Efficacy and Safety Assessment of T4020 Versus Vehicule in Patients With Chronic Neurotrophic Keratitis or Corneal Ulcer
Phase: PHASE3
Conditions: Keratitis, Corneal Ulcer
Sponsor: Laboratoires Thea

Laboratoires THÉA 
Study N°LT4020-PIII-12/11 
 
 
- Protocol - Confidential – Version 13 Fr - Amendment n°8 -  17/12/2015 - 
1/6 
Synopsis 
Title of the study: 
Efficacy and Safety assessment of T4020 versus vehicle in patients 
with chronic neurotrophic keratitis or corneal ulcer. 
Clinical phase: 
III. 
Methodology: 
Multicentre, international, randomised, double-masked, 2 parallel 
groups versus vehicle in 124 evaluable patients treated for 28 days. 
Statistical Method: 
Superiority analysis 
Test product: 
T4020 (CACICOL20®) 
 
1 drop into the pathologic eye once daily every 2 days for 28 days. 
Reference product: 
Vehicle (T4020 Vehicle eye drops) 
 
1 drop into the pathologic eye once daily every 2 days for 28 days. 
Wash-Out: 
Patient must be willing to discontinue their current treatment (*) 7 days 
prior to Day 0, in order to determine the pathology’s eligibility. Patient 
will instil preservative free artificial tears (NaCl 0.9%): one drop into 
the pathologic eye at least three times daily for 7 days. 
(*) except for patients who need a topical ocular treatment by cyclosporine (preservative free), 
which will be continued throughout the study. 
Number of patients: 
124 evaluable patients. 
 
Taking into account about 10% of drop-outs, a total of 138 patients 
should be enrolled in the study. 
International  
Investigator  
Coordinator: 
Professor Beatrice COCHENER. 
Countries: 
Austria, Belgium, Denmark, England, Finland, France, Greece, Italy, 
Netherlands, Norway, Poland, Portugal, Spain, Sweden, Switzerland, 
and Turkey. 
Planned schedule: 
Planned initiation:  
June 2012 
Planned completion of clinical phase:  March 2017. 
Objectives: 
To assess the efficacy and safety of CACICOL20® on corneal healing 
versus vehicle following once daily every 2 days treatment for 28 days. 
 
Primary objective: 
- Reduction of 50% or more in keratitis/ulcer area from baseline 
assessed at Day 28. 

Laboratoires THÉA 
Study N°LT4020-PIII-12/11 
 
 
- Protocol - Confidential – Version 13 Fr - Amendment n°8 -  17/12/2015 - 
2/6 
Secondary efficacy criteria 
- 
Complete corneal healing at Day 28. 
- 
Partial response at Day 28 defined as a reduction in the ulcer/keratitis area of 75% or 
more. 
- 
Partial Response (50%) at Day 28 defined by investigator judgment. 
- 
Complete corneal healing at Day 28 defined by investigator judgment. 
- 
Complete corneal healing at Day 7, Day 14 and Day 21. 
- 
Partial response at Day 7, Day 14 and Day 21 defined as a reduction in the 
ulcer/keratitis area of 75% or more. 
- 
Partial response at Day 7, Day 14 and Day 21 defined as a reduction in the 
ulcer/keratitis area of 50% or more. 
- 
Partial Response (50%) at Day 7, Day 14 and Day 21 defined by investigator 
judgement. 
- 
Complete corneal healing at Day 7, Day 14 and Day 21 defined by investigator 
judgement. 
- 
Corneal ulcer/keratitis depth assessment at Day 7, Day 14, Day 21 and Day 28. 
- 
Corneal affected layers assessment at Day 7, Day 14, Day 21 and Day 28. 
- 
Corneal substance loss assessment at Day 28. 
 
Secondary clinical safety criteria 
- 
Best corrected visual acuity at Day 28. 
- 
Global tolerance assessed by the investigator at Day 7, Day 14, Day 21 and Day 28. 
- 
Global tolerance assessed by the patient at Day 7, Day 14, Day 21 and Day 28. 
- 
Adverse events recorded from Day 0 and throughout the study. 
- 
Ocular pain assessment with the Visual Analog Scale. 
- 
Use of analgesics treatments. 
 
Inclusion and non-inclusion criteria for all the patients: 
Inclusion Criteria: 
Patients will be eligible for inclusion if all these criteria are respected: 
At Selection Visit: 
- 
Signed and dated informed consent, 
- 
Male or female aged  18 years, 
- 
Patient with one chronic neurotrophic keratitis or one chronic neurotrophic corneal 
ulcer defined by: 
- 
A maximal depth ≤ 2/3 of the stroma 
- 
A partial or complete corneal anaesthesia 
 
At Inclusion Visit: 
- 
No improvement of the chronic neurotrophic keratitis or chronic neurotrophic corneal 
ulcer after 7 days with preservative free lachrymal substitute treatment (NaCl 0.9%). 
 

