WAVELIGHT EX500 EXCIMER LASER SYSTEM, ALLEGRETTO WAVE EYE-Q EXCIMER LASER SYSTEM

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) ## I. GENERAL INFORMATION Device Generic Name: Ophthalmic Excimer Laser System Device Trade Name: WaveLight® EX500 Excimer Laser System, ALLEGRETTO WAVE® EYE-Q Excimer Laser System Device Procode: LZS Applicant's Name and Address: Alcon Laboratories, Inc. 6201 South Freeway Fort Worth, Texas 76134 Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P020050/S023 Date of FDA Notice of Approval: November 21, 2016 The original PMA (P020050) was approved on October 7, 2003 for WaveLight Allegretto WAVE Excimer Laser System indicated for use in Laser Assisted in situ Keratomileusis (LASIK) treatment for the following: - The reduction or elimination of myopia of up to -12.0 diopters (D) of sphere and up to -6.0 D of astigmatism at the spectacle plane; - Patients who are 18 years of age or older; and - Patients with documentation of a stable manifest refraction defined as ≤ 0.50 D of preoperative spherical equivalent shift over one year prior to surgery. The SSED to support the indication is available on the CDRH website at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P020050 and is incorporated by reference here. The current supplement was submitted to expand the indication for the ALLEGRETTO WAVE® EYE-Q and WaveLight® EX500 for use in photorefractive keratectomy (PRK) treatments. ## II. INDICATIONS FOR USE PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 1 {1} The WaveLight® EX500 Excimer Laser System and ALLEGRETTO WAVE® Eye-Q Excimer Laser Systems are indicated for use in Photorefractive Keratectomy (PRK) treatments for: - the reduction or elimination of up to -6.0 diopters (D) of spherical equivalent myopia or myopia with astigmatism, with up to -6.0 D of spherical component and up to -3.0 D of astigmatic component at the spectacle plane, - patients who are 18 years of age or older and, - patients with documentation of a stable manifest refraction defined as ≤ 0.5 D preoperative spherical equivalent shift over one year prior to surgery. ### III. CONTRAINDICATIONS The device is contraindicated if any of the following conditions exist: - progressive myopia with or without astigmatism, acute or recurrent ocular disease, previous corneal or intraocular surgery, or trauma in the ablation zone, - patients with a weakened immune system, including diagnosed collagen vascular, atopic syndrome, autoimmune or immunodeficiency disease, - patients with degeneration of structures of the cornea, diagnosed keratoconus or any clinical pictures suggestive to keratoconus, - patients with recurrent corneal erosion. This condition can lead to serious corneal problems during and after PRK, - patients with uncontrolled diabetes, - patients with a thin cornea and which is not thick enough to undergo the necessary ablation for the PRK procedure, - patients with uncontrolled glaucoma. It is unknown whether PRK is safe and effective for such patients, - patients with eyes that have a calculated residual stromal bed thickness that is less than 250 microns, and - patients with severe dry eyes. - Eyes with unstable visual acuity by manifest refraction (change of more than 0.5 diopter in myopia or astigmatism) over the prior 12 months preceding surgery. PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 2 {2} - Herpes (herpes simplex or herpes zoster) eye infection within the past year or corneal damage from prior herpes eye infections. #### IV. **WARNINGS AND PRECAUTIONS** The warnings and precautions can be found in the ALLEGRETTO WAVE® Eye-Q and WaveLight® EX500 Excimer Laser Systems labeling. #### V. **DEVICE DESCRIPTION** Two (2) devices are included in this submission, ALLEGRETTO WAVE EYE-Q Excimer Laser System (EYE-Q) and WAVELIGHT EX500 Excimer Laser System (EX500). These two (2) systems are similar. The primary difference between them is the frequency of the laser pulse, 400 Hz for EYE-Q and 500 Hz for EX500. The functional similarity for LASIK between the two (2) devices was approved by FDA on November 23, 2011 under P020050/S006 and P030008/S006 in which a study demonstrated that the ablation profiles on the bovine cornea were identical for 200 Hz, 400 Hz, and 500 Hz pulse frequencies. ##### ***ALLEGRETTO WAVE EYE-Q Excimer Laser System*** The EYE-Q is a scanning-spot Excimer laser system used in refractive surgery for the treatment of refractive errors of the human eye. The system consists of a compact excimer laser with high pulse frequency, a galvanometer scanner for positioning the laser spot, and a fast eye-tracker for determining eye position and laser beam direction. The integrated eye-tracker offers automatic centration of the ablation and tracking of eye movements. The specially shaped profile of the treatment laser beam and the small spot size ensure the required accuracy to achieve the desired contour of the treated corneal surface. The WaveNet™ Planning Software (WPS) allows the physician to plan treatments on a portable notebook computer outside the surgical area in the same way as if directly on the device. The software is made available to the surgeon on a standard DVD-ROM and can be used with any notebook computer meeting the specified hardware requirements. ##### ***WaveLight EX500 Laser System*** EX500 uses the same scanning technique for positioning the laser spot and same eyetracker to determine the eye position and laser mean direction as in EYE-Q. Similarly the WaveNet Planning Software is used for planning treatment. As for treatment parameter, EX500 provides the same wavelength, fluence, beam diameter, and ablation zone as EYE-Q. PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 3 {3} The comparison of the technical specifications of lasers used in EYE-Q and EX500 are the follows. | | **EYE-Q** | **EX500** | | --- | --- | --- | | Laser Source | ArF excimer laser | ArF excimer laser | | Laser Class | 4 | 4 | | Wavelength | 193 nm | 193 nm | | Pulse Frequency | 400 Hz | 500 Hz | | Pulse Duration | 10 ns + 5 ns | 6 ns + 2 ns | ## **VI. ALTERNATIVE PRACTICES AND PROCEDURES** Alternative methods for the correction of myopia and myopia with astigmatism include the following: wearing prescription spectacles or contact lenses, laser-assisted in situ keratomileusis (LASIK), phakic intraocular lens (IOL) implantation, radial keratotomy, and automated lamellar keratoplasty. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with their physicians to select the method that best meets expectations and lifestyle. ## **VII. MARKETING HISTORY** The WaveLight® EX500 is the 3rd generation of the WaveLight stationary scanning-spot excimer laser system. The 1st and 2nd generations are the ALLEGRETTO WAVE and the ALLEGRETTO WAVE EYE-Q, respectively. As of January, 2015 the following number of excimer laser systems have been installed worldwide: - 528 ALLEGRETTO WAVE, - 1220 ALLEGRETTO WAVE Eye-Q, and - 728 WaveLight® EX500 Of those, 106 ALLEGRETTO WAVE, 312 ALLEGRETTO WAVE Eye-Q, and 125 WaveLight® EX500 laser systems have been installed in the USA. The WaveLight® EX500 is CE marked and is approved in Argentina, Australia, Belarus, Brazil, Canada, China, Colombia, Costa Rica, Honduras, Indonesia, Israel, Kazakhstan, Malaysia, Mexico, New Zealand, Philippines, Peru, Russia, Serbia, Singapore, South Africa, South Korea, Sri Lanka, Taiwan, Thailand, Turkey, Ukraine, USA, Uruguay, Venezuela, and Vietnam. These devices have not been marketed in the United States for the indication of Photorefractive Keratectomy (PRK). PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 4 {4} ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Potential adverse effects (e.g., complications) associated with PRK include the following: Loss of best spectacle corrected visual acuity (BSCVA), under- or over-correction of refractive error, induced astigmatism, worsening of patient complaints (such as double vision, sensitivity to bright lights, glare, increased difficulty with night vision, fluctuations in vision, starbursts, halos), dry eyes, eye pain and/or burning feeling in eyes, foreign body sensation in eyes, watery eyes, increased intraocular pressure (IOP), corneal haze, corneal infiltrate or ulcer, corneal epithelial defect, corneal edema. The occurrence of these events may involve the necessity of secondary (additional) surgical intervention, such as the possibility of corneal transplant due to corneal complications. For the specific adverse events that occurred in the clinical study, please see Section X below. ## IX. SUMMARY OF NON-CLINICAL STUDIES No new nonclinical studies were performed for the new PRK indication proposed in this submission. Previous nonclinical study for LASIK was conducted for the ALLEGRETTO device in the original PMA submission (P020050). A nonclinical study for WaveLight WaveLight EX500 (500 Hz) was conducted for PMA Supplement 6 (P020050/S006) for LASIK indication to demonstrate the same functional performance as ALLEGRETTO WAVE EYE-Q (400 Hz). This study demonstrated that the ablation profiles on the bovine cornea were identical for 200 Hz, 400 Hz, and 500 Hz pulse frequencies. ## X. SUMMARY OF PRIMARY CLINICAL STUDY(IES) Alcon Laboratories, Inc. performed a clinical study to demonstrate a reasonable assurance of safety and effectiveness of photorefractive keratectomy (PRK) with only the ALLEGRETTO WAVE EYE-Q excimer laser system for the elimination of up to -6.0 diopters (D) of spherical equivalent myopia or myopia with astigmatism, with up to -6.0 D of spherical component and up to -3.0 D of astigmatic component at the spectacle plane under IDE G120133. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below. ### A. Study Design Patients were treated between August 2012 and June 2014. The database for this P020050/S023 reflected data collected through September 19, 2014 and included 161 patients. There were 8 investigational sites. The study was a prospective, multi-center, single-arm, open-label, 24-month PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 5 {5} clinical study conducted in two (2) stages. In the first, 66 eyes of 34 participants were treated. An interim analysis was conducted after 44 eyes of 22 participants had completed the Month 3 visit to evaluate the adequacy of the treatment nomogram. In the second stage, additional participants were enrolled for a total cohort of 320 eyes (of 161 participants). There were 17 scheduled study visits. The planned duration of follow-up for each participant is 24 months after the surgery (Day 0 visit). Treatment planning was done with wavefront-optimized corneal profiles, with all eyes targeted for emmetropia. The laser software used the nomogram-adjusted manifest refraction data to determine the treatment plan for PRK. Mitomycin-C was not used during the PRK procedure. The study design and analyses were planned according to recommendations in ANSI Z80.11.2007 and the methodology described by Eydelman et al (2006) for the standardized analysis of correction of astigmatism by laser systems. No effectiveness or safety hypothesis tests were planned for this study. The analyses of the primary endpoints were based solely on observed rates. The observed rate is defined as the number of eyes meeting the objective divided by the number of eyes with data at the time point of refractive stability. The objectives were considered to have been met if the point estimate for each endpoint met or outperformed the target rate. For analysis of refractive outcomes, the sphere component of the manifest refraction tested at 4.0 meters was adjusted for optical infinity by adding -0.25 D to the sphere magnitude. Manifest refraction spherical equivalent (MRSE) was calculated using the adjusted manifest sphere value. For vector analyses of astigmatism, manifest refraction results were converted to cross cylinder form, adjusted for a vertex distance of 12 mm, then converted to plus cylinder form. Analyses of the rates of ocular serious adverse events (SAEs) were based on observed cumulative rates, defined as the number of eyes experiencing the SAE at any time during the study divided by the number of eyes in the intent-to-treat (ITT) analysis set. A safety objective was considered to have been met if the point estimate for a safety endpoint is lower than the target rate. Cumulative rates for protocol-specific AEs were defined in the same way as the rates of ocular SAEs. No targets were specified for the protocol-specific AEs. Cumulative rates, by-visit rates, and participant listings were provided for all other types of AEs collected in the study. All other safety parameters were summarized at the visit at which the data were collected. The sample size was determined based on the ANSI A80.11-2007 recommendation of a minimum number of eyes required to adequately detect SAEs with an expected rate or 1% or greater. With 300 eyes, any ocular SAE that occurs in at least 1% of the population undergoing the procedure would be observed in the study at least once with approximately 95% probability. Therefore, it was planned that up to 350 eyes PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 6 {6} should be enrolled with the goal that at least 300 treated eyes would complete the Month 12 visit. 1. Clinical Inclusion and Exclusion Criteria Enrollment in the ALLEGRETTO WAVE EYE-Q excimer laser system for PRK treatment study was limited to patients who met the following inclusion criteria: - Subjects 18 years of age or older - Subjects desiring refractive correction of myopia up to -6.0 D sphere with or without astigmatism 0 to -3.0 D, and up to -6.0 D MRSE at the spectacle plane measured by manifest refraction - Intended treatment targeted for emmetropia - Bilateral intended treatment - Minimum BSCVA in the treated eye of 20/25 - UCVA of 20/40 or worse in the treated eye - Less than 0.75 D spherical equivalent (SE) difference between cycloplegic and manifest refractions - Stable refraction (within ± 0.5 D), as determined by MRSE for a minimum of 12 months prior to surgery, verified by consecutive manifest refractions and/or medical records or glasses prescription history or lensometry of the glasses - Demonstrated stable refraction for contact lens wearers (any contact lens use in the 3 months before screening) within ± 0.5 D MRSE on 2 consecutive exam dates under the following conditions: (a) lenses were not worn for at least 3 weeks (hard lenses), 2 weeks (toric lenses), or 3 days (soft lenses) prior to the first refraction used to establish stability and through the day of surgery (b) the 2 refractions were performed at least 7 days apart - Signed informed consent document - Willing and able to comply with schedule for follow-up visits PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 7 {7} Patients were not permitted to enroll in the ALLEGRETTO WAVE EYE-Q excimer laser system for PRK treatment study if they met any of the following exclusion criteria: - Females who were pregnant, lactating, or planning a pregnancy or not using an adequate method of birth control during the time course of the study, or had another condition associated with the fluctuation of hormones that could lead to refractive changes - Participation in other clinical trials during the present study - Acute or chronic disease or illness that would have increased the operative risk or confounded the outcomes of the study (immuno-compromised, connective tissue disease, clinically significant atopic disease, diabetes, etc) - Dry eye syndrome, as determined by the short questionnaire for dry eye Syndrome - Systemic medications that may have confounded the outcome of the study or increased the risk to the subject by affecting wound healing or tissue repair, including, but not limited to steroids, antimetabolites, immune response modifying drugs, etc. - Nystagmus or any other condition that would have prevented a steady gaze during the PRK treatment or other diagnostic tests - Mixed astigmatism refractive error - Ocular condition that predisposed the subject to future complications, for example: (a) history or evidence of active or inactive corneal disease (herpes simplex keratitis, herpes zoster keratitis, recurrent erosion syndrome, corneal dystrophy, or cornea guttae, etc.) (b) history of keloid formation (c) evidence of retinal vascular disease (d) keratoconus or keratoconus suspect (e) glaucoma or glaucoma suspect (including IOP > 23 mmHg) by exam findings and/or family history (mother, father, blood sibling with glaucoma) PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 8 {8} (f) evidence of pellucid marginal degeneration or other topographic abnormality (g) pathologic alterations of the anterior eye segment/chamber (h) pathologies of the iris, e.g., coloboma, other irregular changes to the iris margin (i) acute or recurring ocular pathology - Subjects with eyes that had predicted residual stromal bed - thickness < 250 μm - Previous intraocular or corneal surgery - Subjects who desired monovision - A known sensitivity to medications used for study procedures, including PRK - Presence or history of any condition or finding that made the subject unsuitable as a candidate for PRK or study participation or may have confounded the outcome of the study, in the opinion of the Investigator. ## 2. Follow-up Schedule All eyes were evaluated according to the following schedule of assessments (Table 1): Table 1. Schedule of Visits | Visit Schedule | Visit Type | Visit Name* | | --- | --- | --- | | Day -30 to -1 | Screening | Visit 1 | | Day 0 | Surgery | Visit 2A/2B | | Day 1 | Re-epithelialization | Visit 3A/3B | | Day 2-4 | Postoperative | Visit 4A/4B | | Day 5-9 | Postoperative | Visit 5A/5B | | Day 21-35 | Postoperative | Visit 6A/6B | | Day 70-98 | Postoperative | Visit 7A/7B | | Day 147-182 | Postoperative | Visit 8 | | Day 245-301 | Postoperative | Visit 9 | | Day 330-420 | Postoperative | Visit 10 | | Day 690-810 | Postoperative | Visit 11 | * Visit A is for the 1st eye while Visit B for 2nd eye. Study procedures included the following: uncorrected distance and near visual PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 9 {9} acuity (UCVA), best spectacle-corrected distance visual acuity (BSCDVA), photopic and mesopic contrast sensitivity, manifest refraction, cycloplegic refraction, pupillometry, keratometry, corneal topography, pachymetry, tonometry, measurement of axial length by ultrasound, aberrometry, slit-lamp examination, dilated fundus examination, administration of the VSARC questionnaire (Visual Symptoms Associated with Refractive Correction), administration of the RSVP questionnaire (Refractive Status and Vision Profile), and documentation of adverse events and complications. ### 3. Clinical Endpoints The key safety and effectiveness endpoints were evaluated at the time of refractive stability and are summarized below. i. Safety endpoints and objectives - Ocular serious adverse events: <1% of treated eyes with each ocular SAE type. - Decrease in best spectacle-corrected visual acuity (BSCVA): At refractive stability, <5% of treated eyes with BSCVA decrease of ≥2 lines from baseline; at refractive stability, <1% of treated eyes whose preoperative BSCVA was 20/20 or better with BSCVA worse than 20/40. - Induced manifest refractive cylinder (MRC): <5% of eyes with >2.00 D of induced manifest refractive cylinder magnitude at refractive stability compared to baseline. Photopic and mesopic contrast sensitivity and responses on the VSARC and RSVP questionnaires were evaluated. ii. Effectiveness endpoints and objectives - Visual acuity: At refractive stability, ≥85% of eyes with preoperative BSCVA of 20/20 or better should achieve UCVA of 20/40 or better. - Refractive predictability: At refractive stability, ≥75% of eyes should achieve MRSE and MRC within ±1.0 D of zero. ≥50% of eyes should achieve MRSE and MRC within ±0.5 D of zero. - Refractive stability: ≥95% of eyes should have a change of ≤1.0 D in MRSE and MRC between 2 refractions, performed at 1 and 3 months postoperatively, or over a minimum 3 month period thereafter. Cylinder vector and non-vector variables were evaluated. PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 10 {10} ## B. Accountability of PMA Cohort At the time of database lock, of 176 patients enrolled in the PMA study, 88.6 % (156) patients are available for analysis at the completion of the study, the 12 month post-operative visit (Table 2). 