Conditions: Venous Leg Ulcer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 121
Healthy volunteers: no

Brief summary:
Dose-response relationship study of S42909 on leg ulcer healing after oral repeated administration in patients with active venous leg ulcer.

Detailed description:
S42909 is an inhibitor of β-Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase which also inhibits vascular leukocyte adhesion to endothelial cells, Matrix Metalloproteinase-2 (MMP-2) and Plasminogen Activator Inhibitor-1 (PAI-1) activity. It is proposed for development in the treatment of venous and mixed leg ulcers.

This proof of concept study is a randomized, double-blind, placebo-controlled, multicenter, Phase IIa trial to evaluate the dose response of S42909 for the treatment of venous leg ulcers.

Patients suffering from chronic venous disease and having at least one active venous leg ulcer will be selected at the selection visit (ASSE). One Reference Ulcer (RU) defined as the largest ulcer in size that is fitting the area selection criteria will be established. At ASSE, a first picture will be taken before cleansing and debridement and a second picture will be taken after cleansing and debridement. The investigator will check that the selection RU area is compliant with the selection criteria. Patients will start the selection period and will be switched from their current pharmacological and/or local treatment (if any) for venous leg ulcer to local wound care with sterile saline solution or sterile water, "non-active" dressings and standardized compression (same strength and type of compression). They will be administrated the placebo selection treatment for a period of fourteen days.

Three (or four) working days before the inclusion visit, the participants will come to the site for a RU picture in order to get the RU area central measurement for inclusion visit (W000).

At W000, the investigator will check that the inclusion RU area is compliant with the inclusion criteria. The investigator will also check that the participant is compliant with the selection treatment and stockings wearing.

All participants found to be eligible for inclusion will be randomized to one of the following six groups - S42909: 100, 200, 400, 800 or 1200 mg per day- or placebo.

The participants will enter a 6 weeks ambulatory Investigational Medicinal Product (IMP) treatment period on top of standard of care (standardized compression and local wound care with sterile saline solution or sterile water and "non-active" dressing) followed by a 2 weeks follow-up period of standard of care only. During this period the participants will return to the investigator's site for intermediate visits after one week (W001), two weeks (W002), three weeks (W003), four weeks (W004), six weeks (W006) and eight weeks (W008). Participants will continue receiving standardized compression therapy and local wound care (sterile saline solution or sterile water and "non-active" dressing) until the end of the study (W008).

Arms:
arm 1: S42909 dose 100 mg p.o., 50 mg bid arm 2: S42909 dose 200 mg p.o., 100 mg bid arm 3: S42909 dose 400 mg p.o., 200 mg bid arm 4: S42909 dose 800 mg p.o., 400 mg bid arm 5: S42909 dose 1200 mg p.o., 600 mg bid arm 6: Placebo p.o. bid

Interventions: intervention 1: S42909 100 mg intervention 2: S42909 200 mg intervention 3: S42909 400 mg intervention 4: S42909 800 mg intervention 5: S42909 1200 mg intervention 6: Placebo Oral Tablet
Intervention descriptions: intervention 1: 50 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals. intervention 2: 50 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals. intervention 3: 200 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals. intervention 4: 200 mg Film-coated tablets per os administration,twice a day taken at the end of the morning and at evening meals. intervention 5: 200 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals. intervention 6: Matching placebo tablets, per os administration, twice a day taken at the end of the morning and at evening meals.

Protocol document:
Prot_000.pdf: 
 
Document title 
AMENDED CLINICAL STUDY PROTOCOL 
Study official title 
Dose-response relationship study of S42909 on leg ulcer 
healing after oral repeated administration in patients with 
active venous leg ulcer.  
A 10-week randomised, double-blind, placebo-controlled, 
prospective, international, multicentre, phase IIa study. 
Study brief title 
Dose-response relationship study of 42909 on leg ulcer healing 
Test drug code 
S42909 
Indication 
Venous leg ulcer 
Development phase 
Phase IIa 
Protocol code  
CL2-42909-016 
EudraCT Number 
2016-004143-36 
 
