Performance and Safety Assessment of T4020 in Managing Corneal Epithelial Defect Following Epi-off Accelerated Crosslinking
Phase: NA
Conditions: Keratoconus
Sponsor: Laboratoires Thea

Laboratoires THEA 
Clinical investigation  N°LT4020-302 
 
 
- Clinical investigation plan - Final Version 4.0 – 02 Sept 2016– Confidential - 
 
 
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1.4. Synopsis 
 
Title 
of 
the 
clinical 
investigation 
Performance and safety assessment of T4020 combined with standard post-
operative therapy versus standard post-operative therapy in managing corneal 
epithelial defect following epi-off accelerated corneal crosslinking 
International 
Coordinating 
Investigator 
Prof (Associate) Koray Gumus, Kayseri (Turkey) 
 
Clinical 
investigation 
design 
This is a prospective, randomised, double-masked, controlled, multicentre 
international clinical investigation 
Clinical 
investigation 
objective(s) 
Primary objective: To assess performance of T4020 combined with standard post-
operative therapy versus standard post-operative therapy regarding corneal 
epithelial defect (CED) healing following epi-off accelerated corneal crosslinking 
(CXL) 
Other objectives: To assess ocular symptoms and safety 
Clinical 
investigation 
endpoints 
Primary performance endpoint:  
Response defined as complete healing of CED (absence of CED) as assessed by the 
investigator on Corneal Fluorescein Staining (CFS) at slit lamp examination. (A 
patient with complete healing of CED could still present superficial punctate 
keratitis [SPK] or stained healing lines). Two time points will be considered: Day 
3 (D3) and Day 4 (D4). 
 
Secondary performance endpoint: 
- 
CED size assessed by the investigator on CFS at slit lamp examination after 
Contact Lens (CL) removal at D3, D4, and D5. 
 
Other performance endpoints: 
- 
Time to complete healing of CED.  
- 
Superficial punctate keratitis (SPK) (graded using the National Eye Institute 
[NEI] 0 - 15 scale) at D3, D4 and D5.  
- 
Presence or absence of stained typical healing lines at D3, D4 and D5.  
- 
Conjunctival staining (graded using the National Eye Institute [NEI] 0 - 18 
scale) at screening visit and D5. 
- 
Total ocular pain score (graded on 0-10 Numeric Rating Scale) at D1, D2, D3, 
D4, and D5. 
- 
Each symptom including light sensitivity, burning / stinging, tearing, foreign 
body sensation (graded on 0-10 numeric rating scale: 0: absence of the symptom 
and 10: worst imaginable symptom) at D1, D2, D3, D4, and D5.  
- 
Sum of scores of light sensitivity, burning / stinging, tearing, foreign body 

Laboratoires THEA 
Clinical investigation  N°LT4020-302 
 
 
- Clinical investigation plan - Final Version 4.0 – 02 Sept 2016– Confidential - 
 
 
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sensation at D1, D2, D3, D4 and D5. 
- 
Use of painkillers at D1, D2, D3, D4 and D5. 
- 
Measurement of the CED on CFS photos by a reading center at D1, D3, D4, and 
D5 (ancillary). 
 
Safety endpoints: 
- 
Conjunctival hyperaemia (graded using the McMonnies grading [0 to 5]) at D3, 
D4 and D5. 
- 
Uncorrected visual acuity (UCVA) and far best corrected visual acuity (BCVA) 
(using a Snellen chart) at screening visit and D5 after CL removal. 
- 
Non-contact intraocular pressure (IOP) at screening visit and D5 (after CL 
removal). 
- 
Adverse events (AEs)/ Adverse Device Effects (ADEs) recorded throughout the 
clinical investigation by the investigator. 
Investigational 
Product 
 
T4020 will be combined with the standard post-operative therapy. 
Dosing regimen: one administration into the CXL eye every other day for 5 days:  
• The first one at surgery before fitting CL,  
• The second one at D3 (after the visit, on the CL) at the site, 
• The third one at D5 (in the morning at home before the visit, on the CL). 
 Saline solution will be combined with the standard post-operative therapy. 
Dosing regimen: one administration into the CXL eye every other day for 5 days:  
• The first one at surgery before fitting CL,  
• The second one at D3 (after the visit, on the CL) at the site, 
• The third one at D5 (in the morning at home before the visit, on the CL). 
Methodology 
Randomisation: 
Patients will be randomised into two groups. In one group, T4020 will be used and, 
in the other group, saline solution will be used.  
 
