Conditions: Cataract
Keywords: Cataract Eye Chloroprocaine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 338
Healthy volunteers: no

Brief summary:
Randomized clinical trial, multicenter, two-armed, to investigate and compare the clinical efficacy of chloroprocaine 3% gel and tetracaine 0.5% eye drop as topical anestheticsin phacoemulsification. This prospective, observer masked, randomised, controlled, equivalence phase 3 study will be conducted in approximately 4 European Countries. Sintetica intends to perform a phase 3 study on patients undergoing cataract surgery to assess the safety and efficacy of topical anaesthesia using chloroprocaine gel.

Detailed description:
Prospective,randomized, multi-center, active-controlled, masked-observer, parallel-group, competitive equivalence study. The study has been designed to assess the equivalence of chloroprocaine 3% gel (Test) with respect to tetracaine 0.5% solution (Reference) in surface anesthesia. Patients in both groups will receive three drops of study products before surgery. The study will include a Selection visit (Day -90/Day -1), an Inclusion visit (Day 1/surgery day), a Follow-up visit (Day 2, phone visit), a Final visit (Day 8), and a Follow-up phone call - Optional (Day 28, phone visit).

Selection visit (Visit 1, Day -90/Day -1):

Patients scheduled to undergo cataract surgery in a single eye will be informed about the aims, procedures and possible risks of the study and will be asked to sign the informed consent form for the inclusion in the trial.

Inclusion visit/Surgery (Visit 2, Day 1):

Before the anesthesia, patients will be questioned about previous and concomitant ocular and non-ocular treatments. Inclusion /exclusion criteria and patient status will be verified. Patients will be randomized to either chloroprocaine 3% gel (Test) or tetracaine 0.5% eye drop (Reference) treatment group.

Follow-up visit/phone visit (Visit 3, Day 2):

Concomitant ocular and non-ocular treatments, AEs, and patient global satisfaction will be assessed.

Final visit (Visit 4, Day 8 ± 1 day):

Concomitant ocular and non-ocular treatments, ocular symptoms, best far corrected visual acuity in both eyes, endothelial cell count, corneal thickness, blood pressure and heart rate, and AEs will be assessed. Slit lamp examination and fluorescein test, IOP in both eyes, and fundoscopy will be performed.

Optional visit/phone visit (Visit 5, Day 28 ± 3 days):

Concomitant ocular and non-ocular treatments and AEs resolution will be assessed.

Arms:
arm 1: All the eligible patients will be administrated by Chloroprocaine 3 % according to the randomization criteria. arm 2: All the eligible patients will be administrated by Tetracaine 0.5% according to the randomization criteria.

Interventions: intervention 1: Chloroprocaine 3% intervention 2: Tetracaine 0.5%
Intervention descriptions: intervention 1: Administration: three IMP drops instillation as follow:

* 1st Drop instillation, then wait for 5 minutes
* Eye Disinfection, then wait for 2 minutes
* 2nd Drop instillation, then wait for 1 minute
* 3rdDrop instillation, then wait for 1 minute
* Start of Surgery. intervention 2: Administration: three IMP drops instillation as follow:

* 1st Drop instillation, then wait for 5 minutes
* Eye Disinfection, then wait for 2 minutes
* 2nd Drop instillation, then wait for 1 minute
* 3rdDrop instillation, then wait for 1 minute
* Start of Surgery.

Protocol document:
Prot_SAP_000.pdf: 
IRIS PHARMA for SINTETICA 
 
Study Protocol No CHL.3/01-2019/M (S104CH1901) 
 
Version 2.0, 12May2020 
 
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Page 1 of 53 
 
 
 
 
 
Clinical Study Protocol No: CHL.3/01-2019/M 
 
A prospective, observer-masked, randomized clinical trial to investigate and 
compare the clinical efficacy of chloroprocaine 3% gel and tetracaine 0.5% 
eye drop as topical anestheticsin phacoemulsification. 
 
EudraCTNumber: 2019-001660-30 
 
Test product: 
Chloroprocaine3% ophthalmicgel, Sintetica S.A., Switzerland 
 
 
Reference product: 
Tetracaine 0.5% ophthalmic solution 
 
 
Sponsor: 
Sintetica S.A., Via Penate 5, CH-6850 Mendrisio, Switzerland 
Phone: +41.91.640.42.50; Fax: 
+41.91.646.85.61 
 
 
 
 
 
 
Development phase: 
Phase III 
 
 
Version and date: 
Version 2.0May12, 2020 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), ICH topic E6 (R2), applicable 
regulatory requirements and data protection law 
 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
 
 
 
 
 
 
Amendments 
No. 
Date 
 
 
 
 




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INVESTIGATOR SIGNATURE PAGE 
 
 
The signature below: 
§ Confirms my agreement to conduct the trial in compliance with Good Clinical Practices 
(GCP), applicable regulatory, including General Data Protection Regulation, and the 
clinical study protocol requirement(s), 
§ Confirms my agreement to comply with procedures for data recording/reporting, 
§ Confirms my agreement to permit monitoring, auditing, and regulatory inspection, 
§ Confirms my agreement to retain the study essential documents in the Investigator files 
until Sponsor informs me these documents are no longer needed (e.g. over 15 years), 
§ Ensure that all persons assisting with the study are adequately informed about protocol, 
the investigational product(s) and their trial-related duties and functions, 
§ Confirms that I have read this protocol and I agree to comply with all parts or items. 
 
All information regarding this protocol and the investigational product(s) will be treated as 
strictly confidential 
 
TRIAL SITE 
 
Principal Investigator 
 
 
 
__________________________ 
_______________ 
___________________________ 
First Name –Last Name 
date 
signature 
 
 
 
 


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Contacts page for the study 
 
 
Sponsor 
 
Sintetica SA 
Via Penate 5, CH-6850 Mendrisio, Switzerland 
Phone: 
+41.91.640.42.50 
Fax: 
+41.91.646.85.61 
 
Sponsor representative 
 
Clinical Project Leader 
Elisabetta Donati 
CorporateDirector Scientific Affairs 
Via Penate 5, CH-6850 Mendrisio, Switzerland 
 
International 
CoordinatingInvestigator 
Pr Alio Jorge 
Vissum alicante 
C/. Cabañal 1,  
03016 Alicante 
 
Biostatistician 
AlexandrosGryparis 
AGILIS S.A. STATISTICS AND INFORMATICS 
P.O. Box 78609 
Tavros, 177 01, 
Greece 
 
All details regarding the CRO for monitoring will be presented in the Investigator’s File 
 
 
 
 
 


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STUDY SYNOPSIS 
 
 
StudyTitle 
A prospective, observer-masked, randomized clinical trial to investigate and compare 
the clinical efficacy of chloroprocaine 3% gel and tetracaine 0.5% eye drop as topical 
anestheticsin phacoemulsification 
Sponsor 
Sintetica S.A. 
Protocol Sponsor 
code 
CHL.3/01-2019/M 
EudraCT-Number 2019-001660-30 
Clinical phase 
Phase III 
Study design 
Multicenter, international, randomized, competitive Phase III pivotal equivalence study 
Planned Schedule Planned initiation: Q2 2020 
Planned Last Patient Last Visit (LPLV): September 2020 
Planned 
n. 
of 
centers / countries 
Approximately 30centers / 3-4 European countries  
Indication 
Local anesthesia by topical instillation  
Test Product 
Chloroprocaine 3% gel 
Referenceproduct Tetracaine 0.5% eye drops 
Randomization 
Patients will be allocated to the Test (Chloroprocaine) arm or Reference (tetracaine) arm 
according to a 1:1 ratio 
Sample Size 
Approximately 342 male/female outpatients, aged ≥ 18 years, scheduled to undergo 
cataract surgery in a single eye at a time 
Study Duration 
Up to 17weeks duration per subject 
Screening: D-90 to D-1 
Randomization: D1 
Follow-up: D2(on-site visit or phone contact according to site usual practice),  
Final visit: D8,  
Optional visit: D28 (phone contact in case of Adverse Event at D8) 
Inclusion criteria 
To be enrolledin this study, subjects must fulfil all these inclusion criteria: 
1. Signed and datedinformed consent 
2. Male or femaleaged≥ 18 years 
3. Senile or pre-senilecataract 
4. Scheduled to undergo cataract surgery in a single eyeat a time (clear corneal 
self-sealing incisions - phacoemulsification – foldable intra-ocular lens surgery 
with injector) 
Exclusion criteria 
 
Patients fulfilling at the selection visit ONE OR MORE of the following exclusion 
criteria will not be enrolled in the study: 
Ophthalmic exclusion criteria 
Ø Surgical conditions in the eye to be operated: 
1. Combined surgery 
2. Previous intraocular surgery 
3. Previous corneal refractive surgeries less than 6 months before screening 
Ø Non-surgical conditions in the eye to be operated: 
4. Non Senile or non pre-senilecataract (e.g.: traumatic, pathological or 
congenital cataract) 
5. Pupillary abnormalities (irregular, etc.) 
6. Iris synechiae 
7. Eye movement disorder (nystagmus, etc.) 
8. Dacryocystitis and all other pathologies of tears drainage system 
9. History of Inflammatory ocular disease (Iritis, uveitis, herpetic keratitis) 
10. Corneal, epithelial, stromal or endothelial, residual or evolutionary disease 
(including corneal ulceration and superficial punctuate keratitis) 
11. History of ocular traumatism, infection or inflammation within the last 3 months 


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12. Pseudo-exfoliation, exfoliative syndrome 
13. Prior intravitreal injections within 7 days of the surgery 
14. IOP over 25mmHg under treatment 
Ø Ophthalmic conditions in the contra-lateral eye: 
15. Best corrected visual acuity < 1/10 
16. Patient already included in the study for phakoexeresis 
17. History of ophthalmic surgical complication (cystoid macular oedema, etc.) 
Systemic/non ophthalmicexclusioncriteria 
Ø General history: 
18. Diabetesmellitus 
19. Surdity 
20. Pakinsondisease 
21. Excessive anxiety 
22. Any other medical or surgical history, disorder or disease such as acute or 
chronic severe organic disease: hepatic, endocrine neoplasic, hematological 
diseases, severe psychiatric illness, relevant cardiovascular abnormalities (such 
as unstable angina, bradycardia, atrial fibrillation,uncontrolled hypertension: 
systolic blood pressure over 140 mm Hg, diastolic blood pressure over 90 
mmHg) and/or any complicating factor or structural abnormality judged by the 
investigator to be incompatible with the study. 
Ø Allergic history: 
23. Known hypersensitivity to sulfonamides products or any of the components of 
the study medications or to test products 
Specific exclusion criteria for women  
24. Pregnancy (positive pregnancy test), lactation 
25. Women of childbearing potential without an acceptable effective method of 
contraception 
(oral 
contraceptive, 
intra-uterine 
device, 
subcutaneous 
contraceptive implant) until end of the study participation 
OR 
26. Women not hysterectomized, not menopaused nor surgically sterilized. 
Exclusion criteria related to general conditions  
27. Inability of patient and/or relatives to understand the study procedures and thus 
inability to give informed consent 
28. Non-compliant patient and/or relatives (e.g. not willing to attend the follow-up 
visits, way of life interfering with compliance) 
29. Participation in anotherclinicalstudy 
30. Already included once in this study 
31. Ward of court 
32. Patient not covered by the Social Security 
Exclusion criteria related to previous and concomitant medications / non-product 
therapies  
Patient using any of the following previous and concomitant medication / treatment 
(according to the described periods) will not be included in the study:  
NOT ALLOWED CONCOMITANT MEDICATIONS 
Before the surgery 
Surgery  
After surgery 
30 days 
15 days  
7 days 
Day 1 
Day 2 to Day 28 
Any change in concomitant anti-depressant medication ………….……………………………… 
Systemic opioids and morphinic drugs  ......................................................... . 
Topical ocular treatment with anaesthetic action*……………………….…. 
Prior intravitreal injections ……………………………….. 