Universal Trial Number  
 
Sponsor 
ILKOS THERAPEUTIC INC  
 
International 
Coordinator 
Professor Eberhard RABE 
Department of Dermatology University of Bonn 
Sigmund-Freud-Str. 25 
53105 Bonn, Germany 
Tel.: +49-228-287-16630 
Fax : +49-228-287-14333 
E-mail : eberhard.rabe@ukb.uni-bonn.de 
Date of the document 
05-March-2018  
Version of the document 
 
Substantial Amendment 
integrated  
Final version  
 
No 
Final version date  
Countries concerned 
1 
19-May-2017 
ALL 
2 
29-Jun-2017 
CAN, SVK, USA 
3 
29-Jun-2017 
AUT, CZE, DNK, DEU, ESP, ITA 
4 
05-Mar-2018 
ALL 


S42909 
Amended Clinical study protocol n° 4 - Final version 
CONFIDENTIAL 
FOLLOW-UP OF VERSIONS 
 
 
Substantial 
amendment 
No 
Final 
version date 
Countries 
concerned 
Nature of modifications 
Initial 
protocol 
NA 
30-Jan-2017 
ALL 
Not Applicable 
Amended 
protocol 
1 
19-May-2017 
ALL 
This substantial amendment has 
been implemented in order to adapt 
selection/inclusion criteria to new 
medical data, to clarify wording 
relative 
to 
selection/inclusion 
criteria, to add withdrawal criteria, 
to precise items regarding standard 
of care, to adjust the investigation 
schedule 
during 
the 
selection 
period, and to correct errors of 
typology. It also addresses safety 
comments and recommendations 
raised by the FDA in their May 
Proceed Letter to the Sponsor dated 
May 5, 2017.  
 
Amended 
protocol  
2 
29-Jun-2017 
CAN, USA, 
SVK  
This substantial amendment has 
been implemented to tighten up the 
eligibility criteria by removing the 
investigator’s judgement on the 
arterial duplex scan from the non-
selection criterion N°26, since it has 
become apparent that there is 
variability in methodology and 
assessment of the arterial network 
by arterial duplex scan between 
countries and investigators. Protocol 
Appendix 2 has been modified 
accordingly in order to capture the 
data from the arterial duplex scan 
based on the different methods used 
in 
the 
participating 
sites 
and 
countries.  
CEAP classification at ASSE visit 
has been added (Table (4.4.2) 1 – 
Investigation schedule). 
A typo has been corrected in the 
wording 
of 
criterion 
N°34 
(suppression of a reference to 
hepatic 
enzymes 
measured 
at 
ASSE). 
A sentence has been added in the 
statistical paragraph to anticipate 
the 
need 
to 
perform 
some 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
exploratory analyses. 
 
Amended 
protocol 
3 
29-Jun-2017 
AUT, CZE, 
DNK, DEU, 
ESP, ITA 
This 
amendment 
has 
been 
implemented 
to 
integrate 
prior 
amendments N°1 and N°2 (for  
European 
countries, 
where 
amendment N°1 had not yet been 
submitted for Regulatory and Ethic 
review at the time of amendment 
N°2 issuance).   
Amended 
protocol 
4 
05-Mar-2018 
ALL 
This substantial amendment has 
been implemented in order to adapt 
selection/inclusion criteria to new 
considerations and new medical 
data; to clarify new timelines of the 
study; to add a 3D picture of the 
reference ulcer on the day of the 
inclusion visit after randomisation; 
to clarify wording; and to broaden 
the study population. 
© ILKOS THERAPEUTIC INC – 05 March 2018 – INT - Confidential 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
STUDY SUMMARY SHEET 
Name of the sponsor: 
ILKOS THERAPEUTIC INC  
 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
(For National Authority Use only) 
Name of Finished Product: 
 
 
Volume: 
 
 
Name of Active Ingredient: 
S42909 
 
Page: 
 