Auxiliary products and Therapies: 
During the perioperative period, clinical investigation personnel will instil the 
drops. Then, the patients will instil the drops after they go home. All participants 
will be asked to use the same medications before and after the procedure as 
scheduled in the clinical investigation plan and detailed in the investigator manual:  
In addition to cutaneous anti-infective solution and the bandage contact lens, the 
standardised treatment will include topical anaesthetic, direct-acting cholinergic 
agonist, topical antibiotic and artificial tears. Topical corticosteroid will be started 
after complete corneal healing.  
 
Epi-off accelerated cross-linking with isotonic riboflavin will be performed as 
detailed in the protocol.  
Patients will be permitted to take oral paracetamol 1g for ocular pain and 

Laboratoires THEA 
Clinical investigation  N°LT4020-302 
 
 
- Clinical investigation plan - Final Version 4.0 – 02 Sept 2016– Confidential - 
 
 
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paracetamol 500mg with codein 30mg or equivalent in case of severe pain. 
 
Number 
of 
patients 
About 147 screened patients to obtain 132 evaluable patients.  
Inclusion 
criteria 
 
[1.1] 
Patient must provide signed and dated informed consent. 
[1.2] 
Male or female patient at least 18 years of age. 
[1.3] 
Patient with at least one eye:  
o with a progressive keratoconus (KC) occurring during the last 6 
months according to the investigator judgement, 
o AND scheduled for an epi-off CXL procedure with no concomitant 
CXL in the other eye at the same time. 
[1.4] 
Corneal thickness > 400 µm in the eye undergoing CXL. 
[1.5] 
KC staging I-II according to Amsler-Krumeich classification in the eye 
undergoing CXL: 
Exclusion 
criteria 
2.1 Ophthalmic Exclusion Criteria: 
 
in the eye undergoing CXL: 
[2.1.1] 
Anesthetic / Hypoesthetic cornea < 20 mm with a Cochet-Bonnet 
aesthesiometer. 
[2.1.2] 
Ocular surface disease index (OSDI) scores > 23. 
[2.1.3] 
Schirmer test with anaesthesia < 10 mm/5min. 
[2.1.4] 
Tear Break-Up Time (TBUT) < 7 sec. 
[2.1.5] 
Corneal fluorescein staining score > 3 (NEI criteria). 
[2.1.6] 
Conjunctival staining score > 3 (NEI criteria).  
[2.1.7] 
Presence of any abnormalities preventing reliable measurements as 
judged by the investigator. 
[2.1.8] 
History of any ocular injury. 
[2.1.9] 
History within 1 month before the screening visit or any active ocular 
infection (e.g., bacterial, viral, fungal, acanthamoeba), ocular injury, 
and associated corneal ulceration and abscess, occurring during the 
screening period.  
 
at least in one eye: 
[2.1.10] 
History of any atopic keratoconjunctivitis (AKC), any active uveitis, or 
any other ocular disorder or condition that could be in the judgment of 
the investigator, jeopardize patient safety or interfere with the 

Laboratoires THEA 
Clinical investigation  N°LT4020-302 
 
 
- Clinical investigation plan - Final Version 4.0 – 02 Sept 2016– Confidential - 
 
 
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interpretation of clinical investigation results. 
[2.1.11] 
No active vernal keratoconjunctivitis (VKC) within 6 months including 
D1. 
[2.1.12] Ocular hypertension or glaucoma requiring an ophthalmic medicinal 
product. 
[2.1.13] History of ocular Herpes. 
[2.1.14] Far BCVA ≤ 2/10 Snellen. 
[2.1.15] Abnormal eye lid anatomy, blinking, or naso-lachrymal drainage system. 
 
 
2.2 Systemic/non-ophthalmic exclusion criteria  
[2.2.1] 
Known or suspected hypersensitivity to one of the components of: 
 - the investigational products and/or heparinoids or heparin or  
 - the auxiliary products:  
ofloxacin and other quinolones (eg ciprofloxacin, norfloxacin, 
moxifloxacin, levofloxacin),  
dexamethasone,  
povidone and iodine povidone,  
oxybuprocain and other local anaesthetics, 
cholinergic agonists,  
riboflavin and others chemical related susbtances, 
paracetamol, 
other ingredients of the mentioned medicinal products or medical 
devices,  
 - the materials and medicinal products or medical devices used during 
standard ophtalmological examinations.                 
[2.2.2] 
Any condition judged by the investigator to be incompatible with the 
clinical investigation or likely to interfere with the clinical investigation 
results 
e.g.: acute or chronic severe disease (hepatic, renal, endocrine, neoplasic, 
haematological disorder, immunosuppression, infectious diseases, severe 
psychiatric illness, relevant cardiovascular abnormalities, etc) and/or any 
other factor or abnormality. 
[2.2.3] 
On-going malignancy during the screening period or history of 
malignancy within 5 years before D1.  
[2.2.4] 
Any history of known clinically significant conditions: 
i. Graft-versus-host disease, transplanted patient. 
ii. Any other non-controlled systemic disorder. 
iii. History of drug addiction or alcohol abuse. 
 
