enVista Envy™ hydrophobic acrylic intraocular lens (IOL), enVista Envy™ toric hydrophobic acrylic intraocular lens (IOL)

P240005 · Bausch & Lomb, Inc. · MFK · Oct 10, 2024 · Ophthalmic

Device Facts

• Record ID: P240005
• Device Name: enVista Envy™ hydrophobic acrylic intraocular lens (IOL), enVista Envy™ toric hydrophobic acrylic intraocular lens (IOL)
• Applicant: Bausch & Lomb, Inc.
• Product Code: MFK · Ophthalmic
• Decision Date: Oct 10, 2024
• Decision: APPR
• Regulation: 21 CFR 886.3600
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The enVista Envy hydrophobic acrylic IOL (non-preloaded model: EN / preloaded into shuttle model: EPN) is indicated for primary implantation in the capsular bag of the eye in adult patients for the visual correction of aphakia with less than or equal to 1.0 D preoperative corneal astigmatism following removal of a cataractous lens to mitigate the effects of presbyopia by providing improved intermediate and near visual acuity, while maintaining comparable distance visual acuity to an aspheric monofocal IOL. The enVista Envy toric hydrophobic acrylic IOL (non-preloaded model: ETN / preloaded into shuttle model: ETPN) is indicated for primary implantation in the capsular bag of the eye in adult patients for the visual correction of aphakia and corneal astigmatism following removal of a cataractous lens to mitigate the effects of presbyopia by providing improved intermediate and near visual acuity, while maintaining comparable distance visual acuity to an aspheric monofocal IOL.

Device Story

The enVista Envy and Envy toric are one-piece, hydrophobic acrylic, trifocal intraocular lenses (IOLs) designed to replace the natural crystalline lens after cataract removal. The device features an aspheric apodized diffractive anterior surface and an aspheric refractive (or toric) posterior surface, providing +3.1 D near and +1.6 D intermediate add power. The lens is foldable for insertion through a small incision using a compatible injector. During surgery, the physician positions the lens in the capsular bag; fenestration holes facilitate manipulation. The posterior surface includes a 360° square edge to reduce posterior capsular opacification. The device provides patients with improved intermediate and near vision compared to monofocal IOLs, while maintaining distance visual acuity. Healthcare providers use the device to treat aphakia and presbyopia, potentially reducing patient reliance on reading glasses.

Clinical Evidence

Prospective, multicenter, randomized, active-controlled study (IDE G180015) of 501 subjects (332 test, 169 control). Primary endpoints: photopic monocular BCDVA (non-inferiority), DCNVA, and DCIVA (superiority) at 4-6 months. Results: Trifocal IOL met non-inferiority for BCDVA and demonstrated statistical superiority for DCNVA and DCIVA (p<0.0001). Safety endpoints met; no SSIs related to optical properties. Visual disturbances (halos) were more frequent in the trifocal group.

Technological Characteristics

One-piece, hydrophobic acrylic (HEMA-poly(EG)PEA-styrene copolymer) trifocal IOL. Aspheric apodized diffractive optic. 12.5 mm overall diameter, 6.0 mm optic diameter. 0° haptic angulation (modified C-loop). UV-absorbing. Sterilized via gamma radiation. Standalone device used with external inserters/viscoelastics.

Indications for Use

Indicated for adult patients undergoing cataract extraction for the visual correction of aphakia (and corneal astigmatism for toric models) to mitigate presbyopia by improving intermediate and near visual acuity while maintaining distance visual acuity.

Regulatory Classification

Identification

An intraocular lens is a device made of materials such as glass or plastic intended to be implanted to replace the natural lens of an eye.

Predicate Devices

• enVista MX60T (P910056/S027)

Reference Devices

• enVista MX60 (P910056/S051)

Submission Summary (Full Text)

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PMA P240005: FDA Summary of Safety and Effectiveness Data

# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

Device Generic Name:
Lens, Multifocal Intraocular Lens, Intraocular, Toric Optics

Device Trade Name:
enVista Envy™ hydrophobic acrylic intraocular lens (IOL),
enVista Envy™ toric hydrophobic acrylic intraocular lens (IOL)

Device Procode:
MFK, MJP

Applicants Name and Address:
Bausch &amp; Lomb Incorporated
1400 North Goodman Street
Rochester, NY 14609

Date(s) of Panel Recommendation:
None

Premarket Approval Application (PMA) Number: P240005

Date of FDA Notice of Approval:
10/10/2024

## II. INDICATIONS FOR USE

### enVista Envy™ hydrophobic acrylic intraocular lens

The enVista Envy hydrophobic acrylic IOL (non-preloaded model: EN / preloaded into shuttle model: EPN) is indicated for primary implantation in the capsular bag of the eye in adult patients for the visual correction of aphakia with less than or equal to 1.0 D preoperative corneal astigmatism following removal of a cataractous lens to mitigate the effects of presbyopia by providing improved intermediate and near visual acuity, while maintaining comparable distance visual acuity to an aspheric monofocal IOL.

### enVista Envy™ toric hydrophobic acrylic intraocular lens

The enVista Envy toric hydrophobic acrylic IOL (non-preloaded model: ETN / preloaded into shuttle model: ETPN) is indicated for primary implantation in the capsular bag of the eye in adult patients for the visual correction of aphakia and corneal astigmatism following removal of a cataractous lens to mitigate the effects of presbyopia by providing improved intermediate and near visual acuity, while maintaining comparable distance visual acuity to an aspheric monofocal IOL.

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# III. CONTRAINDICATIONS

There are no known contraindications.

# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the enVista Envy and enVista Envy toric IOL labeling.

# V. DEVICE DESCRIPTION

The enVista Envy and enVista Envy toric IOLs are one-piece, hydrophobic acrylic, trifocal intraocular lenses intended to replace the natural crystalline lens in adult patients in whom the cataractous lens has been removed. The IOLs have an aspheric apodized diffractive optic on the anterior surface, the posterior surface is aspheric refractive or aspheric refractive toric and is designed to have -0.15 µm of spherical aberration at focus in an EN ISO 11979-2 Model Eye 1 at 5.1 mm aperture on the optic surface. The IOLs have near add power of +3.1 diopters and intermediate add power of +1.6 diopters. They have a 12.5 mm overall diameter, a 6.0 mm optic body diameter, and 0° haptic angulation. The haptics are modified C-Loop. The clear optical diameter ranges from 4.5 mm to 5.9 mm across the power range. The posterior side of the lens has a continuous 360° square edge to help prevent Posterior Capsular Opacification.

The IOLs are manufactured using a UV absorbing foldable hydrophobic acrylic material. The design and material of the IOLs allow them to be folded and inserted into the capsular bag through a small incision to minimize the extent of surgically induced astigmatism. The IOLs' unique fenestration holes facilitate intraoperative lens manipulation, allowing for both clockwise and counterclockwise manipulation when positioning the lens in the capsular bag. A representative image of the subject devices is included below.

Key physical properties of the enVista Envy or enVista Envy toric IOLs are identified in Table 1 and Figure 1. The enVista Envy toric IOL has axis markings at the haptic-optic junction to identify the flat meridian of the enVista Envy toric IOL and represent an imaginary line of the plus cylinder axis. The astigmatic correction at the corneal plane for each toric model is also shown in Table 1 below.

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Table 1: Physical properties of the IOLs

| Characteristic | enVista Envy IOL | enVista Envy toric IOL | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Optical Type and Powers | Single-piece, aspheric apodized diffractive / +6.0 to +34.0 Diopters (+6.0 to +9.0 in 1.0 Diopter increments, +10.0 to +34.0 in 0.5 Diopter increments) / Intermediate 1.6 Diopters / Near 3.1 Diopters | Single-piece, aspheric apodized diffractive / +6.0 to +34.0 Diopters in 0.5 Diopter increments (SE - Spherical Equivalent) / Intermediate 1.6 Diopters / Near 3.1 Diopters | | | | | | | | |
| Optical Body Diameter | 6.0 mm | 6.0 mm | | | | | | | | |
| Overall Diameter | 12.5 mm | 12.5 mm | | | | | | | | |
| Haptic Angle | 0° | 0° | | | | | | | | |
| Image | Dimensions are in mm | Dimensions are in mm | | | | | | | | |
| Lens Material | UV absorbing foldable hydrophobic acrylic (hydroxyethyl methacrylate (HEMA)-polyethylene glycol phenyl ether acrylate (poly(EG)PEA)-styrene copolymer, crosslinked with ethylene glycol dimethacrylate) | UV absorbing foldable hydrophobic acrylic (hydroxyethyl methacrylate (HEMA)-polyethylene glycol phenyl ether acrylate (poly(EG)PEA)-styrene copolymer, crosslinked with ethylene glycol dimethacrylate) | | | | | | | | |
| Index of Refraction | 1.53 @ 35°C | 1.53 @ 35°C | | | | | | | | |
| Spectral Transmittance | Ultraviolet: UV (389) 10% transmittance for +20.0 Diopter IOL. See Figure 1 | Ultraviolet: UV (389) 10% transmittance for +20.0 Diopter IOL. See Figure 1 | | | | | | | | |
| Cylinder Powers (CYL) - IOL Plane | Not Applicable | 1.25 D | 1.50 D | 2.00 D | 2.50 D | 3.00 D | 3.50 D | 4.25 D | 5.00 D | 5.75 D |
| Cylinder Powers (CYL) - Corneal Plane* | Not Applicable | 0.88 D | 1.05 D | 1.40 D | 1.75 D | 2.10 D | 2.45 D | 2.98 D | 3.50 D | 4.03 D |

*Based on an average pseudophakic human eye

The IOLs are sold standalone and require use of a legally marketed inserter/injector and viscoelastics. The inserters are used for folding and delivering enVista IOL models into the eye during cataract surgery. Compatible inserters include the INJ100 Inserter and the Bausch and Lomb Injector System™ (B.L.I.S.) Reusable Inserter. The B.L.I.S. and INJ100 IOL Inserters have been marketed in the United States for over eight years. The enVista Preloaded

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IOLs are individually "preloaded" into a shuttle assembly that is placed into a plastic vial with BBS solution and then sealed with a foil lid.

enVista Envy IOLs were investigated under IDE G180015 as described in Section X below.

Figure 1: enVista Envy Spectral Transmittance
A = + 20 Diopter enVista IOL and B = 53-Year-Old Human Lens. NOTE: Light transmittance values for an IOL material may vary slightly depending on the method of measurement.
X value = Wavelength (nm) and Y value = % Transmittance; chart compares the transmittance curve of an enVista IOL to a 53-Year-Old Human Lens. Human crystalline lens data is from Boettner and Wolter (1962).

