Long-term Efficacy, Visual Performance and Patient Reported Outcomes With a Trifocal Intraocular Lens: Six-year Follow-up
Conditions: Cataract
Sponsor: Qvision, Ophthalmology Department

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
 
Long-term visual performance and patient 
reported outcomes with a trifocal intraocular 
lens 
Investigational Product: AT LISA 839MP 
Indication: Cataract Surgery and Refractive Lens Exchange 
Study design: Retrospective and cross-sectional observational study 
Sponsor: Qvision, Ophthalmology Department, Vithas Virgen del Mar Hospital, 
Carretera del Mami, s/n, 04120 Almería 
Document date: 30-07-2020 
Protocol Number: QVI-20-02 
Phase Study: Post-market 
Study initiation date: 15-9-2020 
Study completion date: 27-11-2020 
Principal Investigator: 
 
 
 
Joaquín Fernández Pérez 
QVision, Unidad Oftalmológica, Hospital Virgen 
del Mar, Carretera del Mami, s/n, 04120 Almería 
 
Study Coordinator:  
 
 
 
Manuel Rodríguez Vallejo 
QVision, Unidad Oftalmológica, Hospital Virgen 
del Mar, Carretera del Mami, s/n, 04120 Almería 
 
 
The study was conducted in compliance with Good Clinical Practice (ICH E6). The information contained in 
the following document is confidential and will not be shared with third parties without written authorization 
from the Principal Investigator. 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
i 
TABLE OF CONTENTS 
PAGE 
TABLE OF CONTENTS 
I 
LIST OF ABREVIATIONS 
II 
1 
SYNOPSIS 
III 
2 
INVESTIGATORS AND STRUCTURE 
V 
3 
INTRODUCTION 
VI 
4 
STUDY OBJECTIVES 
VII 
5 
METHODS 
VIII 
5.1 
Ethics ...................................................................................................................... viii 
5.1.1 
Ethics Committee for investigation with medicinal products (CEIm) ........... viii 
5.1.2 
Ethical conduct of the study ........................................................................ viii 
5.1.3 
Patient information and consent ................................................................. viii 
5.2 
Investigational Plan .................................................................................................. 1 
5.2.1 
Investigational Product ................................................................................. 1 
5.2.2 
Overall Study Design .................................................................................... 1 
5.3 
Selection of study sample ........................................................................................ 2 
5.3.1 
Phone call interview ...................................................................................... 2 
5.3.2 
Study visit ..................................................................................................... 3 
5.4 
Safety Evaluation ..................................................................................................... 4 
5.4.1 
Definition of adverse events ......................................................................... 4 
5.5 
Procedures followed and devices used for data collection ....................................... 4 
5.5.1 
Clinical history .............................................................................................. 4 
5.5.2 
History obtained during the phone call interview .......................................... 5 
5.5.3 
Patient reported outcomes ........................................................................... 5 
5.5.4 
Slit-lamp evaluation ...................................................................................... 6 
5.5.5 
Pentacam AXL .............................................................................................. 6 
5.5.6 
IOL Master 500 ............................................................................................. 7 
5.5.7 
Keratograph 5M ............................................................................................ 7 
5.5.8 
Subjective Refraction .................................................................................... 7 
5.5.9 
Visual acuity ................................................................................................. 8 
5.5.10 Contrast sensitivity defocus curve ................................................................ 9 
5.5.11 Light Distortion Analyzer ............................................................................... 9 
5.6 
Statistical analysis plan .......................................................................................... 10 
5.6.1 
Hypothesis and sample size calculation ..................................................... 11 
5.6.2 
Statistical analysis methods ....................................................................... 12 
6 
REFERENCES 
14 
7 
APPENDIX B: SUMMARY OF VISITS AND CONDUCTED TESTS 
18 
8 
APPENDIX C: ADDITIONAL QUESTIONS 
19 
 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
ii 
LIST OF ABREVIATIONS 
 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BFC 
Best Fit Circle 
BFCr 
Best Fit Circle Radius 
BFCi 
Best Fit Circle Irregularity 
CDVA 
Corrected Distance Visual Acuity 
CEIm 
Ethics Committee of Drugs and Medical Devices 
CRF 
Case Report Form 
DCIVA 
Distance Corrected Intermediate Visual Acuity 
DCNVA 
Distance Corrected Near Visual Acuity 
FAUC 
Far Area Under the Curve 
GCP 
Good Clinical Practices 
IAUC 
Intermediate Area Under the Curve 
ICH 
International Council for Harmonisation 
IOL 
Intraocular Lens 
IOP 
Intraocular Pressure 
LDI 
Light Distortion Index 
MIOL 
Multifocal Intraocular Lens 
MPMAV 
Maximum Positive Maximum Visual Acuity 
MTF 
Modulation Transfer Function 
NAUC 
Near Area Under the Curve 
NdYAG 
Neodynium YAG laser for Posterior Capsulotomy 
PCO 
Posterior Capsular Opacification 
SAE 
Serious Adverse Event 
TAUC 
Total Area Under the Curve 
UDVA 
Uncorrected Distance Visual Acuity 
UIVA 
Uncorrected Intermediate Visual Acuity 
UNVA 
Uncorrected Near Visual Acuity 
VA 
Visual Acuity 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
iii 
1 SYNOPSIS 
Name of Sponsor: 
Qvision, Ophthalmology Department, Vithas Virgen del Mar Hospital, Carretera del Mami, s/n, 04120 
Almería 
Name of Finished Product: 
AT LISA 839MP 
Title of Study: 
Long-term visual performance and patient reported outcomes with a trifocal intraocular lens 
Principal Investigator: 
Joaquín Fernández Pérez 
Study centre(s): 
Qvision, Ophthalmology Department, Vithas Virgen del Mar Hospital, Carretera del Mami, s/n, 04120 
Almería 
Studied period (years): 
15-9-2020 to 27-11-2020 
Phase of development: 
Post-market 
Objectives: 
The main aims of this study were to evaluate the patient reported outcomes (PROs), safety and efficacy, 
after 6-year (66 - 78 months) from the binocular implantation of the 839MP. A secondary aim was to 
evaluate new metrics such as contrast sensitivity defocus curves and light distortion analysis. 
Methodology: 
 