Laboratoires THÉA 
Study N°LT4020-PIII-12/11 
 
 
- Protocol - Confidential – Version 13 Fr - Amendment n°8 -  17/12/2015 - 
3/6 
Non-inclusion criteria: 
Patients fulfilling at the selection visit ONE OR MORE of the following non-inclusion criteria will 
not be included in the study: 
 
Ophthalmic non-inclusion criteria 
In the affected eye: 
- 
Risk of immediate perforation of corneal ulcer. 
- 
Descemetocele. 
- 
Perforated corneal ulcer. 
- 
Corneal abscess. 
In the controlateral eye: 
- 
Best far corrected visual acuity ≤ 1/10. 
In both eyes: 
- 
Active ocular infection. 
- 
Glaucoma/ocular hypertension. 
Systemic/non ophthalmic non-inclusion criteria 
- 
General history judged by the investigator to be incompatible with the study (life-threatening 
patient condition). 
- 
Known allergic hypersensitivity history to one of the components of the study medications 
or to test products. 
Specific non-inclusion criteria for women 
- 
Pregnancy, lactation. 
- 
Childbearing women without an effective method of contraception (oral contraceptive, intra-
uterine device, subcutaneous contraceptive implant, vaginal ring) or women not 
hysterectomised, menopaused or surgically sterilised. 
Non-inclusion criteria related to general conditions 
- 
Inability of patient and/or relatives to understand the study procedures and thus inability to 
give informed consent. 
- 
Non-compliant patient and/or relatives (e.g. not willing to attend the follow-up visits, way 
of life interfering with compliance). 
- 
Participation in another clinical study within the last 3 months. 
- 
Already included once in this study. 
- 
Ward of court. 
- 
Patient not covered by the Social Security scheme (For France). 
Non-inclusion 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: 
 

Laboratoires THÉA 
Study N°LT4020-PIII-12/11 
 
 
- Protocol - Confidential – Version 13 Fr - Amendment n°8 -  17/12/2015 - 
4/6 
CONCOMITANT MEDICATIONS / NON PRODUCT THERAPIES NOT ALLOWED 
BEFORE AND DURING THE STUDY 
Before the selection visit 
7 days 
Wash-out period 
7-9 days 
Treatment period 
Any plan or predicable change in dose regimen for the following systemic treatments (anti-
inflammatory drugs, psychotropic drugs) .........................................................................................  
Contact lenses wear ...........................................................................................................................  
 
Any topical ocular treatments except allowed treatments (*) (**) .....  
 
Any systemic steroids treatment ....................................................  
(*) Patient needing a topical ocular treatment by cyclosporine (preservative free) will continue this 
treatment at the same dose regimen throughout the study. 
(**) Patient will instil preservative free artificial tears: NaCl 0.9% 3 to 8 times daily. 
 
Sub-group of patients with ulceration/ulcer: 
Patients will be eligible for inclusion if ALL above criteria and the additional non-inclusion 
criterion below are respected: 
- 
Stage 1 neurotrophic keratitis according to the Mackie classification, in the affected 
eye. 
 
Visit schedule: 
 Selection visit: Day-9/ Day-7, 
 Inclusion visit: Day 0, 
 Follow-up visit: Day 7 / Day 9, 
 Follow-up visit: Day 14 (± 1 day), 
 Follow-up visit: Day 21 (± 2 days), 
 Final visit: Day 28 (± 3 days). 
 
According to the investigator’s decision, from Day 7 and to the end of the study: 
- 
in case of improvement or stable status of the neurotrophic keratitis/corneal ulcer, the 
patient may continue the study. 
- 
in case of aggravation of the neurotrophic keratitis/corneal ulcer, the patient may stop the 
study. 
In case of withdrawal from the study, the investigator will prescribe the best appropriate treatment 
to the patient. 
 
Data Monitoring Committee (DMC) and Interim analyses: 
This Data Monitoring Committee will be composed of 4 members: 3 ophthalmologists: Pr. 
Christophe BAUDOUIN, Pr Gerd GEERLING, Pr Kostas BOBORIDIS and an expert statistician: 
Pr. Jean-Marie GROUIN. They will review all patient data as study progresses. 
 
Two interim analyses are planned when 50 patients and 88 patients will be included. Both interim 
analyses could allow for early claim efficacy according to pre-specified rules. The DMC may also 
recommend stopping the study in case of evidence of unexpected major safety issues. DMC 
responsibilities and decision rules for stopping the trial are specified in a DMC charter. 

Laboratoires THÉA 
Study N°LT4020-PIII-12/11 
 
 
- Protocol - Confidential – Version 13 Fr - Amendment n°8 -  17/12/2015 - 
5/6 
 
Independent Masked Adjudication Committee: 
This Independent Masked Adjudication Committee will be composed of 3 independent corneal 
specialists: Pr Antoine Labbé, Dr Serge Doan, Pr Eric Gabison.  
They will review data currently collected in Study LT4020-PIII-12/11, to define presence or 
absence of neurotrophic corneal ulceration/ulcer.  
They will estimate the number of patients currently included with no ulcer/ulceration. 
 