161 participants had one or both eyes treated; in two (2) participants, one eye was treated. A total of 320 eyes were treated (Table 3). Table 2. Subject Disposition, (All Enrolled) | | n (%) | | --- | --- | | Enrolled | 176 | | Screen Failures | 15 | | Treated^{a} | 161 (100.0) | | Completed Study | 152 (94.4) | | Discontinued | 9 (5.6) | | Lost to Follow-up | 7 (4.3) | | Unable to Make Future Office Visits | 2 (1.2) | n = Number of subjects in category $^{a}$ Subjects 1001 and 1002 had only one eye treated. Table 3. Postoperative Visit Status by Eye (Intent-to-Treat Population) | Status | Visit 3 Day 1 | | Visit 4 Re-epithelia lization | | Visit 5 Week 1 | | Visit 6 Month 1 | | Visit 7 Month 3 | | Visit 8 Month 6 | | Visit 9 Month 9 | | Visit 10 Month 12 | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | | Treated (N=320) | | | | | | | | | | | | | | | | | | Available for Analysis | 320 | (100.0) | 318 | (99.4) | 320 | (100.0) | 320 | (100.0) | 317 | (99.1) | 315 | (98.4) | 315 | (98.4) | 311 | (97.2) | | Active | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | Missed Visit | | | | | | | | | | | | | | | | | | Discontinued | | | | | | | | | | | | | | | | | | Retreatment | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | Other Causes | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 2 | (0.6) | 2 | (0.6) | 2 | (0.6) | 2 | (0.6) | | Lost to Follow-up | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.3) | 3 | (0.9) | 3 | (0.9) | 7 | (2.2) | | Missed visit, but seen at later visit | 0 | (0.0) | 2 | (0.6) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | Not seen, but status obtained (e.g. phone) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | % Accountability | | (100.0) | | (99.4) | | (100.0) | | (100.0) | | (99.7) | | (99.1) | | (99.1) | | (97.8) | N = Number of eyes in ITT analysis set n = Number of eyes in category % Accountability = Available for Analysis / (Treated - Discontinued - Active) Active = Number of eyes that have not yet reached the visit ## C. Study Population Demographics and Baseline Parameters The demographics of the study cohort are presented in Table 4 below. 78.3% of the cohort is white and 88.8% non-Hispanic or Latino. The mean age is 31.5±7.4 years (range 19 to 56). PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 11 {11} **Table 4. Demographic Statistics (Intent-to-Treat)** | | (N=161) n (%) | | --- | --- | | **Age (Years)** | | | Mean (SD) | 31.5 (7.4) | | Median | 30.0 | | (Min, Max) | (19, 56) | | **Age Category** | | | 18-64 | 161 (100.0) | | ≥ 65 | 0 (0.0) | | **Sex** | | | Male | 89 (55.3) | | Female | 72 (44.7) | | **Race** | | | White | 126 (78.3) | | Black or African American | 13 (8.1) | | Asian | 12 (7.5) | | Native Hawaiian or Other Pacific Islander | 3 (1.9) | | Other | 7 (4.3) | | **Ethnicity** | | | Hispanic or Latino | 18 (11.2) | | Not Hispanic or Latino | 143 (88.8) | N = Number of subjects in ITT analysis set n = Number of subjects in category SD = Standard deviation, Min = Minimum, Max = Maximum The baseline refractive characteristics of the cohort are provided in the following (Table 5): **Table 5. Baseline Characteristics by Eye, (Intent-to-Treat)** | Baseline Characteristic | Statistic | Results | | --- | --- | --- | | **Manifest Sphere** | **n** | 320 | | | **Mean** | -2.957 | | | **SD** | 1.4843 | | | **Median** | -2.75 | | | **(Min, Max)** | (-6.00, -0.25) | | | **95% CI** | (-3.120, -2.794) | | **Manifest Cylinder** | **n** | 320 | | | **Mean** | -0.788 | | | **SD** | 0.8191 | | | **Median** | -0.50 | | | **(Min, Max)** | (-3.00, 0.00) | | | **95% CI** | (-0.878, -0.697) | | **MRSE** | **n** | 320 | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 12 {12} | Baseline Characteristic | Statistic | Results | | --- | --- | --- | | | Mean | -3.351 | | | SD | 1.4191 | | | Median | -3.25 | | | (Min, Max) | (-6.00, -0.75) | | | 95% CI | (-3.507, -3.195) | | UCVA | n | 320 | | | Mean | 0.870 | | | SD | 0.2656 | | | Median | 0.92 | | | (Min, Max) | (0.28, 1.40) | | | 95% CI | (0.841, 0.900) | | BSCVA | n | 320 | | | Mean | -0.085 | | | SD | 0.0741 | | | Median | -0.10 | | | (Min, Max) | (-0.28, 0.12) | | | 95% CI | (-0.093, -0.076) | n = Number of eyes in ITT analysis set with data SD = Standard deviation, Min = Minimum, Max = Maximum CI = Confidence Interval MRSE = Manifest refraction spherical equivalent UCVA = Uncorrected visual acuity BSCVA = Best-spectacle corrected visual acuity A total of 18 dioptric bins were defined based on each combination of preoperative sphere (0.0 D to -6.0 D) and cylinder (0.0 D to -3.0 D) as shown in Table 6 below. Eligible participants were assigned to dioptric bins based on their preoperative manifest refraction results. The distribution of treated eyes within each dioptric bin was based on a minimum of 20 eyes per bin, except for the bin of less than or equal to 0.5 D cylinder (planned of minimum 75 eyes). Table 6. Frequency of Eyes by Preoperative Sphere & Cylinder Bin (Intent-to-Treat) PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 13 {13} | Myopia Sphere | Cylinder | | | | Eyes per Sphere Bin | | --- | --- | --- | --- | --- | --- | | | 0.00 to -0.500 | -0.501 to -1.000 | -1.001 to -2.000 | -2.001 to -3.000 | | | -0.000 to -1.000 | 11 | 7 | 5 | 11 | 34 | | -1.001 to -2.000 | 39 | 12 | 20 | 7 | 78 | | -2.001 to -3.000 | 38 | 13 | 12 | 7 | 70 | | -3.001 to -4.000 | 32 | 10 | 5 | 6 | 53 | | -4.001 to -5.000 | 33 | 11 | 9 | 1 | 54 | | -5.001 to -6.000 | 27 | 4 | 0 | 0 | 31 | | Eyes per Cylinder Bin | 180 | 57 | 51 | 32 | 320 | #### D. Safety and Effectiveness Results Determination of refractive stability per ANSI Z80.11-2007 was performed using refractive outcomes from the consistent cohort (CC) analysis set (n=310 eyes; defined as all eyes in the ITT analysis set that completed all post-operative visits up to Month 12). Based on these analyses, the time point of refractive stability for the CC set was established at Month 6 (Visit 8)(Table 7). The following conditions were met at the Month 3 to Month 6 interval in order to establish refractive stability: - 99.7% and 100% of eyes had a change of MRSE and manifest refractive cylinder of ≤ 1.0 D, respectively. - The mean rate of change per year was -0.019 D and 0.038 D for MRSE and manifest refractive cylinder, respectively. - The 95% confidence interval for the mean rate of change included zero. - The mean rate of change decreased towards zero over time, although there was clinically non-significant increase or decrease in mean change in MRSE and manifest refractive cylinder between consecutive intervals starting at the Month 3 to Month 6 interval. **Table 7. Criteria for Refractive Stability by Eye, (Intent-to-Treat)** | | n (%) | Week 1 to Month 1 (N=320) | Month 1 to Month 3 (N=317) | Month 3 to Month 6 (N=314) | Month 6 to Month 9 (N=314) | Month 9 to Month 12 (N=310) | | --- | --- | --- | --- | --- | --- | --- | | **Change of MRSE ≤ 1.0 D** | | 306 (95.6) | 310 (97.8) | 313 (99.7) | 314 (100.0) | 309 (99.7) | | **Change of MRSE in Diopters** | **Mean** | -0.017 | 0.019 | -0.005 | 0.012 | 0.025 | | **SD** | 0.5216 | 0.4292 | 0.2611 | 0.2415 | 0.2341 | | **95% CI** | (-0.075, 0.040) | (-0.028, 0.067) | (-0.034, 0.024) | (-0.014, 0.039) | (-0.001, 0.051) | | **Change of MRSE per Year** | **Mean** | -0.206 | 0.116 | -0.019 | 0.049 | 0.100 | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 14 {14} | | | Week 1 to Month 1 (N=320) | Month 1 to Month 3 (N=317) | Month 3 to Month 6 (N=314) | Month 6 to Month 9 (N=314) | Month 9 to Month 12 (N=310) | | --- | --- | --- | --- | --- | --- | --- | | | SD | 6.2589 | 2.5752 | 1.0444 | 0.9658 | 0.9363 | | | 95% CI | (-0.895, 0.482) | (-0.169, 0.401) | (-0.135, 0.097) | (-0.058, 0.157) | (-0.005, 0.205) | | Change of Cylinder ≤ 1.0 D | n (%) | 303 (94.7) | 310 (97.8) | 314 (100.0) | 314 (100.0) | 310 (100.0) | | Change of Cylinder in Diopters | Mean | -0.009 | 0.168 | 0.010 | 0.023 | 0.003 | | | SD | 0.5391 | 0.4081 | 0.2285 | 0.2078 | 0.1799 | | | 95% CI | (-0.069, 0.050) | (0.123, 0.213) | (-0.016, 0.035) | (0.000, 0.046) | (-0.017, 0.023) | | Change of Cylinder per Year | Mean | -0.113 | 1.008 | 0.038 | 0.092 | 0.013 | | | SD | 6.4696 | 2.4483 | 0.9141 | 0.8313 | 0.7195 | | | 95% CI | (-0.824, 0.599) | (0.737, 1.278) | (-0.063, 0.140) | (0.000, 0.185) | (-0.068, 0.093) | Cylinder is manifest refractive cylinder N = Number of eyes with non-missing Cylinder and non-missing MRSE at both visits in visit interval n = Number of eyes in category SD = Standard deviation, Min = Minimum, Max = Maximum CI = Confidence Interval ### 1. Safety Results The analysis of safety was based on the cohort of 320 treated eyes (Intent-to-Treat (ITT) cohort) available for the 12 month evaluation. A summary of key safety variables over time is listed below. - Ocular SAEs – The cumulative rate of any ocular SAE was 0.9%. This meets the primary safety objective of <1% of treated eyes experiencing each ocular SAE type. - Decrease in BSCVA – - No eyes had BSCVA decrease of ≥ 2 lines from baseline at Month 6. This meets the primary safety objective of <5% of treated eyes with BSCVA decrease of ≥2 lines from baseline. - No eyes had BSCVA worse than 20/40 (in eyes with BSCVA of 20/20 or better preoperatively) at Month 6. This meets the primary safety objective of <1% of treated eyes whose preoperative BSCVA was 20/20 or better with BSCVA worse than 20/40. - Induced MRC – No eyes had > 2.0 D of induced manifest refraction cylinder at Month 6 compared to baseline. This meets the primary safety objective of <5% of eyes with >2.00 D of induced manifest refractive cylinder magnitude at refractive stability compared to baseline. The key safety outcomes for this study are presented below in Tables 8 to 24. Results of the other co-primary safety endpoints are presented in Table 8 below. PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 15 {15} **Table 8. Best Spectacle Corrected Visual Acuity and Manifest Cylinder by Eye, (Intent-to-Treat)** | Visit | Parameter | n / N | (%) | 95% CI† | | --- | --- | --- | --- | --- | | **Visit 5 - Week 1** | BSCVA decrease of ≥ 2 lines from baseline | 80 / 320 | (25.0) | (20.4, 30.1) | | | BSCVA worse than 20/40 (BSCVA 20/20 or better preop) | 8 / 299 | (2.7) | (1.2, 5.2) | | | Increase of > 2.00 D of induced manifest refraction cylinder | 0 / 320 | (0.0) | (0.0, 1.1) | | **Visit 6 - Month 1** | BSCVA decrease of ☐ 2 lines from baseline | 13 / 320 | (4.1) | (2.2, 6.8) | | | BSCVA worse than 20/40 (BSCVA 20/20 or better preop) | 0 / 299 | (0.0) | (0.0, 1.2) | | | Increase of > 2.00 D of induced manifest refraction cylinder | 0 / 320 | (0.0) | (0.0, 1.1) | | **Visit 7 - Month 3** | BSCVA decrease of ☐ 2 lines from baseline | 1 / 317 | (0.3) | (0.0, 1.7) | | | BSCVA worse than 20/40 (BSCVA 20/20 or better preop) | 0 / 297 | (0.0) | (0.0, 1.2) | | | Increase of > 2.00 D of induced manifest refraction cylinder | 0 / 317 | (0.0) | (0.0, 1.2) | | **Visit 8 - Month 6** | BSCVA decrease of ☐ 2 lines from baseline | 0 / 314 | (0.0) | (0.0, 1.2) | | | BSCVA worse than 20/40 (BSCVA 20/20 or better preop) | 0 / 294 | (0.0) | (0.0, 1.2) | | | Increase of > 2.00 D of induced manifest refraction cylinder | 0 / 314 | (0.0) | (0.0, 1.2) | | **Visit 9 - Month 9** | BSCVA decrease of ☐ 2 lines from baseline | 0 / 314 | (0.0) | (0.0, 1.2) | | | BSCVA worse than 20/40 (BSCVA 20/20 or better preop) | 0 / 294 | (0.0) | (0.0, 1.2) | | | Increase of > 2.00 D of induced manifest refraction cylinder | 0 / 314 | (0.0) | (0.0, 1.2) | | **Visit 10 - Month 12** | BSCVA decrease of ☐ 2 lines from baseline | 0 / 311 | (0.0) | (0.0, 1.2) | | | BSCVA worse than 20/40 (BSCVA 20/20 or better preop) | 0 / 291 | (0.0) | (0.0, 1.3) | | | Increase of > 2.00 D of induced manifest refraction cylinder | 0 / 311 | (0.0) | (0.0, 1.2) | N = Number of eyes in ITT analysis set with data at visit n = Number of eyes in category † 95% confidence interval from Binomial distribution Adverse effects are reported in Tables 9 to 14. # **Adverse effects that occurred in the PMA clinical study:** The cumulative rate of ocular SAEs is presented in Table 9. **Table 9. Cumulative Incidence of Ocular Serious Adverse Events by Eye (Intent-to-Treat)** | Adverse Event | (N=320) | | | | --- | --- | --- | --- | | | n | (%) | E | | **Eyes with any AE** | 3 | (0.9) | 3 | | Corneal infiltrates | 2 | (0.6) | 2 | | Corneal oedema | 1 | (0.3) | 1 | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 16 {16} | Adverse Event | (N=320) | | | | --- | --- | --- | --- | | | n | (%) | E | N = Number of eyes in ITT analysis set n = Number of eyes with events E = Number of events If an eye has multiple occurrences of an AE, the eye is presented only once in the respective count column (n) for the corresponding AE. Events are counted each time in the event (E) column. Denominators for percentages are the number of treated eyes AEs coded using MedDRA version 15.0 The two (2) cases of corneal infiltrates were treated with topical antibiotic ophthalmic drops and a short course of oral antibiotics. The infiltrates were found to be resolved 14 and 2 days post-operatively. The cumulative rates of ocular non-serious AEs are presented in Table 10. The most frequently observed event was corneal opacity/corneal haze, with a rate of 5.6%. All cases, with the exception of one event, were reported as resolved. One incidence of corneal opacity at Month 6 was device-related. The event was assessed as mild and resolved with treatment by post-operative month 12 month. Table 10. Cumulative Incidence of Ocular Non-Serious Adverse Events by Eye (Intent-to-Treat) | Adverse Event | (N=320) | | | | --- | --- | --- | --- | | | n | (%) | E | | Eyes with any AE | 60 | (18.8) | 86 | | Altered visual depth perception | 1 | (0.3) | 2 | | Chalazion | 1 | (0.3) | 2 | | Conjunctival hyperaemia | 1 | (0.3) | 1 | | Conjunctivitis | 2 | (0.6) | 2 | | Conjunctivitis allergic | 5 | (1.6) | 5 | | Conjunctivitis viral | 1 | (0.3) | 1 | | Corneal abrasion | 3 | (0.9) | 3 | | Corneal disorder | 1 | (0.3) | 1 | | Corneal epithelium defect | 3 | (0.9) | 3 | | Corneal erosion | 3 | (0.9) | 3 | | Corneal oedema | 1 | (0.3) | 1 | | Corneal opacity | 18 | (5.6) | 20 | | Dry eye | 4 | (1.3) | 4 | | Episcleritis | 1 | (0.3) | 1 | | Eye allergy | 6 | (1.9) | 6 | | Eye pain | 3 | (0.9) | 3 | | Eyelid oedema | 1 | (0.3) | 1 | | Foreign body sensation in eyes | 1 | (0.3) | 1 | | Halo vision | 1 | (0.3) | 1 | | Hordeolum | 1 | (0.3) | 1 | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 17 {17} | Adverse Event | n | (N=320) | | | --- | --- | --- | --- | | | | (%) | E | | Iritis | 1 | (0.3) | 1 | | Keratitis | 3 | (0.9) | 3 | | Meibomian gland dysfunction | 2 | (0.6) | 2 | | Photophobia | 2 | (0.6) | 2 | | Photopsia | 1 | (0.3) | 1 | | Punctate keratitis | 5 | (1.6) | 7 | | Vision blurred | 3 | (0.9) | 3 | | Visual acuity reduced | 1 | (0.3) | 1 | | Visual impairment | 2 | (0.6) | 2 | | Vitreous floaters | 2 | (0.6) | 2 | N = Number of eyes in ITT analysis set n = Number of eyes with events E = Number of events If an eye has multiple occurrences of an AE, the eye is presented only once in the respective count column (n) for the corresponding AE. Events are counted each time in the event (E) column. Denominators for percentages are the number of treated eyes AEs coded using MedDRA version 15.0 Table 11 presents the summary of reported corneal haze by severity. The highest rate of grade 1 or greater corneal haze was at Month 1 (9.7%) and progressively decreased through Month 12 to 1.0%. **Table 11. Corneal Haze by Severity and Visit (Intent-to-Treat)** | Severity | | Visit 1 | Visit 6 | Visit 7 | Visit 8 | Visit 9 | Visit 10 | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Screening | Month 1 | Month 3 | Month 6 | Month 9 | Month 12 | | 0 - 0.5 | n/N | 320/320 | 289/320 | 290/317 | 288/314 | 303/314 | 308/311 | | | % | 100.0 | 90.3 | 91.5 | 91.7 | 96.5 | 99.0 | | | 95% CI† | (98.9, 100.0) | (86.5, 93.3) | (87.8, 94.3) | (88.1, 94.5) | (93.8, 98.2) | (97.2, 99.8) | | 1 | n/N | 0/320 | 30/320 | 25/317 | 22/314 | 10/314 | 3/311 | | | % | 0.0 | 9.4 | 7.9 | 7.0 | 3.2 | 1.0 | | | 95% CI† | (0.0, 1.1) | (6.4, 13.1) | (5.2, 11.4) | (4.4, 10.4) | (1.5, 5.8) | (0.2, 2.8) | | 2 | n/N | 0/320 | 1/320 | 2/317 | 4/314 | 1/314 | 0/311 | | | % | 0.0 | 0.3 | 0.6 | 1.3 | 0.3 | 0.0 | | | 95% CI† | (0.0, 1.1) | (0.0, 1.7) | (0.1, 2.3) | (0.3, 3.2) | (0.0, 1.8) | (0.0, 1.2) | | 3 | n/N | 0/320 | 0/320 | 0/317 | 0/314 | 0/314 | 0/311 | | | % | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | | | 95% CI† | (0.0, 1.1) | (0.0, 1.1) | (0.0, 1.2) | (0.0, 1.2) | (0.0, 1.2) | (0.0, 1.2) | | 4 | n/N | 0/320 | 0/320 | 0/317 | 0/314 | 0/314 | 0/311 | | | % | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | | | 95% CI† | (0.0, 1.1) | (0.0, 1.1) | (0.0, 1.2) | (0.0, 1.2) | (0.0, 1.2) | (0.0, 1.2) | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 18 {18} | Severity | Visit 1 Screening | Visit 6 Month 1 | Visit 7 Month 3 | Visit 8 Month 6 | Visit 9 Month 9 | Visit 10 Month 12 | | --- | --- | --- | --- | --- | --- | --- | n = Number of eyes in category N = Number of eyes in ITT analysis set with data at visit † 95% confidence interval from Binomial distribution ### **Non-serious, protocol-specified AEs** The following non-serious protocol specified adverse events were documented (Tables 12-14): - Corneal edema between 1 week and 1 month after the procedure - Peripheral corneal epithelial defect at 1 month or later - Recurrent corneal erosion at 1 month or later - Foreign body sensation at 1 month or later - Pain at 1 month or later - Ghost/double images in the operative eye - Any symptom marked moderate or severe on the VSARC questionnaire at month 6 or