Retrospective cross-sectional study with two stages: 
 
• 
Phone call interview: 
 
First stage included patient reported outcomes of visual function, spectacle independence and satisfaction 
through questionnaires conducted by a phone call in all the patients implanted in our center with AT 
LISA 839MP from March 2014 to June 2015 (n=92) which accomplished inclusion / exclusion criteria and 
were able to be contacted by phone (n=62). 
The incidence of Nd-YAG capsulotomy was retrospectively evaluated through the revision of the medical 
history, in patients for which capsulotomy was conducted in our center, or a question, for those treated in 
another center. 
 
• 
Study visit:  
 
Second stage included the consecutive invitation of these phone interviewed patients to a visit in our 
center for a long-term visual performance assessment up to accomplish the required sample size (n=37).  
Corrected and uncorrected monocular visual acuities were the primary end-points for testing non-
inferiority hypothesis in comparison to 12-month follow-up mean results reported in the literature. 
Secondary variables of assessment were contrast sensitivity defocus curve and light distortion analysis. 
 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
iv 
Number of patients (planned and analyzed): 
92 for PROs planned and 62 analyzed 
37 for visual performance planned and analyzed 
Inclusion Criteria: 
• 
Phone call interview: 
- 
Patients of either sex, 45 years of age or older at the time of surgery and less than 80 
years of age at the time of the phone call. 
- 
Patients implanted bilaterally with the AT LISA 839MP MIOL in the capsular bag. 
- 
No surgical complications reported in the clinical history that could affect postoperative 
visual acuity: damage to the capsular bag, intraocular hemorrhage, etc. 
- 
Operated between 66 months from the first implanted eye and up to 78 months from the 
surgery of the second eye 
- 
Patient able to hear, understand and give express consent orally. 
• 
Study visit: 
- 
To have participated in the first stage of the study corresponding to the phone call 
interview. 
- 
Irregular astigmatism in either eye measured with corneal tomography (total high-order 
corneal aberrations at 4 mm < 0.5 μm). 
- 
Patient able to read, understand and provide a written informed consent form. 
- 
Sufficient availability, willingness, skills, and cognitive awareness to comply with follow-
up/study procedures and study visits. 
 
 Exclusion Criteria: 
• 
Phone call interview: 
- 
Any eye disease documented in the patient's clinical history that may potentially cause a 
loss of visual acuity or diplopia: Active or recurrent pathology of the anterior segment (chronic 
uveitis, iritis, iridocyclitis, rubeosis iridis, uncontrolled glaucoma, etc.), retinal or optic nerve 
pathologies such as diabetic retinopathy, macular degeneration, etc. 
- 
Eye surgery (including laser refractive surgery) performed before or after the operation 
with the intraocular lens. 
 
• 
Study Visit: 
- 
PCO ≥ 2 according to surgeon criteria that produces a loss of CDVA ≥ 0.2 logMAR 
- 
Any eye disorder that can potentially cause a loss of visual acuity or diplopia: Active or 
recurrent pathology of the anterior segment (chronic uveitis, iritis, iridocyclitis, rubeosis 
iridis, uncontrolled glaucoma, etc.), retinal or optic nerve pathologies such as diabetic 
retinopathy, macular degeneration, etc. 
- 
Eye surgery (including laser refractive surgery) performed before or after the operation 
with the intraocular lens. 
- 
Use of systemic or ocular medications that may affect vision in the last 6 months. 
-      Subjects who participate in any clinical trial or research with drugs or medical devices 
within 30 days prior to entry into this research and/or during the period of participation in 
this research. 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
v 
2 INVESTIGATORS AND STRUCTURE 
 
Investigators are included in Appendix A, main investigator was Joaquín Fernández Pérez (MD, 
PhD) and study coordinator was Manuel Rodríguez Vallejo (OD, PhD). The main investigator 
supervised and collaborated, if was required, in all the tasks delegated to research collaborators.  
All measurements and data collection were conducted by Noemí Burguera Giménez (OD, PhD) 
assisted by the clinical area responsible of the center Javier Martínez Peña (OD) who was involved 
together with the main investigator during the surgeries of the patients recruited in this study (all 
surgeries conducted by the main investigator).  
Collected data on printed CRF paper sheets and codified in an Excel spreadsheet (Microsoft, 
Redmond, WA) by Noemí Burguera Giménez were monitored by the study coordinator, university 
trained as Clinical Research Associate. The statistical analysis, study report and medical writing 
was also conducted by the study coordinator. All the documents send for publication were 
previously reviewed by David P. Piñero Llorens (OD, PhD). 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
vi 
3 INTRODUCTION 
 