2.3 Specific exclusion criteria for women: 
[2.3.1] 
Pregnancy or lactation. 
[2.3.2] 
Childbearing potential woman who is not using a reliable method of 
contraception (oral contraceptive, intra-uterine device, subcutaneous 
contraceptive implant, vaginal ring, patch) or is not surgically sterilised.  
 
2.4 Exclusion criteria related to general conditions: 
[2.4.1] 
Inability of patient and/or relatives to understand the clinical investigation 
procedures and thus inability to give informed consent. 
[2.4.2] 
Non-compliant patient and/or relatives (e.g. not willing to attend a visit, 
way of life interfering with compliance).  

Laboratoires THEA 
Clinical investigation  N°LT4020-302 
 
 
- Clinical investigation plan - Final Version 4.0 – 02 Sept 2016– Confidential - 
 
 
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[2.4.3] 
Participation in the present clinical investigation at the same time as 
another clinical investigation.  
[2.4.4] 
Participation in this clinical investigation within 4 weeks after the end of a 
previous clinical investigation (or within 5 half-life of the previously 
tested product if longer than 4 weeks).  
[2.4.5] 
Patient previously randomised in this clinical investigation. 
[2.4.6] 
Patient being institutionalised because of legal or regulatory order, inmate 
of psychiatric wards, prison or state institutions, or employee of the 
clinical investigation sites or of the Sponsor’s company. 
[2.4.7] 
Patient not covered by the government health care scheme when existing 
in the concerned country. 
 
 
 
 
 
2.5 Exclusion Criteria Related to Previous and Concomitant Treatments  
(Medications / non-medicinal therapies / procedures): 
 
Ocular surgery or topical treatment concerned only eye undergoing CXL 
Before inclusion 
After inclusion  
D1 to D5 
At any 
time 
3 Years 
1 Year 
6 Months
1 Month
1 Week
Product period 
Corneal graft or corneal rings  
Corneal refractive surgery (e.g., LASIK, LASEK, PRK) or anticipated during the clinical 
investigation  
 
Intravitreal injection  
 
Previous corneal crosslinking  
 
Systemic or topical calcineurin inhibitors (e.g. Restasis®, 
Ikervis®, pharmacy made formulations) or other non-
steroidal immunosuppressive treatments 
 
Amniotic membrane graft 
 
Isotretinoïn 
 
Other ocular surgery (e.g., palpebral and cataract surgery)  
 
Permanent punctal plugs (with the exception of semi-
permanent or temporary plugs with a prohibition period of 3 
months) 
 
Other laser procedures  
 
Systemic or topical non-steroidal anti-
inflammatory drugs (NSAIDs), corticosteroids 
(except the standardised post-operative topical 
corticosteroid – please refer to the investigator 

Laboratoires THEA 
Clinical investigation  N°LT4020-302 
 
 
- Clinical investigation plan - Final Version 4.0 – 02 Sept 2016– Confidential - 
 
 
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manual)  
 
Any ophthalmic or systemic antibiotic treatment
(except the standardised post-operative topical 
antibiotic – please refer to the investigator 
manual) 
   
Any anticipated changes of systemic 
medications that could affect a dry eye 
condition and healing process (e.g., 
antihistaminics, tricyclic antidepressants, 
anxiolytics, antimuscarinics, beta-blocking 
agents, phenothiazines, omega 3,  oestrogen-
progesterone or other oestrogen derivatives)  
 
Any change in eye lid hygiene 
Before inclusion 
After inclusion  
D1 to D5 
At any 
time 
3 Years 
1 Year 
6 Months
1 Month
1 Week
Product period 
 
Contact 
lens  
Standardised bandage 
contact lens should be 
kept from D1 to D5 
(please refer to the 
investigator manual) 
 
Any ophthalmic treatment other 
than authorised ones  
 
Any Solution with 
silver salts, iodine or 
copper 
 
Patient should be instructed to refrain from administration of any chronic 
ophthalmic medication (except for investigational product and auxiliary products 
authorised by the clinical investigation plan). 
Clinical 
visits 
and  
investigation 
duration 
 
An individual patient’s participation will involve 6 visits (screening, CXL [D1], 
post CXL at D2 (phone call), D3, D4 and D5) over up to a 65-day period. 
Follow up of the patient can be extended if complete healing isn’t reached, 
according to the investigator judgement. 
 