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for correction of aphakia. Patients who undergo cataract extraction presently have several non-surgical and surgical alternatives for restoring functional vision of the aphakic eye. Non-surgical options include special cataract glasses or contact lenses. Surgical options such as monofocal, multifocal, extended depth of focus or accommodative IOLs are also available. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

# VII. MARKETING HISTORY

The enVista Envy and enVista Envy toric IOLs are currently commercially available in Canada. The lenses have not been withdrawn from any country for any reason related to safety or effectiveness.

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# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device include the following:

- lens epithelial cell down-growth
- corneal endothelial damage
- infection (endophthalmitis)
- retinal detachment/tear
- vitritis
- cystoid macular edema
- corneal edema
- pupillary block
- cyclitic membrane
- iris prolapse
- hypopyon
- anterior uveitis
- hyphema
- pigment dispersion
- posterior capsule opacification
- transient or persistent glaucoma
- IOL dislocation, tilt, or decentration requiring repositioning
- residual refractive error resulting in secondary intervention
- increased visual disturbances (compared to a monofocal IOL) related to the optical characteristics of the IOL, including bothersome stray-light artifacts such as halo, starbursts, or glare

Secondary surgical interventions include, but are not limited to lens repositioning, lens replacement, vitreous aspiration, iridectomy for pupillary block, wound leak repair, and retinal detachment repair.

For the specific adverse events that occurred in the clinical study, please see Section X below.

# IX. SUMMARY OF NON-CLINICAL STUDIES

## Biocompatibility Testing

The enVista Envy and enVista Envy toric IOLs are made of the same material that was used with previously approved enVista IOLs (P910056/S051). Biocompatibility testing (see Table 2) was performed to support P910056/S051 in accordance with all relevant ISO Standards ISO 11979-5 and ISO 10993-1), as well as the United States Food and Drug Administration. Use of International Standards ISO 10993-1, "Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process".

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All tests to evaluate the biocompatibility were conducted in accordance with provisions of 21 CFR 58, Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies.

Table 2: Biocompatibility assessment of the enVista Envy and enVista Envy toric IOLs

| Test (ISO Standard) | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Cytotoxicity - MEM elution (ISO 10993-5, ISO 11979-5) | Evaluates the potential for cellular toxicity | Non-cytotoxic | Pass |
| Cytotoxicity – Agar Diffusion (ISO 10993-5, ISO 11979-5) | Evaluates the potential for cellular toxicity | Non-cytotoxic | Pass |
| Sensitization - Guinea Pig Maximization (ISO 10993-10, ISO 11979-5) | Evaluates the potential for sensitization | Non-sensitizer | Pass |
| Irritation – Rabbit Intracameral (intraocular) Irritation (ISO 10993-23) | Evaluates the potential for irritation | Non-irritant | Pass |
| Rabbit Intramuscular Implantation – 12-week Study with Histopathology (ISO 10993-6, ISO 11979-5) | Evaluate the potential local tissue response | Good tissue tolerability | Pass |
| Acute Systemic Toxicity in Mice (ISO 10993-11) | Evaluates the potential for systemic toxicity | Non-toxic | Pass |
| Genotoxicity - Bacterial Reverse Mutation Test (Ames Test) (ISO 10993-3, ISO 11979-5) | Evaluates the potential for mutagenic changes | Non-mutagenic | Pass |
| Genotoxicity - In vitro chromosome aberration test (ISO 10993-3, ISO 11979-5) | Evaluates the clastogenic (large scale genetic damage) potential of the implant in Chinese hamster ovary cells | Non-clastogenic | Pass |
| Ocular Implantation – 12-Month Ocular Implantation (ISO 10993-6, ISO 11979-5) | Evaluate the potential local tissue response | Good tissue tolerability | Pass |

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# Physiochemical Tests

The enVista Envy and enVista Envy toric IOLs are made of the same material that was used for previously approved enVista IOLs (P910056/S051). Chemical Characterization (Table 3) was performed to support P910056/S051 in accordance with the recommendations in ISO 11979-5 Ophthalmic Implants – Intraocular Lenses Part 5 – Biocompatibility. New leachable and particulate testing was performed on sterile, finished enVista Envy IOLs (preloaded in shuttle) at baseline and after shelf-life conditioning.

Table 3: Physiochemical tests of the enVista Envy and enVista Envy toric IOLs

| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Exhaustive Extraction (ISO 11979-5, ISO 10993-18) | Soxhlet extraction to recover polymerization residuals, impurities, and additives, quantitative analysis of extracts | Extraction profile is similar to previous enVista IOL material (e.g., no higher concentration of UV absorber compounds).
New IOL materials passes biocompatibility and toxicology assessment. | Pass |
| Leachables (ISO 11979-5, ISO 10993-18) | Extraction procedure to simulate leachable components that are expected to be released in-vivo | New IOL material passes biocompatibility and toxicology assessment. | Pass |
| Insoluble Inorganics (ISO 11979-5) | Test to verify removal of residual inorganics residues from the manufacturing process | Residual profile and concentrations are similar to previous enVista material. | Pass |
| Hydrostatic Stability (ISO 11979-5) | Test to verify material does not degrade by hydrolysis | New material is stable under exaggerated hydrolytic conditions equivalent to 5 years real time exposure. | Pass |
| Photostability (ISO 11979-5) | Test to evaluate photostability over 20 years | No significant difference in physical appearance, spectral transmittance, or dioptric power. | Pass |
| Nd:YAG Laser (ISO 11979-5) | Test to evaluate material stability when exposed to Nd-YAG laser treatment, and no leakage of toxic components | No significant difference in physical appearance, spectral transmittance, or dioptric power. | Pass |

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# Optical and Mechanical Testing

Pre-clinical optical / mechanical tests were performed with the enVista Envy and enVista Envy toric IOLs and were measured in accordance with ISO 11979-2 Ophthalmic Implants – Intraocular Lenses – Part 2: Optical Properties and Test Methods and ISO 11979-3 Ophthalmic Implants – Intraocular Lenses – Part 3: Mechanical Properties and Test Methods. Test results are presented in Table 4.

Table 4: Optical and Mechanical Test Results

| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Surface and Bulk Homogeneity (Pre and Post Folding) | To ensure IOL is free of surface and bulk defects | ISO 11979-3:2012 Section 4.12 | Pass |
| Dioptric Power and Image Quality (Pre and Post Folding) | To assess conformance to optical power and image quality tolerances | ISO 11979-2:2014 Sections 4.2.1, 4.2.2, 4.2.3, 4.3 | Pass |
| Dimensions (Pre and Post Folding) | To assess conformance to dimensional tolerances | ISO 11979-3:2012 Section 4.2 | Pass |
| Recovery of Properties | To assess the ability of the IOL to return to optical, dimensional, and cosmetic specifications after simulated surgical manipulation | ISO 11979-3:2012 Section 5 | Pass |
| Axial Displacement | To characterize the axial displacement in compression | ISO 11979-3:2012 Section 4.5 | Pass |
| Optic Decentration | To assess optic decentration under compression | ISO 11979-3:2012 Section 4.6 | Pass |
| Optic Tilt | To assess optic tilt under compression | ISO 11979-3:2012 Section 4.7 | Pass |
| Mechanical Characterization (Compression Force, Force Decay, Angle of Contact) | To characterize the mechanical properties of the IOL | Must match criteria for a Level A modification described in ISO/TR 22979 when compared to enVista MX60 design verification test results. | Pass |
| Dynamic Fatigue | To assess the ability of the haptics to withstand cyclic compressive loading | ISO 11979-3:2012 Section 4.10 | Pass |
| Surgical Manipulation (Haptic Pull Test) | To assess the force required to separate the haptic from the optic | ISO 11979-3:2012 Section 4.11 | Pass |
| Spectral Transmittance | To characterize the spectral transmittance of the IOL | ISO 11979-2:2014 Section 4.4.2 | Pass |
| Glistening Testing | To characterize glistenings performance of the IOL | No glistenings observed | Pass |

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# Sterilization and Stability Evaluation

Sterilization evaluation, shelf-life and transport stability testing, and bacterial endotoxin testing were performed to support the enVista Envy and Envy toric IOLs. The results are summarized in Table 5.

Table 5: Sterilization Evaluation Results

| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Gamma radiation sterilization validation (VDmax25 method) (ISO 11137-1 & ISO 11137-2) | Substantiate a 25 kGy dose for routine sterilization of product, and demonstrate process can achieve a Sterility Assurance Level (SAL) of 10-6, based upon the average product bioburden. | Successful performance of verification dose experiment (i.e., ≤ 1 positive test of sterility result [growth of microorganisms on solid, or in liquid, microbial growth media]) to demonstrate process can achieve an SAL ≤ 10-6, based upon the average product bioburden. | Pass |
| Transport stability (ISO 11979-6, ISO 11607-1, ASTM F2096, ASTM F1886) | Confirm that the sterile barrier packaging can maintain device sterility throughout anticipated transport conditions. Testing includes visual inspection, whole package integrity, and seal integrity assessments after transport conditioning (e.g., ISTA 3A sequence). | Meets lens cosmetics and functional delivery requirements. Meets sterile barrier packaging visual inspection, whole package integrity & seal integrity requirements. For visual inspection, no channels, voids, punctures, or breaches observed, and labels are legible. For whole package integrity assessed by bubble leak testing of the Tyvek pouch packaging, no leaks are observed. For seal integrity, assessed by leak testing of the vial packaging, no leaks are observed. | Pass |
| Shelf-life stability (ISO 11979-6 & ISO 11607-1) | Confirm that device performance is maintained throughout claimed shelf-life. | Meets optical, mechanical, chemical and biological testing requirements | Pass |
| Package Integrity (ISO 11979-6, ISO 11607-1, ASTM F2096, ASTM F1886) | Confirm that the primary sterile barrier packaging can maintain device sterility throughout claimed shelf life. Testing includes visual inspection, whole package integrity, and seal integrity assessments after aging (both accelerated aging and real-time aging conditions). | Meets sterile barrier packaging visual inspection, whole package integrity & seal integrity requirements. For visual inspection, no channels, voids, punctures, or breaches observed, and labels are legible. For whole package integrity assessed by bubble leak testing of the Tyvek pouch packaging, no leaks are observed. For seal integrity, assessed by leak testing of the vial packaging, no leaks are observed. | Pass |
| Bacterial Endotoxin Testing (ANSI/AAMI ST72, USP<85>, FDA Guidance on Endotoxin Testing Recommendations for Single-Use Intraocular Ophthalmic Devices) | Confirms Endotoxin present on product is below the permanent intraocular device limit to confirm product is non-pyrogenic. | ≤ 0.2 Endotoxin Units (EU)/device | Pass |

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# Inserter Validations

The objective of the inserter validations was to document that the enVista Envy and Envy toric IOLs can be successfully delivered using the compatible INJ100 and B.L.I.S (with BLIS-X1) inserters. Testing was performed to demonstrate that the enVista Envy and Envy toric IOLs can be successfully delivered across the entire range of IOLs using Amvisc, Amvisc Plus, or OcuCoat viscoelastics. Test results are presented in Table 6.