The implantation of multifocal intraocular lens (MIOL) has become a settled method for cataract 
treatment mainly due to the high rate patient satisfaction ranging from 81.4% to 96.3%.1 Although 
there is a lot of clinical evidence that demonstrates the safety and efficacy achieved with MIOLs 
in the short term period, which explain the high satisfaction rates,2–10 long-term results still remain 
poorly investigated. First long-term study with 8-year follow-up was reported for 3M diffractive 
MIOL which was made of a poly(methyl methacrylate) material, nowadays outdated technology.11 
Most recent bifocal optic and material such as the provided by the Acrysof ReSTOR (SN60D3, 
Alcon) has also long-term results available.12 Yoshino et al.12 reported 5-year follow-up with no 
differences in distance and near visual acuities in comparison to 1-year, contrast sensitivity 
function in the normal range and 14.3% of neodymium-YAG (Nd-YAG) capsulotomy rates 
performed in a mean time of 44.64 months. However, as far as we know, no more long-term studies 
for bifocal MIOLs have been published, probably because of the decrease on interest by the replace 
for the current more popular trifocal intraocular lenses (IOLs).   
 
The AT LISA tri 839MP (henceforth 839MP, Carl Zeiss Meditec AG, Germany) was together 
with the FineVision (Physiol S.A., Liege, Belgium) the first trifocal MIOLs which received the 
CE mark in 2012 and 2010, respectively.13 Safety and efficacy for 839MP has been widely reported 
for short term follow-up periods (1 to 6 month follow-up).2–10 Long-term studies with 839MP are 
commonly referred to those which involve 1 or 2 year follow-up period14–18 and as far as we know 
there is only one retrospective study for a higher period of 3-4 years follow-up which only covers 
Nd-YAG rates.19 839MP remains one of the most popular and implanted MIOLs and therefore the 
results for longer periods of time can be considered of great interest. 
 
 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
vii 
4 STUDY OBJECTIVES 
 
The main aims of this study were to evaluate the patient reported outcomes (PROs), safety and 
efficacy, after 6-year from the binocular implantation of the 839MP. A secondary aim was to 
evaluate new metrics such as contrast sensitivity defocus curves and light distortion analysis. 
 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
viii 
5 METHODS 
5.1 
Ethics 
5.1.1 
Ethics Committee for investigation with medicinal products (CEIm) 
The protocol, informed consent forms, recruitment materials and all participant materials were 
submitted to the CEIm for review and approval. The study was approved on 29/07/2020 by the 
local ethics committee (Hospital Universitario de Torrecárdenas, calle hermandad de donantes de 
sangre s/n 04009-Almería) before participant enrrollment. No amendments of the protocol were 
conducted.   
5.1.2 
Ethical conduct of the study 
The study was conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki and the standards of Good Clinical Practice, as well as European 
legislation Regulation 536/2014, National Law 14/2007 on Biomedical Research and Autonomous 
Decree 439/2010, Law on Patient Autonomy 41/2020 and Law 3/2018 on Data Protection and 
Digital Rights Guarantee.   
5.1.3 
Patient information and consent 
Two informed consents were given depending on the phase of the study: 
• 
For the first stage, the consent was obtained by telephone, the patient was informed about 
the study and expressed verbal consent for using his/her pseudonymized data in the 
research. The participant gave the consent orally, the investigator signed the consent form 
and the date of consent was notified in the patient's medical record. The consent form was 
stored with the source documents of the study to be provided to the patient to obtain his/her 
written signature and to receive a copy at the time of his/her visit to the center. This 
procedure was carried out according to version 12 of June 29, 2020 of the Spanish Agency 
of Medicines and Healthcare Products' document of instructions for conducting clinical 
trials in Spain in reference to obtaining consent in COVID-19 studies. 
• 
For the second stage at the clinical center, participants were provided with a patient 
information sheet with the risks and possible benefits of participating in the study as well 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
ix 
as the sheet corresponding to the first part of the study. The participant signed both 
informed consent documents before any evaluation or procedure related to study visit. A 
copy was given to the participants. 
The rights and well-being of participants were protected by emphasizing that the quality of their 
clinical care was not adversely affected if they refused to participate in the study.  

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
1 
5.2 
Investigational Plan 
5.2.1 
Investigational Product 
 
The AT Lisa Tri 839MP is a trifocal intraocular lens with a 6.0 mm biconvex optic (360° posterior 
square edges) and overall diameter of 11.0 mm including the non-angulated plate haptic. The 
material consists of a hydrophilic acrylate with a water content of 25% with hydrophobic surface 
and blocks ultraviolet light according to manufacturer description. The optic structure is diffractive 
with additions at the IOL plane of +3.33 D for near focus and +1.66 D for intermediate focus and 
a posterior aspheric surface lead to an induction of negative spherical aberration of -0.18 m.13,20  
5.2.2 
Overall Study Design 
 
The study design was retrospective and cross-sectional. The study consisted of two stages, the first 
one with a phone call inverview for collecting the PROs, and a second stage with the consecutive 
invitation of these patients to a visit at our center to measure the visual performance up to achieve 
the required sample size. Each stage with some inclusion and exclusion criteria detailed below. 
The diagram in Figure 1 summarizes the study stages. 
 