later which the investigator has determined is not easily resolved when the subject is wearing correction or has some simple explanation unrelated to the treatment. - Clinical signs consistent with marked to severe dry eye at 6 months or later - Any symptoms of dry eye that significantly affect comfort or activities of daily living (as reported to the investigator) at 6 months or later - Any symptoms of glare or haloes that significantly affect comfort or activities of daily living (as reported to the investigator) at 6 months or later The overall rate of “Any symptom marked moderate or severe on the VSARC questionnaire at Month 6 or later” was 18.4%. Within this category, the highest rates were observed for dryness in eyes (10.9%), eyes sensitive to light (5.9%), foreign body sensation (4.4%) and pain in eyes (4.1%). **Table 12. Cumulative Incidence of Non-Serious Protocol-Specified Adverse Events by Eye (N=320)** | Adverse Event | n | (%) | E | | --- | --- | --- | --- | | Recurrent corneal erosion at 1 month or later | 3 | (0.9) | 3 | | Any symptoms of dry eye that significantly affect comfort or activities of daily living at 6 months or later | 64 | (20.0) | 64 | | Any symptoms of glare or haloes that significantly affect comfort or activities of daily living at 6 months or later | 14 | (4.4) | 18 | | Clinical signs consistent with marked to severe dry eye at 6 months or later | 1 | (0.3) | 1 | | Any symptom marked moderate or severe on the VSARC questionnaire at month 6 or later | 59 | (18.4) | 128 | | 1 - Pain in eyes | 13 | (4.1) | 13 | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 19 {19} | Adverse Event | (N=320) | | | | --- | --- | --- | --- | | | n | (%) | E | | 2 - Dryness in eyes | 35 | (10.9) | 35 | | 3 - Burning feeling in eyes | 10 | (3.1) | 10 | | 4 – Glare | 2 | (0.6) | 2 | | 5 - Eyes sensitive to light | 19 | (5.9) | 19 | | 6 - Halos (circle shapes around lights) | 10 | (3.1) | 10 | | 7 - Starbursts (star shapes around lights) | 4 | (1.3) | 4 | | 8 - Blurry vision | 6 | (1.9) | 8 | | 10 - Fluctuation (changes) in vision | 6 | (1.9) | 6 | | 11 - Difficulty focusing in dim or low light | 2 | (0.6) | 2 | | 12 - Watery Eyes / Tearing | 5 | (1.6) | 5 | | 13 - Foreign body sensation (feeling like something is in your eye) | 14 | (4.4) | 14 | | Foreign body sensation at 1 month or later | 23 | (7.2) | 29 | | Ghost/double images in the operative eye | 30 | (9.4) | 31 | | Pain at 1 month or later | 22 | (6.9) | 26 | N = Number of eyes in ITT analysis set n = Number of eyes with events E = Number of events If an eye has multiple occurrences of an AE, the eye is presented only once in the respective count column (n) for the corresponding AE. Events are counted each time in the event (E) column. Denominators for percentages are the number of treated eyes. **Table 13. Cumulative Incidence of Ocular Protocol Specified Adverse Event – Severity** | Protocol Specified Adverse Event Category | Adverse Event | E | Mild | | Moderate | | Severe | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | N | (%) | n | (%) | n | (%) | | Corneal edema between 1 week and 1 month after the procedure | Corneal Oedema | 1 | 1 | (100.0) | 0 | (-) | 0 | (-) | | Corneal infiltrate or ulcer | Corneal Infiltrates | 2 | 2 | (100.0) | 0 | (-) | 0 | (-) | | Recurrent corneal erosion at 1 month or later | Corneal Erosion | 3 | 2 | (66.7) | 1 | (33.3) | 0 | (-) | | Any symptoms of dry eye that significantly affect comfort or activities of daily living at 6 months or later | Dry Eye | 64 | 37 | (57.8) | 23 | (35.9) | 4 | (6.3) | | Any symptoms of glare or haloes that significantly affect comfort or activities of daily living at 6 months or later | Glare | 10 | 10 | (100.0) | 0 | (-) | 0 | (-) | | | Halo Vision | 8 | 6 | (75.0) | 0 | (-) | 2 | (25.0) | | Clinical signs consistent with marked to severe dry eye at 6 months or later | Dry Eye | 1 | 1 | (100.0) | 0 | (-) | 0 | (-) | | Any symptom marked moderate or severe on the VSARC questionnaire at month 6 or later | Dry Eye | 35 | 12 | (34.3) | 19 | (54.3) | 4 | (11.4) | | | Eye Irritation | 10 | 0 | (-) | 8 | (80.0) | 2 | (20.0) | | | Eye Pain | 13 | 1 | (7.7) | 10 | (76.9) | 2 | (15.4) | | | Foreign Body Sensation In Eyes | 14 | 2 | (14.3) | 10 | (71.4) | 2 | (14.3) | | | Glare^{a} | 2 | 2 | (100.0) | 0 | (-) | 0 | (-) | | | Halo Vision^{a} | 10 | 2 | (20.0) | 6 | (60.0) | 2 | (20.0) | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 20 {20} | Protocol Specified Adverse Event Category | Adverse Event | E | Mild | | Moderate | | Severe | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | N | (%) | n | (%) | n | (%) | | | Lacrimation Increased | 5 | 3 | (60.0) | 2 | (40.0) | 0 | (-) | | | Photophobia | 19 | 2 | (10.5) | 15 | (78.9) | 2 | (10.5) | | | Photopsia | 4 | 2 | (50.0) | 2 | (50.0) | 0 | (-) | | | Vision Blurred^{a} | 10 | 0 | (-) | 10 | (100.0) | 0 | (-) | | | Visual Impairment | 6 | 2 | (33.3) | 4 | (66.7) | 0 | (-) | | Foreign body sensation at 1 month or later^{b} | Foreign Body Sensation In Eyes | 186 | 167 | (89.8) | 17 | (9.1) | 2 | (1.1) | | Ghost/double images in the operative eye^{b} | Diplopia | 86 | 60 | (69.8) | 19 | (22.1) | 7 | (8.1) | | Pain at 1 month or later^{b} | Eye Pain | 139 | 121 | (87.1) | 16 | (11.5) | 2 | (1.4) | E = Number of events n = Number of events in severity category Percentage is calculated as n/E. $^{a}$ The events glare (n=2, E=4), halos (n=2, E=6), and blurry vision (n=1, E=2) were reported by investigators as AEs based on VSARC responses. Although these events do not meet the protocol specified definition of “Any symptom marked moderate or severe on the VSARC questionnaire at month 6 or later”, Alcon considers that they are best accounted for in this table. $^{b}$ Events for these categories were identified through the VSARC questionnaire. Self- reported responses other than none were reported as adverse events. **Table 14. Cumulative Incidence of Ocular Protocol Specified Adverse Event – Resolution** | Protocol Specified Adverse Event Category | Adverse Event | E | Not Resolved | | Resolved | | Unknown | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | n | (%) | n | (%) | n | (%) | | Corneal edema between 1 week and 1 month after the procedure | Corneal Oedema | 1 | 1 | (100.0) | 0 | (-) | 0 | (-) | | Corneal infiltrate or ulcer | Corneal Infiltrates | 2 | 2 | (100.0) | 0 | (-) | 0 | (-) | | Recurrent corneal erosion at 1 month or later | Corneal Erosion | 3 | 2 | (66.7) | 1 | (33.3) | 0 | (-) | | Any symptoms of dry eye that significantly affect comfort or activities of daily living at 6 months or later | Dry Eye | 64 | 29 | (45.3) | 33 | (51.6) | 2 | (3.1) | | Any symptoms of glare or haloes that significantly affect comfort or activities of daily living at 6 months or later | Glare | 10 | 6 | (60.0) | 4 | (40.0) | 0 | (-) | | | Halo Vision | 8 | 4 | (50.0) | 4 | (50.0) | 0 | (-) | | Clinical signs consistent with marked to severe dry eye at 6 months or later | Dry Eye | 1 | 1 | (100.0) | 0 | (-) | 0 | (-) | | Any symptom marked moderate or severe on the VSARC questionnaire at month 6 or later | Dry Eye | 35 | 11 | (31.4) | 22 | (62.9) | 2 | (5.7) | | | Eye Irritation | 10 | 4 | (40.0) | 4 | (40.0) | 2 | (20.0) | | | Eye Pain | 13 | 4 | (30.8) | 7 | (53.8) | 2 | (15.4) | | | Foreign Body Sensation In Eyes | 14 | 6 | (42.9) | 8 | (57.1) | 0 | (-) | | | Glare^{a} | 2 | 2 | (100.0) | 0 | (-) | 0 | (-) | | | Halo Vision^{a} | 10 | 10 | (100.0) | 0 | (-) | 0 | (-) | | | Lacrimation Increased | 5 | 0 | (-) | 3 | (60.0) | 2 | (40.0) | | | Photophobia | 19 | 7 | (36.8) | 10 | (52.6) | 2 | (10.5) | | | Photopsia | 4 | 4 | (100.0) | 0 | (-) | 0 | (-) | | | Vision Blurred^{a} | 10 | 4 | (40.0) | 6 | (60.0) | 0 | (-) | | | Visual Impairment | 6 | 4 | (66.7) | 2 | (33.3) | 0 | (-) | | Foreign body sensation at 1 month or later^{b} | Foreign Body Sensation In Eyes | 186 | 156 | (83.9) | 28 | (15.1) | 2 | (1.1) | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 21 {21} | Protocol Specified Adverse Event Category | Adverse Event | E | Resolved | | Not Resolved | | Unknown | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | n | (%) | n | (%) | n | (%) | | Ghost/double images in the operative eye^{a} | Diplopia | 86 | 84 | (97.7) | 0 | (-) | 2 | (2.3) | | Pain at 1 month or later^{b} | Eye Pain | 139 | 94 | (67.6) | 40 | (28.8) | 5 | (3.6) | E = Number of events n = Number of events in resolution category Percentage is calculated as n/E. $^{a}$The events glare (n=2, E=4), halos (n=2, E=6), and blurry vision (n=1, E=2) were reported by investigators as AEs based on VSARC responses. Although these events do not meet the protocol specified definition of “Any symptom marked moderate or severe on the VSARC questionnaire at month 6 or later”, Alcon considers that they are best accounted for in this table. $^{b}$Events for these categories were identified through the VSARC questionnaire. Self-reported responses other than none were reported as adverse events. ### Contrast sensitivity Contrast sensitivity (CS) testing was performed on all subjects to evaluate clinically significant changes from baseline. CS testing was performed in photopic conditions with and without glare at spatial frequencies of 3, 6, 12, and 18 cd/m$^{2}$, and in mesopic conditions with and without glare at spatial frequencies of 1.5, 3, 6, and 12 cd/m$^{2}$. For each lighting condition, the percentage of eyes with a clinically significant increase or decrease in CS, defined as either an increase or decrease from baseline of greater than or equal to 