Table 6: Inserter Validation Results

| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Surface and Bulk Homogeneity (Post-Delivery) | To assess conformance to dimensional tolerances and free of surface defects | ISO 11979-3:2012 Section 5 > ISO 11979-3:2012 Section 4.12 | Pass |
| Dioptric Power and Image Quality (Post-Delivery) | To assess accuracy of optical power and image quality of the IOL | ISO 11979-3:2012 Section 5 > ISO 11979-2:2014 | Pass |
| Lens Dimensions (Post-Delivery) | To assess conformance to dimensional tolerances | ISO 11979-3:2012 Section 5> ISO 11979-3:2012 Section 4.2 | Pass |
| Recovery of Properties (Post-Delivery) | To assess the ability of the IOL to withstand simulated surgical implantation without damage | ISO 11979-3:2012 Section 5 | Pass |
| Insertion Device Cosmetic Inspection (Post-Delivery) | To assess the ability of the insertion device to withstand simulated surgical implantation without damage | No damage to the insertion device during the delivery (i.e. split tips) when viewed at 10x magnification | Pass |
| Delivery Outcome (Post-Delivery) | To assess the ability of the insertion device to deliver the IOL | IOL cannot flip over upon delivery, IOL must exit inserter upon completion of delivery, and folding and/or delivery process shall not cause IOL cosmetic defects | Pass |

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# X. SUMMARY OF CLINICAL STUDIES

## Overview of Clinical Studies

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of implantation with the enVista Envy IOL for the visual correction of aphakia with less than or equal to 1.0 D preoperative corneal astigmatism following removal of a cataractous lens to mitigate the effects of presbyopia by providing improved intermediate and near visual acuity, while maintaining comparable distance visual acuity to an aspheric monofocal IOL, in the US under IDE #G180015.

The toric model of the enVista Envy IOL combines the optical designs of the enVista Envy trifocal IOL and the posterior surface toric feature of the parent enVista monofocal toric IOL (model MX60T). The applicant previously performed a clinical study to establish a reasonable assurance of safety and effectiveness of implantation with the enVista monofocal toric IOL for visual correction of aphakia and corneal astigmatism following removal of a cataractous lens in the US under IDE #G120193. The study data support a significant dioptric reduction in refractive cylinder and reduction in absolute cylinder, rotational stability of the lens, and UDVA following implantation of the enVista monofocal toric IOL. The enVista monofocal toric IOL received marketing approval from the Agency on June 8, 2018, under Panel-Track Supplement, P910056/S027.

Since the enVista toric monofocal IOL (model MX60T) has received marketing approval, the enVista toric monofocal IOL (model MX60T) clinical study established the safety profile of toric device, and the materials used to manufacture the enVista Envy IOL received marketing approval from the Agency under 180-Day Supplement, P910056/S051 (on August, 21, 2023), additional clinical data were not required to support the safety and effectiveness of the enVista Envy IOL toric model.

The summary of the enVista Envy trifocal IOL clinical study is presented below.

## A. STUDY DESIGN

Subjects were treated between 2018 and 2023. The database for this PMA reflected data collected through 2023 and included 501 subjects. There were 23 investigational sites in the United States.

This was a prospective, multicenter, randomized, active-controlled binocularly implanted study of the enVista one-piece hydrophobic acrylic trifocal IOL in subjects undergoing cataract extraction compared to the enVista one-piece hydrophobic acrylic monofocal IOL. Subjects scheduled to undergo cataract surgery by phacoemulsification and implantation of bilateral IOLs were screened for eligibility through extensive inclusion exclusion criteria, and with extensive preoperative assessments with both eyes of each subject included in the study after having met eligibility criteria at the Preoperative Visit. At the time of the first surgery,

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subjects were enrolled and randomly assigned by an Interactive Response Technology system in a 2:1 ratio to either the test - enVista trifocal IOL or the control- enVista monofocal IOL, respectively. The monofocal control IOL is a legally marketed alternative with similar indications for use, except that it is not intended to provide improved vision at intermediate and near distances.

All subjects underwent bilateral implantation of the enVista trifocal IOL or the enVista monofocal IOL and were followed up through post-operative scheduled visits through Postoperative Visit # 5 (11-14 Months) with ophthalmic examinations and standardized pre-, peri-, and postoperative care under the supervision of the Physician/ Investigator.

The sample size, which assumed a dropout rate of up to 10%, was based on the assumptions shown in Table 7 and on the requirements of ISO 11979-7.

Table 7: Sample Size Assumptions

| | Margin | Expected Difference | SD | Type I error (1-sided) | Power |
| --- | --- | --- | --- | --- | --- |
| Non-inferiority | | | | | |
| SSI Proportion | 0.034 | 0.005-0.001 | N/A | 5% | 99% |
| BCDVA | 0.10 | 0.00 | 0.15 | 5% | 99% |
| Superiority | | | | | |
| DCNVA | | -0.10 | 0.15 | 2.5% | 99% |
| DCIVA | | -0.10 | 0.15 | 2.5% | 99% |

Abbreviations: BCDVA = Best Corrected Distance Visual Acuity; DCIVA = Distance-Corrected Intermediate Visual Acuity; DCNVA = Distance-Corrected Near Visual Acuity; N/A = Not Applicable; SD = Standard Deviation; SSI = Secondary surgical interventions.

Study enrollment occurred in 3 phases covering Phase 1/ pilot, Phase II and Phase III. Enrolled subjects who met eligibility criteria were seen at 11 or 12 visits, including a preoperative visit, 2 operative visits (1 for each eye), and 8 mandatory postoperative visits (3 for each eye and 2 for both eyes), as well as an additional 1 postoperative visit only for those subjects who consented at participating sites (Day 2 to 30 after otherwise last visit/Postoperative Visit 5) for the Trial Frame Astigmatism Sub-Study.

The subject was considered enrolled in the study at the time of randomization at the first Operative Visit (Visit 00A). Randomization followed the completion of uncomplicated cataract extraction in the first eye. Only subjects who were randomized but did not have the lens inserted into the eye could be replaced. For those eligible subjects who consented to participate in the Trial Frame Astigmatism Simulation Sub-Study, a Postoperative Visit 6 (Day 2 to 30 after otherwise last visit/Postoperative Visit 5) was conducted as the final visit to complete the study.

# 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the enVista Envy Trifocal Intraocular lens study was limited to patients

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who met the following inclusion criteria in both eyes:

1. Subjects must be 22 years of age or older on the date the Informed Consent Form (ICF) is signed.
2. Subjects must have the capability to understand and provide written informed consent on the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved Informed Consent Form (ICF) and authorization as appropriate for local privacy regulations.
3. Subjects must have a BCDVA equal to or worse than 20/40 in each eye, with or without a glare source, due to a clinically significant cataract (cortical, nuclear, subcapsular, or combination) that is considered amenable to treatment with standard phacoemulsification cataract extraction and capsular IOL implantation.
4. Subjects must have a BCDVA projected to be better than 20/32 after IOL implantation in each eye, as determined by the medical judgment of the Investigator or measured by potential acuity meter (PAM) testing, if necessary.
5. Subjects must have clear intraocular media other than the cataract in both eyes.
6. Contact lens wearers must demonstrate a stable refraction (within ±0.50 D for both sphere and cylinder) in both eyes, as determined by manifest refraction on two consecutive examination dates after discontinuation of contact lens wear.
7. Subjects must require an IOL power from +16.0 diopter (D) to +24.0 D in both eyes.
8. Subjects must be willing and able to comply with all treatment and follow-up study visits and procedures, and to undergo second eye surgery within 7-30 days of the first eye surgery.

Subjects were not permitted to enroll in the enVista Envy Trifocal Intraocular lens study if they met any of the following exclusion criteria:

1. Subjects who have used an investigational drug or device within 30 days prior to entry into this study and/or will participate in another investigation during the period of study participation.
2. Subjects who have any corneal pathology (e.g., significant scarring, guttata, inflammation, edema, dystrophy, etc.) in either eye.
3. Subjects who have significant anterior segment pathology that might increase intraoperative risk or compromise IOL stability (e.g., pseudoexfoliation syndrome, synechiae, iris atrophy, traumatic cataract, lens subluxation, traumatic zonulolysis, zonular dialysis, evident zonular weakness or dehiscence, hypermature or brunescent cataract, etc.) in either eye.
4. Subjects who have uncontrolled glaucoma in either eye.
5. Subjects who have previous retinal detachment or clinically significant retinal pathology involving the macula in either eye.
6. Subjects who have proliferative or non-proliferative diabetic retinopathy in either eye.

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7. Subjects who have a congenital ocular anomaly (e.g., aniridia, congenital cataract) in either eye.
8. Subjects using any systemic or topical drug known to interfere with visual performance, pupil dilation, or iris structure within 30 days of enrollment or during the study.
9. Subjects who have a history of chronic or recurrent inflammatory eye disease (e.g., iritis, scleritis, iridocyclitis, or rubeosis iridis) in either eye.
10. Subjects who have a visual disorder, other than cataracts, that could potentially cause future acuity losses to a level of 20/100 or worse in either eye.
11. Subjects who have had previous intraocular or corneal surgery in either eye, with the exception of laser trabeculoplasty.
12. Subjects with any preoperative infectious conjunctivitis, keratitis, or uveitis in either eye.
13. Subjects who have a preoperative corneal astigmatism &gt; 1.0 D in either eye, irregular astigmatism, or skewed radial axis (note: corneal incisions intended specifically to reduce astigmatism are not allowed during the study).
14. Subjects who cannot achieve a minimum pharmacologic pupil dilation of 5.0 mm in both eyes.
15. Subjects who may be expected to require a combined or other secondary surgical procedure in either eye.
16. Subjects who during the first cataract extraction experience an anterior or posterior capsule tear or rupture, zonular dialysis, significant iris trauma, or other complications that may cause untoward effects in the judgment of the Investigator.
17. Females of childbearing potential (those who are not surgically sterilized or at least 12 months postmenopausal) are excluded from enrollment in the study if they are currently pregnant or plan to become pregnant during the study. Females of childbearing potential must be willing to practice effective contraception for the duration of the study.
18. Subjects with any other serious ocular pathology or underlying systemic medical condition (e.g., uncontrolled diabetes) or circumstance that, based on the Investigator's judgment, poses a concern for the subjects' safety or could confound the results of the study.
19. Subjects who have current or previous usage of an alpha-1-selective adrenoceptor blocking agent or an antagonist of alpha 1A adrenoceptor (e.g., Flomax® (tamsulosin HCl), Terazosin, or Cardura).