 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
2 
 
 
Retrospective Review  
Historical review of all patients implanted with AT LISA 839MP between 
March 2014 and June 2015 (N=92) 
Inclusion and exclusion criteria for phone call interview 
 
 
Phone Call Interview 
Verbal informed consent 
Retrospective data collection 
Questionnaire for patient-reported outcomes 
Inclusion and exclusion criteria for study visit  
Invitation to participate in study visit (n = 37) 
 
 
Study Visit Recruitment 
Day 0 
Written informed consent 
Confirmation of inclusion and exclusion criteria for follow-up visit 
          Capsulotomy requireda                       Capsulotomy not requiredb         
 
 
 Additional Visit 
Day 15 ± 7 days 
Nd:YAG Capsulotomy 
 
 
 
Study Visit 
Day 0 or 
Day 45 ± 7 days 
Evaluation of long-term refractive error and visual performance 
Study closure 
aStudy Visit delayed until the resolution of the subsequent capsular opacification by Nd:YAG capsulotomy 
 
Figure 1. Study design summary 
 
5.3 
Selection of study sample  
5.3.1 
Phone call interview 
5.3.1.1 
Inclusion criteria  
 
- 
Patients of either sex, 45 years of age or older at the time of surgery and less than 80 years 
of age at the time of the phone call. 
- 
Patients implanted bilaterally with the AT LISA 839MP MIOL in the capsular bag. 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
3 
- 
No surgical complications reported in the clinical history that could affect postoperative 
visual acuity: damage to the capsular bag, intraocular hemorrhage, etc. 
- 
Operated between 66 months from the first implanted eye and up to 78 months from the 
surgery of the second eye. 
- 
Patient able to hear, understand and give express consent orally. 
5.3.1.2 
Exclusion criteria  
 
- 
Any eye disease documented in the patient's clinical history that may potentially cause a 
loss of visual acuity or diplopia: Active or recurrent pathology of the anterior segment 
(chronic uveitis, iritis, iridocyclitis, rubeosis iridis, uncontrolled glaucoma, etc.), retinal or 
optic nerve pathologies such as diabetic retinopathy, macular degeneration, etc. 
- 
Eye surgery (including laser refractive surgery) performed before or after the operation 
with the intraocular lens. 
5.3.2 
Study visit 
5.3.2.1 
Inclusion criteria  
 
- 
To have participated in the first stage of the study corresponding to the Phone Call 
Interview. 
- 
Irregular astigmatism in either eye measured with corneal tomography (total high-order 
corneal aberrations at 4 mm < 0.5 μm). 
- 
Patient able to read, understand and provide a written informed consent form. 
- 
Sufficient availability, willingness, skills, and cognitive awareness to comply with follow-
up/study procedures and study visits. 
5.3.2.2 
Exclusion criteria  
 