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Sulfonamides products,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 
Others systemic antalgics drugs (except paracetamol) ............... 
Any change in other systemic medication already ongoing 
before selection visit 
 
 
 
*except the pre-, peri-operative and post-operative therapeutics procedure to be followed 
according to the protocol. 
Primary objective Equivalence evaluation of Test versus Reference products in terms of proportion of 
subjects with a successful surface anesthesia for cataract surgery, without any 
supplementation (see definitions below) at T4(just before Intra Ocular Lens 
implantation) 
Successful surface anesthesia: The patient assessment of ocular discomfort during 
surgery must be 0 (=No pain or discomfort) or 1 (=Occasional pressure sensation, less 
than 5 separated times during procedure) without any supplementation at T4.  
Supplementation:Intra-operative analgesia, including additional LA drops administration,after 
the beginning of the surgery. 
Secondary 
objective  
Assess the clinical efficacy and safety of 3% chloroprocaine gel compared to those of 
tetracaine 0.5% eye drop. 
Primaryendpoint 
Τhe proportion of subjects in each treatment group with a successful surface anesthesia, without 
any supplementation at the time point T4.  
A successful surface anesthesia is equal to 1 and is defined as ocular discomfort equal to 0 (=no 
pain or pressure) or 1 (=occasional pressure sensation, less than 5 separated times during 
procedure).It is equal to 0 otherwise (e.g. ocular discomfort > 1). 
Secondaryendpoi
nts 
 
Efficacy end-points during surgery: 
Ø Successful surface anesthesia at T1, T2and T3  based on patient questioning: 
Patient’s operated eye discomfort.  
Ø Time to obtain sufficient anesthesia (use of forceps). 
Ø Total time of anesthesia 
Ø Blinking reflex dropping a water drop at the end of the surgery 
Ø Number of supplemental drops necessary for obtaining and/or maintaining 
anesthesia 
Ø Supplementary treatments (general anesthesia or intra-operative systemic 
analgesia) necessary for obtaining and/or maintaining anesthesia 
Ø Total surgical time 
Ø Assessment of surgical comfort by the surgeon of each stage of the surgical 
procedure. 
Ø Assessment of the global efficacy by the surgeon for anesthesia. 
Secondaryendpoi
nts 
 
Safety end-points: 
- Ocular symptoms (pain, irritation/burning/stinging, photophobia, foreign body 
sensation) will be graded by the patients according to the following scale: 0 = absent, 1 
= mild, 2 = moderate, 3 = severe.  
- Objective ocular signs (palpebral edema, chemosis, conjunctival hyperemia, 
conjunctival discharge, follico-papillary conjunctivitis, corneal staining punctuations, 
anterior chamber cells) assessed by slit lamp examination, flare, and other objective 
ocular signs will be graded according to the following scale: 0 = none, 1 = mild, 2 = 
moderate, 3 = severe.  
Modification of the basal status of the following assessments: 
- Slit lamp examination and fluorescein test 
- Endothelial cell counts (specular microscopy) 
- Corneal thickness (pachymetry) 
- Best far corrected visual acuity 
- Fundoscopy 
- Intra-ocular pressure 
- Vital signs (blood pressure and heart rate) 


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- AEs occurrence 
- Surgeon satisfaction: “How do you consider the study product global tolerance” will 
be graded according to the following scale: 0 = very satisfactory, 1 = satisfactory, 2 = 
not very satisfactory, 3 = unsatisfactory.  
- Patient global satisfaction at Visit 3/D2 (5-scale pointsquestionaireread by a masked 
observer). 
Study Procedures 
 
The study will include a Selection visit (Day -90/Day -1), an Inclusion visit (Day 
1/surgery day), a Follow-up visit (Day 2, phone visit), a Final visit (Day 8), and a 
Follow-up phone call - Optional (Day 28, phone visit).  
Selection visit (Visit 1, Day -90/Day -1) 
Patients scheduled to undergo cataract surgery in a single eye will be informed about 
the aims, procedures and possible risks of the study and will be asked to sign the 
informed consent form for the inclusion in the trial. Patients will be assigned a screening 
number. Routine pre-surgery assessments will be performed according to the hospitals’ 
standard procedures, and the study inclusion/exclusion criteria will be verified. Protocol 
specific assessments will be performed according to table 1 (see table 1- study schedule). 
Inclusion visit/Surgery (Visit 2, Day 1) 
Before the anesthesia, patients will be questioned about previous and concomitant ocular 
and non-ocular treatments. Inclusion /exclusion criteria and patient status will be 
verified. Blood pressure, heart rate, AEs occurrence will be assessed.  
Patients will be randomized to either chloroprocaine 3% gel (Test) or tetracaine 0.5% 
eye drop (Reference) treatment group.  
Patient discomfort in the operated eye will be assessed( see table 1- study schedule). 
Follow-up visit/phone visit (Visit 3, Day 2) 
Concomitant ocular and non-ocular treatments, AEs, and patient global satisfaction will 
be assessed (see table 1- study schedule). 
Final visitvisit (Visit 4, Day 8 ± 1 day) 
Concomitant ocular and non-ocular treatments, ocular symptoms, best far corrected 
visual acuity in both eyes, endothelial cell count, corneal thickness, blood pressure and 
heart rate, and AEs will be assessed. Slit lamp examination and fluorescein test, IOP in 
both eyes, and fundoscopy will be performed. 
In case an AE is not resolved at vist 4 Day 8, a final follow-up phone contact will be 
performed at D28(see table 1- study schedule). 
Optional visit/phone visit (Visit 5, Day 28 ± 3 days) 
Concomitant ocular and non-ocular treatments and AEs resolution will be assessed(see 
table 1- study schedule). 
Definition 
of 
analysis sets 
 
1. Safety Set: the safety set is defined as all the patients enrolled in the study for whom 
there is evidence that they used study medication and for whom any follow-up 
information is available. 
2. Full Analysis Set (FAS): the FAS will include all the patients enrolled in the study 
for whom any follow-up efficacy information is available. 
3. Per Protocol Set (PPS): the PP set will include all the patients of the FAS who did 
not show any major protocol violation.  
The statistical analysis of the onset data and of efficacy will be performed on the basis 
of the FAS and the PPS. The primary population for the assessment of efficacy will be 
the PPS, while the statistical analysis on the FAS population will be considered as 
sensitivity analysis. The analysis of safety will be performed on the basis of the safety 
set. 
Statisticalanalysis 
 
Data documented in this study and the parameters measured will be evaluated and 
presented using descriptive statistics, i.e. arithmetic mean, SD, minimum, median and 
maximum values for quantitative variables, and absolute and relative (%) frequencies 
for qualitative variables. The statistics will be reported by treatment group.  For the 


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variables recorded for both eyes, the statistics will be reported by treatment group, 
separately for the eye to be operated and for the other eye. Confidence intervals will be 
reported, where appropriate. If not stated elsewhere, these intervals will be two sided in 
each case and provide 95% confidence.  
Efficacy will be evaluated in the operated eye using mixed effects models (adjusting for 
center and country using random effects). The primary endpoint of the study is defined 
as the proportion of subjects in each treatment group with a successful surface 
anesthesia, without any supplementation at the time point T4. A successful surface 
anesthesia (=1) is defined as ocular discomfort equal to 0 (=no pain or pressure) or 1 
(=occasional pressure sensation, less than 5 separated times during procedure), and it is 
equal to 0 otherwise.  
A statistical analysis plan (SAP) will be provided before database closure. The statistical 
analysis will be performed using RStudio v. 1.2.5001 and/or IBM SPSS Statistics v. 25 
(or newer) for Windows. 


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TABLE 1. - STUDY SCHEDULE 
Study procedure 
Visit 1 
Selection visit 
D-90/D-1 
By Masked-
observer 
Visit 2 
Inclusion Visit 
Surgery D1 
By Surgeon 
Visit 3 
Follow-up visit 
D2 (phone visit) 
By Masked-
observer 
Visit 4 
Final visit 
D8 (+/- 1 day) 
By Masked-
observer 
Visit 5(3) 
Optional visit 
D 28 (+/- 3 
days)phone visit 
By Masked-
observer 
Informed consent 
X 
 
 
 
 
Demography 
X 
 
 
 
 
Ocular medical and surgical history 
X 
 
 
 
 
Systemic medical and surgical history 
X 
 
 
 
 
Urine pregnancy test 
X 
X(4) 
 
 
 
Previous and concomitant ocular and non-ocular treatments 
X 
X 
X 
X 
X 
Assessment of patient’s discomfort 
 
X(1) (2) 
 
 
 
Ocular symptoms  
X 
 
 
X 
 
Best far corrected visual acuity in study eye 
X 
 
 
X 
 
Slit lamp examination and fluorescein test   
X 
 
 
X 
 
IOP in botheyes 
X 
 
 
X 
 
Assessment of surgical performance 
 
X 
 
 
 
Funduscopy 
X 
 
 
X 
 
Endothelial cells count by specular microscopy 
X 
 
 
X 
 
Corneal thickness by pachymetry 
X 
 
 
X 
 
Retinal thickness by Optical Coherence Tomography 
X 
 
 
 
 
Cardiovascular parameter (blood pressure and heart rate) 
X 
X(2) 
 
X 
 
Adverse events 
 
X 
X 
X 
X 
Verification of inclusion and exclusion criteria / Status of the patient  
X 
X 
 
 
 
Allocated treatment group  
 
X 
 
 
 


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Study procedure 
Visit 1 
Selection visit 
D-90/D-1 
By Masked-
observer 
Visit 2 
Inclusion Visit 
Surgery D1 
By Surgeon 
Visit 3 
Follow-up visit 
D2 (phone visit) 
By Masked-
observer 
Visit 4 
Final visit 
D8 (+/- 1 day) 
By Masked-
observer 
Visit 5(3) 
Optional visit 
D 28 (+/- 3 
days)phone visit 
By Masked-
observer 
Dose regimen compliance 
 
X 
 
 
 
Patient global satisfaction (questionnaire read by a masked observer) 
 
 
X 
 
 
Surgeon global satisfaction  
 
X 
 
 
 
(1) -T1:just before first incision 
-T2:end of capsulorehexis 
-T3:end of phacoemulsification 
-T4:just before intra ocular lens implantation 
 
(2) By masked-observer 
 
(3) Visit 5 must be conducted only in case of AE at Visit 4 
 
(4) only if Visit 2  more than 30 days after visit 1


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TABLE OF CONTENTS 
 
Page 
 
1 
INTRODUCTION 
15 
1.1 
Background 
15 
1.2 
Rationale 
15 
1.2.1 
Nonclinical background information 
15 
1.2.2 
Clinical background information 
16 
1.2.3 
Clinical pharmacology 
16 
1.2.4 
Pharmacokinetics 
17 
1.2.5 
Pharmacodynamics 
17 
1.2.6 
Clinical efficacy 
17 
1.2.7 
Clinical safety 
17 
1.2.8 
Risk and benefits 
19 
2 
STUDY OBJECTIVES 
19 
2.1 
Primary objective 
19 
2.2 
Secondary objectives 
20 
3 
INVESTIGATIONAL PLAN 
20 
3.1 
Overallstudy design 
20 
3.2 
Visit schedule: 
20 
3.3 
Discussion of design 
20 
3.4 
Study endpoints 
21 
3.4.1 
Primary endpoint 
21 
3.4.2 
Secondary endpoints 
22 
4 
STUDY POPULATION 
23 
4.1 
Target population 
23 
4.2 
Inclusion criteria 
23 
4.3 
Exclusion criteria 
23 
4.4 
Withdrawal criteria 
25 
4.4.1 
Discontinuation procedures 
26 
5 
CLINICAL SUPPLIES 
26 
5.1 
Study Treatment 
26 
5.1.1 
Description of products 
26 
5.1.1.1 
Test product 
26 
5.1.1.2 
Reference product 
27 
5.1.2 
Dose regimen 
27 
5.1.3 
Investigational product distribution 
27 
5.1.4 
Packaging and labelling 
27 
5.1.5 
Storage conditions 
27 
5.1.6 
Drug accountability 
28 
5.2 
Randomization 
28 
5.3 
Treatment allocation 
28 
5.4 
Masking 
28 
5.5 
Other Treatments 
29 
6 
STUDYCONDUCT 
30 
6.1 
Study visits 
30 
6.2 
Diet and lifestyle 
32 
6.3 
Study procedures 
32 
6.3.1 
Efficacy measures 
32 
6.3.1.1 
Patient’s discomfort assessement during surgery 
32 
6.3.1.2 
Blinking assessement 
33 
6.3.1.3 
Anesthesia assessement 
33 
6.3.1.4 
Total Surgical Time (using chronometer) 
33 
6.3.1.5 
Surgeon assessments 
33 
6.3.2 
Safety measures 
34 
6.3.2.1 
Ocular and systemic tolerability assessment at visit 1 and visit 4 
34 
6.3.2.2 
Endothelial cells count (specular microscopy) at visit 1 and visit 4 
34 


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6.3.2.3 
Corneal thickness (pachymetry) at visit 1 and visit 4 
34 
6.3.2.4 
Best far corrected visual acuity at visit 1 and visit 4 
34 
6.3.2.5 
Fundoscopy at visit 1 and visit 4 
34 
6.3.2.6 
Slit lamp examination at visit 1 and visit 4 
34 
6.3.2.7 
Corneal fluorescein staining at visit 1 and visit 4 
34 
6.3.2.8 
Intra-Ocular Pressure at visit 1 and visit 4 
34 
6.3.2.9 
Vital signs measurements (blood pressure, heart rate) 
35 
6.3.2.10 Surgeon satisfaction “How do you consider the study product global tolerance?”: 
35 
6.3.2.11 Patient global satisfaction at Follow-up visit(Visit 3 - D2) 
35 
6.3.2.12 Adverse events recorded throughout the study 
35 
6.3.2.13 Definitions 
35 
6.3.2.13.1.1 
AEs monitoring window 
36 
6.3.2.13.1.2 
AEs recording 
37 
6.3.2.13.1.3 
SAEs reporting 
38 
6.3.2.13.1.4 
SUSARs management 
38 
6.3.2.13.1.5 
Otherevents qualified for expedited reporting 
39 
6.3.2.13.1.6 
SAEs: contacts 
39 
6.4 
Description of specificprocedures 
39 
6.4.1 
Procedures for post-operative recovery 
39 
6.4.2 
Procedures for telephonic follow-up 
39 
7 
STATISTICAL METHODS 
40 
7.1 
Analysis Sets 
40 
7.2 
Sample size and power considerations 
41 
7.3 
Handling of missing data 
42 
7.3.1 
Methods for replacing missing data 
42 
7.3.2 
Replacement rules for each analysis set 
42 
7.4 
Demographic, baseline and background characteristics 
43 
7.5 
Analysis of efficacy parameters 
43 
7.6 
Safetyand tolerability evaluation 
44 
8 
DATA MANAGEMENT PROCEDURES 
44 
8.1 
Data collection – CRFs 
44 
8.2 
Unique subject identifier 
44 
8.3 
Data management 
44 
9 
STUDY MONITORING AND AUDITING 
45 
9.1 
Monitoring 
45 
9.2 
Quality Control and Quality Assurance 
46 
9.3 
Applicable SOPs 
46 
9.4 
Data access 
46 
9.5 
Audits and inspections 
46 
10 
ETHICAL CONSIDERATIONS 
47 
10.1 
Ethics and Good Clinical Practice (GCP) 
47 
10.2 
Informed consent 
47 
10.3 
Insurance policy 
48 
10.4 
Study termination 
48 
10.5 
Premature discontinuation of the trial 
48 
11 
ADMINISTRATIVE PROCEDURES 
48 
11.1 
Material supplied to the clinical center 
48 
11.2 
Protocol amendments 
49 
11.3 
Study documentation and record keeping 
49 
11.4 
Studysubjects’ recruitment 
50 
11.5 
Confidentiality and data protection 
50 
11.6 
Publication policy 
50 
12 
APPENDICES 
51 
12.1 
Appendix 1 Oxford Scale 
51 
13 
REFERENCES 
52 
 