The following were intraoperative criteria for not implanting the device:

- Capsulorhexis tear, iris damage, posterior capsular rupture, vitreous prolapse, or zonular weakness or dehiscence
- Zonular rupture
- Evident zonular weakness or dehiscence
- Posterior capsule rupture

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Vitreous loss
Significant detachment of Descemet's membrane
Wound burn or damage
Anterior chamber bleeding
- Iris incarceration or damage
- Corneal endothelial touch
Unsuccessful/incomplete phacoemulsification
Posterior capsule plaque
Optic and/or haptic damage/amputation

# 2. Follow-up Schedule

The follow-up visit schedule is presented in Table 8. Specific examinations and scheduled clinical assessments are presented in Table 9.

Table 8: Follow up Schedule

| Visit Name | Eyes Evaluated | Visit Window |
| --- | --- | --- |
| Preoperative Visit 0A/B | Both Eyes | Day -30 to -5 |
| Operative Visit 00A | 1stEye | Day 0 |
| Post-Operative Visit 1A | 1stEye | Day 1 to 2 post Visit 00A |
| Post-Operative Visit 2A | 1stEye | Day 7 to 14 post Visit 00A |
| Post-Operative Visit 3A | 1stEye | Day 30 to 60 post Visit 00A |
| Operative Visit 00B | 2ndEye | Day 7 to 30 post Visit 00A |
| Post-Operative Visit 1B | 2ndEye | Day 1 to 2 post Visit 00B |
| Post-Operative Visit 2B | 2ndEye | Day 7 to 14 post Visit 00B |
| Post-Operative Visit 3B | 2ndEye | Day 30 to 60 post Visit 00B |
| Post-Operative Visit 4 | Both Eyes | Day 120 to 180 post Visit 00B |
| Post-Operative Visit 5 | Both Eyes | Day 330 to 420 post Visit 00B |
| Post-Operative Visit 6 | Both Eyes | Day 2 to 30 post Visit 5 |

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Table 9: Schedule of Clinical Assessments

| Examination | Pre-Op 0A/B (Both Eyes) | Operative 00A (1stEye) | Post-Op 1A (1stEye) | Post-Op 2A^{a} (1stEye) | Post-Op 3A (1stEye) | Operative 00B (2ndEye) | Post-Op 1B (2ndEye) | Post-Op 2B (2ndEye) | Post-Op 3B (2ndEye) | Post-Op 4 (Both Eyes) | Post-Op 5 (Both Eyes) | For sub-study only: Post-Op 6 (Both eyes) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Day -30 to -5 | Day 0 | Day 1 to 2 | Day 7 to 14 | Day 30 to 60 | Day 7 to 30 | Day 1 to 2 Post Visit 00B | Day 7 to 14 Post Visit 00B | Day 30 to 60 Post Visit 00B | Day 120 to 180 Post Visit 00B | Day 330 to 420 Post Visit 00B | Day 2-30 post Visit 5 |
| Informed Consent | X | | | | | | | | | | X^{a} | |
| Demographics | X | | | | | | | | | | | |
| Ocular and Non-Ocular Medical History | X | | | | | | | | | | | |
| Inclusion/Exclusion | X | X^{b} | | | | X^{b} | | | | | | X^{p} |
| Subject Questionnaires^{c} | X | | | | | | | | | X | | |
| Potential Visual Acuity | X | | | | | | | | | | | |
| Corneal Topography | X | | | | | | | | | | | |
| Targeted Refraction / IOL Power Calculation / Axial Length Determination/Anterior Chamber Depth | X | | | | | | | | | | | |
| Chord length μ | X | | | | | | | | | X | X | |
| Keratometry | X | | | | X | | | | X | X | X | |
| Manifest Refraction (ETDRS) | X | | | X | X | | | X^{d} | X^{d} | X | X | |
| Randomization | | X | | | | | | | | | | |
| Operative Procedures | | X | | | | X | | | | | | |
| Photopic Pupil Size | X | | | | | | | | X^{d} | X | | |
| Mesopic Pupil Size | X | | | | | | | | | X | | |
| UCDVA – photopic, monocular (ETDRS) | X | | X | X | X | | X | X | X | X | X | |
| UCDVA- photopic, binocular (ETDRS) | | | | | | | | X | X | X | X | |

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| Examination | Pre-Op 0A/B (Both Eyes) | Operative 00A (1^{st} Eye) | Post-Op 1A (1^{st} Eye) | Post-Op 2A^{a} (1^{st} Eye) | Post-Op 3A (1^{st} Eye) | Operative 00B (2^{nd} Eye) | Post-Op 1B (2^{nd} Eye) | Post-Op 2B (2^{nd} Eye) | Post-Op 3B (2^{nd} Eye) | Post-Op 4 (Both Eyes) | Post-Op 5 (Both Eyes) | For sub-study only: Post-Op 6 (Both eyes) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Day -30 to -5 | Day 0 | Day 1 to 2 | Day 7 to 14 | Day 30 to 60 | Day 7 to 30 | Day 1 to 2 Post Visit 00B | Day 7 to 14 Post Visit 00B | Day 30 to 60 Post Visit 00B | Day 120 to 180 Post Visit 00B | Day 330 to 420 Post Visit 00B | Day 2- 30 post Visit 5 |
| BCDVA – photopic, monocular (ETDRS) | X | | | X | X | | | X | X | X | X | |
| BCDVA – photopic, binocular (ETDRS) | | | | | | | | X | X | X | X | |
| UCNVA^{c,f} – photopic, monocular | | | | | X | | | | X | X | X | |
| UCNVA^{c,f} – photopic, binocular | | | | | | | | | X | X | X | |
| DCNVA^{c} – photopic, monocular | | | | | X^{g} | | X | X | f X | f | f | |
| DCNVA^{c,f} – photopic, binocular | | | | | | | | | | X | X | |
| DCNVA^{c,f} – mesopic, monocular | | | | | X | | | | X | X | X | |
| DCNVA^{c,f} – mesopic, binocular | | | | | | | | | | X | X | |
| UCIVA^{h,i} – photopic, monocular | | | | | X | | | | X | X | X | |
| UCIVA^{h,i} – photopic, binocular | | | | | | | | | X | X | X | |
| DCIVA^{h} – photopic, monocular | | | | | X^{i} | | | | X^{i} | X^{i} | X^{i} | |
| DCIVA^{h,i} – mesopic, binocular | | | | | | | | | | X | X | |
| DCIVA^{h,i} – mesopic, binocular | | | | | X | | | | X | X | X | |
| Bnocular best-corrected distance contrast sensitivity testing (photopic with glare at 3, 6, 12 and 18 cpd)^{k} | | | | | | | | | | X | X^{i} | |

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| Examination | Pre-Op 0A/B (Both Eyes) | Operative 00A (1^{st} Eye) | Post-Op 1A (1^{st} Eye) | Post-Op 2A^{a} (1^{st} Eye) | Post-Op 3A (1^{st} Eye) | Operative 00B (2^{nd} Eye) | Post-Op 1B (2^{nd} Eye) | Post-Op 2B (2^{nd} Eye) | Post-Op 3B (2^{nd} Eye) | Post-Op 4 (Both Eyes) | Post-Op 5 (Both Eyes) | For sub-study only: Post-Op 6 (Both eyes) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Day -30 to -5 | Day 0 | Day 1 to 2 | Day 7 to 14 | Day 30 to 60 | Day 7 to 30 | Day 1 to 2 Post Visit 00B | Day 7 to 14 Post Visit 00B | Day 30 to 60 Post Visit 00B | Day 120 to 180 Post Visit 00B | Day 330 to 420 Post Visit 00B | Day 2- 30 post Visit 5 |
| Binocular best-corrected distance contrast sensitivity (mesopic with and without glare at 1.5, 3, 6, and 12 cpd)^{b} | | | | | | | | | | X | X^{1} | |
| Binocular BCDVA Defocus Curves^{b} | | | | | | | | | | X | | |
| Intraocular Pressure | X | | X | X | X | | X | X | X | X | X | |
| Slit-Lamp Exam^{m} | X | | X | X | X | | X | X | X | X | X | |
| Dilated Fundus Exam | X | | | | X | | | | X | X | X^{a} | |
| OCT Imaging^{b} | | | | | | | | | | X | | |
| Trial Frame Astigmatism Simulation sub-study (assessments below) | | | | | | | | | | | | X |
| BCDVA photopic monocular (no additional sphere, cylinder or axis) | | | | | | | | | | | | X |
| BCDVA photopic, monocular (simulated astigmatism 2.0 D plus cylinder, 180°) | | | | | | | | | | | | X |
| BCDVA photopic, monocular (simulated astigmatism 2.0 D plus cylinder, 90°) | | | | | | | | | | | | X |
| BCDVA photopic, monocular (simulated astigmatism 1.50 D plus cylinder, 180°) | | | | | | | | | | | | X |

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| Examination | Pre-Op 0A/B (Both Eyes) | Operative 00A (1^{st} Eye) | Post-Op 1A (1^{st} Eye) | Post-Op 2A^{®} (1^{st} Eye) | Post-Op 3A (1^{st} Eye) | Operative 00B (2^{nd} Eye) | Post-Op 1B (2^{nd} Eye) | Post-Op 2B (2^{nd} Eye) | Post-Op 3B (2^{nd} Eye) | Post-Op 4 (Both Eyes) | Post-Op 5 (Both Eyes) | For sub-study only: Post-Op 6 (Both eyes) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Day -30 to -5 | Day 0 | Day 1 to 2 | Day 7 to 14 | Day 30 to 60 | Day 7 to 30 | Day 1 to 2 Post Visit 00B | Day 7 to 14 Post Visit 00B | Day 30 to 60 Post Visit 00B | Day 120 to 180 Post Visit 00B | Day 330 to 420 Post Visit 00B | Day 2- 30 post Visit 5 |
| BCDVA photopic, monocular (simulated astigmatism 1.5 D plus cylinder, 90°) | | | | | | | | | | | | X |
| BCDVA photopic, monocular (simulated astigmatism 1.0 D plus cylinder, 180°) | | | | | | | | | | | | X |
| BCDVA photopic, monocular (simulated astigmatism 1.0 D plus cylinder, 90°) | | | | | | | | | | | | X |
| DCIVA photopic monocular (no additional sphere, cylinder or axis) | | | | | | | | | | | | X |
| DCIVA photopic, monocular (simulated astigmatism 2.0 D plus cylinder, 180°) | | | | | | | | | | | | X |
| DCIVA photopic, monocular (simulated astigmatism 2.0 D plus cylinder, 90°) | | | | | | | | | | | | X |
| DCIVA photopic, monocular (simulated astigmatism 1.5 D plus cylinder, 180°) | | | | | | | | | | | | X |
| DCIVA photopic, monocular (simulated astigmatism 1.5 D plus cylinder, 90°) | | | | | | | | | | | | X |