0.3 log units (at 2 or more spatial frequencies), was evaluated. In addition, a transition from seeing to not seeing, or from not seeing to seeing a grating at the highest available contrast, was considered equivalent to greater than or equal to 0.3 log units of change, and assessed as clinically significant. At all visits and lighting conditions, a higher percentage of eyes showed a clinically significant increase from baseline in contrast sensitivity compared to those with a clinically significant decrease from baseline in CS, although most eyes had no significant change in contrast sensitivity. A clinically significant decrease in CS under photopic lighting conditions was observed in no more than 6.8% and 5.1% of eyes when tested with and without a glare source, respectively. Furthermore, a clinically significant decrease from baseline in contrast sensitivity from baseline under mesopic lighting conditions was observed in no more than 9.8% and 10.4% of eyes when tested with and without a glare source, respectively (Table 15). **Table 15. Proportion of Eyes with Clinically Significant Change from Preoperative Measurement in Contrast Sensitivity, (Intent-to-Treat)** | Visit 7 Month 3 | Mesopic | Clinically Significant Increase | | Clinically Significant Decrease | | | --- | --- | --- | --- | --- | --- | | | | n / N | (%) | n / N | (%) | | | | With Glare | 74 / 317 | (23.3) | 31 / 317 (9.8) | | | | Without Glare | 52 / 317 | (16.4) | 33 / 317 (10.4) | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 22 {22} | **Visit 8 Month 6** | Photopic | With Glare | 36 / 317 (11.4) | 8 / 317 (2.5) | | --- | --- | --- | --- | --- | | | | Without Glare | 27 / 317 (8.5) | 14 / 317 (4.4) | | | Mesopic | With Glare | 74 / 314 (23.6) | 26 / 314 (8.3) | | | | Without Glare | 80 / 314 (25.5) | 32 / 314 (10.2) | | **Visit 9 Month 9** | Photopic | With Glare | 48 / 314 (15.3) | 17 / 314 (5.4) | | | | Without Glare | 30 / 314 (9.6) | 16 / 314 (5.1) | | | Mesopic | With Glare | 84 / 314 (26.8) | 20 / 314 (6.4) | | | | Without Glare | 65 / 314 (20.7) | 29 / 314 (9.2) | | **Visit 10 Month 12** | Photopic | With Glare | 36 / 314 (11.5) | 20 / 314 (6.4) | | | | Without Glare | 25 / 314 (8.0) | 15 / 314 (4.8) | | | Mesopic | With Glare | 88 / 311 (28.3) | 19 / 311 (6.1) | | | | Without Glare | 70 / 311 (22.5) | 20 / 311 (6.4) | | | Photopic | With Glare | 42 / 311 (13.5) | 21 / 311 (6.8) | | | | Without Glare | 33 / 311 (10.6) | 10 / 311 (3.2) | N = Number of eyes in ITT analysis set with data at visit n = Number of eyes in category ### VSARC Questionnaire Results for the VSARC questionnaire are presented in Table 16 and were used to assess post-operative symptoms and protocol-specified adverse events. Of note, the VSARC was not found to reliably measure patient symptoms. At all postoperative visits, most participants rated their symptoms as none or mild. However, it is not known whether subjects reported their symptoms in the presence or absence of corrective lenses. Furthermore, the VSARC questionnaire does not measure the functional impact of these symptoms; instead, the investigators determined the significance of the impact. **Table 16. Visual Symptoms Associated with Refractive Correction Questionnaire by Subject** | Question/Result | Visit 1 | | Visit 6A | | Visit 6B | | Visit 7A | | Visit 7B | | Visit 8 | | Visit 9 | | Visit 10 | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Screening | Month 1 | Screening | Month 1 | Screening | Month 1 | Screening | Month 3 | Screening | Month 3 | Screening | Month 6 | Screening | Month 9 | Screening | Month 12 | | | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | | **1. Pain in eyes** | | | | | | | | | | | | | | | | | | None | 152 | (94.4) | 127 | (80.9) | 128 | (82.1) | 133 | (83.6) | 132 | (83.5) | 139 | (88.0) | 138 | (87.3) | 135 | (86.5) | | Mild | 7 | (4.3) | 28 | (17.8) | 27 | (17.3) | 20 | (12.6) | 20 | (12.7) | 16 | (10.1) | 14 | (8.9) | 19 | (12.2) | | Moderate | 2 | (1.2) | 1 | (0.6) | 1 | (0.6) | 6 | (3.8) | 6 | (3.8) | 3 | (1.9) | 5 | (3.2) | 1 | (0.6) | | Severe | 0 | (0.0) | 1 | (0.6) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.6) | 1 | (0.6) | | **2. Dryness in eyes** | | | | | | | | | | | | | | | | | | None | 140 | (87.0) | 37 | (23.6) | 34 | (21.8) | 61 | (38.4) | 61 | (38.6) | 70 | (44.3) | 78 | (49.4) | 85 | (54.5) | | Mild | 18 | (11.2) | 101 | (64.3) | 103 | (66.0) | 86 | (54.1) | 85 | (53.8) | 81 | (51.3) | 69 | (43.7) | 64 | (41.0) | | Moderate | 3 | (1.9) | 19 | (12.1) | 19 | (12.2) | 12 | (7.5) | 12 | (7.6) | 6 | (3.8) | 9 | (5.7) | 7 | (4.5) | | Severe | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.6) | 2 | (1.3) | 0 | (0.0) | | **3. Burning feeling in the eye** | | | | | | | | | | | | | | | | | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 23 {23} | Question/Result | Visit 1 | | Visit 6A | | Visit 6B | | Visit 7A | | Visit 7B | | Visit 8 | | Visit 9 | | Visit 10 | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Screening | Month 1 | Month 1 | Month 1 | Month 1 | Month 1 | Month 3 | Month 3 | Month 3 | Month 6 | Month 6 | Month 6 | Month 9 | Month 9 | Month 12 | Month 12 | | | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | | **None** | 152 | (94.4) | 134 | (85.4) | 134 | (85.9) | 130 | (81.8) | 130 | (82.3) | 134 | (84.8) | 143 | (90.5) | 139 | (89.1) | | **Mild** | 6 | (3.7) | 21 | (13.4) | 21 | (13.5) | 25 | (15.7) | 24 | (15.2) | 21 | (13.3) | 11 | (7.0) | 16 | (10.3) | | **Moderate** | 1 | (0.6) | 1 | (0.6) | 1 | (0.6) | 4 | (2.5) | 4 | (2.5) | 3 | (1.9) | 3 | (1.9) | 1 | (0.6) | | **Severe** | 2 | (1.2) | 1 | (0.6) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.6) | 0 | (0.0) | | **4. Glare** | | | | | | | | | | | | | | | | | | **None** | 132 | (82.5) | 90 | (57.3) | 86 | (55.1) | 125 | (78.6) | 126 | (79.7) | 133 | (84.2) | 136 | (86.1) | 139 | (89.1) | | **Mild** | 19 | (11.9) | 57 | (36.3) | 62 | (39.7) | 33 | (20.8) | 31 | (19.6) | 25 | (15.8) | 21 | (13.3) | 17 | (10.9) | | **Moderate** | 7 | (4.4) | 10 | (6.4) | 8 | (5.1) | 1 | (0.6) | 1 | (0.6) | 0 | (0.0) | 1 | (0.6) | 0 | (0.0) | | **Severe** | 2 | (1.3) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | **5. Eyes sensitive to light** | | | | | | | | | | | | | | | | | | **None** | 123 | (76.4) | 54 | (34.4) | 56 | (35.9) | 94 | (59.1) | 95 | (60.1) | 113 | (72.0) | 122 | (77.2) | 126 | (80.8) | | **Mild** | 30 | (18.6) | 81 | (51.6) | 78 | (50.0) | 56 | (35.2) | 54 | (34.2) | 39 | (24.8) | 32 | (20.3) | 26 | (16.7) | | **Moderate** | 7 | (4.3) | 18 | (11.5) | 19 | (12.2) | 8 | (5.0) | 8 | (5.1) | 4 | (2.5) | 3 | (1.9) | 4 | (2.6) | | **Severe** | 1 | (0.6) | 4 | (2.5) | 3 | (1.9) | 1 | (0.6) | 1 | (0.6) | 1 | (0.6) | 1 | (0.6) | 0 | (0.0) | | **6. Halos (circle shapes around lights)** | | | | | | | | | | | | | | | | | | **None** | 135 | (84.4) | 90 | (57.3) | 89 | (57.1) | 122 | (76.7) | 124 | (78.5) | 135 | (85.4) | 144 | (91.1) | 141 | (90.4) | | **Mild** | 21 | (13.1) | 46 | (29.3) | 47 | (30.1) | 33 | (20.8) | 30 | (19.0) | 20 | (12.7) | 12 | (7.6) | 15 | (9.6) | | **Moderate** | 2 | (1.3) | 19 | (12.1) | 18 | (11.5) | 3 | (1.9) | 3 | (1.9) | 3 | (1.9) | 2 | (1.3) | 0 | (0.0) | | **Severe** | 2 | (1.3) | 2 | (1.3) | 2 | (1.3) | 1 | (0.6) | 1 | (0.6) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | **7. Starbursts (star shapes around lights)** | | | | | | | | | | | | | | | | | | **None** | 147 | (91.3) | 108 | (68.8) | 106 | (67.9) | 129 | (81.1) | 131 | (82.9) | 136 | (86.1) | 138 | (87.3) | 140 | (89.7) | | **Mild** | 11 | (6.8) | 37 | (23.6) | 39 | (25.0) | 27 | (17.0) | 24 | (15.2) | 20 | (12.7) | 19 | (12.0) | 16 | (10.3) | | **Moderate** | 1 | (0.6) | 10 | (6.4) | 9 | (5.8) | 3 | (1.9) | 3 | (1.9) | 2 | (1.3) | 1 | (0.6) | 0 | (0.0) | | **Severe** | 2 | (1.2) | 2 | (1.3) | 2 | (1.3) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | **8. Blurry vision** | | | | | | | | | | | | | | | | | | **None** | 105 | (65.2) | 60 | (38.2) | 57 | (36.5) | 125 | (78.6) | 126 | (79.7) | 133 | (84.2) | 141 | (89.2) | 140 | (89.7) | | **Mild** | 24 | (14.9) | 77 | (49.0) | 80 | (51.3) | 29 | (18.2) | 29 | (18.4) | 24 | (15.2) | 14 | (8.9) | 15 | (9.6) | | **Moderate** | 11 | (6.8) | 18 | (11.5) | 19 | (12.2) | 5 | (3.1) | 3 | (1.9) | 1 | (0.6) | 3 | (1.9) | 1 | (0.6) | | **Severe** | 21 | (13.0) | 2 | (1.3) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | **9. Double vision (seeing two images of the same thing)** | | | | | | | | | | | | | | | | | | **None** | 150 | (93.2) | 119 | (75.8) | 118 | (75.6) | 146 | (91.8) | 145 | (91.8) | 153 | (96.8) | 157 | (99.4) | 156 | (100.0) | | **Mild** | 8 | (5.0) | 23 | (14.6) | 25 | (16.0) | 8 | (5.0) | 9 | (5.7) | 5 | (3.2) | 1 | (0.6) | 0 | (0.0) | | **Moderate** | 2 | (1.2) | 12 | (7.6) | 10 | (6.4) | 3 | (1.9) | 3 | (1.9) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | **Severe** | 1 | (0.6) | 3 | (1.9) | 3 | (1.9) | 2 | (1.3) | 1 | (0.6) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | **10. Fluctuation (changes) in vision** | | | | | | | | | | | | | | | | | | **None** | 147 | (91.3) | 63 | (40.1) | 62 | (39.7) | 125 | (78.6) | 125 | (79.1) | 131 | (82.9) | 140 | (88.6) | 145 | (92.9) | | **Mild** | 11 | (6.8) | 68 | (43.3) | 70 | (44.9) | 30 | (18.9) | 31 | (19.6) | 25 | (15.8) | 15 | (9.5) | 10 | (6.4) | | **Moderate** | 3 | (1.9) | 25 | (15.9) | 23 | (14.7) | 4 | (2.5) | 2 | (1.3) | 2 | (1.3) | 3 | (1.9) | 1 | (0.6) | | **Severe** | 0 | (0.0) | 1 | (0.6) | 1 | (0.6) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | **11. Difficulty focusing in dim or low