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LIST OF ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALCOA 
Attributable-Legible-Contemporaneous-Original-Accurate 
ANOVA 
Analysis of Variance 
BP 
Blood Pressure 
BSS 
Balanced Salt Solution 
CA 
CompetentAuthority 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
ContractResearchOrganization 
CSP 
ClinicalStudy Protocol 
CRS 
ClinicalStudy Report 
CV 
Coefficient of Variation 
D 
Day 
DBP 
Diastolic Blood Pressure 
EC 
EthicsCommittee 
ETV 
EarlyTerminationVisit 
FAS 
Full Analysis Set 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
Hg 
Mercury 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IOL 
Intra Ocular Lens 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IMP 
InvestigationalMedicinal Product 
IV 
Intravenous 
LSLV 
Last Subject Last Visit 
LA 
Local Anaesthesia 
MAR 
MissingatRandom 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Missing as Failure 
MI 
Multiple Imputation 
NA 
NotApplicable 
NSAIDs 
Non-Steroidal Anti-InflammatoryDrugs 
PK 
Pharmacokinetics 
PNB 
Peripheal Nerve Block 
PP 
Per Protocol 
PT 
PreferredTerm 
PTAE 
Pre-TreatmentAdverse Event 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SDTM 
Study Data Tabulation Model 
TEAE 
Treatment-Emergent Adverse Event 
T 
Time 
WC 
Worst Case 
WHODDE 
World Health Organization Drug Dictionary Enhanced 


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1 
INTRODUCTION 
 
1.1 
Background 
 
Cataract surgery has become one of the most prevalent surgical procedures due to changes in 
population structure and increased life expectancy. Continually improving surgical techniques 
require less extensive anesthesia and decrease the need for hospitalization and postoperative 
controls.  
Topical local anaesthetics (LAs) play an important role in the practice of ophthalmology, 
especially for less invasive outpatient surgeries, including cataract surgery. 
Cataract surgery consists of the replacement of the natural lens of the eye that has become 
cloudy with a new and transparent intraocular lens.  
Several improvements have been implemented in the past for this type of surgery. The eye 
incision decreased from 12 mm to 2.2 mm with the development of phacoemulsification and 
foldable intraocular lenses that are injected into the eye through special delivery systems. 
The procedure is bloodless, because conjunctival incisions are no longer performed. The 
procedure lasts only 10–15 minutes in uncomplicated cases, with a very high success rate and 
is performed on an outpatient basis. Intraoperative and postoperative complications are very 
low.  
As a result, the retrobulbar or peribulbar needle anaesthesia that had been used for more than a 
century was almost entirely abandoned about 15 years ago in favour of a new type of 
anaesthesia, which only requires application of anaesthetic drops (5). Topical anaesthesia has 
been adopted in cataract surgery because there is no blood in cut or touched tissues that could 
remove the anaesthetic drug, eyeball akinesia is no longer required, the procedure is usually 
short, additional anaesthesia by either drop or needle can be applied at any time, and there is no 
risk of globe perforation by needles. 
Anaesthetics topically applied to the eye act directly on the corneal epithelium and stroma, and 
the portion of drug penetrating into the anterior chamber suppresses pain arising from the iris 
and ciliary body. The duration of effect of topically applied anaesthetics depends on the 
properties of the drug used. Usually it lasts up to 15–20 minutes for the commonly used agents, 
but eye drop instillation can be repeated at intervals during surgery if needed. 
Current practices for ocular topical anaesthesia in Europe include topical liquid oxybuprocaine, 
tetracaine and lidocaine. It has been theorized, and recent studies support the idea, that gel 
formulations of local anesthetic may enhance anaesthetic effect, and therefore be superior to 
anaesthetic solutions for topical cataract surgery.  
 
 
1.2 
Rationale 
 
1.2.1 
Nonclinical background information 
Animal studies conducted by the intended route of administration demonstrated that 
chloroprocaine 3% hydrochloride eye gel is efficacious and locally well tolerated. In none of 
these studies, systemic signs of toxicity were recorded at clinical observation. 
Furthermore, repeat-dose toxicity studies performed in rats and dogs by the intrathecal route 
did not reveal any macroscopic or microscopic finding in any organ. 
Taking into consideration that chloroprocaine is a local anaesthetic which is intended for a “one-
shot” administration, there are acute toxicity studies performed by intraperitoneal route in mice 
and intravenous route in guinea pigs and dogs which can be useful to roughly estimate safety 
margins, with respect to the maximum recommended human dose for chloroprocaine 
hydrochloride 3% eye gel. 


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1.2.2 
Clinical background information 
 
There is a long history of use of chloroprocaine and the amino ester class of anaesthetics in 
USA, Canada and Switzerland. In particular, chloroprocaine has been FDA-approved since 
1955 and is currently marketed in the US and Canada as Nesacaine® (1% and 2%), Nesacaine®-
MPF (2% and 3%), both sponsored by Fresenius Kabi for infiltration, nerve block (up to 800 
mg) and epidural block and in US as Sintetica’s Clorotekal® 1% for intrathecal injection since 
2017.  
In Europe, Sintetica’s Ampres® 1% is approved for intrathecal administration. Since July 2015, 
it is present on the Swiss market for local anaesthesia by infiltration, for Peripheral Nerve Block 
(PNB) and for epidural block, respectively. 
Thanks to very favourable PK characteristics, chloroprocaine is currently considered the local 
anaesthetic with the safest toxicological profile, and Sintetica already performed 3 different 
clinical trials testing the efficacy and safety of intrathecal administration of chloroprocaine 1% 
and 1 trial testing efficacy and safety of perineural injection of chloroprocaine 2% on about 600 
subjects in total. Moreover, another clinical trial assessing the efficacy and safety of 
chloroprocaine 3% administered via epidural route in parturients and a pediatric study assessing 
the efficacy and safety of chloroprocaine 1% and 2% for PNB are currently ongoing. 
Chloroprocaine proved to be highly efficacious in all the above-mentioned clinical trials, and 
the very favourable safety profile has been strongly confirmed for the intrathecal and perineural 
route of administration. 
Chloroprocaine 3% proved to be efficacious and well tolerated also in the full package of 
preclinical studies introduced in section “Non-clinical background information”. Moreover, an 
anaesthesia effect was observed from 5 min after the instillation until 60 min for chloroprocaine 
3% gel and this is coherent with the known anaesthetic action of the product and comparable to 
other ocular topical product tested on animal models both liquid or in jelly formulation.(3) 
Importantly, the drug product is topically applied to the site of action and has minimal systemic 
absorption. The proposed gel formulation contains hydroxyethylcellulose to allow extended 
contact with the cornea, which is theorized to result in extended anaesthesia. The gel 
formulation allows a reduction of absorption of the anaesthetic through the nasolacrimal 
system, thereby resulting in undetectable or negligible systemic exposure of chloroprocaine. 
 
1.2.3 
Clinical pharmacology 
 
Topical anaesthetic agents block trigeminal nerve endings in the cornea and the conjunctiva 
only, leaving the intraocular structures in the anterior segment unanaesthetised.(4) 
The sensitive terminations of the fifth cranial nerve are concentrated in the cornea and ciliary 
body in the anterior part of the eye. These fibers are generally nonmyelinated type A-delta and 
type C. They are able to transmit the sensations of pain, temperature, and touch, and are blocked 
by lower concentrations of drugs in comparison with motor fibers. To suppress pain, sensitive 
nerves have to be blocked by anaesthetic agents along the nerve itself, or at its sensory 
terminations. Sensory termination block is the most important feature of topical anaesthesia. It 
involves the inhibition of sodium channels at nerve endings or receptors by the anaesthetic 
agents, thus blocking the production (and not the transmission) of nervous impulses.(5) 
The drug product is topically applied to the cornea. There is little or no measurable systemic 
absorption. 
 
 
 


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1.2.4 
Pharmacokinetics 
 
Chloroprocaine onset of action is rapid (usually within very few minutes) for infiltration, 
epidural, spinal anaesthesia and peripheral blocks and the duration of action is short, depending 
on the route and dosage used (usually not longer than 100 minutes). Chloroprocaine is rapidly 
metabolized in the plasma by hydrolysis of the ester linkage by the enzyme 
pseudocholinesterase resulting in the production of two major metabolites that can be 
considered 
pharmacologically 
inactive, 
i.e. 
β-diethylaminoethanol 
and 
2-chloro-4-
aminobenzoic acid (ACBA).(6) 
 
1.2.5 
Pharmacodynamics 
 
The mechanism of action of 2-chloroprocaine is the same of LAs that produce reversible loss 
of sensation, when applied to nervous tissue. Their primary site of action is the cell membrane 
and they produce their effect interacting directly with voltage-gated Na+ channels. It is now 
generally accepted that the mechanism of action of these compounds is based on the interaction 
with specific binding sites within the Na+ channels resulting in a blockade of the Na+ current. 
In higher concentrations, the other ion channels (K+, Ca++) might be affected as well.(7) 
 
1.2.6 
Clinical efficacy 
 
Similarly to lidocaine, chloroprocaine is used for short duration surgical procedures, mainly in 
the ambulatory setting, when a fast recovery and prompt home readiness are required. 
Based on data obtained from the clinical trials, the data available in literature as well as the 
post-marketing experience, several aspects underline the importance of chloroprocaine in the 
clinical practice supporting its reliable efficacy and safety profile. 
Chloroprocaine may be advantageous regarding ultra-short and short surgery, matching the 
important key benefits required for a local anaesthetic of choice in this setting. 
In particular, its effects lead to well tolerated and reliable blocks with rapid onset and quick 
recovery. 
As regards the specific development of chloroprocaine gel formulation of ophthalmological 
indication, it is important to point out that topical ocular anaesthesia is presently administered 
as oxybuprocaine (in Europe), proparacaine (in US) or tetracaine (both in Eu and US) drops, or 
lidocaine jelly (in US only). Topical anaesthetic agents are used with or without intravenous 
sedation. Topical anaesthesia should be reserved for the cooperative cataract patient who, with 
a dilated pupil, can tolerate the microscope light. 
Importantly, during recent years there has been an increase in the off-label use of lidocaine 2% 
gel for ophthalmic procedures.(8) A majority of these reports reported favourable patient-pain 
profiles with the use of viscous preparation as the sole anaesthetic agent. This led to 
development and approval by the Food and Drug Administration of Lidocaine hydrochloride 
3.5 % ophthalmic gel (Akten, Akorn Inc.) for ocular surface anaesthesia during ophthalmologic 
procedures. 
 
1.2.7 
Clinical safety 
 
The general overview of safety profile of chloroprocaine comes from large amount of data 
collected during the development of chloroprocaine 1% formulation indicated for intrathecal 
block and chloroprocaine 2% indicated for perineural block and also from the post marketing 
experience.  


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According to historical and literature evidence, data collected from the clinical studies 
confirmed the improved safety profile and the more favourable pharmacokinetic properties of 
chloroprocaine for the intended indications. All adverse events registered in clinical studies 
were consistent with the known safety profile of chloroprocaine. 
As a matter of fact, chloroprocaine is the most rapidly metabolized local anaesthetic currently 
used. In vitro chloroprocaine half-life is approximately 25 sec and it is cleared efficiently even 
in former preterm neonates also when receiving high epidural infusion rates.(9, 10) Rapid 
plasma degradation, rapid onset, lack of accumulation, makes chloroprocaine systemic toxicity 
less likely compared to other amide-type LAs.(11) Importantly, chloroprocaine is considered 
the local anaesthetic with the safest toxicological profile compared to other LAs, with a very 
low liability to induce cardiotoxic effects, due to its broad margin of safety and due to its ultra-
rapid metabolism (ester hydrolysis) after systemic resorption. Toxicity due to inadvertent 
systemic injection as well as toxicity due to absorption of LA may be avoided using the ester-
type LA, chloroprocaine. 
Plasma concentrations of chloroprocaine and its metabolite ACBA, as well as urinary ACBA 
excretion, were assessed as secondary endpoint in a phase 2 study, to confirm low systemic 
exposure to chloroprocaine following intrathecal administration, the most sensitive model to 
asses systemic toxicity. As expected, chloroprocaine was not detectable in any plasma sample 
of any patient. On the contrary, the metabolite ACBA was quantifiable in most plasma samples. 
The results of the study confirm the correlation between the peculiar plasmatic metabolism of 
chloroprocaine to its well-known safety profile. Indeed, even after administration via spinal 
route, the drug metabolite ACBA results quantifiable already after 10 minutes, meaning that as 
soon as chloroprocaine reaches the blood stream, its degradation is almost instantaneous. 
Of note, the ultra-rapid plasmatic degradation of chloroprocaine allows to avoid any systemic 
toxicity risk even in the rare case of inadvertent intravascular injection or unusually rapid 
absorption in areas with a high density of blood vessels. 
Also post marketing data strongly confirms the favourable safety profile of chloroprocaine. 
Chloroprocaine hydrochloride 10 mg/ml, solution for injection (under the brand names of 
Ampres®/Clorotekal®/Decelex®), has been commercialized in the EU countries as new 
chemical entity starting from 2013. No other product with chloroprocaine as active substance 
for intrathecal administration is present on the European market. Ampres 10 mg/ml, solution 
for injection is a LA used as one-shot product. According to the clinical practice, no defined 
daily dose has been established for chloroprocaine HCl because administered dose depends by 
different factors, such as indication and patient’s characteristics. Nonetheless calculations of 
exposure is based upon estimate number of ampoules sold in EU countries. According to the 
current European SmPCs for intrathecal use the maximum recommended dose of 
chloroprocaine hydrochloride in adult population is 50 mg (= 5 ml, one ampoule). Therefore, 
based on this exposure calculation, during the European and Swiss marketing experience 
approximately 300’000 patients were treated with intrathecal Chloroprocaine HCl in EU 
Countries.  
In Switzerland, where chloroprocaine is marketed as 0.5%, 1%, 2% and 3% solutions for 
injection, for local anaesthesia by infiltration, for intravenous anaesthesia, for peripheral nerve 
block and for epidural block, approximately 250’000 patients were exposed to the drug product 
till now.  
Evaluation of all safety data collected during the European post-marketing experience shows 
that no newly safety concerns have been identified in relation to the drug product and its safety 
profile. 
 