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| Examination | Pre-Op 0A/B (Both Eyes) | Operative 00A (1^{st} Eye) | Post-Op 1A (1^{st} Eye) | Post-Op 2A^{®} (1^{st} Eye) | Post-Op 3A (1^{st} Eye) | Operative 00B (2^{nd} Eye) | Post-Op 1B (2^{nd} Eye) | Post-Op 2B (2^{nd} Eye) | Post-Op 3B (2^{nd} Eye) | Post-Op 4 (Both Eyes) | Post-Op 5 (Both Eyes) | For sub-study only: Post-Op 6 (Both eyes) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Day -30 to -5 | Day 0 | Day 1 to 2 | Day 7 to 14 | Day 30 to 60 | Day 7 to 30 | Day 1 to 2 Post Visit 00B | Day 7 to 14 Post Visit 00B | Day 30 to 60 Post Visit 00B | Day 120 to 180 Post Visit 00B | Day 330 to 420 Post Visit 00B | Day 2- 30 post Visit 5 |
| DCIVA photopic, monocular (simulated astigmatism 1.0 D plus cylinder, 180°) | | | | | | | | | | | | X |
| DCIVA photopic, monocular (simulated astigmatism 1.0 D plus cylinder, 90°) | | | | | | | | | | | | X |
| DCNVA photopic monocular (no additional sphere, cylinder or axis) | | | | | | | | | | | | X |
| DCNVA photopic, monocular (simulated astigmatism 2.0 D plus cylinder, 180°) | | | | | | | | | | | | X |
| DCNVA photopic, monocular (simulated astigmatism 2.0 D plus cylinder, 90°) | | | | | | | | | | | | X |
| DCNVA photopic, monocular (simulated astigmatism 1.5 D plus cylinder, 180°) | | | | | | | | | | | | X |
| DCNVA photopic, monocular (simulated astigmatism 1.0 D plus cylinder, 90°) | | | | | | | | | | | | X |
| DCNVA photopic, monocular (simulated astigmatism 1.0 D plus cylinder, 180°) | | | | | | | | | | | | X |

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| Examination | Pre-Op 0A/B (Both Eyes) | Operative 00A (1stEye) | Post-Op 1A (1stEye) | Post-Op 2Ae (1stEye) | Post-Op 3A (1stEye) | Operative 00B (2ndEye) | Post-Op 1B (2ndEye) | Post-Op 2B (2ndEye) | Post-Op 3B (2ndEye) | Post-Op 4 (Both Eyes) | Post-Op 5 (Both Eyes) | For sub-study only: Post-Op 6 (Both eyes) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Day -30 to -5 | Day 0 | Day 1 to 2 | Day 7 to 14 | Day 30 to 60 | Day 7 to 30 | Day 1 to 2 Post Visit 00B | Day 7 to 14 Post Visit 00B | Day 30 to 60 Post Visit 00B | Day 120 to 180 Post Visit 00B | Day 330 to 420 Post Visit 00B | Day 2-30 post Visit 5 |
| DCNVA photopic, monocular (simulated astigmatism 1.0 D plus cylinder, 90°) | | | | | | | | | | | | X |
| Posterior capsulotomy assessment | | | X | X | X | | X | X | X | X | X | |
| Adverse Events | X | X | X | X | X | X | X | X | X | X | X | X |
| Concomitant Medications | X | X | X | X | X | X | X | X | X | X | X | X |

ETDRS=Early Treatment Diabetic Retinopathy Study visual acuity testing charts, UCDVA=Uncorrected Distance Visual Acuity, BCDVA=Best Corrected Distance Visual Acuity, UCNVA=Uncorrected Near Visual Acuity, DCNVA=Distance Corrected Near Visual Acuity, UCIVA=Uncorrected Intermediate Visual Acuity, DCIVA=Distance Corrected Intermediate Visual Acuity, OCT=Optical Coherence Tomography, D=Diopter
aMust occur before Operative Visit 00B
b Review of inclusion/exclusion criteria prior to surgery
To additionally be completed at any post-operative Unscheduled Visit and prior to unscheduled study exit (e.g., IOL explanation).
d Completed for both eyes
e Distance for Phase II and Phase III subjects of 40 cm
Phase I/Pilot: Distance of 40 cm
Phase I/Pilot: Distance of 30 cm, 35cm, and 40 cm
b Distances for Phase II and Phase III subjects of 60 cm and 66 cm
Phase I/Pilot: Distance of 66 cm
Phase I/Pilot: Distance of 56 cm, 66 cm, and 76cm
Conducted on a subset of subjects
Done only if subject has posterior capsulotomy after Visit 4; if subject is scheduled for posterior capsulotomy during Visit 4, testing is deferred to Visit 5
Includes determination of medical and lens findings/complications, including decentration, tilt and PCO (note: lens findings/complications, including decentration, tilt and PCO evaluated post-operatively only).
If clinically indicated
Subjects must consent to participate in the Visit 6 Trial Frame Astigmatism Simulation sub-study. New subjects who are enrolled in the study once protocol amendment 6 is instituted will consent to the Trial Frames Astigmatism Simulation sub-study at the Pre-Op Visit, if they so choose, but at a point no later than Visit 5. Existing subjects who are in the study at the time protocol amendment 6 is instituted must provide their consent to participate in the Trial Frame Astigmatism Simulation sub-study no later than Visit 5.
Specific to Visit 6, overall study eligibility will be confirmed as well as criteria for participation in the Trial Frame Astigmatism Simulation sub-study

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# 3. Clinical Endpoints

With regards to safety:

## Co-primary Safety Endpoints

- The incidence of all serious adverse events, including secondary surgical interventions (SSIs) related to the optical properties of the IOL, in first eyes through study exit (No specific success criteria were pre-specified.)
- The rate of secondary surgical interventions due to the optical properties of the lens for first eyes through study exit (No specific success criteria were pre-specified.)
- The incidence of adverse events in first eyes compared to ISO Safety and Performance Endpoint (SPE) rates as defined in ISO 11979-7 through study exit (Success criteria for each type of event was a rate not statistically greater than the control rate.)

## Secondary Safety Endpoints

- The rates of visual disturbances reported as “severe” by subjects, as well as the rates of visual disturbances reported as “very” bothersome by subjects, using the QoV questionnaire measure through Post-Operative Visit 4 (Day 120 to 180 after second eye IOL implantation)
- Mean photopic contrast sensitivity with glare and mesopic contrast sensitivity with and without glare at Post-Operative Visit 4 (Day 120 to 180 after second eye IOL implantation) and Post-Operative Visit 5 (Day 330 to 420 after second eye IOL implantation)
- Incidence of the types of AEs specified in the co-primary safety endpoints, but for fellow and “all” eyes
- Incidence of all other types of adverse events in primary eyes, fellow eyes, and “all” eyes

## Other safety endpoints included:

- Binocular defocus curve sub study
- OCT sub study (evaluate image quality)
- Manifest refraction
- Slit Lamp Examination
- Device Deficiencies
- Intraocular Pressure
- Dilated Fundus Examination
- Fundus Visualization

With regards to effectiveness:

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# Primary Effectiveness Endpoints

- Photopic monocular best-corrected distance visual acuity (BCDVA) in first eyes at Post-Operative Visit 4 (Day 120 to 180 after second eye IOL implantation) (The success criteria was statistical non-inferiority of BCDVA compared to the control. The non-inferiority margin was set at 0.10 logMAR.)
- Photopic monocular distance-corrected near visual acuity (DCNVA) in first eyes at 40 cm at Post-Operative Visit 4 (Day 120 to 180 after second eye IOL implantation) (The success criteria was statistical superiority of DCNVA compared to the control. The superiority margin was set at 0.0 logMAR.)
- Photopic monocular distance-corrected intermediate visual acuity (DCIVA) in first eyes at 66 cm at Post-Operative Visit 4 (Day 120 to 180 after second eye IOL implantation) (The success criteria was statistical superiority of DCIVA compared to the control. The superiority margin was set at 0.0 logMAR.)

# Secondary Effectiveness Endpoints

- Photopic binocular distance-corrected near visual acuity (DCNVA) at 40 cm at Post-Operative Visit 4 (Day 120 to 180 after second eye IOL implantation)
- Photopic binocular uncorrected near visual acuity (UCNVA) at 40 cm at Post-Operative Visit 4 (Day 120 to 180 after second eye IOL implantation)
- Photopic binocular distance-corrected intermediate visual acuity (DCIVA) at 66 cm at Post-Operative Visit 4 (Day 120 to 180 after second eye IOL implantation)
- Photopic binocular uncorrected intermediate visual acuity (UCIVA) at 66 cm at Post-Operative Visit 4 (Day 120 to 180 after second eye IOL implantation)
- First eye BCDVA, DCNVA, and DCIVA evaluated at Visit 5 (Day 330 to 420 after second eye IOL implantation)

# Other effectiveness endpoints included:

- Astigmatic Blur Sub study: photopic logMAR monocular visual acuities at distance, intermediate and near with and without induced astigmatism to evaluate impact of residual astigmatism

With regard to study success, all primary safety and effectiveness endpoints with success criteria were required to demonstrate statistical study success. Individual subject success was not defined.

# Intent-to-Treat (ITT) Set

The ITT Set included all randomized subjects.

# Modified Intent-to-Treat (mITT) Set

The mITT Set included all randomized subjects with at least one eye in which the IOL touches the eye with a study lens. Randomized subjects excluded from this set were identified prior to database lock and unmasking.

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## Modified Safety Set

The Modified Safety set included all subjects with at least one eye in which the IOL touched the eye with a study lens.

## B. ACCOUNTABILITY OF THE PMA COHORT

At the time of the database lock, of 501 patients enrolled in the PMA, 91.8% (460) patients are available for analysis at the completion of the study, the approximately 12-month post-operative visit. The ITT Set, mITT Set, and the Modified Safety Set all included all 501 randomized subjects and 998 of the 1002 randomized eyes (Table 10). The disposition of all 501 randomized subjects is summarized in Table 11.