Countries 
Turkey, France, Spain, Morocco 
Statistical 
Considerations 
 
Analysis sets: 
Safety set:  
All enrolled patients, having received at least one dose of investigational product 
and considered as-treated. 
 
Intent-to-Treat (ITT) set: All randomised patients having received at least one dose 
of the investigational product and considered as-randomised. 
 
Modified Intent-to-Treat set (mITT): 

Laboratoires THEA 
Clinical investigation  N°LT4020-302 
 
 
- Clinical investigation plan - Final Version 4.0 – 02 Sept 2016– Confidential - 
 
 
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All randomised patients having received at least one dose of investigational product 
and with at least one post-baseline performance assessment on product. 
 
Per protocol (PP) set:  
All mITT patients without any major clinical investigation plan violation. 
 
Safety endpoints will be analysed in the safety set. 
Performance endpoints will be primarily analysed in the mITT set. 
 
Baseline: 
The baseline visit is the inclusion visit (D1) for all assessments. 
 
Sample size: 
The principal statistical hypothesis is the superiority of T4020 compared to control 
for the primary efficacy variable.   
The sample size determination is based on the primary efficacy endpoint, i.e. the 
response defined as complete healing of CED (absence of CED) in the eye 
undergoing CXL as assessed by the investigator on Corneal Fluorescein Staining 
(CFS) at slit lamp examination at Day 3 (D3) and Day 4 (D4) using the Hochberg 
procedure for multiple testing. 
Using this step-up procedure, unadjusted p-values are ordered from the largest (p1) 
to the smallest (p2). If the largest p-value (p1) is lower than 0.05, both null 
hypotheses can be rejected at the overall 5%-level of significance. If the largest p-
value (p1) is greater than 0.05 and the smallest p-value (p2) lower than 0.025, only 
the null hypothesis corresponding to p2 can be rejected at the overall 5%-level of 
significance. 
Bases on estimated response rates of 60% in the T4020 group and 30% in the 
control group, 132 evaluable patients (66 per group) are needed to achieve at least 
90% power using a two-sided 0.025 significant nominal level. 
 
Interim analysis: 
No interim analysis is planned. 
Planned 
schedule 
Planned initiation of the clinical investigation: September 2016 
Planned completion date of the clinical investigation: June 2017 
 
 
 
FLOW CHART: Clinical investigations are to be conducted as per the following schedule of 
investigation procedures:

Laboratoires THEA 
Clinical investigation  N°LT4020-302 
 
 
- Clinical investigation plan - Final Version 4.0 – 02 Sept 2016– Confidential - 
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Clinical investigation procedure 
Screening 
Within 60 Days 
[D] before D1  
 
Visit D1 
Visit D2= 24h 
(± 2h) (a) 
Visit D3 = 48h  
(± 2h) 
Visit D4 = 72h  
(± 2h) 
Final Visit 
D5 = 96h  
(± 2h)(n) 
Pre-op. 
Intra-op. 
Post-op. 
Phone call 4 
hours post-
op.(a) 
Phone call 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demography / Smoking status 
X 
 
 
 
 
 
 
 
 
Keratoconus (KC) history 
X 
 
 
 
 
 
 
 
 
Ocular medical and surgical history 
X 
 
 
 
 
 
 
 
 
Ocular surface disease index (OSDI) 
X 
 
 
 
 
 
 
 
X 
Systemic medical and surgical history 
X 
 
 
 
 
 
 
 
 
Verification of inclusion and exclusion criteria  
X 
X 
 
 
 
 
 
 
 
Previous and concomitant ocular/non ocular products 
X 
X 
 
 
 
X 
X 
X 
X 
Patient diary :  
 
 
 
 
 
 
 
 
 
- 
Painkiller(s) use (b) 
 
X(c) 
 
X 
X 
X 
X 
X 
X 
- 
Ocular pain assessment (Numeric Rating Scale, NRS) 
X(c) 
X(c) 
 
X 
X (d) 
X(e) 
X(e) 
X(e) 
X(e) 
Ocular symptoms (f) 
 
 
 
 
X 
X 
X 
X 
X 
Corneal topography with pachymetry 
X 
 
 
 
 
 
 
 