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1.2.8 
Risk and benefits 
 
Expected benefit of anaesthetic gel formulation include: 
 
• Coating of the eye without requiring repeated doses.  
• Longer duration than the drops solution due to its viscosity. This permits to obtain a 
better anaesthesia and higherexposure to the drug. 
• Reduced systemic absorption through the nasolacrimal system which translates into a 
reduced potential for systemic toxicity.  
• The majority of patients treated with gel preparations do not suffer from the corneal 
epithelial and surface irregularities that typically occur due to the toxic nature of other 
anaesthetic drop preparations.  
• Improved lubrication of surgical instruments and easier entry and exit through surgical 
wounds. 
 
Therefore, while all currently marketed in Europe ophthalmic preparations of topical 
anaesthesia are in drop solution form, a chloroprocaine gel formulation may represent an 
improved product that could lead to better anaesthesia.  
Chloroprocaine is the ideal anaesthetic for local anaesthesia in patients undergoing short-
duration surgeries, because it provides rapid onset of action, adequate potency, predictable 
duration, fast recovery, and the safest toxicological profile when compared to lidocaine and 
other LAs. 
This led Sintetica to the development of chloroprocaine 3% gel, a preservative-free, single-use 
ophthalmic preparation, as the sole anaesthetic agent to achieve ocular surface anaesthesia.  
 
Sintetica intends to perform a phase 3 study on patients undergoing cataract surgeryto assess 
the safety and efficacy of topical anaesthesia using chloroprocaine gel. 
This prospective, observer masked, randomised, controlled, equivalence phase 3 study will be 
conducted in approximately 4 European Countries. We consider that neither intrinsic ethnic 
factors such as race, genetic polymorphisms and genetic diseases, nor extrinsic ethnic factors 
such as culture, socio-economical factors, local medical practice and therapeutic approach may 
affect the efficacy and the safety of the drug product. As reported by internationally recognized 
guideline (CPMP/ICH/364/96, § 2.5.1) the effect of anaesthesia is dramatic, occurs as expected 
after treatment and is unlikely to have occurred spontaneously, the success of the anaesthesia 
can be evaluated with objective assessments. The anaesthetic qualities are related primarily to 
physicochemical properties of the various compounds. 
 
 
2 
STUDY OBJECTIVES 
 
2.1 
Primary objective 
 
The primary objective of the study is to assessthe equivalence of chloroprocaine3% gel, 
Sintetica SA (Test)to tetracaine 0.5% eye drop solution (Reference) in terms of proportion of 
subjects with a successful surface anesthesia*, without any supplementation**at T4(i.e., just 
before Intra Ocular Lens implantation)with chloroprocaine compared to tetracaine. 
 


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*Successful surface anesthesia: the ocular discomfort must be 0 (=No pain or discomfort)or 1 
(=Occasional pressure sensation, less than 5 separated times during procedure)without any 
supplementation at T4. 
**Supplementation: 
Intra-operative 
analgesia, 
including 
additional 
LA 
drops 
administration,after the beginning of the surgery. 
 
Light sedation before the start of the surgery is allowed for anxious patients, according to 
surgeon experience. 
Patients that will need general anesthesia or additional sedation because of excessive anxiety 
during the surgery will be excluded from the per protocol analysis, but they will not be 
considered as failures. 
 
2.2 
Secondary objectives 
 
The secondary study objectives are to comparethe clinical efficacy and safety of chloroprocaine 
3% gel to those of tetracaine 0.5% eye drop solution. 
 
 
3 
INVESTIGATIONAL PLAN 
 
3.1 
Overallstudy design 
 
This will be a prospective,randomized, multi-center, active-controlled, masked-observer, 
parallel-group, competitive equivalence study. 
 
The first patient first visit (FPFV) is defined as the 1st visit performed at the clinical center by 
the 1st screened subject (1stsigned inform consent).  
The last patient last visit (LPLV) is defined as the last visit performed by the last subject, i.e. 
the last visit foreseen by the study protocol, independently of the fact that the subject is a 
completer or a withdrawn subject. 
 
3.2 
Visit schedule: 
ü Selection visit (Day-90/Day-1), 
ü Inclusion visit (Day 1/ surgery day), 
ü Follow-up visit (Day 2, on site/phone visit), 
ü Final visit (Day 8±1), 
ü Optionalvisit (Day 28±3, phone visit). 
 
3.3 
Discussion of design 
 
The study has been designed to assessthe equivalence of chloroprocaine 3% gel (Test) with 
respect to tetracaine 0.5% solution (Reference) in surface anesthesia. 
 
In designing the study, the following guidelines were taken into consideration: ICH E9 
guideline on Statistical principles for clinical trials; the Guideline on the choice of the non-
inferiority margin (CPMP/EWP/2158/99); and the Points to consider on switching between 
superiority and non-inferiority guideline (CPMP/EWP/482/99). 
 


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With regards to anesthesia, topical has become the most common form for routine cataract. 
Each patient will be allocated to a treatment arm according to a computer-generated 
randomization list. Patients in both groups will receive three drops of study products before 
surgery. (16) 
 
Choice for a masked observer:   
• The surgeon will be aware of the treatment administered. 
He will be in charge of instillation of the gel/drop, or a delegate if necessary.  
He will not be further involved in patient’s care and data recording for the study, and 
all the study variables will be evaluated and recorded by another investigator, masked 
to the formulation applied. 
The surgeon will be only involved in patient surgery and in assessment of surgical 
performance and surgeon global satisfaction. 
• An independent masked investigator will perform screening assessments, assess 
primary endpoint at D1 (patient discomfort), then patient global satisfaction and 
Adverse Event at D2 and overall secondary endpoints (clinical efficacy and ocular and 
systemic safety parameters) for each patient at D8. 
• The patient will be masked. 
 
 
3.4 
Study endpoints 
 
3.4.1 
Primary endpoint 
 
Τheprimary endpoint is the proportion of subjects in each treatment group with a successful 
surface anesthesia, without any supplementation at the time point T4.  
A successful surface anesthesia is equal to 1 and is defined as ocular discomfort equal to 0 (=no 
pain or pressure) or 1 (=occasional pressure sensation, less than 5 separated times during 
procedure). It is equal to 0 otherwise (e.g. ocular discomfort > 1).The discomfort of the patient’s 
operated eye will be assessed on the following 6-point ordinal scale: 
 
0. No pain or discomfort  
1. Occasional pressure sensation, less than 5 separated times during procedure 
2. Occasional burning or stinging sensation, less than 5 separated times during procedure 
3. Occasional burning or stinging sensation, more than 5 separated times during procedure 
4. Continuous sensation of stinging, burning, or pressure during procedure, tolerable 
5. Sensations in point 3 intensified, described as severe or non-tolerable. 
 
Treatments will be assessed at 4 different timepoints of the surgery by a masked observer: 
- 
T1: just before first incision 
- 
T2: end of capsulorhexis 
- 
T3: end of phacoemulsification 
- 
T4: right before IOL implantation. 
 
 
 


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3.4.2 
Secondary endpoints 
 
Clinical efficacy during surgery 
 
- 
Successful surface anesthesia at T1, T2 and  T3  based on patient questioning 
aboutthePatient’s operated eye discomfort, on the same 6-point ordinal scale.  
- 
Time to obtain sufficient anesthesia (use of forceps). 
- 
Total time of anesthesia 
- 
Blinking reflex dropping a water drop at the end of the surgery 
- 
Number of supplemental drops necessary for obtaining and/or maintaining anesthesia 
- 
Supplementary 
treatments 
(general 
anesthesia 
or 
intra-operative 
systemic 
analgesia,necessary for obtaining and/or maintaining, anesthesia 
- 
Total surgical time (time between the first incision and the end of surgery, 
corresponding to eye lid speculum removal) 
- 
Assessment of surgical comfort by the surgeon at each stage of the surgical procedure. 
(0) = uncomplicated 
(1) = slightly complicated 
(2) = complicated 
 
- 
Assessment of the global efficacy by the surgeon for anesthesia.  
(0) = Very satisfactory 
(1) = Satisfactory 
(2) = Unsatisfactory 
(3) = Very unsatisfactory 
 
Ocular and systemic safety 
- 
Ocular symptoms: pain, irritation/burning/stinging, photophobia, foreign body 
sensation. 
The ocular symptoms will be graded by the patient according to the following scale: 
(0) = Absent 
(1) = Mild 
(2) = Moderate 
(3) = Severe 
 
- 
Objective ocular signs (Slit Lamp Examination):palpebral edema, chemosis, 
conjunctival hyperemia, conjunctival discharge, follico-papillary conjunctivitis, corneal 
staining punctuations, anterior chamber cells and flare, and other objective ocular signs. 
(0) = None 
(1) = Mild 
(2) = Moderate 
(3) = Severe 
 
- 
Slit lamp examination and fluorescein test 
- 
Endothelial cells count (specular microscopy) 


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- 
Cornealthickness (pachymetry) 
- 
Best far corrected visual acuity 
- 
Funduscopy 
- 
Intra-Ocular Pressure 
- 
Vital signs (blood pressure and heart rate) 
- 
Adverse eventsoccurrence 
- 
Surgeon satisfaction “How do you consider the study product global tolerance?’’:  
 
(0) = Very satisfactory 
 
(1) = Satisfactory 
 (2) = Unsatisfactory 
(3) = Very unsatisfactory 
- 
Patient global satisfaction at D1 based on a 5-question questionnaire read by a masked 
observer. 
 
4 
STUDY POPULATION 
 
4.1 
Target population 
 
The study population will consist ofapproximately 342 evaluable subjects who will have to 
undergo cataract surgery in a single eye at a time. 
In case both eyes have to be operated, the patient could be included in the study only if both 
eyes are operated separately.  
The eye that will be randomized in the study will be the first eye that will be operated based on 
investigator decision. 
The second eye could be operated 7 days after the end of the study (that means 14 days after 
the surgery). 
 
4.2 
Inclusion criteria 
To be enrolledin this study, subjects must fulfil all these criteria: 
1. Signed and datedinformed consent 
2. Male or femaleaged ≥ 18 years 
3. Senile or pre-senilecataract 
4. Scheduled to undergo cataract surgery in a single eyeat a time (clear corneal self-sealing 
incisions - phacoemulsification – foldable intra-ocular lens surgery with injector) 
 
4.3 
Exclusion criteria 
Subjects meetingONE OR MORE of the following criteria at the selection visit will not be 
enrolled in the study: 
Ophthalmic exclusion criteria 
Ø Surgical conditions in the eye to be operated: 
1. Combined surgery 
2. Previous intraocular surgery 
3. Previous corneal refractive surgeries less than 6 months before screening 
 


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Ø Non-surgical conditions in the eye to be operated: 
4. Non Senile or non pre-senilecataract (e.g.: traumatic, pathological or congenital 
cataract) 
5. Pupillary abnormalities (irregular, etc.) 
6. Iris synechiae 
7. Eye movementdisorder (nystagmus, etc.) 
8. Dacryocystitis and all other pathologies of tears drainage system 
9. History of Inflammatory ocular disease (Iritis, uveitis, herpetic keratitis) 
10. Corneal, epithelial, stromal or endothelial, residual or evolutionary disease (including 
corneal ulceration and superficial punctuate keratitis) 
11. History of ocular traumatism, infection or inflammation within the last 3 months 
12. Pseudo-exfoliation, exfoliative syndrome 
13. Prior intravitreal injections within 7 days of the surgery 
14. Intra Ocular Pressur over 25mmHg under treatment  
Ø Ophthalmic conditions in the contra-lateral eye: 
15. Best corrected visual acuity < 1/10 
16. Patient already included in the study for phakoexeresis 
17. History of ophthalmic surgical complication (cystoid macular oedema, etc.) 
Systemic/non ophthalmic exclusion criteria 
Ø General history: 
18. Diabetesmellitus 
19. Surdity 
20. Parkinson disease 
21. Excessive anxiety 
22. Any other medical or surgical history, disorder or disease such as acute or chronic severe 
organic disease: hepatic, endocrine neoplasic, hematological diseases, severe 
psychiatric illness, relevant cardiovascular abnormalities (such as unstable angina, 
bradycardia, atrial fibrillation,uncontrolled hypertension: systolic blood pressure over 
140mm Hg, diastolic blood pressure over 90mmHg) and/or any complicating factor or 
structural abnormality judged by the investigator to be incompatible with the study. 
Ø Allergic history: 
23. Known hypersensitivity to sulfonamides products or any of the components of the study 
medications or to test products 
Specific exclusion criteria for women  
24. Pregnancy (positive pregnancy test), lactation 
25. Women of childbearing potential without an acceptable effective method of contraception 
(oral contraceptive, intra-uterine device, subcutaneous contraceptive implant)until end 
of the study participation 
OR 
26. Women not hysterectomized, not menopaused nor surgically sterilized. 
Exclusion criteria related to general conditions  
27. Inability of patient and/or relatives to understand the study procedures and thus inability 
to give informed consent 
28. Non-compliant patient and/or relatives (e.g. not willing to attend the follow-up visits, 
way of life interfering with compliance) 
29. Participation in anotherclinicalstudy 
30. Already included once in this study 


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31. Ward of court 
32. Patient not covered by the Social Security 
Exclusion criteria related to previous and concomitant medications / non-product therapies  
Patient using any of the following previous and concomitant medication / treatment (according 
to the described periods) will not be included in the study:  
 
NOT ALLOWED CONCOMITANT MEDICATIONS 
Before the surgery 
Surgery  
After surgery 
30 days 
15 days  
7 days 
Day 1 
Day 2 to Day 28 
Any change in concomitant anti-depressant medication ………….……………………………… 
Systemic opioids and morphinic drugs  ......................................................... . 
Topical ocular treatment with anaesthetic action*……………………….…. 
Prior intravitreal injections ……………………………….. 
 