- 
PCO ≥ 2 according to surgeon criteria that produces a loss of CDVA ≥ 0.2 logMAR 
- 
Any eye disorder that can potentially cause a loss of visual acuity or diplopia: Active or 
recurrent pathology of the anterior segment (chronic uveitis, iritis, iridocyclitis, rubeosis 
iridis, uncontrolled glaucoma, etc.), retinal or optic nerve pathologies such as diabetic 
retinopathy, macular degeneration, etc. 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
4 
- 
Eye surgery (including laser refractive surgery) performed before or after the operation 
with the intraocular lens. 
- 
Use of systemic or ocular medications that may affect vision in the last 6 months. 
- 
Subjects who participate in any clinical trial or research with drugs or medical devices 
within 30 days prior to entry into this research and/or during the period of participation in 
this research. 
5.4 
Safety Evaluation 
5.4.1 
Definition of adverse events 
An adverse event (AE) was defined as an adverse or unfavorable medical occurrence in a subject, 
including any abnormal sign (e.g., an abnormal physical examination), symptom, or disease, 
temporally associated with the subject's participation in the research, whether or not it is considered 
related to the subject's participation in the research. Some adverse events could happen during the 
6 years period between the surgery date and the study visit, some of these adverse events were 
identified and reported even these could be part from the Exclusion Criteria. In this case, those 
were reported as a recruitment failure together with the adverse event reason. A list of possible 
adverse events anticipated can be found in ISO-11979-7:2018.21  
5.5 
Procedures followed and devices used for data collection 
A summary of procedures conducted are listed in Appendix B. Phone call interview with collection 
of PROs was done by one of the research collaborators also in charge of performing the clinical 
measurements at the center during study visit. The explorations prior to patient recruitment were 
carried out by an experienced optometrist or physician depending on the required test and the 
competencies of each professional. For example, the optometrist performed visual acuity and 
refraction measurements but the physician was responsible of evaluating the PCO, establishing 
whether the Nd-YAG could lead to improved visual acuity as well as any other tests related to eye 
health.  
5.5.1 
Clinical history 
• Each patient's medical history was reviewed prior to making the phone call interview. 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
5 
• This first review aims to explore whether the inclusion/exclusion criteria were met before 
making the call. 
• The variables reviewed in the medical history were: 
o Surgery date 
o Eye and general health 
o Intraocular lens implanted power 
o Adverse events reported in the history during surgery or post-operative follow-up 
o Date of patient's last visit to the clinic 
o Months after surgery on which Nd-YAG capsulotomy was done, if it was the 
case, and the eye/s 
5.5.2 
History obtained during the phone call interview 
• During the phone call and study visit the patient was consulted about possible diseases 
and concomitant medications in the 6 months prior to the call or visit. 
• The inclusion/exclusion criteria were confirmed through a patient interview for all those 
issues related to the patient's eye and general health history that might not be found in the 
medical records. 
5.5.3 
Patient reported outcomes 
• The following questionnaires were carried out during the phone call interview: 
o VF-14 to assess vision-related difficulty in performing everyday tasks.22 
o PRSIQ to assess independence of spectacles at far, intermediate and near 
distances.23 
o Additional questions related to satisfaction, dysphotopsia and decision to have the 
same MIOL procedure (Appendix C). 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
6 
5.5.4 
Slit-lamp evaluation 
The slit lamp examination was performed during the study visit. An examination of the eyelids, 
conjunctiva, cornea, intraocular lens and anterior vitreous was performed.  
• Eye lids: Normal / Non-Normal 
• Conjuntive:  
o Hyperemia (Normal / Mild / Moderate / Severe) 
o Oedema (Normal / Mild / Moderate / Severe) 
• Cornea: Oedema (Normal / Mild / Moderate / Severe) 
• Staining: Anterior chamber cells and flare.24  
• Anterior Capsular Opacification:25 From 0 to 4 grading 
• Posterior Capsular Opacification (PCO):26 From 0 to 4 grading density 
• Intraocular lens centration: 27 From 0 to 4 grading  
• Vitreous:28 From 0 to 4 grading 
• IOL calcification:29 (None / primary / secondary) 
5.5.5 
Pentacam AXL 
A measurement was performed with Pentacam AXL (corneal tomograph with Scheimpflug 
technology and ocular biometer, Oculus, Germany) to evaluate that the patient met the inclusion 
criteria in reference to irregular corneal astigmatism and to collect the necessary ocular 
demographic data for the results report. The following variables were collected with the Pentacam 
AXL: 
• Irregular astigmatism at 4 mm (µm): For Total Cornea (anterior and posterior corneal 
surfaces combination). 
• Anterior lens position (mm): Distance from anterior corneal vertex to anterior intraocular 
lens. 
• Regular astigmatism (D): For Total Cornea. 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
7 
• Corneal spherical aberration for mesopic pupil size (µm): Recalculated for the mesopic 
pupil diameter and the Total Cornea. 
5.5.6 
IOL Master 500 
A measurement was performed with IOL Master 500 to obtain: 
• Axial length (mm) 
• Mean corneal anterior keratometry (D). Average from the steep and flat axis measured 
for the anterior cornea. 
5.5.7 
Keratograph 5M 
A measurement was carried out for collecting the following variables: 
• Photopic pupil diameter (mm) 
• Mesopic pupil diameter (mm) 
5.5.8 
Subjective Refraction 
Subjective refraction was performed with a trial frame following our specific protocol for MIOLs. 
• The optotype used to carry out the refraction (ETDRS) was placed at a distance of 4 m with 
a background luminance of 85 cd/m2 (VisionC ETDRS chart, test-eye.com). 
• Based on the patient's spectacle refraction (if used), the objective refraction with auto-
refractometer, and the corneal astigmatism obtained with Pentacam, the starting sphere and 
cylinder were selected. 
• A 1.00 D myopization with positive spherical lenses was performed in order to shift the 
defocus curve enough to avoid refraction at a distance over the near focus. 
• After reaching the maximum positive maximum visual acuity (MPMVA), patient was 
myopized with +0.50 D and the axis and magnitude of the cylinder was fitted with a cross 
cylinder of +/- 0.50 D. 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
8 
• The procedure was completed by returning to the MPMVA and adding -0.25D on the 
sphere to obtain the equivalent refraction in infinity considering the proximal distance 
induced myopia (1/-0.25 = 4m). 
• The procedure was completed with a confirmation of +/- 2.50 D so that the negative lens 
slightly decreases visual acuity (2 lines) and the positive lens significantly decreases visual 
acuity. This procedure served as confirmation that the refraction was carried out at the 
focus corresponding to distant vision. 
5.5.9 
Visual acuity 
• Measured in monocular vision with and without the best correction obtained in the 
subjective refraction. 
• Measured in binocular vision without correction. 
• Measurements conducted at three distances: 
o Infinity: 4 m with distance vergence correction (+0.25 D) 
o Intermediate: 67 cm 
o Near: 40 cm 
• The procedure for measuring visual acuity was carried out with the ETDRS optotype chart 
(VisionC ETDRS chart, test-eye.com), selecting different sets of letters for each eye and 
distance in order to avoid a possible bias due to the effect of memorizing letters. 
• The procedure for determining the visual acuity threshold was carried out as follows: 
o Read only the first letter from the left and go down. 
o At the first failure, stayed on the previous line and read the whole line. 
o If correct answers were ≥ 3/5 advanced to the next line. 
o If correct answers were < 3/5 read the previous line. 
o Visual acuity was the last with correct answers ≥ 3/5. 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
9 
5.5.10 Contrast sensitivity defocus curve 
• The Multifocal Lens Analyzer App (defocuscurve.com) was used to evaluate the Contrast 
Sensitivity Defocus Curve in monocular vision (one eye selected at random). 
• Patient sitting 4 m from the iPad with +0.25 D vergence correction lens on trial frame over 
the best correction at infinity. 
• The automated procedure varies the contrast for a 0.3 logMAR Snellen optotype equivalent 
size in steps of 0.1 logCS and uses a staircase psychophysical method to determine the 
contrast sensitivity threshold. 
• The procedure is repeated for each defocus lens until a range of 11 lenses is completed 
from +1.00 D to -4.00 D in steps of -0.50 D.  
• Areas Under the Curve (AUCs) were computed along the total range (Total Area Under 
the Curve (TAUC), +1.00 to −4.00 D) and for the ranges of Far (Far Area Under the Curve 
(FAUC), +0.50 to −0.50 D), (Intermediate Area Under the Curve (IAUC), −0.50 to −2.00 
D) and Near vision (Near Area Under the Curve (NAUC), −2.00 to −4.00 D).  
5.5.11 Light Distortion Analyzer 
• Measurement with the Light Distortion Analyzer (CEORLab, University of Minho, Braga, 
Portugal) were performed under monocular conditions (one eye randomly selected) with 
the subjective refraction at distance and uncorrected binocular vision or with the usual 
correction used by the patient. 
• The Light Distortion Analyzer was used to psychophysically measure the light effects 
perceived by the patient around light sources such as car headlights, streetlights, etc. 
• The test consists of a central LED and peripheral LEDs with a luminance ratio of 100/1 so 
that the central LED generates the light distortion and the peripheral LEDs are activated in 
an automated way by scanning the visual field through the random inspection of each semi-
meridian and 3 repeated measurements in each semi-meridian. 
• The scanning protocol is called "in-out 30°" in which the peripheral points around the 
central source are presented from the inside to the outside of the evaluated field in random 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
10 
time intervals between 500 and 750 milliseconds. The peripheral LEDs turn on and off 
sequentially in the same semimeridian from the center to the periphery, the scanning of the 
different semimeridians were randomized by the device.    
• The measurement was carried out at 2 m with +0.50 D to correct the vergence produced by 
the presentation distance with the lighting of the room in mesopic conditions. 
 