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Table 10: Subject Accountability by Visit up to Visit 5 (11-14 months)

| Modified Intent-to-Treat Set
Treatment: All Subjects | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Total Number | Visit 0A/B (Pre-Op) n (%) | Operative Visit 00A n (%) | Visit 1A n (%) | Visit 2A n (%) | Visit 3A n (%) |
| All Subjects | 501 | - | - | - | - | - |
| Subjects with an Eye Touched with Study IOL | 501 | - | - | - | - | - |
| Implanted Subjects | 501 | - | - | - | - | - |
| Available for Analysis (1) | - | 501 (100.0) | 501 (100.0) | 501 (100.0) | 493 (98.4) | 480 (95.8) |
| Discontinued (2) | - | 0 | 0 | 0 | 0 | 1 (0.2) |
| Missing at Scheduled Visit but Seen Later (3) | - | 0 | 0 | 0 | 8 (1.6) | 19 (3.8) |
| Not Seen but Accounted for (4) | - | 0 | 0 | 0 | 0 | 0 |
| Lost to Follow-up | - | 0 | 0 | 0 | 0 | 1 (0.2) |
| % Accountability | - | 100.0 | 100.0 | 100.0 | 98.4 | 96.0 |
| | Operative Visit 00B n (%) | Visit 1B n (%) | Visit 2B n (%) | Visit 3B n (%) | Visit 4 n (%) | Visit 5 n (%) |
| --- | --- | --- | --- | --- | --- | --- |
| Available for Analysis (1) | 499 (99.6) | 495 (98.8) | 486 (97.0) | 481 (96.0) | 470 (93.8) | 460 (91.8) |
| Discontinued (2) | 1 (0.2) | 1 (0.2) | 2 (0.4) | 3 (0.6) | 10 (2.0) | 20 (4.0) |
| Missing at Scheduled Visit but Seen Later (3) | 0 | 3 (0.6) | 10 (2.0) | 14 (2.8) | 17 (3.4) | 16 (3.2) |
| Not Seen but Accounted for (4) | 0 | 0 | 0 | 0 | 0 | 0 |
| Lost to Follow-up | 1 (0.2) | 2 (0.4) | 3 (0.6) | 3 (0.6) | 4 (0.8) | 5 (1.0) |
| % Accountability | 99.8 | 99.0 | 97.4 | 96.6 | 95.7 | 95.6 |

Abbreviations: IOL = Intraocular Lens; Op = Operative.
Note: Percentages are based on the total number of subjects in the analysis population. % Accountability = 100*(Available for Analysis)/(All Modified Intent-to-Treat Subjects – Discontinued).
[1] Represents the total number of subjects for whom data are available at the visit
[2] Represents the total number of subjects that have discontinued treatment prior to the visit for any reason (e.g., death or device replacement), but does not include subjects that are lost to follow-up.
[3] Represents the total number of subjects that were seen outside the time window associated with the visit.
[4] Represents the total number of subjects that were missing at the scheduled visit but were accounted for by being contacted (e.g., by phone).

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Table 11: Subject Disposition (All Subjects)

| Subject Disposition | enVista Trifocal IOL (N=332) | enVista Monofocal IOL (N=169) | All Participants (N=501) |
| --- | --- | --- | --- |
| Screen Failures (n) | - | - | 166 |
| Randomized (n) | 332 | 169 | 501 |
| Discontinued Prior to Attempted Implantation (n) | 0 | 0 | 0 |
| Attempted Implantation (n) | 332 (100%) | 169 (100%) | 501 (100%) |
| Successful First Implantation (n) | 332 (100%) | 169 (100%) | 501 (100%) |
| Completed Study (n) | 319 (96.1%) | 157 (92.9%) | 476 (95.0%) |
| Discontinued after First Implantation (n) | 13 (3.9%) | 12 (7.1%) | 25 (5.0%) |

# C. STUDY POPULATION DEMOGRAPHICS AND BASELINE PARAMETERS

The demographics of the study population are typical for a randomized, prospective, multicenter clinical study of intraocular lenses performed in the US. All 501 subjects randomized were implanted (enVista trifocal IOL group, $n = 332$ ; enVista monofocal IOL group, $n = 169$ ). Of 1002 eyes randomized, 996 were implanted (enVista trifocal IOL group, $n = 659$ ; enVista monofocal IOL group, $n = 337$ ); 2 subjects each had 1 eye (OS- Left eye and OD- Right eye, respectively) that was touched by an IOL that was not implanted.

The Modified Safety Set population was primarily White (92.0%), not Hispanic/Latino (88.0%), and female (63.9%; Table 12). The mean ± SD age of the population was 68.0 ± 7.76 years. Similar demographics were observed across treatment groups.

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Table 12: Demographics (Modified Safety Set)

| Variable | enVista Trifocal IOL (N=332) | enVista Monofocal IOL (N=169) | All Participants (N=501) |
| --- | --- | --- | --- |
| Age, years | | | |
| n | 332 | 169 | 501 |
| Mean (SD) | 67.6 (7.89) | 68.8 (7.46) | 68.0 (7.76) |
| Median | 68.0 | 70.0 | 69.0 |
| Minimum, maximum | 32, 85 | 41, 85 | 32, 85 |
| Age categories, n (%) | | | |
| 18–64 years | 95 (28.6) | 35 (20.7) | 130 (25.9) |
| 65–84 years | 235 (70.8) | 133 (78.7) | 368 (73.5) |
| ≥85 years | 2 (0.6) | 1 (0.6) | 3 (0.6) |
| Gender, n (%) | | | |
| Male | 120 (36.1) | 61 (36.1) | 181 (36.1) |
| Female | 212 (63.9) | 108 (63.9) | 320 (63.9) |
| Race, n (%) | | | |
| American Indian/Alaska Native | 0 | 0 | 0 |
| Asian | 11 (3.3) | 4 (2.4) | 15 (3.0) |
| Chinese | 1 (0.3) | 1 (0.6) | 2 (0.4) |
| Non-Chinese | 10 (3.0) | 3 (1.8) | 13 (2.6) |
| Black/African American | 14 (4.2) | 9 (5.3) | 23 (4.6) |
| Native Hawaiian/Pacific Islander | 1 (0.3) | 0 | 1 (0.2) |
| White | 305 (91.9) | 156 (92.3) | 461 (92.0) |
| Multiple^{a} | 1 (0.3) | 0 | 1 (0.2) |
| Other | 0 | 0 | 0 |
| Ethnicity, n (%) | | | |
| Hispanic/Latino | 40 (12.0) | 20 (11.8) | 60 (12.0) |
| Not Hispanic/Latino | 292 (88.0) | 149 (88.2) | 441 (88.0) |
| First eye, n (%) | | | |
| OD | 218 (65.7) | 95 (56.2) | 313 (62.5) |
| OS | 114 (34.3) | 74 (43.8) | 188 (37.5) |
| Study phase under which participant enrolled, n (%) | | | |
| Phase I/Pilot | 29 (8.7) | 13 (7.7) | 42 (8.4) |
| Phase II | 49 (14.8) | 24 (14.2) | 73 (14.6) |
| Phase III | 254 (76.5) | 132 (78.1) | 386 (77.0) |

eCRF = electronic Case Report Form; IOL = intraocular lens; OD = right eye; OS = left eye; SD = standard deviation.
a Participants who selected more than 1 race on the eCRF are grouped into the "Multiple" category.

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D. SAFETY AND EFFECTIVENESS RESULTS

1. Safety Results

The analysis of safety was based on the safety cohort of 501 implanted subjects: 332 enVista Envy subjects (327 bilaterally implanted) and 169 monofocal subjects (168 bilaterally implanted) available for the 12-month evaluation. Implanted subjects were followed for approximately 12 months (i.e., for 330-420 days after fellow eye implantation at Operative Visit 00B, which occurred 7-30 days after initial eye implantation at Operative Visit 00A [range 337-450 days]). The key safety outcomes for this study are presented below in Tables 13 to 20. Ocular (Serious and Non-Serious) Adverse Events are reported in Tables 13 and 14. ISO Grid Adverse Events are reported in Tables 15 and 16. Ocular Adverse Events based on a Modified Version of the American Academy of Ophthalmology (AAO) Consensus (Masket, 2017) are reported in Tables 17 and 18. Ocular Treatment-Emergent Serious Adverse Events by Treatment are reported in Tables 19 and 20.

Co-primary Safety Endpoints

- The incidence of all serious adverse events, including secondary surgical interventions (SSIs) related to the optical properties of the IOL, in first eyes through study exit
- The rate of secondary surgical interventions due to the optical properties of the lens for first eyes through study exit
- The incidence of adverse events in first eyes compared to ISO Safety and Performance Endpoint (SPE) rates as defined in ISO 11979-7 through study exit

No SSIs related to the optical properties of the IOLs were reported in the clinical study. All SPE rates for the enVista Envy IOL were below the SPE threshold as set forth by ISO 11979-7:2018 (Tables 15 and 16).

Secondary Safety Endpoints

- The rates of visual disturbances reported as “severe” by subjects, as well as the rates of visual disturbances reported as “very” bothersome by subjects, using the QoV questionnaire measure through Post-Operative Visit 4 (Day 120 to 180 after second eye IOL implantation) (Table 21)
- Mean photopic contrast sensitivity with glare and mesopic contrast sensitivity with and without glare at Post-Operative Visit 4 (Day 120 to 180 after second eye IOL implantation) and Post-Operative Visit 5 (Day 330 to 420 after second eye IOL implantation) (Figures 2-4; Tables 22-24)
- Incidence of the types of AEs specified in the co-primary safety endpoints, but for fellow and “all” eyes (Table 14)
- Incidence of all other types of adverse events in primary eyes, fellow eyes, and “all” eyes (Tables 16, 18, and 20)

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The differences in mean binocular contrast sensitivity between the Trifocal and Monofocal IOLs were clinically insignificant, i.e.; $&lt; 0.15$ log unit for 4 of the 12 test conditions (Mesopic with and without glare at 1.5 cpd, Mesopic without glare at 3 and 12 cpd); clinically significant differences favored the Monofocal IOL for the remaining test conditions. The mean binocular contrast sensitivity was worse in the trifocal cohort than monofocal cohort for all tested conditions, except for the lowest spatial frequency tested (i.e., thickest stripes) for the mesopic with glare, and mesopic without glare conditions.

Subjects in the Trifocal group stated a greater frequency of halos (36.9% [116/314] quite often or very often) compared to the control (7.1% [11/154]) with 6.1% (19/309) of the Trifocal subjects describing the halos as severe and 7.1% (22/309) calling them very bothersome. Moderate to severe difficulty with focusing and depth perception was reported by 8.8% (27/309) and 5.5% (15/310) of subjects with the Trifocal group compared to 13.2% (20/151) and 7.9% (10/151) of subjects in the Monofocal group respectively.

# Adverse events that occurred in the PMA clinical study:

The ocular adverse events (serious and non-serious) for both the study and control lens, first eye, are presented in Table 13. A similar proportion of subjects and eyes across treatment groups had at least 1 ocular TEAE (trifocal IOL, $49.4\%$ (164/332) of subjects and $37.7\%$ (249/661) of all eyes; monofocal IOL, $40.8\%$ (69/169) of subjects and $28.8\%$ (97/337) of all eyes). The most common ocular TEAEs in both treatment groups were punctate keratitis, intraocular pressure increased, and vitreous detachment. All other adverse events in the first eyes were reported at a rate of $&lt; 2.4\%$ in both groups. Results for the second eyes were similar to first eyes, Table 14.