Sulfonamides products,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 
Others systemic antalgics drugs (except paracetamol) ............... 
Any change in other systemic medication already ongoing 
before selection visit 
 
*except the pre-, peri-operative and post-operative therapeutics procedure to be followed according to the 
protocol. 
 
4.4 
Withdrawal criteria 
 
It will be documented whether or not each subject completed the clinical study. If, for a subject, 
study treatment or observations are discontinued, the type of discontinuation and the primary 
reason for discontinuation will be recorded. 
In case of lack of efficacy of the investigational products, the patient will be regarded as not 
having had a successful anesthesia. The patient will not be discontinued from the study. 
Patients who will present per-operative complications preventing primary endpoint assessment 
to be performed, will be withdrawn from the efficacy analysisand the standard treatment of the 
hospital will be applied. 
However, these patients will be followed for safety parameters assessments. 
The complications are the followings: 
• Capsular rupture. 
• Zonular disinsertion. 
• Vitreous exit. 
• Residual mass. 
• Implantation localised in the sulcus. 
• Implantation localised in the anterior chamber. 
• Long-lasting surgery (more than 30 minutes) 


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Moreover, if, in the opinion of the investigator, there is any other situation or condition which 
puts the subject at significant risk patients should be withdrawn from the study too. 
Any patient may voluntarily discontinue the study at any time he or she chooses (Declaration 
of Helsinki), without prejudice. The investigator may elect to discontinue a patient for reasons 
related to the study product (AE or unsatisfactory therapeutic response). In either event, details 
should be recorded on the patient source data and CRF and reported separately. 
Possible reasons for withdrawal include the following: 
• AEs leading to discontinuation from the study. 
• Patient’s request. 
• The patient is lost to follow-up: investigator must contact his/her patient to obtain more 
information (by phone, fax, regular mail or email…).  
If a patient discontinues prematurely the study after randomisation, the investigator will 
perform all the investigations planned at the final visit (visit 4). 
 
4.4.1 
Discontinuation procedures 
 
For any subject discontinuing from interventions and findings, the investigator will: 
Ø ask the subject to undergo, as far as possible, a final medical visit (Visit 4) to examine the 
subject's health conditions  
Ø arrange for alternative medical care of the withdrawn subject, if necessary 
Ø report in the source data and CRF date and time of the investigational product 
administration, and date and primary reason of study discontinuation 
Ø record in the source data and CRF any follow-up, if the subject is withdrawn for an AE 
 
Discontinued subjects will not be replaced. 
 
5 
CLINICAL SUPPLIES 
 
5.1 
Study Treatment 
 
5.1.1 
Description of products 
 
The analytical certificates will be enclosed with the investigational medicinal products (IMPs). 
 
5.1.1.1 
Test product 
 
TEST (T) 
 
IMP 
Chloroprocaine 3% 
Distributor 
Sintetica S.A., Switzerland 
Manufacturer 
Laboratoire Unither, France 
Pharmaceutical form 
Gel  
Dose 
Frequency 
1 drops 
3 times 
Administration route 
Topical instillation  


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5.1.1.2 
Reference product 
 
REFERENCE (R) 
 
 
IMP 
Tetracaine 0.5% 
Active substance 
Tetracaine 
Distributor 
Bausch &Lomb UK Ltd 
Pharmaceutical form 
Solution  
Dose 
Frequency 
1 drops 
3 times 
Administration route 
Topical instillation 
 
5.1.2 
Dose regimen 
 
Patients will be randomized to one of the two treatment groups to receive either chloroprocaine 
3% gel (Test) or tetracaine 0.5% solution (Reference) as topical anesthetics in 
phacoemulsification before surgery, according to the randomized, parallel-group design of the 
study. 
 
For Chloroprocaine 3% and Tetracaine 0,5% administration: three IMP drops 
instillation as follow: 
- 
1st Drop instillation, then wait for 5 minutes 
- 
Eye Disinfection, then wait for 2 minutes 
- 
2nd Drop instillation, then wait for 1 minute 
- 
3rdDrop instillation, then wait for 1 minute 
- 
Start of Surgery. 
 
Details on the IMP preparation before installation  will be given in the study manual. 
 
5.1.3 
Investigational product distribution 
 
The test and reference products will be administered by the surgeonor by his/her delegate. The 
investigational products will be exclusively used for the present clinical study and will only be 
administered to the subjects enrolled in the study.  
 
5.1.4 
Packaging and labelling 
 
Packaging and labelling will be carried out by the Sponsor according to the randomization list.  
All labels will be written in the local language. The content of the labelling is in accordance 
with the GMP specifications, according to the Annex 13 to the Good Manufacturing Practice 
and local requirements. 
 
5.1.5 
Storage conditions 
 
The test product will be stored at 15 - 25°C in a dry locked place, sheltered from light. The 
reference product will be stored at < 30°C and must not be frozen. 
Further details about study drug preparation and handling are reported in the IMP Manual 
provided to the investigators. 
 


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5.1.6 
Drug accountability 
 
The test and reference investigational products will be provided directly to the investigator by 
the sponsor. 
After receipt of the investigational products supply, the pharmacist or the person identified as 
the recipient of the study drug supply will confirm receipt throught the IRT system. 
At the end of the study, used, unused and partially used supplies of Test and Reference 
investigational products provided by the sponsor/manufacturer will either be destroyed on site 
(upon written authorization) or returned to the sponsor/manufacturer(upon written 
authorization), after assessment of drug accountability. 
 
5.2 
Randomization 
 
Patients will be centrally allocated to one of the two treatment groups by a dynamic 
minimization procedure stratifying bycenter. The dynamic minimization will use a stochastic 
treatment allocation algorithm based on the variance method. 
 
5.3 
Treatment allocation 
 
Patients will be allocated to the Test (chloroprocaine) arm or Reference (tetracaine) arm in a 
1:1 ratio.  
Each study center will receive a set of Test and Reference treatments. Each treatment unidose 
will be individually labelled and packaged (see section 5.2). 
 
5.4 
Masking 
 
This is a masked-observer study.  
 
• 
The surgeon placing the gel/drop will be aware of the treatment administered.  He/She 
will not be further involved in patient’s care, and data recording and all the study variables will 
be evaluated and recorded by another investigator, or his/her deputy, masked to the formulation 
applied. 
The surgeon will be only involved in patient surgery and in satisfaction assessment. 
• 
An independent masked investigator will evaluate sensory block and safety parameters 
for each patient. 
• 
The patient will be masked. 
The masking of the trial will be maintained for the entire duration of the study for the masked 
observer until database lock.However, participants may be unmasked during the trial for the 
occurrence of a medical emergency.  
 
Each IMP kit will be numbered according to a randomized kits list created by IDDI masked 
team and provided to supplier before the start of the study. The tracking, delivery and allocation 
of IMP kit numbers will be handled throught the IRT system.  
In case of emergency the investigator will connect the IRT system to perform a code break, 
revealing the treatment received by the patient and the exact content of each kits allocated to 
this patient. The investigators will be trained to the code break procedure at the beginning of 
the study and a user manual will be available for download into the IRT for the whole study 
lifecycle. 


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5.5 
Other Treatments 
 
No other drugs than Test and Reference products will be provided for the study. 
Patients included in the study will undergo the following medical care before surgery, the day 
of surgery and after surgery, according to site practice.  
Patients will be asked to stop their authorized ocular treatments the day before the surgery. 
 
Preparation of surgery: 
Ø In case ofanxious patients, the use of light sedation is allowed before the start of the 
surgery.  
The aim is anxiolysis without deep sedation, as patient are at risk of moving if they 
suddenly wake up. To prevent over sedation, small doses should be used and verbal 
contact maintained during surgery. 
Type of product that can be use: benzodiazepine drugs (e.g.: Midazolam, due to its short 
action time and short plasmatic half-life). 
Ø Eye disinfection according to sites practice,using topical antiseptic (e.g.: Povidone 
iodine 4% (on the skin) and ophthalmic Povidone iodine (ocular irrigation)) in order to 
keep the asepsis condition of the surgical area 
Ø Pupil dilatation: according to site practice, using mydriatic products that must not 
contain any analgesic. 
Ø Intraocular injectionof Ophthalmic viscoelastic:according to site practice,using 
products that must not contains any analgesic.  
Ø Intraocular irrigating solution: balanced salt solution (BSS) only. 
Ø Before start of the surgery, use sterile forceps to pinch bulbar nasal conjunctiva, once 
the operative drape is in place.  
It is of high importance that the patient does not see the forceps precisely. 
This procedure is to be performed with the drape on, under the light of the microscope.  
If the pinch to the conjunctiva is painful, then additional LA drops administration or 
intravenous analgesia using an analgesic with short duration of action and rapid 
elimination (e.gAlfentanyl),is to be performed according to surgeon decision, to 
decrease pain perception during surgery. 
 
During the surgery: 
Ø The incision length must be adapted to the size of the implant chosen by the surgeon 
(according to instructions for use) so that the pressure applied on the eye ball during 
implantation is not excessive. 
Ø Injection into the capsular bag at the last step of cataract extraction of antibiotic drug 
(e.g.: 0.1 ml cefuroxime solution at the concentration of 10 mg/ml prepared in sterile 
conditions with saline 0.9% (15)). 
Ø In case of excessive dilation of the pupil at the end of surgery (≥ 8mm after IOL injection 
and washing of viscoelastics), use of a miotic substance will be left to the investigator’s 
surgical habits. 


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Ø General anaesthesia or additional light sedation could be used during surgery in case of 
situations in which anxiety and/or movement of the patient prevents the investigator 
from performing the procedure in a sufficiently safe manner. 
In that case, patients will be excluded from per protocol analysis but will not be 
considered as failure. 
 
After surgery 
 
Post operative surgery follow-up will be conducted in accordance with sites current practices, 
using usual anti-inflammatory, corticosteroid and antibiotic drugs. 
Here is a list of class of postoperative drugs that could be used at each site for patient care 
according to sites practices: 
- Antibiotics (e.g.: Tobramycin, Azythromycin). 
- Corticoid (e.g.: dexamethasone). 
- Non-steroid anti-inflammatory drugs (e.g.: Indomethacin, Ketorolac, Flurbiprofen) after 
surgery. 
 
6 
STUDYCONDUCT 
 
The study procedures and their implantation schedule are summarizedin Table 1. 
 
6.1 
Study visits 
 
The study protocol foresees one study treatment for each patient, followed by post-operative 
recovery and discharge.Maximum study duration will be approximatively28 days.  
 
The study will include a Selection visit (Visit 1 - Day -90/Day -1), an Inclusion visit (Visit 2 - 
Day 1/surgery day), a Follow-up visit (Visit 3 - Day 2, phone call), a finalFinalvisit (Visit 4 - 
Day 8), and anOptionalvisit in case of AEat visit 4 (Visit 5 - Day 28, phone call):  
 
Ø Screening phase 
§ Selection-Visit 1: between Day -90 and Day -1. The procedures will be conducted by 
the masked-observer.  
- Patient information about the aims, procedures and possible risks of the study and 
signature of the informed consent form before any study related procedures 
- Urine pregnancy test 
- Recording of demography data 
- Ocular and systemic medical and surgical histories  
- Previous and concomitant ocular and non-ocular treatments 
- Ocularsymptoms 
- Best-far corrected visual acuity in both eyes 
- Slit lamp examination and fluorescein test  
- IOP in both eyes  


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- Endothelial cell count by specular microscopy 
- Funduscopy 
- Pachymetry 
- Macular optical coherence tomography  
- Cardiovascular parameters (blood pressure and heart rate) 
- Verification of the study inclusion/exclusion criteria 
Ø Interventional phase 
§ Inclusion - Visit 2: Day 1 (surgery day). The procedures will be conducted by the 
surgeon except the assessement of primary criteria and the check of cardiovascular 
parameters that will be carried out by the masked-observer. 
- Before anesthesia, patient’s questioning about previous and concomitant ocular and 
non-ocular treatments 
- Verification of the study inclusion/exclusion criteria 
- Urine pregnancy test (only if Visit 2 is more than 30 days after visit 1) 
- AEs occurrencesincepreviousvisit 
- Patient’s allocation in one of a treatment group (chloroprocaine 3% gel (Test) or 
tetracaine 0.5% eye) 
- Cardiovascular parameters monitoring (blood pressure and heart rate) 
- Patient discomfort assessment at T1 with forceps (just before the first incision), T2 
(end of capsulorhexis), T3 (end of phacoemulsification), and T4 (just before Intra 
Ocular Lens implantation) 
- Surgical performance assessment 
- Surgeon global satisfaction assessment 
- Dose-regimen compliance  
Ø Follow-up phase 
§ Follow-up - Visit 3: Day 2 (on-site visit or phone visit according to site current practice). 
The procedures will be carried out by the masked-observer. 
- Patient’s questioning about concomitant ocular and non-ocular treatments 
- AEs occurrence  
- Patient global satisfaction (questionnaire read by masked-observer)of the surgery. 
 