 
Far Uncorrected and Best Corrected Visual acuity (UCVA 
and BCVA) with manifest refraction 
X 
 
 
 
 
 
 
 
X 
Slit-lamp examination (g) 
X 
X 
 
 
 
 
X 
X 
X 
Tear Break-up time (TBUT) with fluorescein 
X 
 
 
 
 
 
 
 
 
Corneal fluorescein staining with CED assessment and 
photos (blue light) (h) 
X 
 
 
 
 
 
X 
X 
X 
Conjunctival staining with lissamine green 
X 
 
 
 
 
 
 
 
X 
Conjunctival hyperaemia 
 
 
 
 
 
 
X 
X 
X 
Corneal sensitivity assessment (by the Cochet-Bonnet 
aesthesiometer)  
X 
 
 
 
 
 
 
 
 
Peri-operative pachymetry 
 
 
X 
 
 
 
 
 
 

Laboratoires THEA 
Clinical investigation  N°LT4020-302 
 
 
- Clinical investigation plan - Final Version 4.0 – 02 Sept 2016– Confidential - 
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(a) A phone call will be performed 4 hours after the CXL procedure by the investigator/delegate to collect the ocular symptoms and to remind the patient to complete the diary. Visit D2 
will be also a phone call done by the investigator/delegate.  
 (b) Number of painkiller(s) pills recorded by the patient in the patient diary will be collected. The 1st administration of the painkiller (Paracetamol 1g) will be done 1 hour after CXL. The 
2nd administration will be at least 4 hours later and no more than 4 times daily. In case of real severe pain, patient can take Paracetamol 500mg with 30mg Codein instead of Paracetamol 
1g, not exceeding 4 tablets/day (including tablets with paracetamol and tablets with paracetamol/codein). 
(c) For training purposes. 
(d) The patient should be instructed to note the NRS pain score 1 hour after CXL procedure before the 1st painkiller administration, then 3, 6 and 12 hours after CXL procedure and before 
painkiller administration. 
(e) The patient should be instructed to note the NRS pain score at wake up time(8:00 am +/- 2h), midday (2:00 pm+/- 2h) and bedtime (8:00 pm +/- 2h) and before painkiller 
administration. 
(f) Ocular symptoms (light sensitivity, burning/stinging, tearing, foreign body sensation) will be collected by the investigator/delegate. 
(g) Slit lamp examination: any clinically relevant finding will be recorded. 
(h) The CED will be measured with caliper / with the slit lamp after contact lens (CL) removal if applicable. 
(i) IOP at visit D5 if complete healing. 
(j) The investigational product will be instilled by the medical staff before CL insertion at the end of the CXL procedure at visit D1. 
(k) The investigational product will be instilled by the medical staff after CL insertion at Visit D3. 
(l) The investigational product will be instilled by the patient (on the CL) in the morning D5 before the Visit. 
(m) The removal of the CL will be done with forceps after hydration before ocular examination and a new CL will be used at visit D3 and visit D4. 
(n) Women of child bearing potential must have a negative urinary pregnancy test prior to the initial instillation of investigational product. 
 (o) Follow up of the patient can be done if complete healing isn’t reached, according to the investigator judgement. All procedures will be performed as scheduled for the final visit D5. 
Op.: Operatively 
Clinical investigation procedure 
Screening 
Within 60 Days 
[D] before D1  
 
Visit D1 
Visit D2= 24h 
(± 2h) (a) 
Visit D3 = 48h  
(± 2h) 
Visit D4 = 
72h  
(± 2h) 
 
Final Visit 
D5 = 96h  
(± 2h)(o) 
Pre-op. 
Intra-op. 
Post-op. 
Phone call 4 
hours post-
op.(a) 
Phone call 
Intraocular pressure (IOP) measurement on both eyes 
(non-contact tonometry) 
X 
 
 
 
 
 
 
 
X(i) 
Schirmer test with anaesthesia 
X 
 
 
 
 
 
 
 
 
Surgery: epi-off corneal collagen cross-linking (CXL) 
procedure  
 
 
X 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
Investigational product instillation 
 
 
X(j) 
 
 
 
X(k) 
 
X(l) 
Contact lens (CL) insertion (m) 
 
 
X 
 
 
 
X 
X 
 
Peri-operative photos  
 
 
 
X 
 
 
 
 
 
Urinary pregnancy test (n) 
X 
 
 
 
 
 
 
 
 
Adverse Event(s) (AE) / Adverse Device Effect(s) (ADEs) 
collection  
 
X 
X 
X 
X 
X 
X 
X 
X