Title of study:  
Dose-response relationship study of S42909 on leg ulcer healing after oral repeated administration in 
patients with active venous leg ulcer. A 10-week randomised, double-blind, placebo-controlled, 
prospective, international, multicentre, phase IIa study 
Protocol No.:CL2-42909-016 
Coordinator 
International Coordinator: Professor Eberhard Rabe (Bonn, Germany) 
National coordinators and investigators: listed in a separate document 
Study centre(s): 
Total number of centres: around 55  
Total number of countries: 10  
Study period: 
- 
Study duration for the participant: up to 10 weeks 
- 
Study initiation date:  July 2017 
- 
Study completion date: Q1 2020 
Study development phase: IIa 
Objective(s):  
Primary objective: 
To detect the existence of an overall dose-response relationship with S42909 on improving healing of venous 
leg ulcers on top of standard of care (compression and local wound care) after 4 weeks of treatment. 
Secondary objectives: 
­ To determine a dose window for the Minimal Effective Dose (MED) on improving healing of venous leg 
ulcers. 
­ To explore the effect of S42909 on improving healing of venous leg ulcers on top of standard of care 
(compression and local wound care) after 6 weeks of treatment. 
­ To explore the effect of S42909 on improving pain related to venous leg ulcer over 6 weeks. 
­ To explore the effect of S42909 in decreasing analgesic drug consumption related to venous leg ulcer over 
6 weeks. 
­ To assess the safety profile of each tested dose of S42909 (adverse events, biochemistry, haematology, 
ECG, vital signs, body weight and standard urinalysis). 
­ To assess the pharmacokinetics of S42909 and its metabolites in patients after repeated administration of 
S42909. 
Additional objectives 
­ To assess any potential PK/PD relationship (mainly on improving healing of venous leg ulcers and pain 
related to venous leg ulcers). 
­ Genomic assessment of S42909: 
. 
To evaluate associations between polymorphisms in relevant genes and the pharmacokinetics of 
S42909. 
. 
To identify subgroups of patients with genomic susceptibility to develop non healing venous leg 
ulcer or to identify novel genes that may play a critical role in the treatment response  
­ To collect the blood non genomic biomarkers which can be related to venous leg ulcer healing, underlying 
chronic venous disease, response to S42909 treatment (bio-collection in a bio-repository). 
 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
Name of the sponsor: 
ILKOS THERAPEUTIC INC  
 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
(For National Authority Use only) 
Name of Finished Product: 
 
 
Volume: 
 
 
Name of Active Ingredient: 
S42909 
 
Page: 
 
Methodology:  
Study design  
 
 
Phase IIa, prospective, international, multicentre, randomised, double-blind, placebo-controlled, parallel group, 
dose-finding study in patients with venous leg ulcer. 
Patients suffering from chronic venous disease and having at least one active venous leg ulcer will be selected 
at the selection visit (ASSE). One Reference Ulcer (RU) defined as the largest ulcer in size that is fitting the 
area selection criteria will be established. At ASSE, a first picture will be taken before cleansing and 
debridement and a second picture will be taken after cleansing and debridement. The investigator will check 
that the selection RU area is compliant with the selection criteria. Patients will start the selection period and 
will be switched from their current pharmacological and/or local treatment (if any) for venous leg ulcer to local 
wound care with sterile saline solution or sterile water, “non-active” dressings and standardized compression 
(same strength and type of compression). They will be administrated the placebo selection treatment for a 
period of fourteen days. 
Three (or four) working days before the inclusion visit, the participants will come to the site for a RU picture 
in order to get the RU area central measurement for inclusion visit (W000). 
At W000, the investigator will check that the inclusion RU area is compliant with the inclusion criteria. The 
relative change of Reference Ulcer area compared with the RU area measured at the selection visit must be less 
or equal to 20% in order for patients to be eligible. The investigator will also check that the participant is 
compliant with the selection treatment and stockings wearing. Patients found to be eligible for randomisation 
will have a 3D picture of the RU on the day of W000, taken after randomisation and after wound bed 
preparation. This picture (W000-B) will be the baseline measure for comparison with all subsequent pictures 
taken at following visits. 
RU  
pictures 
at selection 
 
RU pictures 
3 or 4 working Days 
before W000
Inclusion / 
randomisation 
14 Days after  
ASSE 
 
Last dose of 
treatment 
End of study 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
Name of the sponsor: 
ILKOS THERAPEUTIC INC  
 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
(For National Authority Use only) 
Name of Finished Product: 
 
 
Volume: 
 
 
Name of Active Ingredient: 
S42909 
 
Page: 
 