§ Final Visit - Visit 4: Day 8 ± 1 dayon-site visit. The procedures will be carried out by 
the masked-observer. 
- Patient’s questioning about concomitant ocular and non-ocular treatments 
- Ocular symptoms 
- Best-far corrected visual acuity in both eyes 


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- Slit lamp examination and fluorescein test  
- IOP in both eyes  
- Endothelial cell count by specular microscopy 
- Funduscopy 
- Pachymetry 
- Cardiovascular parameters (blood pressure and heart rate) 
- AEs occurrence  
If AE occurred during Follow-up of the study (between Day 1 and Day 8, an optional visit 
will be performed at day 28 (phone call). 
 
§ Optionalvisit – Visit 5: Day 28 ± 3 days (phone visit). The procedures will be carried 
out by the masked-observer only in case of AE on-going at V4. 
- Patient’s questioning about concomitant ocular and non-ocular treatments 
- AEs occurrence  
 
§ Premature Discontinuation Visit 
If premature discontinuation occurs before randomization, assessments of visit 2 (until before 
randomization) are to be performed. 
If premature discontinuation occurs after randomization, assessments of visit 4 are to be 
performed. 
 
6.2 
Diet and lifestyle 
 
Study participants will undergo study procedures as outpatients (day case surgery). Patients will 
arrive at the clinical center in the morning of the scheduled surgery dayand will be discharged 
in the evening of the same day, except in the event of unforeseen complications or safety 
concerns. 
 
 
6.3 
Study procedures 
 
6.3.1 
Efficacy measures 
6.3.1.1 
Patient’s discomfort assessement during surgery 
The discomfort of the patient’s operated eye will be assessed on a 6-point ordinal scale at 4time 
points during surgery:   
- 
0: No pain or discomfort  
- 
1:  Occasional pressure sensation, less than 5 separated times during procedure 
- 
2: Occasional burning or stinging sensation, less than 5 separated times during 
 
procedure 
- 
3: Occasional burning or stinging sensation, more than 5 separated times during 
 
procedure 
- 
4:  Continuous sensation of stinging, burning, or pressure during procedure, tolerable 
- 
5:  Sensations in point 3 intensified, described as severe or non-tolerable. 


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Based on the aforementioned scale, successful surface anaesthesia is defined as no 
pain/discomfort (scale=0) or occasional pressure sensation,less than 5 separated times during 
procedure (scale=1).  
 
The discomfort of the patient’s operated eye will be assessed at4 different timepoints of the 
surgery: 
-T1: just before first incision 
-T2: end of capsulorehexis 
-T3: end of phacoemulsification 
-T4: right before Intra Ocular Lens implantation 
 
6.3.1.2 
Blinking assessement 
§ At the end of surgery: the blinking reflex will be assessed by dropping a water drop.  
 
6.3.1.3 
Anesthesia assessement 
§ Time to obtain sufficient anesthesiaassessed with forceps (after 3rd drop instillation, just 
before start of surgery):  
§ 
Total time of anesthesia:from the instillation of the 3 drops of chloroprocaine 3% gel 
(Test) or tetracaine 0.5% (Reference) to the end of surgery (end of anesthesia assessed 
with forceps, every 5 minutes from the end of surgery):  To assess the duration of 
anesthesia, the testing will be concluded when the study subject reported 'pain' on two 
successive tests with 5 minutes in between.   
§ Number of supplemental drops necessary for obtaining and/or maintaining anesthesia 
§ Supplementary treatments (general anesthesia or intra-operative systemic analgesia) 
necessary for obtaining and/or maintaining anesthesia 
 
6.3.1.4 
Total Surgical Time (using chronometer) 
It is the total time between the first incision and the end of surgery, corresponding to 
eyelid speculum removal.  
 
6.3.1.5 
Surgeon assessments 
§ Surgical confortassessement at each stage of the surgical procedure (T1, T2, T3 and 
T4): 
(0) = uncomplicated 
(1) = slightly complicated 
(2) = complicated 
 
§ Global efficacy assessemeent for anesthesia: 
(0) = Very satisfactory 
(1) = Satisfactory 
(2) = Not very satisfactory 
(3) = Unsatisfactory) 
 


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6.3.2 
Safety measures 
6.3.2.1 
Ocular and systemic tolerability assessment at visit 1 and visit 4 
§ Ocular symptoms: pain, irritation/burning/stinging, photophobia, foreign body 
sensation. The ocular symptoms will be graded by the patient according to the following 
scale: 
(0) = Absent 
(1) = Mild 
(2) = Moderate 
(3) = Severe 
§ Objective ocular signs (Slit Lamp Examination): palpebral edema, chemosis, 
conjunctival hyperemia, conjunctival discharge, follico-papillary conjunctivitis, corneal 
staining punctuations, anterior chamber cells and flare, and other objective ocular signs. 
(0) = None 
(1) = Mild 
(2) = Moderate 
(3) = Severe 
 
6.3.2.2 
Endothelial cells count (specular microscopy) at visit 1 and visit 4 
The number of endothelial cells count will be performed in the central cornea with 
specular microscopy and will be reported in cell/mm2. 
 
6.3.2.3 
Corneal thickness (pachymetry) at visit 1 and visit 4 
Measurement of the central corneal thickness will be performed with a pachymeter 
 
6.3.2.4 
Best far corrected visual acuity at visit 1 and visit 4 
Far BCVA will be measured on both eyes using the same chart throughout the study. 
 
6.3.2.5 
Fundoscopy at visit 1 and visit 4 
Fundus examination in both eyes: any detected abnormalitywill be recorded. 
 
6.3.2.6 
Slit lamp examination at visit 1 and visit 4 
The following ocular signs will be evaluated at the slit lamp examination on a 0-3 scale: 
- 
Blepharitis 
- 
Eyelid oedema 
- 
Iris pigmentation modification  
- 
Abnormal eyelashes aspect 
- 
Folliculo-papillary conjunctivitis 
- 
Other ocular abnormality. 
 
6.3.2.7 
Corneal fluorescein staining at visit 1 and visit 4 
Approximately 2-3 minutes following fluorescein instillation, corneal staining will be 
evaluated in both eye, using a slit lamp, based on the Oxford scale (grades of 0-5). See 
appendix 1. 
 
6.3.2.8 
Intra-Ocular Pressure at visit 1 and visit 4 
IOP will be assessed according site current practice (air puff or applanation tonometer); 
the same measurement is to be used for the same patient throughout the study. 
 


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6.3.2.9 
Vital signs measurements (blood pressure, heart rate) 
Will be assessedat visit 1 and visit 4 andmonitored during the surgery) 
 
6.3.2.10 
Surgeon satisfaction “How do you consider the study product global tolerance?”: 
(0) = Very satisfactory 
(1) = Satisfactory 
 (2) = Not very satisfactory 
 (3) = Unsatisfactory 
 
6.3.2.11 
Patient global satisfaction at Follow-up visit(Visit 3 - D2) 
Based on a question read by a masked observer, with 5 possible answers (Likert 
satisfaction scale) to assess the patient satisfaction about the overall anesthesia during 
the surgery: 
“Overall, how satisfied are you with the topical study product used for your local 
anesthesia during your cataract surgery?” 
• 
Verysatisfied 
• 
Globallysatisfied 
• 
Neithersatified, norunsatisfied 
• 
Globallyunsatisfied 
• 
Veryunsatisfied 
 
The patient will have the opportunity to add any comment to complete his/her answer. 
 
6.3.2.12 
Adverse events recorded throughout the study 
Surgery-related pain at the site of surgery will not be recorded as an adverse event, but 
assessed as traitement success or failure. 
A brief summary of AE definition, classification and management is reported below. 
 
6.3.2.13 
Definitions 
 
Ø Adverse event (AE) 
Any untoward medical occurrence in a subject or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have to have a causal relationship 
with treatment. 
 
Ø Adverse Drug Reaction (ADR) 
Any noxious and unintended response to a medicinal product (i.e. a causal relationship 
between a medicinal product and an AE is at least reasonably possible in the investigator's 
or sponsor's opinion, the relationship cannot be ruled out) resulting not only from the 
authorized use of a medicinal product at normal doses, but also from medication errors and 
uses outside the terms of the marketing authorization, including the misuse and abuse of the 
medicinal product. 
 
Ø Pre-treatment AE (PTAE) 
Any AE occurring before the first dose of a medicinal product and not worsening after the 
first dose. The following medical occurrences and clinical investigations are the only 
clinically significant events which, according to the investigator judgement, can be defined 
and recorded as PTAEs: 


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Ø trauma(fractures,sprains, strains, falls, domestic accidents, car accidents, etc.) 
occurred after thesignature of theinformed consentand before the first medicinal 
product administration 
Ø new measurements(vital signs, ECG, laboratory parameters, etc.), performed after 
thesignature of theinformed consentand before the first medicinal product 
administration, which show aclinically significant worseningin comparison with a 
previous (baseline)measurement performed after thesignature of theinformed consent 
Ø any disease diagnosedafter the anamnesis recorded at visit 1and before the first 
medicinal product administration 
Ø physical and mentalstatus changes(pre-syncope, anxiety, dizziness, fainting, etc.) 
occurred after thesignature of theinformed consentand before the first medicinal 
product administration 
 
Ø Treatment-emergent AE (TEAE) 
Any AE occurring or worsening after the first dose of a medicinal product 
 
Ø Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose:  
Ø results in death 
Ø is life-threatening 
Ø requires inpatient hospitalization or prolongation of existing hospitalization 
Ø results in persistent or significant disability/incapacity 
Ø is a congenital anomaly/birth defect 
Ø is an important medical event that may jeopardize the subject’s health status or may 
require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events are cancer, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse 
 
Ø Unexpected ADR:  
An ADR the nature or severity of which is not consistent with the Reference Safety 
Information (RSI) 
 
Ø Reference Safety Information (RSI):  
In order to assess whether an adverse reaction is expected, the Investigator’s Brochure (IB) 
for the test formulation and the SmPC for the reference formulation will be used. 
 
Ø Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An ADR that is both unexpected (not consistent with the RSI) and also meets the definition 
of a SAE. 
 
6.3.2.13.1.1 AEs monitoring window 
Ø Start of monitoring: from immediately after the signature of the informed consent 
Ø End of monitoring: last follow-up visit/ETV  
An AE occurring after the last follow-up visit/ETV and coming to knowledge of the 
investigator (e.g. by spontaneous reporting by study subjects) must be recorded only if it is 
an ADR, according to the investigator’s judgment. 
 


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6.3.2.13.1.2 AEs recording 
All AEs derived by spontaneous, unsolicited reports of the subjects, by observation and by 
routine open questioning should be collected and reported. 
The following minimal information will be recorded for an AE in the source documents and 
later transcribed into the CRF: 
 
1. Adverse Event: progressive number of the adverse event or progressive number of 
follow-up of the adverse event  
2. Description: verbatim description of the adverse event 
 
Start Date/Time: start date/time of the adverse event or  
Follow-up Date/Time: follow-up date/time of the adverse event  
3. End Date/Time: end date/time of the adverse event  
4. Affected Body Area: anatomical location relevant for the event; in case of an 
ophthalmological AE, then it needs to be recorded whether or not it is the study eye 
5. Whether the adverse event start before or after the first intake of the study drugor 
whether the adverse event has worsened or not after the first intake of the study drug 
6. Last Study Drug Administration Date/Time Before Onset: if the adverse event started 
after the first administration of the study drug, the date/time of last administration of 
the study drug before the onset of the adverse event or 
Last Study Drug Administration Date/Time Before Worsening: In case of treatment 
emergent adverse event, the date/time of the last administration of the study drug(s) 
before the worsening of the adverse event.  
7. Investigator's opinion about the reasonable possibility of a causal relationship with the 
study drug.  
8. Investigator's opinion about other causal relationship (e.g. non study drug, concomitant 
therapy, study device, etc.).  
9. Severity: the severity or intensity of the event 
1 Mild 
2 Moderate 
3 Severe 
 
10. Pattern: Used to indicate the pattern of the event over time 
1 Single Event 
2 Continuous 
3 Intermittent 
11. Serious Adverse Event  
12. Action Taken with Study Drug: describes changes to the study drug as a result of the 
event. It is specifically for actions taken with the study drug 
1 Dose Not Changed 
2 Dose Increased 
3 Dose Reduced 
4 Drug Interrupted (i.e. temporary stop) 
5 Drug Withdrawn (i.e. definitive stop) 
6 Not Applicable (e.g. drug administration not started yet or completed) 
7 Unknown 
13. Concomitant Therapy: if a concomitant therapy is given, it must be reported in the 
specific CRF forms 


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14. Study Discontinuation: if the adverse event cause the subject to be discontinued from 
the study 
15. Other Action Taken: other actions taken as a result of the event that are unrelated to 
dose adjustments of study drug 
16. Outcome: Outcome of the event 
1 Recovered/Resolved 
2 Recovered/ResolvedwithSequelae 
3 Recovering/Resolving 
4 Not Recovered/Not Resolved 
5 Fatal 
6 Unknown 
 
6.3.2.13.1.3 SAEs reporting 
The pharmacovigilance will be under the control of the Sponsor, Sintetica SA.  
The investigator must report to the sponsor any SAE within 24 h of becoming aware of the 
event. The Investigator, within the same timeframe, should also inform the study monitor 
and the CRO. The investigator shall notify the competent Ethics Committee (EC) within 7 
days of any SAE with lethal outcome occurred during a study, when required. If the 
Investigator is initially unable to obtain all the necessary details for completing the form, 
he/she should in any case transmit all the available information. The Investigator should 
provide an appropriate follow-up of SAEs to all concerned parties. 
Seriousness and causality must be assessed by the investigator. Expectedness is usually 
assessed by the sponsor. 
If the investigator is unable to assess the causality it is recommended to adopt a conservative 
approach and treat the event as a suspected adverse reaction until follow-up information is 
available. 
The sponsor may also make an assessment of causality, independent of that of the 
investigator. The most conservative approach should be taken when it comes to regulatory 
reporting. Under no circumstances should the sponsor downgrade the investigator's opinion 
or put the investigator under pressure to change his/her assessment. In case of disagreement, 
both the opinion of the investigator and the sponsor should be provided on the report. 
The sponsor will evaluate the SAE expectedness on the basis of the RSI. 
 