light** | | | | | | | | | | | | | | | | | | **None** | 124 | (77.0) | 98 | (62.4) | 98 | (62.8) | 135 | (84.9) | 136 | (86.1) | 135 | (85.4) | 144 | (91.1) | 145 | (92.9) | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 24 {24} | Question/Result | Visit 1 | | Visit 6A | | Visit 6B | | Visit 7A | | Visit 7B | | Visit 8 | | Visit 9 | | Visit 10 | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Screening | Month 1 | Month 1 | Month 1 | Month 1 | Month 1 | Month 3 | Month 3 | Month 3 | Month 6 | Month 6 | Month 6 | Month 9 | Month 9 | Month 12 | Month 12 | | | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | n | (%) | | **Mild** | 26 | (16.1) | 50 | (31.8) | 48 | (30.8) | 21 | (13.2) | 20 | (12.7) | 20 | (12.7) | 14 | (8.9) | 10 | (6.4) | | **Moderate** | 7 | (4.3) | 7 | (4.5) | 7 | (4.5) | 2 | (1.3) | 2 | (1.3) | 3 | (1.9) | 0 | (0.0) | 1 | (0.6) | | **Severe** | 4 | (2.5) | 2 | (1.3) | 3 | (1.9) | 1 | (0.6) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | **12. Watery eyes/tearing** | | | | | | | | | | | | | | | | | | **None** | 130 | (80.7) | 132 | (84.1) | 130 | (83.3) | 139 | (87.4) | 140 | (88.6) | 145 | (91.8) | 138 | (87.3) | 139 | (89.1) | | **Mild** | 26 | (16.1) | 22 | (14.0) | 24 | (15.4) | 20 | (12.6) | 18 | (11.4) | 13 | (8.2) | 18 | (11.4) | 14 | (9.0) | | **Moderate** | 5 | (3.1) | 2 | (1.3) | 2 | (1.3) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 2 | (1.3) | 3 | (1.9) | | **Severe** | 0 | (0.0) | 1 | (0.6) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | | **13. Foreign body sensation (feeling like something is in your eye)** | | | | | | | | | | | | | | | | | | **None** | 142 | (88.2) | 106 | (67.5) | 107 | (68.6) | 117 | (73.6) | 114 | (72.2) | 129 | (81.6) | 138 | (87.3) | 141 | (90.4) | | **Mild** | 16 | (9.9) | 46 | (29.3) | 45 | (28.8) | 37 | (23.3) | 39 | (24.7) | 24 | (15.2) | 18 | (11.4) | 13 | (8.3) | | **Moderate** | 2 | (1.2) | 5 | (3.2) | 4 | (2.6) | 5 | (3.1) | 5 | (3.2) | 4 | (2.5) | 2 | (1.3) | 2 | (1.3) | | **Severe** | 1 | (0.6) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.6) | 0 | (0.0) | 0 | (0.0) | n = Number of subjects in category Percentages based on number of subjects with data for each question at visit. ### RSVP Questionnaire The RSVP questionnaire (Vitale et al) is designed to measure self-reported functioning, symptoms, health perceptions, and expectations in individuals with refractive error. It contains 42 items covering eight domains: concern, expectations, physical/social functioning, driving, symptoms, optical problems, glare, and problems with corrective lenses. Results for the RSVP questionnaire are presented in Table 17. Information on whether subjects reported their symptoms in the presence or absence of corrective lenses was not collected. The RSVP results show that there was no worsening in vision-related health status post-operatively. **Table 17. Descriptive Statistics for RSVP Subscales by Visit by Subject** | Subscale | Statistic | Visit 1 | Visit 6A | Visit 6B | Visit 7A | Visit 7B | Visit 8 | Visit 9 | Visit 10 | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | Screening | Month 1 | Month 1 | Month 3 | Month 3 | Month 6 | Month 9 | Month 12 | | **Concern** | **N** | 161 | 154 | 154 | 159 | 158 | 158 | 158 | 156 | | | **Mean** | 39.9 | 23.0 | 22.6 | 10.1 | 9.9 | 7.9 | 8.0 | 6.7 | | | **SD** | 23.16 | 16.63 | 16.56 | 11.65 | 11.48 | 10.91 | 11.54 | 10.30 | | | **Median** | 37.5 | 20.8 | 20.8 | 8.3 | 4.2 | 0.0 | 0.0 | 0.0 | | | **(Min, Max)** | (0.0, 100.0) | (0.0, 75.0) | (0.0, 66.7) | (0.0, 54.2) | (0.0, 54.2) | (0.0, 58.3) | (0.0, 58.3) | (0.0, 66.7) | | **Driving** | **N** | 157 | 135 | 140 | 155 | 152 | 152 | 156 | 155 | | | **Mean** | 17.2 | 18.2 | 17.9 | 6.3 | 5.9 | 5.8 | 5.0 | 3.9 | | | **SD** | 22.78 | 20.37 | 20.37 | 11.61 | 11.42 | 13.83 | 9.91 | 8.67 | | | **Median** | 8.3 | 8.3 | 8.3 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | | | **(Min, Max)** | (0.0, 100.0) | (0.0, 100.0) | (0.0, 100.0) | (0.0, 50.0) | (0.0, 50.0) | (0.0, 100.0) | (0.0, 50.0) | (0.0, 41.7) | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 25 {25} | Subscale | Statistic | Visit 1 | Visit 6A | Visit 6B | Visit 7A | Visit 7B | Visit 8 | Visit 9 | Visit 10 | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | Screening | Month 1 | Month 1 | Month 3 | Month 3 | Month 6 | Month 9 | Month 12 | | **Expectations** | **N** | 161 | 154 | 154 | 158 | 157 | 157 | 158 | 156 | | | **Mean** | 62.0 | 64.1 | 64.2 | 64.7 | 64.2 | 67.3 | 64.9 | 66.6 | | | **SD** | 26.18 | 27.85 | 27.97 | 29.51 | 29.52 | 29.50 | 31.23 | 30.92 | | | **Median** | 75.0 | 75.0 | 75.0 | 75.0 | 75.0 | 75.0 | 75.0 | 75.0 | | | **(Min, Max)** | (0.0, 100.0) | (0.0, 100.0) | (0.0, 100.0) | (0.0, 100.0) | (0.0, 100.0) | (0.0, 100.0) | (0.0, 100.0) | (0.0, 100.0) | | **Functioning** | **N** | 159 | 139 | 144 | 156 | 153 | 153 | 155 | 155 | | | **Mean** | 13.7 | 12.7 | 12.2 | 2.1 | 2.1 | 2.3 | 1.3 | 1.1 | | | **SD** | 16.61 | 16.55 | 16.02 | 4.10 | 4.14 | 8.80 | 3.38 | 3.17 | | | **Median** | 8.3 | 7.5 | 7.2 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | | | **(Min, Max)** | (0.0, 86.4) | (0.0, 100.0) | (0.0, 100.0) | (0.0, 25.0) | (0.0, 29.5) | (0.0, 100.0) | (0.0, 20.0) | (0.0, 25.0) | | **Symptoms** | **N** | 159 | 136 | 141 | 156 | 153 | 153 | 154 | 155 | | | **Mean** | 7.6 | 15.3 | 15.0 | 6.5 | 6.4 | 6.1 | 5.2 | 4.2 | | | **SD** | 11.23 | 13.14 | 12.33 | 7.69 | 7.77 | 8.09 | 8.66 | 6.87 | | | **Median** | 5.0 | 15.0 | 12.5 | 5.0 | 5.0 | 5.0 | 0.0 | 0.0 | | | **(Min, Max)** | (0.0, 62.5) | (0.0, 70.0) | (0.0, 50.0) | (0.0, 45.0) | (0.0, 45.0) | (0.0, 35.0) | (0.0, 45.0) | (0.0, 35.0) | | **Optical Problems** | **N** | 160 | 137 | 142 | 156 | 153 | 152 | 154 | 155 | | | **Mean** | 5.0 | 12.8 | 12.6 | 3.5 | 3.1 | 2.5 | 1.8 | 1.2 | | | **SD** | 9.87 | 13.80 | 13.88 | 6.61 | 6.01 | 5.40 | 3.91 | 3.28 | | | **Median** | 0.0 | 10.0 | 10.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | | | **(Min, Max)** | (0.0, 75.0) | (0.0, 70.0) | (0.0, 70.0) | (0.0, 30.0) | (0.0, 30.0) | (0.0, 40.0) | (0.0, 20.0) | (0.0, 18.8) | | **Glare** | **N** | 158 | 137 | 141 | 156 | 153 | 154 | 156 | 155 | | | **Mean** | 9.4 | 19.2 | 19.1 | 7.7 | 7.6 | 5.8 | 5.0 | 3.7 | | | **SD** | 13.14 | 15.59 | 15.86 | 9.98 | 10.05 | 9.41 | 8.01 | 7.90 | | | **Median** | 0.0 | 16.7 | 16.7 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | | | **(Min, Max)** | (0.0, 66.7) | (0.0, 66.7) | (0.0, 66.7) | (0.0, 50.0) | (0.0, 50.0) | (0.0, 41.7) | (0.0, 33.3) | (0.0, 41.7) | | **Problems with Corrective Lenses** | **N** | 156 | 22 | 20 | 13 | 13 | 20 | 17 | 15 | | | **Mean** | 34.7 | 20.5 | 16.9 | 17.9 | 16.0 | 7.3 | 5.1 | 0.8 | | | **SD** | 22.64 | 25.31 | 24.43 | 19.20 | 19.68 | 13.64 | 8.90 | 3.23 | | | **Median** | 30.4 | 18.8 | 6.3 | 25.0 | 0.0 | 0.0 | 0.0 | 0.0 | | | **(Min, Max)** | (0.0, 75.0) | (0.0, 100.0) | (0.0, 100.0) | (0.0, 50.0) | (0.0, 50.0) | (0.0, 50.0) | (0.0, 25.0) | (0.0, 12.5) | | **S** | **N** | 161 | 154 | 154 | 159 | 158 | 158 | 158 | 156 | | | **Mean** | 20.2 | 19.9 | 19.3 | 8.3 | 8.4 | 7.8 | 6.8 | 5.9 | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 26 {26} | Subscale | Statistic | Visit 1 Screening | Visit 6A Month 1 | Visit 6B Month 1 | Visit 7A Month 3 | Visit 7B Month 3 | Visit 8 Month 6 | Visit 9 Month 9 | Visit 10 Month 12 | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | SD | 11.55 | 12.57 | 12.48 | 6.64 | 6.99 | 7.22 | 5.90 | 4.78 | | | Median (Min, Max) | 18.3 | 17.6 | 17.6 | 6.4 | 6.4 | 5.7 | 4.9 | 4.7 | | | | (3.1, 61.2) | (0.7, 75.7) | (0.7, 75.7) | (0.0, 34.4) | (0.0, 39.3) | (0.0, 47.9) | (0.0, 29.9) | (0.0, 30.6) | n = Number of eyes in category SD = Standard deviation, Min = Minimum, Max = Maximum S=Overall score ## 2. Effectiveness Results The analysis of effectiveness was based on results from 320 eyes of 161 evaluable patients at the 12-month time point. Key effectiveness outcomes are presented in Tables 18 to 23. At Month 6, 100% of the 294 eyes with preoperative BSCVA of 20/20 or better had UCVA of 20/40 or better, 99.7% of eyes were within ± 1.0 D of zero MRSE, and 93.3% were within ± 0.5 D of zero MRSE. In addition, at Month 6, 99.0% of eyes had refractive cylinder within ± 1.0 D of zero, and 92.7% of eyes had manifest refractive cylinder within ± 0.5 D of zero. Within the Month 3 to Month 6 interval, 99.7% of eyes had a change in MRSE and manifest refractive cylinder of ≤ 1.0 D in manifest refractive cylinder. **Table 18 Proportion of Eyes Meeting Visual and Refractive Outcome Criteria (Intent-to-Treat)** | Visit | Parameter | n / N | (%) | 95% CI† | | --- | --- | --- | --- | --- | | **Visit 5 - Week 1** | UCVA 20/40 or better (BSCVA 20/20 or better pre-op) | 270 / 299 | (90.3) | (86.4, 93.4) | | | MRSE within ± 1.00 D of emmetropia | 307 / 320 | (95.9) | (93.2, 97.8) | | | MRSE within ± 0.50 D of emmetropia | 255 / 320 | (79.7) | (74.9, 84.0) | | | Manifest refractive cylinder within ± 1.00 D of plano | 296 / 320 | (92.5) | (89.0, 95.1) | | | Manifest refractive cylinder within ± 0.50 D of plano | 250 / 320 | (78.1) | (73.2, 82.5) | | **Visit 6 - Month 1** | UCVA 20/40 or better (BSCVA 20/20 or better pre-op) | 293 / 299 | (98.0) | (95.7, 99.3) | | | MRSE within ± 1.00 D of emmetropia | 312 / 320 | (97.5) | (95.1, 98.9) | | | MRSE within ± 0.50 D of emmetropia | 258 / 320 | (80.6) | (75.9, 84.8) | | | Manifest refractive cylinder within ± 1.00 D of plano | 303 / 320 | (94.7) | (91.6, 96.9) | | | Manifest refractive cylinder within ± 0.50 D of plano | 239 / 320 | (74.7) | (69.6, 79.4) | | **Visit 7 - Month 3** | UCVA 