after LASIK to 
be 0.70 D.56 A one-tailed F-test will be used to test if the variances of the two populations are 
equal, or that the variance of SMILE is not greater than the variance of LASIK, using a 
difference of 0.15 D in standard deviation. 
Null hypothesis: Variance(LASIK) = Variance(SMILE) 
Test hypothesis: Variance(LASIK) < Variance(SMILE) 
Given standard deviations of 0.70 and 0.85 D, the ratio of variances is 1.47. Using an α error 
probability of 0.05 and a statistical power (1-β error probability) of 0.8, the a priori sample 
size calculation indicates that a population size of 168 eyes is required. 
The 1 year follow-up rate for routine refractive surgery patients at London Vision Clinic has 
been >90%, so it is reasonable to expect this level of follow-up would be achieved for the 
study population. Therefore, a total population of 187 eyes is required. 


 
 
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10 
DATA MANAGEMENT 
The data will be entered directly into the London Vision Clinic EMR software (Nextech) 
during the patient examination. This includes all measurements made by the 
ophthalmologist/optometrist as well as images of all automated eye scans obtained (e.g. 
corneal topography, aberrometry, etc). The data are then exported from the EMR database 
and transferred electronically by an automated process to a study database (in Microsoft 
Excel 2010) which will be used for the final analysis. See appendix 2 for details. All data will 
be fully pseudonymized. Plausibility checks are programmed in the study database to catch 
1st order errors, which are then checked manually. 
 
11  
MONITORING  
Monitoring visits will be performed periodically throughout the study to ensure that the data 
captured in the study database is correct. 
All the data will be checked for any patients presenting with one or more serious adverse 
events or who withdraw or are withdrawn prematurely from the clinical investigation.  
100% monitoring of the informed consent forms will be done.  
Random Sample Monitoring will be performed on 50% of the data collected. 
 
12 
ETHICAL PRINCIPLES 
12.1  REFERENCE DOCUMENTS 
This clinical trial will be carried out in accordance with the ethical principles stated in the 
Helsinki Declaration (and its subsequent modifications), the recommendations consolidated 
by the International Conference of Harmonization in respect of Good Clinical Practice, ISO 
14155 and the local and national applicable regulations. 
 
12.2  PROVISION OF INFORMATION TO PATIENTS AND CONSENT  
Patients may participate in this investigation only after being informed by the investigator of 
the nature of this investigation and of its objectives, risks, disadvantages and benefits, 


 
 
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prerequisites and obligations, confidentiality, specific risks covered by law in order to protect 
their integrity and notification of the investigation to the Ethics Committee. 
No examination, outside of those performed for standard refractive surgery patients, relating 
to this investigation will be carried out before the written consent has been received. The 
patients will receive a copy of the study consent form. Only subjects who have the legal 
capacity, are able to understand the nature, significance and objectives of the clinical 
investigation, and are able to make a decision can be included in the study. Moreover, any 
subject whose freedom is impaired by an administrative or court order cannot be selected to 
participate in the study. 
  
12.3 RESPECT OF ANONYMITY  
A unique identification code, assigned by the investigator (automatically assigned within the 
EMR software), will be used as means of pseudonymization for each patient participating in 
this investigation, in order to protect his or her identity. This patient identification code will be 
used instead of the patient's name for any communication of data or reporting of adverse 
reactions by the investigator. The patient identification consists of numbers: 
Example: 
13991 
 
12.4 
SUBMISSION TO THE ETHICS COMMITTEE AND COMPETENT AUTHORITIES 
Approval will be obtained prior to the start of the study according to local regulations. 
 
13 ACCESS TO DATA AND ARCHIVING 
13.1 PERSONNEL PARTICIPATING IN THE INVESTIGATION 
The investigator is responsible for filing all the documents related to the IIT. The investigator 
must employ a sufficient number of qualified personnel and have the required facilities 
available to him/her for the provisional duration of the investigation in order to conduct the 
study properly and in complete safety. The investigator must ensure that the personnel 
involved in the IIT are sufficiently well informed about the protocol, the study products, their 
responsibilities and their functions in the IIT.  
 


 
 
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13.3 ARCHIVING 
After the normal or premature termination of the investigation, the essential study documents 
will be archived confidentially according to local regulations and GCP guidelines. 
 
 
14 
REPORTS AND PUBLICATION 
All data or results from this IIT are the property of London Vision Clinic.  
  


 
 
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APPENDIX 1: ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
REPORTING 
ADVERSE EVENTS1 
The following adverse events, although not an all-inclusive list, should be considered to be 
reportable.  
Any adverse event (AE), whether ascribed to the surgical procedure or not, have to be 
identified by an updated version of the CRF.  
 
Diffuse lamellar keratitis (Grade 2 or above)  
 
Corneal infiltrate or ulcer 
 
Corneal epithelial defect only at 1 month or later 
 
Corneal edema (Grade 2 or above) only at 1 month or later  
 
Epithelium in the interface with loss of 2 lines or more CDVA  
 
Decrease in CDVA of greater than or equal to 2 lines at 3 months or later 
 
Any other vision-threatening event 
 
Ocular penetration 
 
Ectasia 
 
Others (describe) 
 
Additional possible adverse events: 
 
Foreign body sensation only at 3 months or later 
 
Pain at 3 months or later 
 
Ghost/double images in the operative eye 
 
Dry eye at 6 months or later 
 
Significant night vision disturbances at 6 months or later 
 
SERIOUS ADVERSE EVENTS 
Any Serious Adverse Event (SAE), whether ascribed to the surgical procedure or not, will be 
communicated promptly (within 24 hours after knowledge) according to local regulations and 
GCP guidelines.  
 
death  
 
life-threatening illness or injury  
                                                     
1 American National Standard ANSI Z80.11-2007 


 
 
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 
a permanent impairment of a body structure or a body function  
 
in-patient hospitalization or prolongation of existing hospitalization  
 
medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function  
 
fetal distress, fetal death or a congenital abnormality or birth defect  
 
device deficiencies that might have led to a serious adverse event if a) suitable action 
had not been taken or b) intervention had not been made or c) if circumstances had 
been less fortunate 


 
 
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APPENDIX 2: NEXTECH EMR DATA MANAGEMENT 
Below is an example screen shot of the EMR source data entry. Further tables are included 
to record all other data to be collected. 
 
 
Below is an example screen shot of the data after it has been transferred into Excel for 
analysis. Highlighted values demonstrate the successful transfer of the data (refraction, 
keratometry, date). 
Preop values: 
 
Postop values: 
 
 


 
 
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