6.3.2.13.1.4 SUSARs management 
The clock for initial expedited reporting starts as soon as the information containing the 
minimum reporting criteria has been received by the sponsor (day 0). 
For fatal and life-threatening SUSARs the EC and Competent Authority (CA) should be 
informed as soon as possible and in any case within 7 days. 
If the initial report is incomplete, e.g. not all the information/assessments were available, a 
complete report should be sent within an additional 8 days. 
SUSARs which are not fatal and not life-threatening are to be reported within 15 days. 
The minimum information to be reported includes: 
Ø Valid EudraCT number (where applicable) 
Ø Sponsor studynumber 
Ø One identifiable codedsubject 
Ø One identifiable reporter 
Ø One SUSAR 
Ø One suspect IMP (including active substance name, code) 


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Ø A causality assessment (a reasonable possibility of a causal relationship with the study 
drug can be excluded only if there is information supporting this decision, otherwise 
it cannot be excluded). 
 
6.3.2.13.1.5 Otherevents qualified for expedited reporting 
Other safety issues also qualify for expedited reporting when they might materially alter the 
current benefit-risk assessment of a medicinal product or would be sufficient to consider 
changes in the medicinal product administration or in the overall conduct of the trial, for 
instance: 
Ø single case reports of an expected serious adverse reaction with an unexpected 
outcome (e.g.: a fatal outcome) 
Ø an increase in the rate of occurrence of an expected serious adverse reaction, which is 
judged to be clinically important. 
Ø post-study SUSARs that occur after the subject has completed a clinical trial and are 
reported to the investigator by the subject. 
Ø new events relating to the conduct of the trial or the development of the medicinal 
product likely to affect the safety of the subjects, such as: 
- a SAE which could be associated with the trial procedures and which could modify 
the conduct of the trial 
- a significant hazard to the subject population such as lack of efficacy of a medicinal 
product used for the treatment of a life-threatening disease 
- a major safety finding from a newly completed animal study (such as carcinogenicity) 
or from other clinical trials. 
 
6.3.2.13.1.6 SAEs: contacts 
The Pharmacovigilance can be contacted using the phone and fax numbers stated in this 
protocol.  
SAEs must be reported on SAE reporting forms and faxed/emailed within 24 H to sponsor - 
contact details below: 
Corporate Drug Safety Unit 
Fax: +41(0)91.646.85.61 - Phone: +41(0)91.640.42.50 
Email: corporate_drug_safety@sintetica.com 
 
6.4 
Description of specificprocedures 
 
6.4.1 
Procedures for post-operative recovery 
 
At the end of the surgical procedure, patients will be moved to the post-operative recovery 
room, where they will stay until the criteria for discharge are met according to the hospitals’ 
standard procedures. In general, to be discharged patients must have a score ≥ 9 on the modified 
Aldrete’s scoring scale for day case surgery and no pain. Hemodynamic variables must be stable 
and SpO2 must be acceptable (> 92%) without oxygen therapy. Patients will be asked about any 
adverse events, and to possible allergic reactions (e.g. urticaria). If all the criteria are met and 
no adverse reactions occur, the patient will be discharged. 
 
6.4.2 
Procedures for telephonic follow-up 
 
On Day 1 and on Day 28 (± 3 days) after surgery, a deputy of the Investigator, not aware of the 
administered treatment, will contact the patients by telephone and will question them about any 
adverse reactions which might have occurred after discharge, with particular attention to any 


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sign of late systemic toxicity, local toxicity, neurological symptoms and allergic 
reactions.Concomitant ocular and non-ocular treatments will also be assessed on these days. A 
questionnaire on patient global satisfaction will be read by a masked observer on D1.   
 
 
7 
STATISTICAL METHODS 
 
Data documented in this study and the parameters measured will be evaluated and presented 
using descriptive statistics, i.e. arithmetic mean, SD, minimum, median and maximum values 
for quantitative variables, and absolute and relative (%) frequencies for qualitative variables. 
The statistics will be reported by treatment group.  For the variables recorded for both eyes, the 
statistics will be reported by treatment group, separately for the eye to be operated and for the 
other eye. Confidence intervals will be reported, where appropriate. If not stated elsewhere, 
these intervals will be two sided in each case and provide 95% confidence.  
Efficacy will be evaluated in the operated eye using mixed effects models (adjusting for center 
and country using random effects).  
 
Not available data will be evaluated as “missing values”.A statistical analysis plan (SAP) will 
be provided before database closure. The statistical analysis will be performed using RStudio 
v. 1.2.5001 and/or IBM SPSS Statistics v. 25 (or newer) for Windows. 
 
7.1 
Analysis Sets 
 
The following analysis sets will be considered: 
Safety set: 
All patients enrolled in the study, for whom there is evidence that 
they used study medication and for whom any follow-up information 
is available. 
Full Analysis Set (FAS): All patients enrolled in the study for whom any follow-up efficacy 
information is available. 
Per Protocol Set (PPS): 
All patients of the FAS who did not show any major 
protocolviolation. 
The exclusion of patients from the analysis sets will be discussed during a blind review meeting 
that will be held before database lock. 
The statistical analysis of the onset data and of efficacy will be performed on the basis of the 
FAS and the PPS.  The primary population for the assessment of efficacy will be the PPS, while 
the statistical analysis on the FAS population will be considered as sensitivity analysis. If there 
are any major discrepancies between the results of the 2 analyses, they will be  the  subject  of  
explicit  discussion  and  interpretation. The analysis of safety will be performed on the basis 
of the safety set.Patients who will present per-operative complications preventing primary 
endpoint assessment to be performed, will be withdrawn from the efficacy analysis and the 
standard treatment of the hospital will be applied. Such patients' characteristics will be tabulated 
and compared with the characteristics of the rest of the patients (i.e. patients who will not 
present per-operative complications) to investigate potential between group differences. 
 


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7.2 
Sample size and power considerations 
 
Given the followingdefinitions: 
πE = Proportion of success: Experimental treatment (Chloroprocaine 3% gel formulation); 
πS = Proportion of success: Standard treatment (Tetracaine 0.5% eye drop); 
є = πE – πS (difference between Experimental and Standard treatment proportion of success); 
d = Equivalence margin. 
The sample size for the two-sided equivalence hypothesis test:  
H0: |є|≥ d vs.  HA: |є|<d 
can be computed according to the formulas: 
NS = ceiling {[(Z1-α+ Z1-β/2) 2/ (|є| - d) 2] * [πE x (1- πE)/k + πS x (1- πS)]} and  
NE = k * NS(18) 
where: 
k = Balancing ratio between the two treatment arms (k=1 for balanced group) 
NE = Number of subjects included into the per protocol set for the Experimental treatment 
(Chloroprocaine 3% gel formulations); 
NS = Number of subjects included into the per protocol set for the Standard treatment 
(Tetracaine 0.5% eye drop).  
In such anequivalence study, sample size depends on the type I error (α) (which is usually set 
equal to 0.05), the type II error (β) (set equal to 0.20 for the present trial, corresponding to a 
power of 80%), the equivalence margin d and the expected proportion of success in both 
treatment groups. In such trials, sample size increases as α and/or β and/or d decrease. The 
expected proportion of success and the equivalence margin d is estimated based on studies 
carried out in the past, whose results are reported in the literature. In our case, no such study 
was available. Nevertheless, we would expect an equivalence margin d to range between 0.05 
to 0.15. 
To interpret the aforementioned range for the margin d, the estimate of d=0.10 corresponds to 
a difference in efficiency of 20%. The margin d=0.15 corresponds to a stricter difference in 
efficiency of 30%. Since there were no previous results available in the literature for our case, 
we tried different parameter values to check how they affect the estimated sample size. Table 2 
provides the estimates for sample size per arm, given that the type I error (α) is set equal to 0.05 
and assuming that the expected proportion of success is set equal to 90% for both treatment 
arms. Note, that in the last column of Table 2 we provide the sample size estimates per arm 
given that there would be an exclusion rate equal to 10%, which is typical in such a study. 
 


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Table 2 
Sample size per arm: type I error (α)=0.05 and expected proportion of 
success =90%, for both treatment arms 
Type I error 
(α) 
Type I error 
(β) 
Equivalencemargin 
d 
Sample 
size 
per arm 
Sample size per 
arm adjusted for 
a 10% exclusion 
rate 
0.05 
0.20 
0.10 
155 
171 
As shown in Table 2, for the expected equivalence d=0.10, the estimated sample size is 
171subjectsper group, after adjusting for a possible exclusion rate of 10%. Taking these results 
into account along with the fact that in the literature we could not find studies that tested topical 
anaesthesia in cataract surgery enrolling more than about 200 patients overall, we suggest to 
enrol 171patients per arm, i.e. 342patients overall. Such a sample size would allow for a robust 
and reliable estimate of the clinical efficacy of 3% chloroprocaine gel and tetracaine 0.5% eye 
drop as topical anaesthesia in phacoemulsification. 
 
7.3 
Handling of missing data 
 
7.3.1 
Methods for replacing missing data 
 
Ø Multiple imputation (MI) under missing at random (MAR) assumption: multiple imputation 
is a general approach to the problem of missing data that aims to allow for the uncertainty 
about the missing data by creating several different plausible imputed data sets and 
appropriately combining results obtained from each of them. Missing at random (MAR) 
approach assumes that any systematic difference between the missing values and the 
observed values can be explained by differences in observed data. The use of multiple 
imputation under MAR assumption provides unbiased estimations of the parameters and 
allows evaluating the uncertainty of parameters’ estimation due to the presence of missing 
data. Separate multiple imputations will be performed for each treatment arm. 
Ø Missing as Failure (MF): missing values of the primary end-point are considered as block 
failures regardless of the treatment arm. 
Ø Worst Case (WC): missing values of the primary end-point are considered as block failures 
if the patients receive Test product and as block successes if the patients receive Reference 
product. 
 
7.3.2 
Replacement rules for each analysis set 
 
Ø FAS: missing data of the primary end-point (if any) will be replaced according to MI under 
MAR assumption method, MF method and WC method in three different sensitivity 
analyses. Missing data of the secondary end-points will not be replaced. 
Ø PPS: all missing data will not be replaced. 
Ø Safety set: all missing data will not be replaced. 
 


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7.4 
Demographic, baseline and background characteristics 
 
Critical demographic characteristics will be examined according to qualitative or quantitative 
data. Qualitative data will be summarized in contingency tables. Quantitative data will be 
summarized using classic descriptive statistics, i.e. arithmetic mean, SD, minimum, median and 
maximum values. 
 
7.5 
Analysis of efficacy parameters 
 
The efficacy analysis will be performed on the PPS set (primary efficacy analysis) and FAS 
(sensitivity analysis). The primary endpoint of the study is defined as the proportion of subjects 
in each treatment group with a successful surface anesthesia, without any supplementation at 
the time point T4.  
Since randomization will take centers into account, centers need to be accounted for in the 
statistical analysis. Therefore, mixed effects analysis will be used adjusting for potential centers 
and/or country effect using random effects models. Specifically, since the primary endpoint 
concerns proportions, mixed effects logistic regression will be performed, in which the log odds 
of the outcomes are modeled as a linear combination of treatment and random effects account 
for potential clustering. 
If βis the coefficient that corresponds to mixed effects model treatment effect, then the null 
hypothesis under investigation is(19): 
 
H0: |β| ≥ d vs.  HA: |β| <d, 
 
which correspond to: 
 
H0: β ≥ d  or β≤-d vs.  HA: β< d  or β>-d  . 
 
The two test statistics are computed as: 
 
!" =
$%&'
()*
+   and   !, =
$%&(&')
()*
+       , 
 
where /0 and 12$
3 are the estimated treatment effect and its associated standard error from the 
mixed effects model. The overall null hypothesis that the treatment effect β falls outside the 
equivalence interval is rejected if both test statistics are rejected:  
 
t1 ≤  -tα, dfand t2 ≥ t1-α, df, 
 
where df refers to the appropriate degrees of freedom from the mixed effects model. 
 