20/40 or better (BSCVA 20/20 or better pre-op) | 297 / 297 | (100.0) | (98.8, 100.0) | | | MRSE within ± 1.00 D of emmetropia | 315 / 317 | (99.4) | (97.7, 99.9) | | | MRSE within ± 0.50 D of emmetropia | 293 / 317 | (92.4) | (88.9, 95.1) | | | Manifest refractive cylinder within ± 1.00 D of plano | 314 / 317 | (99.1) | (97.3, 99.8) | | | Manifest refractive cylinder within ± 0.50 D of plano | 292 / 317 | (92.1) | (88.6, 94.8) | | **Visit 8 - Month 6** | UCVA 20/40 or better (BSCVA 20/20 or better pre-op) | 294 / 294 | (100.0) | (98.8, 100.0) | | | MRSE within ± 1.00 D of emmetropia | 313 / 314 | (99.7) | (98.2, 100.0) | | | MRSE within ± 0.50 D of emmetropia | 293 / 314 | (93.3) | (90.0, 95.8) | | | Manifest refractive cylinder within ± 1.00 D of plano | 311 / 314 | (99.0) | (97.2, 99.8) | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 27 {27} | Visit | Parameter | n / N | (%) | 95% CI† | | --- | --- | --- | --- | --- | | | Manifest refractive cylinder within ± 0.50 D of plano | 291 / 314 | (92.7) | (89.2, 95.3) | | **Visit 9 - Month 9** | UCVA 20/40 or better (BSCVA 20/20 or better pre-op) | 294 / 294 | (100.0) | (98.8, 100.0) | | | MRSE within ± 1.00 D of emmetropia | 314 / 314 | (100.0) | (98.8, 100.0) | | | MRSE within ± 0.50 D of emmetropia | 300 / 314 | (95.5) | (92.6, 97.5) | | | Manifest refractive cylinder within ± 1.00 D of plano | 311 / 314 | (99.0) | (97.2, 99.8) | | | Manifest refractive cylinder within ± 0.50 D of plano | 300 / 314 | (95.5) | (92.6, 97.5) | | **Visit 10 - Month 12** | UCVA 20/40 or better (BSCVA 20/20 or better pre-op) | 291 / 291 | (100.0) | (98.7, 100.0) | | | MRSE within ± 1.00 D of emmetropia | 309 / 311 | (99.4) | (97.7, 99.9) | | | MRSE within ± 0.50 D of emmetropia | 294 / 311 | (94.5) | (91.4, 96.8) | | | Manifest refractive cylinder within ± 1.00 D of plano | 308 / 311 | (99.0) | (97.2, 99.8) | | | Manifest refractive cylinder within ± 0.50 D of plano | 297 / 311 | (95.5) | (92.6, 97.5) | N = Number of eyes in ITT analysis set with data at visit n = Number of eyes in category † 95% confidence interval from Binomial distribution **Table 19 Proportion of Eyes Meeting MRSE and Manifest Refractive Cylinder Change Criteria, (Intent-to-Treat)** | Visit Interval | Parameter | n/N | (%) | 95% CI† | | --- | --- | --- | --- | --- | | **Visit 5 - Week 1 to Visit 6 - Month 1** | Change ≤ 1.00 D in MRSE and manifest refractive cylinder | 291 / 320 | (90.9) | (87.2, 93.8) | | **Visit 6 - Month 1 to Visit 7 - Month 3** | Change ≤ 1.00 D in MRSE and manifest refractive cylinder | 303 / 317 | (95.6) | (92.7, 97.6) | | **Visit 7 - Month 3 to Visit 8 - Month 6** | Change ≤ 1.00 D in MRSE and manifest refractive cylinder | 313 / 314 | (99.7) | (98.2, 100.0) | | **Visit 8 - Month 6 to Visit 9 - Month 9** | Change ≤ 1.00 D in MRSE and manifest refractive cylinder | 314 / 314 | (100.0) | (98.8, 100.0) | | **Visit 9 - Month 9 to Visit 10 - Month 12** | Change ≤ 1.00 D in MRSE and manifest refractive cylinder | 309 / 310 | (99.7) | (98.2, 100.0) | N = Number of eyes in ITT analysis set with data at visit n = Number of eyes in category An eye must meet the criteria for both MRSE and manifest refractive cylinder to be considered a success. † 95% confidence interval from Binomial distribution The following table (Table 20) presents the results for eyes that achieved the visual acuity thresholds. At Month 6, 93.0% of eyes had UCVA of 20/20 or better and 100% of eyes had UCVA of 20/40 or better. **Table 20 Proportion of Eyes Achieving Visual Acuity Threshold, (Intent-to-Treat)** | Visit | Parameter | n/N | (%) | 95% CI† | | --- | --- | --- | --- | --- | | **Visit 5 - Week 1** | UCVA 20/20 or better | 93 / 320 | (29.1) | (24.1, 34.4) | | | UCVA 20/40 or better | 285 / 320 | (89.1) | (85.1, 92.3) | | **Visit 6 - Month 1** | UCVA 20/20 or better | 166 / 320 | (51.9) | (46.2, 57.5) | PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 28 {28} | Visit | Parameter | n/N | (%) | 95% CI† | | --- | --- | --- | --- | --- | | | UCVA 20/40 or better | 314/320 | (98.1) | (96.0, 99.3) | | **Visit 7 - Month 3** | UCVA 20/20 or better | 288/317 | (90.9) | (87.1, 93.8) | | | UCVA 20/40 or better | 317/317 | (100.0) | (98.8, 100.0) | | **Visit 8 - Month 6** | UCVA 20/20 or better | 292/314 | (93.0) | (89.6, 95.6) | | | UCVA 20/40 or better | 314/314 | (100.0) | (98.8, 100.0) | | **Visit 9 - Month 9** | UCVA 20/20 or better | 292/314 | (93.0) | (89.6, 95.6) | | | UCVA 20/40 or better | 314/314 | (100.0) | (98.8, 100.0) | | **Visit 10 - Month 12** | UCVA 20/20 or better | 294/311 | (94.5) | (91.4, 96.8) | | | UCVA 20/40 or better | 311/311 | (100.0) | (98.8, 100.0) | N = Number of eyes in ITT analysis set with data at visit n = Number of eyes in category † 95% confidence interval from Binomial distribution The summary of the non-vector results for MRSE and visual acuity results at Month 6 are presented in Table 21. All eyes had MRSE within ± 2.0 D of zero. The percentage of eyes undercorrected by greater than 1.0 D was 0.3%; no eyes were overcorrected by more than 1.0 D. The majority of eyes (68.5%) had UCVA at Month 6 that was better than or equal to their preoperative BSCVA. No eyes showed a decrease in BSCVA of 2 lines or greater as compared to baseline. **Table 21 Non-Vector Analyses by Eye at Stability Time Point (Month 6) (Intent-to-Treat)** | Parameter | n/N | (%) | 95% CI† | | --- | --- | --- | --- | | MRSE ± 2.00 D of emmetropia | 314/314 | (100.0) | (98.8, 100.0) | | Overcorrected by > 1.00 D MRSE | 0/314 | (0.0) | (0.0, 1.2) | | Overcorrected by > 2.00 D MRSE | 0/314 | (0.0) | (0.0, 1.2) | | Undercorrected by > 1.00 D MRSE | 1/314 | (0.3) | (0.0, 1.8) | | Undercorrected by > 2.00 D MRSE | 0/314 | (0.0) | (0.0, 1.2) | | UCVA equal to or better than preoperative BSCVA | 215/314 | (68.5) | (63.0, 73.6) | | Difference in postoperative and preoperative BSCVA | | | | | < -2 lines | 3/314 | (1.0) | (0.2, 2.8) | | -2 lines | 7/314 | (2.2) | (0.9, 4.5) | | -1 line | 83/314 | (26.4) | (21.6, 31.7) | | 0 lines | 218/314 | (69.4) | (64.0, 74.5) | | 1 line | 3/314 | (1.0) | (0.2, 2.8) | | 2 lines | 0/314 | (0.0) | (0.0, 1.2) | | > 2 lines | 0/314 | (0.0) | (0.0, 1.2) | N = Number of eyes in ITT analysis set with data at visit n = Number of eyes in category † 95% confidence interval from Binomial distribution PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 29 {29} Table 22 presents the results for eyes with a preoperative cylinder component that achieved accuracy of cylinder to target. At Month 6, 98.7 % of eyes were within $\pm 1.0$ D of the intended target cylinder (zero), and 91.1% were within $\pm 0.5$ D of cylinder target. **Table 22. Accuracy of Cylinder to Target by Eye, (Intent-to-Treat)** | Cylinder | Visit 1 Screening | Visit 6 Month 1 | Visit 7 Month 3 | Visit 8 Month 6 | Visit 9 Month 9 | Visit 10 Month 12 | | --- | --- | --- | --- | --- | --- | --- | | No. Eyes (N) | 230 | 230 | 227 | 224 | 224 | 223 | | Mean $\pm$ SD | -1.096 $\pm$ 0.77 | -0.393 $\pm$ 0.43 | -0.227 $\pm$ 0.30 | -0.209 $\pm$ 0.29 | -0.185 $\pm$ 0.28 | -0.179 $\pm$ 0.29 | | Attempted change $\pm$ SD | 1.096 $\pm$ 0.77 | | | | | | | Achieved change $\pm$ SD | | 0.702 $\pm$ 0.90 | 0.866 $\pm$ 0.78 | 0.886 $\pm$ 0.78 | 0.910 $\pm$ 0.77 | 0.904 $\pm$ 0.76 | | % of eyes within $\pm$ 0.50 D of target | | 69.1 | 90.3 | 91.1 | 94.2 | 94.2 | | % of eyes within $\pm$ 1.00 D of target | | 93.0 | 98.7 | 98.7 | 98.7 | 98.7 | N = Number of eyes with preoperative cylindrical component with data at visit SD = Standard deviation Results of the vector analyses at Month 6 are presented in Table 23. The mean error vector (EV), defined as the vector difference between the intended refractive correction and the surgically induced refractive correction (IRC - SIRC), was $< 0.2$. The mean correction ratio (CR; the ratio of the achieved correction magnitude to the required correction magnitude) was close to 1 in each category. Error ratio (ER; the proportion of the intended correction not successfully treated) showed a progressive decrease in mean with increasing preoperative cylinder. **Table 23. Vector Analysis Summary at Stability Time Point (Month 6) (Intent-to-Treat)** | Preoperative Cylinder | n | |IRC| (Mean $\pm$ SD) | |SIRC| (Mean $\pm$ SD) | |EV| (Mean $\pm$ SD) | CR (Mean $\pm$ SD) | ER (Mean $\pm$ SD) | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | All Eyes (N) | 224 | 1.013 $\pm$ 0.7161 | 1.130 $\pm$ 0.7722 | 0.159 $\pm$ 0.2449 | 1.180 $\pm$ 0.4493 | 0.229 $\pm$ 0.4261 | | 0.0 D to $\leq$0.5 D | 89 | 0.397 $\pm$ 0.1075 | 0.502 $\pm$ 0.2241 | 0.120 $\pm$ 0.1943 | 1.302 $\pm$ 0.5989 | 0.343 $\pm$ 0.5763 | | >0.5 D to $\leq$1.0 D | 54 | 0.808 $\pm$ 0.1186 | 0.908 $\pm$ 0.3467 | 0.174 $\pm$ 0.2664 | 1.115 $\pm$ 0.4018 | 0.216 $\pm$ 0.3570 | | >1.0 D to $\leq$2.0 D | 50 | 1.450 $\pm$ 0.2240 | 1.628 $\pm$ 0.3866 | 0.189 $\pm$ 0.2827 | 1.122 $\pm$ 0.1950 | 0.129 $\pm$ 0.1899 | | >2.0 D to $\leq$3.0 D | 31 | 2.434 $\pm$ 0.2510 | 2.514 $\pm$ 0.4194 | 0.198 $\pm$ 0.2670 | 1.033 $\pm$ 0.1450 | 0.085 $\pm$ 0.1209 | n = Number of eyes with preoperative cylindrical component with data at visit SD = Standard deviation, Min = Minimum, Max = Maximum IRC = Intended Refractive Correction, SIRC = Surgically Induced Refractive Correction, EV = Error Vector, CR = Correction Ratio, ER = Error Ratio The outcomes summarized above provide reasonable assurance of safety and effectiveness for the device. ### 3. Subgroup Analyses PMA P020050/S023: FDA Summary of Safety and Effectiveness Data Page 30 {30} The following preoperative character…