All participants found to be eligible for inclusion will be randomised to one of the following six groups – 
S42909: 100, 200, 400, 800 or 1200 mg per day- or placebo, using a centralised, dynamic, balanced with 
1:1:1:1:1:1 ratio, stratified randomisation according to the country, a combined prognosis criteria (size and age 
of ulcer) ), and diabetic status (yes/no), by Interactive Web Response System (IWRS). 
The combined prognosis criteria (size and age of ulcer) for ulcer healing are: 
o 
A : ≤ 10 cm² and ≤ 6 months 
o 
B : > 10 cm² or > 6 months  
The participants will enter a 6 weeks ambulatory Investigational Medicinal Product (IMP) treatment period on 
top of standard of care (standardized compression and local wound care with sterile saline solution or sterile 
water and “non-active” dressing) followed by a 2 weeks follow-up period of standard of care only. During this 
period the participants will return to the investigator’s site for intermediate visits after one week (W001), two 
weeks (W002), three weeks (W003), four weeks (W004), six weeks (W006) and eight weeks (W008). 
Participants will continue receiving standardized compression therapy and local wound care (sterile saline 
solution or sterile water and “non-active” dressing) until the end of the study (W008). 
At each visit, the clinical features of the RU will be recorded and a 3D picture of the RU will also be taken 
after wound bed preparation except at ASSE visit where a 3D picture of the RU will be taken before and after 
wound bed preparation and where an additional picture of entire leg will also be taken. All 3D pictures will be 
recorded and uploaded for central review, measurement of ulcer area, perimeter and volume for the primary 
and secondary endpoints of the study. Independent experts from patients, CRO, and investigators, will review 
the 3D pictures centrally at selection (and inclusion, if applicable) as well as the clinical aspect of the RU and 
will confirm or not the selection (or the inclusion, if applicable). At W000, W004 and W006, the pain level 
will be assessed before the recording of clinical features of RU. 
The primary endpoint will be assessed at 4 weeks. 
Four PK samples will be collected at the W000, W004 and W006 visits and one predose PK sample will be 
taken at W001and W002 visits in all participants. Participants who agreed to participate in the optional PK 
analysis in participating centres will have 9 PK samples collected over 12 hours at the W000 visit and 13 PK 
samples collected over 24 hours at the W004 visit. 
Number of participants: 
Planned selected: 250 participants 
Planned included participants: 204 included participants (34 participants per group)  
Diagnosis and main criteria for inclusion:  
Main selection criteria: 
Caucasian (defined for this study as having 2 Caucasian parents)  men or women ≥ 18 years of age who have 
given their written informed consent, with chronic venous disease documented by duplex ultrasonography and 
with at least one active venous leg ulcer (CEAP C6 stage) diagnosed or reoccurred for more than 6 weeks and 
less than 2 years at selection. The Reference Ulcer (RU) should be 3 cm away from other ulcers. 
­ The size of Reference Ulcer (defined as the largest ulcer in size that is fitting the area selection criteria) 
should be ≥ 5 cm² and ≤ 100 cm2 
­ Ankle Brachial Pressure Index (ABPI)  should be ≥ 0.8 and ≤ 1.3 
Main non-selection criteria: 
­ Ulcer bed with black necrotic tissue  
­ Infected ulcer that require local or systemic antibiotherapy  
­ Recent history of lower extremity deep venous thrombosis within the last 3 months 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
Name of the sponsor: 
ILKOS THERAPEUTIC INC  
 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
(For National Authority Use only) 
Name of Finished Product: 
 
 
Volume: 
 
 
Name of Active Ingredient: 
S42909 
 
Page: 
 