 
 


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7.6 
Safetyand tolerability evaluation 
 
Ø AEs 
Adverse events (AEs) are described analytically in 6.3.2 and will be coded by System Organ 
Class (SOC) and Preferred Term (PT), using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), 
according to the period of occurrence, as follows:  
Ø PTAEs: all AEs occurring before the first dose of IMP and not worsening after the first 
dose of IMP 
Ø TEAEs: all AEs occurring or worsening after the first dose of IMP 
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarised by treatment and overall. The number and 
percentage of subjects with any TEAE and the number of TEAEs will be tabulated by SOC and 
PT, seriousness, relationship to treatment and severity. 
 
Ø Physical examination 
Significant findings/illnesses, reported after the start of the study and that meet the definition 
of an AE (see section6.3.2.12), will be recorded in the subject source documents.Date of the 
physical examination andoverall investigator’s interpretation (as normal, abnormal not 
clinically significant [NCS] or abnormal clinically significant [CS]) will be reported in the CRF. 
 
Ø Vital signs 
Values of vital signs will be listed and summarized by descriptive statistics. 
 
 
8 
DATA MANAGEMENT PROCEDURES 
 
8.1 
Data collection – CRFs 
 
The investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the electronic CRFs. He must also check that the data reported in the eCRFs 
correspond to those in the subject’s source documents.  
 
8.2 
Unique subject identifier 
 
All the subjects who sign the informed consent form for the present study will be coded with 
“unique subject identifiers” when data are extracted from the study database into the domains 
of the CDISC SDTM model. 
 
The unique subject identifier consists of the 3-letter country code (ITA, ESP, SVK), the center 
number (301, 302, …), and the 3-digit patient number (001, 002, …). 
 
8.3 
Data management 
 
Data management will be performed by IDDI under the responsibility of the sponsor.  The 
sponsor will provide the investigator site with a web base electronic data capture (EDC) system 


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that is fully validated and conforms to 21 CFR Part 11 requirements.  Investigator site staff will 
not be given access to EDC system until they have been trained on the EDC system.  
 
Adverse events and medical history will be coded using MedDRA.   
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Dictionary. 
Data queries will be raised for inconsistent, implausible or missing data which will allow for 
modification or verification of the entered data by the investigator staff. All entries to the study 
database will be available in an audit trail. The data will be validated as defined in the Data 
Management Plan.  Quality control procedures will be applied to each stage of data handling to 
ensure that all data are reliable and have been processed correctly. 
 
When all data have been declared to be cleaned, validated and coded, the database will be 
locked and the treatment codes will be unblinded to be made available for data analysis.  
 
 
9 
STUDY MONITORING AND AUDITING 
 
9.1 
Monitoring 
 
The monitoring visits will be conducted by appropriate staff of  Iris Pharma and its 
representatives, Link Neuroscience and health Care and of the Sponsor. Two monitors will be 
involved: masked monitor will perform the checks of the study evaluations and procedures and 
will not be involved in the drug accountability. A second one, unmasked monitor will be defined 
before the start of the study and will be responsible for performing the drug accountability. 
He/she will not be involved in any other monitoring activities. This will be done to safeguard 
the observer-masked of the study. Due care will be applied in order to avoid any disclosure of 
unmasked observer information to masked staff. 
Co-monitoring visit could be performed by the sponsor if required. 
 
Monitoring will comply with ICH-GCP chapter 5.18 requirements for what concerns 
monitoring purpose, selection and qualifications of monitors, extent and nature of monitoring, 
monitoring procedures, monitoring reports. 
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The investigator agrees, by written consent to this protocol, to fully co-operate with compliance 
checks by allowing authorized individuals to have access to all the study documentation. In 
addition to the monitoring activities performed by the study monitor, the sponsor could perform 
some quality control activities to verify the compliance with the study procedures and the ICH-
GCP guidelines.  
 
 
 


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9.2 
Quality Control and Quality Assurance 
 
The CRO has implemented and maintains a Quality System that includes quality controls and 
audits at different study steps with written SOPs to ensure that the study is conducted in 
compliance with the protocol and all effective amendments, ICH-GCP, and the applicable 
regulatory requirement(s) and that data have been reliably and correctly generated, recorded, 
processed and reported, in agreement with the ALCOA principles (Attributable-Legible-
Contemporaneous-Original-Accurate). 
 
The clinical centers are responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, documented 
(recorded), and reported in compliance with the protocol, ICH-GCP, and the applicable 
regulatory requirement(s). 
 
The CROs and the sponsor will be responsible each one for their respective activities. 
 
The sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a CRO, 
but the ultimate responsibility for the quality and integrity of the trial data always resides with 
the sponsor. 
 
9.3 
Applicable SOPs 
 
The sponsor, the clinical center and the CRO will follow their respective SOPs in the conduct 
of the respective activities, unless otherwise stated in written agreements. SOPswillbe made 
available for review, if required. 
 
9.4 
Data access 
 
The investigator and the CRO will ensure that all raw data records, medical records, CRFs and 
all other documentation that is relevant to this study will be made accessible to monitoring 
activities, audits, IEC review, and regulatory inspection. 
 
9.5 
Audits and inspections 
 
The sponsor, any independent body acting on behalf of the sponsor and the CRO have the right 
to perform audits according to ICH-GCP responsibilities. 
The study may also be inspected by regulatory authorities.  
The investigators agree, by written consent to this protocol, to fully co-operate and support 
audits and inspections compliance checks by allowing authorized individuals to have access to 
all the study documentation. 
 
 
 
 
 
 
 
 


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10 
ETHICAL CONSIDERATIONS 
 
10.1 
Ethics and Good Clinical Practice (GCP) 
 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
 
The approval of the study protocol by the relevantEthics Committees and Health Authorities 
will be obtained before the start of the study.  
 
Study notification to the Competent Authorities will be performed according to the current 
regulations. 
 
The present clinical study will be carried out according to the general principles of “ICH Topic 
E6, CPMP/ICH/135/95”, July 1996 including post Step 4 errata, status September 1997 and 
post Step errata (linguistic corrections), July 2002. 
 
10.2 
Informed consent 
 
Before being enrolled into the clinical study, the subjects must have expressed their consent to 
participate, after the investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. Information will be given in 
both oral and written form. The information sheet and informed consent form will be prepared 
in the local language by the CRO and must be approved by the EC and regulatory authorities. 
It will include all the elements required by law according to the ICH-GCP recommendations.  
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
Ø a description of the aims of the study and how it will be organized 
Ø thetype of treatment 
Ø any potential negative effects attributable to the study treatment 
Ø the freedom to ask for further information at any time 
Ø the subjects’right to withdraw from the clinical study at any time without giving reasons 
and without jeopardizingtheir further course of medical treatment  
Ø the existence of subject insurance cover and obligations following from this cover 
Adequate time and opportunity to satisfy questions will be given to the subjects and the time 
will be recorded. 
 
The investigator will be supplied with an adequate number of blank informed consent forms to 
be used. The forms will be signed and dated by both the investigator and the subject.  
A copy of the signed form will be given to the subject. 
 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the investigator's study file according to the regulatory requirements 
(see section 11.3). The investigator will allow inspection of the forms by authorized 
representatives of the sponsor, EC members and regulatory authorities. He will confirm, by 
signing and dating the forms, that informed consent has been obtained. 
 


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10.3 
Insurance policy 
 
An insurance cover has been issued in favor of the subjects participating in this clinical study. 
The insurance is in compliance with the local regulation and with the requirements of the Health 
Authorities. 
 
10.4 
Study termination 
 
The end of the trial is defined as the Last Visit of the Last Patient. 
The study will be considered terminated at the date of the last visit of the last subject,upon 
completion of any follow-up procedure described in protocol. The investigator and thesponsor 
have the right to discontinue the study at any time for reasonable medical and/or administrative 
reasons. As far as possible, this should occur after mutual consultation. Reasons for 
discontinuation have to bedocumentedappropriately. 
 
10.5 
Premature discontinuation of the trial 
 
The whole trial may be discontinued prematurely in the event of any of the following: 
− New information leading to unfavorable risk-benefit judgment of the IMPs, e.g. due to:   
o Evidence of inefficacy of the IMPs, 
o Occurrence of significant previously unknown adverse reactions or 
unexpectedly high intensity or incidence of known adverse reactions, or 
o  Other unfavorable safety findings. 
− Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical 
reasons. 
− Poor enrollment of subjects making completion of the trial within an acceptable time 
frame unlikely. 
− Discontinuation of development of the Sponsor’s IMP. 
− Withdrawal of IMPs from the market for safety reasons. 
 
Health Authorities and Independent Ethics Committees (IECs) will be informed about the 
discontinuation of the trial in accordance with applicable regulations. The whole trial may be 
terminated or suspended upon request of Health Authorities. 
 
11 
ADMINISTRATIVE PROCEDURES 
 
11.1 
Material supplied to the clinical center 
 
Besidethe investigational products, the following study material will be supplied to the clinical 
center: 
Ø final version of the study protocol 
Ø e-CRF access (login and password) for each study member declared and involved in data 
entry 
Ø copy of the investigator’s brochure (IB) relative to the test investigational product 
Ø product information for the reference investigational product 
Ø informedconsent forms 


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Moreover, before the start of the study, the investigator(s) will be provided with the following 
documents: ICH guidelines, confidentiality agreement (if applicable), protocol amendments (if 
any), declaration of Helsinki, insurance statement, SAE forms, financial agreement (if 
applicable), confidential subject identification code list form, drug accountability forms, 
investigator and study staff list form. 
 
11.2 
Protocol amendments 
 
In order to obtain interpretable results, neither the investigator nor the sponsor will alter the 
study conditions agreed upon and set out in this protocol. Amendments should be made by 
mutual agreement between the investigator and the sponsor. Any amendment must be set out 
in writing, giving the reasons, and being signed by all concerned parties. The amendment 
becomes then part of the protocol. 
 
All amendments will be sent to the EC and concerned Competent Authorities, according to the 
current regulations in the EU and Switzerland. 
 
The amendment will be applicable only when it is approved by the concerned authorities, unless 
the changes consist of urgent safety measures to protect study subjects. 
 
Non substantial amendments will be notified according to the current regulations. 
 
11.3 
Study documentation and record keeping 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the sponsor in the CRFs and in all required reports. 
 
The investigator must keep source documents for each subject in the study. All information on 
the CRFs must be traceable to these source documents, which are generally stored in the 
subject's medical file. The source documents should contain all demographic and medical 
information, including ECGs etc., and the original signed informed consent forms. 
 
Data reported on the CRF, that are derived from source documents, should be consistent with 
the source documents or the discrepancies should be explained. 
 
The investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirement(s).  
 
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are not 
limited to,study protocol, amendments, submission and approval of EC, raw data of subjects 
including ECG tracing, insurance contracts, certificate of analysis of the IMP(s), drug 
accountability records, signed informed consent forms, confidential subjects identification 
code, CRFs, curricula vitae of the investigator and other participants in the study, study staff 
lists and responsibilities, monitoring reports and final study report. 
 
The investigator and the sponsor should take measures to prevent accidental or premature 
destruction of these documents. 


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Study documents must be retained by the investigator and the sponsor as long as needed to 
comply with ICH-GCP, national and international regulations.By signing the protocol, the 
investigator and the sponsor agree to adhere to these requirements. 
 
11.4 
Studysubjects’ recruitment 
 
Study participants will be recruited at each clinical centre among those patients attending the clinic 
for cataract surgery in single eye at a time. Ten to fifteenpatients should be recruited at each clinical 
center.  
 
11.5 
Confidentiality and data protection 
 
By signing this protocol, the investigator and the CRO agree to keep all the information 
provided by the sponsor in strict confidentiality and to request similar confidentiality from 
his/her staff. Study documents provided by the sponsor (protocols, IB, CRFs and other 
materials) will be stored appropriately to ensure confidentiality. The information provided by 
the sponsor to the investigator and to the CRO cannot be disclosed to others without direct 
written authorization from the sponsor, except for the extent necessary to obtain the informed 
consent from the subjects wishing to participate in the study. 
 
Data on subjects collected on the CRFs during the study will be documented in an anonymous 
way (see section8.2). If, as an exception, it becomes necessary to identify a subject for safety 
or regulatory reasons, the monitor, the sponsor and the investigator will be bound to keep this 
information confidential. 
 
11.6 
Publication policy 
 
The sponsor agrees that the study results (including negative and inconclusive as well as 
positive results) can be made publicly available by the investigator publishing in peer reviewed 
journals, presenting results at scientific congresses and posting information and results on 
internet-based public registers and databases. 
Study results will be communicated in full to the competent Health Authorities by the 
submission of a complete clinical study report. 
 
As the sponsor agrees that the study results can be published by the investigator(s), the 
investigator agrees to submit any manuscript (abstract, publication, paper, etc.) to the sponsor 
before any public disclosure. 
This will be done in order to ensure that clinical study results are reported in an objective, 
accurate and balanced manner. The sponsor reviews the proposed manuscripts,before 
submission, within a reasonable period of time (30-90 days in relation with the complexity of 
the work). 
 
The investigator(s) will also be provided by the sponsor with the clinical study report and the 
results of any additional analysis, tables, figures, etc. undertaken for the purposes of the article, 
in order to take responsibility for the content of the publication(s). 
On an exceptional basis, the sponsor may temporarily delay registration of certain data elements 
(e.g. compound, name, outcome, measures, etc.) to seek necessary intellectual property 
protection. This is because early disclosure of such data could, in some circumstances, prevent 
or negatively impact patentability. 
 


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12 
APPENDICES 
 
12.1 
Appendix 1 Oxford Scale 
 
 
 
 
 


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REFERENCES 
 
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