Table 13: Ocular Adverse Events (Serious and Non-Serious Combined), First Eye (Modified Safety Set)

| Preferred Term | enVista Trifocal IOL (N=332) | | | enVista Monofocal IOL (N = 169) | | |
| --- | --- | --- | --- | --- | --- | --- |
| | n (%) | 2-sided 95% CI | E | n (%) | 2-sided 95% CI | E |
| Punctate keratitis | 48 (14.5) | 10.86, 18.71 | 53 | 13 7.7 | (4.16, 12.79) | 14 |
| Intraocular pressure increased | 26 7.8 | (5.18, 11.26) | 27 | 15 (8.9) | (5.05, 14.22) | 15 |
| Vitreous detachment | 22 (6.6) | (4.20, 9.86) | 22 | 10 (5.9) | (2.87, 10.61) | 10 |
| Dry eye | 7 2.1 | (0.85, 4.30) | 7 | 3 (1.8) | (0.37, 5.10) | 4 |
| Blepharitis | 5 (1.5) | (0.49, 3.48) | 5 | 4 (2.4) | (0.65, 5.95) | 4 |
| Meibomian gland dysfunction | 5 (1.5) | (0.49, 3.48) | 5 | 3 (1.8) | (0.37, 5.10) | 3 |
| Visual acuity reduced | 5 (1.5) | (0.49, 3.48) | 5 | 2 (1.2) | (0.14, 4.21) | 2 |
| Cystoid macular oedema | 0 | (0.00, 1.10) | 0 | 1 (0.6) | (0.01, 3.25) | 1 |
| Vitreous floaters | 2 (0.6) | 0.07, 2.16 | 2 | 1 (0.6) | (0.01, 3.25) | 1 |
| Diplopia | 3 (0.9) | (0.19, 2.62) | 3 | 0 | (0.00, 2.16) | 0 |
| Iritis | 3 (0.9) | (0.19, 2.62) | 3 | 1 (0.6) | (0.01, 3.25) | 1 |
| Blepharochalasis | 2 (0.6) | 0.07, 2.16 | 2 | 1 (0.6) | (0.01, 3.25) | 1 |

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Table 14: Ocular Adverse Events (Serious and Non-Serious Combined), Second Eye (Modified Safety Set)

| Preferred Term | enVista Trifocal IOL (N=332) | | | enVista Monofocal IOL (N = 169) | | |
| --- | --- | --- | --- | --- | --- | --- |
| | n (%) | 2-sided 95% CI | E | n (%) | 2-sided 95% CI | E |
| Macular fibrosis | 3 (0.9) | (0.19, 2.62) | 3 | 0 | (0.00, 2.16) | 0 |
| Chalazion | 3 (0.9) | (0.19, 2.62) | 3 | 0 | (0.00, 2.16) | 0 |
| Glare | 1 (0.3) | 0.01, 1.67 | 1 | 1 (0.6) | (0.01, 3.25) | 1 |
| Halo vision | 2 (0.6) | 0.07, 2.16 | 2 | 0 | (0.00, 2.16) | 0 |
| Conjunctivitis allergic | 1 (0.3) | 0.01, 1.67 | 1 | 1 (0.6) | (0.01, 3.25) | 1 |
| Eye irritation | 2 (0.6) | 0.07, 2.16 | 2 | 0 | (0.00, 2.16) | 0 |
| Eyelid irritation | 2 (0.6) | 0.07, 2.16 | 2 | 0 | (0.00, 2.16) | 0 |
| Conjunctival hyperaemia | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Conjunctivochalasis | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Diabetic retinopathy | 0 | (0.00, 1.10) | 0 | 1 (0.6) | (0.01, 3.25) | 1 |
| Iridocyclitis | 0 | (0.00, 1.10) | 0 | 1 (0.6) | (0.01, 3.25) | 1 |
| Retinal tear | 2 (0.6) | 0.07, 2.16 | 2 | 0 | (0.00, 2.16) | 0 |
| Corneal epithelium defect | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Eye pruritus | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Macular hole | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Retinal vein occlusion | 1 (0.3) | 0.01, 1.67 | 2 | 0 | (0.00, 2.16) | 0 |
| Trichiasis | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Ulcerative keratitis | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Vitreous haemorrhage | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Seidel test positive | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Cataract operation complication | 1 (0.3) | 0.01, 1.67 | 1 | 2 (1.2) | (0.14, 4.21) | 2 |
| Corneal abrasion | 2 (0.6) | 0.07, 2.16 | 2 | 0 | (0.00, 2.16) | 0 |
| Foreign body in eye | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Ocular procedural complication | 0 | (0.00, 1.10) | 0 | 1 (0.6) | (0.01, 3.25) | 1 |
| Conjunctivitis | 1 (0.3) | 0.01, 1.67 | 1 | 1 (0.6) | (0.01, 3.25) | 1 |
| Hordeolum | 1 (0.3) | 0.01, 1.67 | 1 | 2 (1.2) | (0.14, 4.21) | 2 |
| Ophthalmic herpes simplex | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Ophthalmic herpes zoster | 0 | (0.00, 1.10) | 0 | 1 (0.6) | (0.01, 3.25) | 2 |
| Visual field defect | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Dermatitis contact | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |
| Madarosis | 0 | (0.00, 1.10) | 0 | 1 (0.6) | (0.01, 3.25) | 1 |
| Seasonal allergy | 1 (0.3) | 0.01, 1.67 | 1 | 0 | (0.00, 2.16) | 0 |

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| | enVista Trifocal IOL (N=329) | | | enVista Monofocal IOL (N = 168) | | |
| --- | --- | --- | --- | --- | --- | --- |
| Preferred Term | n (%) | 2-sided 95% CI | E | n (%) | 2-sided 95% CI | E |
| Vitreous detachment | 21 (6.4) | (3.99, 9.59) | 21 | 7 4.2 | (1.69, 8.40) | 7 |
| Dry eye | 6 (1.8) | 0.67, 3.93 | 6 | 4 (2.4) | (0.65, 5.98) | 5 |
| Blepharitis | 5 (1.5) | (0.50, 3.51) | 5 | 4 (2.4) | (0.65, 5.98) | 4 |
| Meibomian gland dysfunction | 5 (1.5) | (0.50, 3.51) | 5 | 4 (2.4) | (0.65, 5.98) | 4 |
| Visual acuity reduced | 4 (1.2) | (0.33, 3.08) | 4 | 2 (1.2) | (0.14, 4.23) | 2 |
| Cystoid macular oedema | 3 (0.9) | (0.19, 2.64) | 3 | 3 (1.8) | (0.37, 5.13) | 4 |
| Vitreous floaters | 0 | (0.00, 1.11) | 0 | 4 (2.4) | (0.65, 5.98) | 5 |
| Diplopia | 3 (0.9) | (0.19, 2.64) | 3 | 0 | (0.00, 2.17) | 0 |
| Iritis | 2 (0.6) | 0.07, 2.18 | 2 | 0 | (0.00, 2.17) | 0 |
| Blepharochalasis | 2 (0.6) | 0.07, 2.18) | 2 | 0 | (0.00, 2.17) | 0 |
| Macular fibrosis | 1 (0.3) | (0.01, 1.68) | 1 | 1 (0.6) | (0.02, 3.27) | 1 |
| Chalazion | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Glare | 1 (0.3) | (0.01, 1.68) | 1 | 1 (0.6) | (0.02, 3.27) | 1 |
| Halo vision | 2 (0.6) | 0.07, 2.18 | 2 | 0 | (0.00, 2.17) | 0 |
| Conjunctivitis allergic | 0 | (0.00, 1.11) | 0 | 1 (0.6) | (0.02, 3.27) | 1 |
| Eye irritation | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Eyelid irritation | 0 | (0.00, 1.11) | 0 | 1 (0.6) | (0.02, 3.27) | 1 |
| Ocular hypertension | 2 (0.6) | 0.07, 2.18 | 2 | 1 (0.6) | (0.02, 3.27) | 1 |
| Conjunctival hyperaemia | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Conjunctivochalasis | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Diabetic retinopathy | 0 | (0.00, 1.11) | 0 | 1 (0.6) | (0.02, 3.27) | 1 |
| Iridocyclitis | 0 | (0.00, 1.11) | 0 | 1 (0.6) | (0.02, 3.27) | 1 |
| Anterior chamber cell | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Conjunctival cyst | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Conjunctival haemorrhage | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Eye discharge | 0 | (0.00, 1.11) | 0 | 1 (0.6) | (0.02, 3.27) | 1 |
| Eye inflammation | 0 | (0.00, 1.11) | 0 | 1 (0.6) | (0.02, 3.27) | 1 |
| Eye pain | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Photopsia | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Vitreous prolapse | 0 | (0.00, 1.11) | 0 | 1 (0.6) | (0.02, 3.27) | 1 |
| Seidel test positive | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Cataract operation complication | 1 (0.3) | (0.01, 1.68) | 1 | 1 (0.6) | (0.02, 3.27) | 2 |
| Corneal abrasion | 2 (0.6) | 0.07, 2.18 | 2 | 0 | (0.00, 2.17) | 0 |
| Iris injury | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Conjunctivitis | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Endophthalmitis | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Visual field defect | 2 (0.6) | 0.07, 2.18 | 2 | 0 | (0.00, 2.17) | 0 |
| Dermatitis contact | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Corneal dystrophy | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Device dislocation | 0 | (0.00, 1.11) | 0 | 1 (0.6) | (0.02, 3.27) | 1 |

The incidences of cumulative adverse events for the enVista Envy IOL and the control Monofocal IOL as compared to the ISO 11979-7:2018 historical grid (SPE) rates are

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provided in Table 15 and Table 16. If the same event occurred multiple times in an eye, only the first occurrence is counted in the table below. All SPE rates for the enVista Envy IOL were not statistically significantly above the SPE thresholds as set forth by ISO 11979-7:2018. The results of adverse events analyses based on the consensus definitions as set forth by American Academy of Ophthalmology's Task Force (Masket et al. Ophthalmology 2017) are shown in Table 17 and Table 18.