Figure 2. Example of a measurement with the Light Distortion Analyzer. 
 
 
Figure 2 shows and example of the field explored described by three main variables:  
• BFC Irregularity (mm): Average distance from disturbance to Best Fit Circle (BFC) along 
each semi meridian. 
• BFC Radius (mm): radius of the circle that best fits the distortion area. 
• Disturbance Index (%): percentage of the area over the Total Tested Area. 
 
5.6 
Statistical analysis plan 
• Statistical analysis was performed with SPSS 24  

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
11 
• Standardized descriptive graphics were represented with the Refractive Analysis Toolbox 
library (version 1.0.5) for MATLAB (https://www.test-eye.com/en/refractive-analysis) 
5.6.1 
Hypothesis and sample size calculation 
5.6.1.1 
Main hypothesis (non-inferiority) 
The primary objective was to assess long-term efficacy by measuring monocular visual acuity with 
and without correction at distance (CDVA and UDVA), intermediate (DCIVA and UIVA) and 
near (DCNVA and UNVA). The mean monocular visual acuity and the standard deviations taken 
as reference were obtained from previous literature.15 Visual acuity was measured on a logMAR 
scale so that the smaller the variable, the higher the visual acuity. 
A contrast of non-inferiority hypotheses with unilateral significance was carried out, rejection of 
null hypothesis means than non-inferiority was accomplished: 
Ho = µa ≥  + µb  
HA = µa <  + µb 
 
Ho = Visual acuity at 6 years was higher or equal (poorer) than at 12 months plus a margin  
HA = Visual acuity at 6 years was lower (better) than at 12 months plus a margin  
µa = Mean monocular visual acuity obtained after 6 years of follow-up 
µb = Mean monocular visual acuity reported in a previous clinical study with 12 months of follow-
up.15 
 = 0.1 logMAR or 0.02 logMAR 
 
5.6.1.2 
Study power 
The statistical test planned in the protocol for testing the hypothesis was the one-sided one-sample 
t-test but the one-sided one-sample Wilcoxon Signed test was finally used due to non-normal 
distribution of the variables. The margin () selected in the protocol was 0.1 logMAR but the 
hypothesis was finally also confirmed with a margin of 0.02 logMAR. The software G-Power 
3.9.1.2 (Universität Düsseldorf) for an alpha level of 0.05 was used to calculated the power 
considering the standard deviation obtained in our study.  

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
12 
Table 1. Sample size confirmation 
 
Variables 
µa  
µb 
Power 
 = 0.1 
Power 
 = 0.02 
UDVA 
0.06 ± 0.12 
0.1 [0.1] 
0.03 ± 0.13  
0 [ - ] 
0.96 
0.12 
CDVA 
-0.05 ± 0.07 
-0.1 [0.1] 
0.01 ± 0.11  
0 [ - ] 
1 
0.99 
UIVA 
0.07 ± 0.09 
 0.0 [0.1] 
0.12 ± 0.13  
0.1 [ - ] 
1 
0.99 
DCIVA 
0.08 ± 0.09 
0.1 [0.1] 
0.11 ± 0.12  
0.1 [ - ] 
1 
0.94 
UNVA 
0.08 ± 0.10 
0.1 [0.1] 
0.27 ± 0.15  
0.2 [ - ] 
1 
1 
DCNVA 
0.05 ± 0.06 
0 [0.1] 
0.25 ± 0.14  
0.2 [ - ] 
1 
1 
 
5.6.2 
Statistical analysis methods 
 
• Normal distributions were tested with the Shapiro-Wilk test  
• Wilcoxon-signed rank test one sample was finally selected for testing the hypothesis for 
median differences because of the non-normal distribution of the variables.  
• Correlations were assessed with the Spearman rho or Multiple Linear Regression for 
multiple correlations and a single dependent variable. 
• Descriptive statistics are detailed in the results section as mean ± standard deviation 
[median (interquartile-range)].  
• A survival analysis was performed for the assessment of Nd:YAG rates. 
• SPSS version 24 software (SPSS Inc, Chicago, IL, USA) was used for the statistical 
analysis.  