 
Study Follow-up: 
At the day 28 visit, in case of improvement, without complete healing, of the chronic neurotrophic 
keratitis or chronic neurotrophic corneal ulcer, and according to the investigator’s judgment, a six-
month follow-up (or till healing before this delay) should be done by the investigator in order to 
collect data on the evolution of the keratitis/ulcer. During this follow-up, the patient will instil 
CACICOL20® at the same dose regimen, i.e. 1 drop into the pathologic eye once daily every 2 
days. All details will be defined in the ancillary protocol. 
These data will be integrated in the clinical study report. 
 
Statistical Considerations: 
The primary efficacy endpoint will be the response defined as the reduction of 50% or more in 
keratitis/ulcer area from baseline assessed at Day 28. 
 
The primary efficacy analysis will be conducted in the modified Intent-To-Treat Set using the 
Fisher’s exact test at the 0.025 one-sided significance nominal level. Missing data will be handled 
using the Last Observed Carried forward technique. Multiple Imputation Methods will be 
performed to investigate the robustness of results. 
 
The main secondary efficacy endpoints will be the complete response and the partial response 
(defined as the reduction of 75% or more in the ulcer/keratitis area) assessed at Day 28 and 
analysed like the primary endpoint. 
Time to response will be analysed by the Kaplan-Meier method and groups will be compared by 
the Log-rank test. 
Safety variables will be described and analysed according to usual statistical methods. 
 
Sample Size Considerations 
The sample size determination is based on the primary efficacy endpoint, i.e. the response defined 
as the reduction of 50% or more in keratitis/ulcer area from baseline assessed at Day 28. 
Based on an expected vehicle responder rate of 20% and a difference in rates of at least 30% with 
T4020 compared to vehicle, 124 evaluable patients maximum (62 per group) are needed to achieve 
at least a 90% power using a one-sided Fisher’s exact test at the 0.025 one-sided significance 
nominal level. 
 
FLOW CHART: Study investigations are to be conducted as per the following schedule of 
study procedures:

Laboratoires THÉA 
Study N°LT4020-PIII-12/11 
 
 
- Protocol - Confidential – Version 13 Fr - Amendment n°8 - 17/12/2015 - 
6/6 
(*) The ulcer/keratitis area should be assessed by measuring the longest linear diameter and the greatest perpendicular width using calliper and by photo. 
 
The ulcer/keratitis evolution should be assessed by: r = (L x l) at Dn / (L x l) at D0 where L denotes the longest linear diameter and l the greatest perpendicular width. 
 
(**) The ulcer/keratitis depth should be assessed by OCT.
Study procedure 
Day -9 / Day -7 
 
Day 0 
Day 7 / Day 9 
Day 14 (± 1 day) 
Day 21 (± 2 days) 
Day 28 (± 3 days) 
Visit 1 
Selection Visit
Visit 2 
Inclusion Visit 
Visit 3 
Follow-up Visit
Visit 4 
Follow-up Visit
Visit 5 
Follow-up Visit
Visit 6 
Final Visit 
Informed consent 
X 
Wash-out period with preservative free artificial tears NaCl 0.9% 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
Ocular medical and surgical history 
X 
 
 
 
 
 
Systemic medical and surgical history 
X 
 
 
 
 
 
Verification of inclusion and non-inclusion criteria / Status of 
the patient 
X 
X 
 
 
 
 
Previous and concomitant ocular/non ocular treatments 
X 
X 
X 
X 
X 
X 
Ocular symptoms  
X 
X 
X 
X 
X 
X 
Best corrected visual acuity in both eyes (near and far) 
X 
X 
X 
X 
X 
X 
Slit Lamp examination + Fluorescein test 
X 
X 
X 
X 
X 
X 
Corneal sensitivity assessment (by the aesthesiometer) 
X 
X 
 
 
 
X 
Ulcer/Keratitis assessment(*)  
X 
X 
X 
X 
X 
X 
OCT examination (**) 
X 
X 
X 
X 
X 
X 
IOP measurement on both eyes (non-contact tonometry) 
X 
X 
 
X 
 
X 
Ocular pain assessment (VAS) 
X 
X 
X 
X 
X 
X 
Dispensation of the treatment for the wash-out period 
X 
 
 
 
 
 
Dispensation of the study drug  
 
X 
 
X 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
Global efficacy assessment by the investigator 
 
 
X 
X 
X 
X 
Global tolerance assessment by the investigator 
 
 
X 
X 
X 
X 
Global tolerance assessment by the patient 
 
 
X 
X 
X 
X 
Selection treatment compliance 
 
X 
 
 
 
 
Study treatment compliance 
 
 
X 
X 
X 
X 

Laboratoires THÉA 
Study N°LT4020-PIII-12/11 
 
 
- Protocol - Confidential - Version 13 Fr – Amendment n°8 - 17/12/2015 - 
7/95