Table 15: ISO Grid Adverse Events (First Eyes; Modified Safety Set)

| Adverse Event | Observed Event Rate for enVista Trifocal IOL n (%) | 2-sided 95% CI | 1-sided 95% Lower CL | SPE Rate (%)b |
| --- | --- | --- | --- | --- |
| Cumulativea | N=332 | | | |
| Cystoid macular oedemac | 0 | (0.00, 1.10) | 0.00 | 3.0 |
| Hypopyon | 0 | (0.00, 1.10) | 0.00 | 0.3 |
| Endophthalmitis | 0 | (0.00, 1.10) | 0.00 | 0.1 |
| Lens dislocated from posterior chamberd | 0 | (0.00, 1.10) | 0.00 | 0.1 |
| Pupillary block | 0 | (0.00, 1.10) | 0.00 | 0.1 |
| Retinal detachmente | 0 | (0.00, 1.10) | 0.00 | 0.3 |
| SSI | 3 (0.9) | (0.19, 2.62) | 0.25 | 0.8 |
| Persistenta | N=314 | | | |
| Corneal stroma oedemaf | 0 | (0.0, 1.17 | 0.00 | 0.3 |
| Cystoid macular oedema | 0 | (0.0, 1.17 | 0.00 | 0.5 |
| Iritisg | 0 | (0.0, 1.17 | 0.00 | 0.3 |
| Raised IOP requiring treatmenth | 0 | (0.0, 1.17 | 0.00 | 0.4 |

AE = adverse event; IOL = intraocular lens; IOP = intraocular pressure; ISO = International Organization of Standardization; SPE = Safety and Performance Endpoint, SSI = secondary surgical intervention.
a For cumulative AEs, observed AE rate is calculated as 100 multiplied by the number of eyes with the specific treatment-emergent event divided by the number of eyes (m). For persistent AE rates, the number of eyes (m) present at Visit 5 (11-14 months) is the denominator.
b The ISO standard SPE rate in ISO 11979-7:2018.
c Per protocol, the definition of Cystoid Macular Oedema (CME) on this study was cystoid macular edema diagnosed by clinical exam and adjunct testing (e.g. Optical Coherence Tomography [OCT], Fluorescein Angiography [FA] or other method), resulting in BCDVA of $\leq 20/40$ at Visit 3 or later. No participants were diagnosed with CME based on OCT alone.
$^{\mathrm{d}}$ IOL decentration or tilt likely to affect visual outcome and resulting in secondary intervention
e Partial or complete Retinal Detachment associated with retinal tear. There were no retinal detachments without retinal tears.
f Corneal or corneal wound edema resulting in BCDVA of $\leq 20 / 40$ at Visit 3A or later in the first implanted eye or at Visit 3B or later in the second implanted eye, or any persistent corneal or corneal wound edema present at Visit 5 (11-14 months).
$^{\mathrm{g}}$ Iritis/cells/flare characterized by grade $1+$ cells or greater using Standardization of Uveitis Nomenclature (SUN) criteria 37 if persistent for greater than 3 months after surgery, or relapses in less than 3 months after discontinuation of therapy, or the participant is maintained on therapy for more than 3 months to control inflammation.
$^{\mathrm{h}}$ Elevation of IOP by $\geq 10\mathrm{mmHg}$ above baseline (pre-operative) to a minimum of $25\mathrm{mmHg}$ (Masket S, et al. Special Report: The American Academy of Ophthalmology Task Force Consensus Statement on Adverse Events with Intraocular Lenses. Ophthalmology 2017;124 1):142-144) after IOL implantation, or elevated IOP requiring treatment if present at Visit 5.

The three secondary surgical interventions that occurred with the first eye for the enVista Envy IOL were suturing of a Seidel positive wound, a Pars Plana Vitrectomy with internal limiting membrane peeling due to a macular hole and an Argon laser retinopexy for an operculated retinal hole. These SSIs were determined not to be related to the optical properties of the IOL.

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Table 16: ISO Grid Adverse Events (Second Eyes; Modified Safety Set)

| Adverse Event | Observed Event Rate for enVista Trifocal IOL n (%) | 2-sided 95% CI | 1-sided 95% LCL | SPE Rate (%)^{b} |
| --- | --- | --- | --- | --- |
| Cumulative^{a} | N=329 | | | |
| Cystoid macular oedema^{c} | 3 (0.9) | (0.19, 2.64) | 0.25 | 3.0 |
| Hypopyon | 0 | (0.00, 1.11) | 0.00 | 0.3 |
| Endophthalmitis | 1 (0.3) | (0.01, 1.68) | 0.02 | 0.1 |
| Lens dislocated from posterior chamber^{d} | 0 | (0.00, 1.11) | 0.00 | 0.1 |
| Pupillary block | 0 | (0.00, 1.11) | 0.00 | 0.1 |
| Retinal detachment^{e} | 0 | (0.00, 1.11) | 0.00 | 0.3 |
| SSI | 2 (0.6) | (0.07, 2.18) | 0.11 | 0.8 |
| Persistent^{a} | N=314 | | | |
| Corneal stroma oedema^{f} | 0 | (0.0, 1.17 | 0.00 | 0.3 |
| Cystoid macular oedema | 0 | (0.0, 1.17 | 0.00 | 0.5 |
| Iritis^{g} | 0 | (0.0, 1.17 | 0.00 | 0.3 |
| Raised IOP requiring treatment^{h} | 0 | (0.0, 1.17 | 0.00 | 0.4 |

AE = adverse event; CI = confidence interval; IOL = intraocular lens; IOP = intraocular pressure; ISO = International Organization of Standardization; LCL = lower confidence limit; SPE = Safety and Performance Endpoint, SSI = secondary surgical intervention.
a For cumulative AEs, observed AE rate is calculated as 100 multiplied by the number of eyes with the specific treatment-emergent event divided by the number of eyes (m). For persistent AE rates, the number of eyes (m) present at Visit 5 (11-14 Months) is the denominator.
b The ISO standard SPE rate in ISO 11979-7:2018 and ISO 11979-7:2018.
c Per protocol, the definition of CME on this study was cystoid macular edema diagnosed by clinical exam and adjunct testing (e.g. OCT, FA or other method), resulting in BCDVA of ≤ 20/40 at Visit 3 or later. No participants were diagnosed with CME based on OCT alone.
d IOL decentration or tilt likely to affect visual outcome and resulting in secondary intervention
e Partial or complete Retinal Detachment associated with retinal tear. There were no retinal detachments without retinal tears.
f Corneal or corneal wound edema resulting in BCDVA of ≤20/40 at Visit 3A or later in the first implanted eye or at Visit 3B or later in the second implanted eye, or any persistent corneal or corneal wound edema present at Visit 5 (11-14 months).
g Iritis/cells/flare characterized by grade 1+ cells or greater using Standardization of Uveitis Nomenclature (SUN) criteria 37 if persistent for greater than 3 months after surgery, or relapses in less than 3 months after discontinuation of therapy, or the participant is maintained on therapy for more than 3 months to control inflammation.
h Elevation of IOP by ≥ 10 mmHg above baseline (pre-operative) to a minimum of 25 mmHg (Masket S, et al. Special Report: The American Academy of Ophthalmology Task Force Consensus Statement on Adverse Events with Intraocular Lenses. Ophthalmology 2017;124 1):142-144) after IOL implantation, or elevated IOP requiring treatment if present at Visit 5.

The two secondary surgical interventions that occurred with the second eyes for the enVista Envy IOL were a Pars Plana Vitrectomy for endophthalmitis and removal of a retained lens fragment. Among second eyes, the trifocal IOL group had 3/329 subjects (95% Confidence interval between 0.2-2.6) with cystoid macular edema, which was not statistically significantly greater than the SPE rate of 3.0%, and 1/329 subject (0.3%, 95% CI: 0.0-1.7) with endophthalmitis, which was not significantly greater than the SPE rate of 0.1%. In addition, 2/329 participants (0.6%, 95% CI: 0.07-2.18%) had secondary surgical interventions, which was not significantly greater than the SPE rate of 0.8% (Table 16).

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None of the other ISO grid cumulative AEs or any persistent AEs were reported in the trifocal IOL group.

Table 17: Ocular Adverse Events based on a Modified Version of AAO Consensus (Masket et al., 2017), First Eye (Modified Safety Set)

| Adverse Event | enVista Trifocal IOL (N=332) | | | enVista Monofocal IOL (N=169) | | |
| --- | --- | --- | --- | --- | --- | --- |
| | n (%) | 2-sided 95% CI | E | n (%) | 2-sided 95% CI | E |
| Chronic anterior uveitis | 0 | (0.00, 1.10) | 0 | 0 | (0.00, 2.16) | 0 |
| Clinically significant cystoid macular edema | 0 | (0.00, 1.10) | 0 | 1 (0.6) | (0.01, 3.25) | 1 |
| Visually significant corneal edema | 0 | (0.00, 1.10) | 0 | 0 | (0.00, 2.16) | 0 |
| Endophthalmitis | 0 | (0.00, 1.10) | 0 | 0 | (0.00, 2.16) | 0 |
| Mechanical pupillary block | 0 | (0.00, 1.10) | 0 | 0 | (0.00, 2.16) | 0 |
| Increased IOP | 26 (7.8) | (5.18, 11.26) | 27 | 15 (8.9) | (5.05, 14.22) | 15 |
| Rhegmatogenous Retinal Detachment | 0 | (0.00, 1.10) | 0 | 0 | (0.00, 2.16) | 0 |
| Toxic anterior segment syndrome | 0 | (0.00, 1.10) | 0 | 0 | (0.00, 2.16) | 0 |
| Secondary IOL intervention - Exchange | 0 | (0.00, 1.10) | 0 | 0 | (0.00, 2.16) | 0 |
| Secondary IOL intervention - Removal | 0 | (0.00, 1.10) | 0 | 0 | (0.00, 2.16) | 0 |
| Secondary IOL intervention - Reposition | 0 | (0.00, 1.10) | 0 | 0 | (0.00, 2.16) | 0 |

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Table 18: Ocular Adverse Events based on a Modified Version of AAO Consensus (Masket et al., 2017), Second Eye (Modified Safety Set)

| Adverse Event | enVista Trifocal IOL (N=329) | | | enVista Monofocal IOL (N=168) | | |
| --- | --- | --- | --- | --- | --- | --- |
| | n (%) | 2-sided 95% CI | E | n (%) | 2-sided 95% CI | E |
| Chronic anterior uveitis | 0 | (0.00, 1.11) | 0 | 0 | (0.00, 2.17) | 0 |
| Clinically significant cystoid macular edema | 3 (0.9) | (0.19, 2.64) | 3 | 3 (1.8) | (0.37, 5.13) | 4 |
| Visually significant corneal edema | 0 | (0.00, 1.11) | 0 | 0 | (0.00, 2.17) | 0 |
| Endophthalmitis | 1 (0.3) | (0.01, 1.68) | 1 | 0 | (0.00, 2.17) | 0 |
| Mechanical pupillary block | 0 | (0.00, 1.11) | 0 | 0 | (0.00, 2.17) | 0 |
| Increased IOP | 26 (7.9) | (5.23, 11.37) | 26 | 8 (4.8) | (2.08, 9.17) | 8 |
| Rhegmatogenous Retinal Detachment | 0 | (0.00, 1.11) | 0 | 0 | (0.00, 2.17) | 0 |
| Toxic anterior segment syndrome | 0 | (0.00, 1.11) | 0 | 0 | (0.00, 2.17) | 0 |
| Secondary IOL intervention - Exchange | 0 | (0.00, 1.11) | 0 | 0 | (0.00, 2.17) | 0 |
| Secondary IOL intervention - Removal | 0 | (0.00, 1.11) | 0 | 0 | (0.00, 2.17) | 0 |
| Second…