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
13 
• The Refractive Analysis toolbox for MATLAB (R2019; MathWorks, Natick, MA, USA) 
was used for conducting the standard plots.30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
14 
6 REFERENCES 
 
1.  
Fernández J, Rodríguez-Vallejo M, Martínez J, Tauste A, Piñero DP. Standard Clinical 
Outcomes With a New Low Addition Trifocal Intraocular Lens. J Refract Surg. 
2019;35(4):214-221. 
2.  
Mendicute J, Kapp A, Lévy P, et al. Evaluation of visual outcomes and patient satisfaction 
after implantation of a diffractive trifocal intraocular lens. J Cataract Refract Surg. 
2016;42(2):203-210. doi:10.1016/j.jcrs.2015.11.037 
3.  
Mojzis P, Peña-García P, Liehneova I, Ziak P, Alió JL. Outcomes of a new diffractive 
trifocal intraocular lens. J Cataract Refract Surg. 2014;40(1):60-69. 
doi:10.1016/j.jcrs.2013.06.025 
4.  
Law EM, Aggarwal RK, Kasaby H. Clinical outcomes with a new trifocal intraocular lens. 
Eur J Ophthalmol. 2013;24(4):501-508. doi:10.5301/ejo.5000407 
5.  
Marques EF, Ferreira TB. Comparison of visual outcomes of 2 diffractive trifocal 
intraocular lenses. J Cataract Refract Surg. 2015;41(2):354-363. 
6.  
Kretz FTA, Breyer D, Diakonis VF, et al. Clinical Outcomes after Binocular Implantation 
of a New Trifocal Diffractive Intraocular Lens. J Ophthalmol. 2015;2015(962891):1-6. 
doi:10.1155/2015/962891 
7.  
Kohnen T, Titke C, Böhm M. Trifocal Intraocular Lens Implantation to Treat Visual 
Demands in Various Distances Following Lens Removal. Am J Ophthalmol. 2016;161:71-
77.e1. doi:10.1016/j.ajo.2015.09.030 
8.  
Alfonso JF, Cueto LFV, Belda-Salmerón L, Montés-Micó R, Fernández-Vega L. Visual 
function after implantation of a diffractive aspheric trifocal intraocular lens. Eur J 
Ophthalmol. 2016;26(5):405-411. doi:10.5301/ejo.5000741 
9.  
Plaza-Puche AB, Alio JL. Analysis of defocus curves of different modern multifocal 
intraocular lenses. Eur J Ophthalmol. 2016;26(5):412-417. doi:10.5301/ejo.5000780 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
15 
10.  
Plaza-Puche AB, Alio JL, Sala E, Mojzis P. Impact of low mesopic contrast sensitivity 
outcomes in different types of modern multifocal intraocular lenses. Eur J Ophthalmol. 
2016;26(6):612-617. doi:10.5301/ejo.5000777 
11.  
Slagsvold JE. 3M diffractive multifocal intraocular lens: Eight year follow-up. J Cataract 
Refract Surg. 2000;26(3):402-407. doi:10.1016/S0886-3350(99)00437-X 
12.  
Yoshino M, Bissen-Miyajima H, Minami K, Taira Y. Five-year postoperative outcomes of 
apodized diffractive multifocal intraocular lens implantation. Jpn J Ophthalmol. 
2013;57(6):510-513. doi:10.1007/s10384-013-0277-1 
13.  
Sudhir RR, Dey A, Bhattacharrya S, Bahulayan A. Acrysof IQ panoptix intraocular lens 
versus extended depth of focus intraocular lens and trifocal intraocular lens: A clinical 
overview. Asia-Pacific J Ophthalmol. 2019;8(4):335-349. 
doi:10.1097/APO.0000000000000253 
14.  
Brito P, Salgado-Borges J, Neves H, Gonzalez-Meijome J, Monteiro M. Light-distortion 
analysis as a possible indicator of visual quality after refractive lens exchange with 
diffractive multifocal intraocular lenses. J Cataract Refract Surg. 2015;41(3):613-622. 
doi:10.1016/j.jcrs.2014.07.033 
15.  
Mojzis P, Majerova K, Hrckova L, Piñero DP. Implantation of a diffractive trifocal 
intraocular lens: One-year follow-up. J Cataract Refract Surg. 2015;41(8):1623-1630. 
16.  
Gundersen KG, Potvin R. Comparison of visual outcomes and subjective visual quality 
after bilateral implantation of a diffractive trifocal intraocular lens and blended 
implantation of apodized diffractive bifocal intraocular lenses. Clin Ophthalmol. 
2016;10:805-811. doi:10.2147/OPTH.S107162 
17.  
Ganesh S, Brar S, Pawar A. Long-term visual outcomes and patient satisfaction following 
bilateral implantation of trifocal intraocular lenses. Clin Ophthalmol. 2017;11:1453-1459. 
doi:10.2147/OPTH.S125921 
18.  
Kaymak H, Breyer D, Alió JL, Coche B. Visual performance with bifocal and trifocal 
diffractive intraocular lenses: A prospective three-Armed randomized multicenter clinical 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
16 
trial. J Refract Surg. 2017;33(10):655-662. doi:10.3928/1081597X-20170504-04 
19.  
Bilbao-Calabuig R, Llovet-Osuna F, González-López F, Beltrán J. Nd:YAG Capsulotomy 
Rates With Two Trifocal Intraocular Lenses. J Refract Surg. 2016;32(11):748-752. 
doi:10.3928/1081597X-20160803-02 
20.  
Hill W, Carson D, Hong X, Karakelle M. Optical bench performance of Acrysof® IQ 
reSTOR® , AT LISA® tri, and FineVision® intraocular lenses. Clin Ophthalmol. 
2014;8:2105–2113. doi:10.2147/OPTH.S66760 
21.  
ISO-11979-7:2018. Ophthalmic implants - Intraocular lenses - Part 7: Clinical 
investigations. 2018. 
22.  
Riusala A, Sarna S, Immonen I. Visual function index (VF-14) in exudative age-related 
macular degeneration of long duration. Am J Ophthalmol. 2003;135(2):206-212. 
doi:10.1016/S0002-9394(02)01832-9 
23.  
Morlock R, Wirth RJ, Tally SR, Garufis C, Heichel CWD. Patient-Reported Spectacle 
Independence Questionnaire (PRSIQ): Development and Validation. Am J Ophthalmol. 
2017;178:101-114. doi:10.1016/j.ajo.2017.03.018 
24.  
Mcneil B. Grading of ocular inflammation in uveitis: an overview. Eyenews. 2016;22(5). 
25.  
Mendicute J, Úbeda M. Opacificación y contracción de la cápsula anterior. In: Ramón 
Lorente JM, ed. Cirugía Del Cristalino. Sociedad Española de Oftalmología (SEO); 
2008:1695. 
26.  
Tetz MR, Auffarth GU, Sperker M, Blum M, Volcker HE. Photographic image analysis 
system of posterior capsule opacification. J Cataract Refract Surg. 1997;23(10):1515-
1520. doi:10.1016/S0886-3350(97)80022-3 
27.  
Fernández J, Rodríguez-Vallejo M, Martínez J, Tauste A, Piñero DP. Patient selection to 
optimize near vision performance with a low-addition trifocal lens. J Optom. 
2020;13(1):50-58. doi:10.1016/j.optom.2019.06.003 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
17 
28.  
Jabs DA, Nussenblatt RB, Rosenbaum JT, et al. Standardization of uveitis nomenclature 
for reporting clinical data. Results of the first international workshop. Am J Ophthalmol. 
2005;140(3):509-516. doi:10.1016/j.ajo.2005.03.057 
29.  
Neuhann IM, Kleinmann G, Apple DJ. A New Classification of Calcification of 
Intraocular Lenses. Ophthalmology. 2008;115(1):73-79. doi:10.1016/j.ophtha.2007.02.016 
30.  
Rodríguez-Vallejo M. Refractive Analysis. 1.0.5. A Matlab toolbox for the analysis of 
refractive results in anterior segment surgery. http://test-eye.com/index.php/en/refractive-
analysis. Published 2020. Accessed October 25, 2020. 
 
 
 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
18 
7 APPENDIX B: SUMMARY OF VISITS AND CONDUCTED TESTS 
 
Procedures 
Phone Call 
Interview 
Study Visit 
(Day 0 or 
Day 45 ± 7) 
Phone Call Eligibility 
X 
Verbal Consent 
X 
Medical History / Adverse Events 
X 
X 
VF-14 Questionnaire 
X 
PRSIQ Questionnaire 
X 
Additional Questions 
X 
Study Visit Eligibility 
X 
Written Consent 
X 
Implanted IOL Power 
R 
Slit Lamp 
RE / LE 
Subjective Refraction 
RE / LE 
UDVA 
RE / LE / Bino 
CDVA 
RE / LE 
UIVA 
RE / LE / Bino 
DCIVA 
RE / LE 
UNVA 
RE / LE / Bino 
DCNVA 
RE / LE 
CSDC 
R 
Light Distortion Analyzer 
R 
PENTACAM 
Irregular astigmatism 4 mm  
R 
Total regular astigmatism  
R 
Spherical aberration for mesopic pupil  
R 
Intraocular Lens Position  
R 
IOL MASTER 
 
Axial length  
R 
Mean Corneal Power 
R 
KERATOGRAPH 5M 
Photopic pupil diameter 
R 
Mesopic pupila diameter 
R 
RE: Right eye measurement 
LE: Left eye measurement 
Bino: Binocular vision conditions 
R: A single eye RE or LE randomly selected at the Study Visit 
 

Long-term with a trifocal intraocular lens 
Protocol Translation 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
Protocol translation 
19 
8 APPENDIX C: ADDITIONAL QUESTIONS 
 
 
 
 
 
Original questions were conducted in Spanish. Translation has not been validated. 
How satisfied are you nowadays with your vision without spectacles in ... 
 
 
Very 
Unsatisfied 
Unsatisfied 
Neutral 
Satisfied 
Very 
Satisfied 
Far (1.5 meters or more) 
 
 
 
 
 
 
Intermediate (Between 
1.5 meters and 45 cm) 
 
 
 
 
 
 
Near (Menos de 45 cm) 
 
 
 
 
 
 
 
 
Nothing 
bothering 
A Little Bit 
bothering 
Neutral 
Bothering 
Very 
Bothering 
How bothering are the 
light effects around the 
lights at night? For 
example, streetlights, 
headlights or taillights of 
cars 
 
 
 
 
 
 
 
 
Very 
unlikely 
Unlikely 
Neutral 
Likely 
Very likely 
If you were operated on 
again, is it likely that you 
would decide to be 
implanted with the same 
intraocular lens?