­ Other non-venous leg ulcer or other associated skin conditions which may influence healing 
­ Inadequately controlled type 1 and type 2 diabetes, treated or not treated, with an HbA1c > 8%  either from 
the result of a test done within the 3 months before selection or from a result discovered at the laboratory 
test done within the 5 calendar days prior to the W000 visit. 
­ Contra-indication to lower limb compression with an applied pressure of approximately 45 mmHg 
­ Participants who are undergoing treatments known to affect healing within the month prior to selection: 
pentoxifylline, immunosuppressive drugs, immunomodulators, cytotoxic chemotherapy or oral 
corticosteroids 
­ Topical corticosteroids application on and around the ulcer within 15 days prior to selection  
­ Acetylsalicylic acid treatment started within the last 6 weeks prior to the selection or during the study. 
Acetylsalicylic acid is allowed if started more than 6 weeks before the selection and remaining stable until 
the end of the study (i.e.: low dose prophylactic acetylsalicylic acid at antiaggregant dose ≤ 350 mg daily) 
­ Drugs known to be Breast Cancer Resistance Protein (BCRP) substrates (e.g.: rosuvastatine, 
sulfasalazine…). 
­ Participants treated with oral anticoagulant treatments known to be BCRP substrates such as 
acenocoumarol, fluindione, apixaban, rivaroxaban  
­ Venoactive drugs within the month prior to selection 
­ Participants on oral or parenteral antibiotherapy. Long-term, low dose prophylactic antibiotherapy started at 
least one month before the selection is however acceptable if there is no change in the treatment during the 
study. 
­ NSAIDs on long-term chronic treatment within last month, except if taken for less than one week within 
the last month. 
Main inclusion criteria:  
­ Still eligible as per requirement of selection/non-selection criteria (except for reference ulcer area which 
should be ≥ 4.5 cm2 and ≤ 100 cm2) 
­ Presence of venous disease characterized by imaging methods (duplex ultrasonography) to detect a venous 
disorder on both sub- and extra-fascial venous systems. The disorder may be a combination of different 
manifestations such as venous reflux, venous dilation, thickening of venous wall, etc. The results of the 
examinations should be available for the inclusion visit 
­ No clinically significant change in the ulcer healing process available and confirmed by central reading 
(size and clinical features if applicable). 
Main non inclusion criteria: 
­ Tablet compliance < 80% and > 120 % during the placebo selection period. 
­ Compliance with the standardized compression regimen < 80% during the placebo selection period. 
- 
standardized compression regimen:  one understocking and one overstocking. The understocking to 
be worn 24/7. The overstocking applied over the understocking during the day must be removed 
during the night. 
­ Clinically significant change in the ulcer healing process showing a change in reference ulcer area of more 
than 20% or showing unstable evolution or complications (i.e. by infection, erosion) between selection and 
inclusion. 
­ Clinically significant abnormalities in laboratory examination (haematology, biochemistry) sampled within 
the 5 calendar days prior to W000 visit, with the results available at W000 visit (at the latest) before 
randomisation: 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
Name of the sponsor: 
ILKOS THERAPEUTIC INC  
 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
(For National Authority Use only) 
Name of Finished Product: 
 
 
Volume: 
 
 
Name of Active Ingredient: 
S42909 
 
Page: 
 
o 
Serum albumin < 20g/l  
o 
eGFR <30 ml/min calculated with MDRD formula  
o 
AST or ALT > 3ULN (Upper Limit of normal laboratory range)  
o 
GGT > 3 ULN 
o 
Total bilirubin > 2 ULN  
o 
Clinically significant anaemia (i.e. Hb <10 g/dL) 
o 
HbA1c > 8% in an available result from the previous 3 months in a known diabetic patient or 
discovered between selection and inclusion (HbA1c > 8% in the laboratory test done within 
the 5 calendar days prior to the W000 visit). 
Note: If a patient is discovered with hyperglycaemia (fasting blood sugar ≥7 mmol/L) and/or 
with an elevated HbA1c ≥ 6.5% but ≤ 8% between selection and inclusion, the patient can be 
included in the study and will be stratified as a diabetic. 
Test drug: S42909 
S42909 50 mg and 200 mg tablets per os administration, 3 tablets twice a day taken at the end of the morning 
and evening meals 
 
Comparator: placebo  
Matching placebo tablets, per os administration, 3 tablets twice a day taken at the end of the morning and 
evening meals 
 
Duration of treatment:  
- Selection period: 14 days 
- Active treatment period: 6 weeks 
- Follow-up period: 2 weeks 
 
Criteria for evaluation: 
Efficacy measurements: 
­ Primary endpoint: 
Relative reduction of Reference Ulcer area after 4 weeks of treatment on top of standard of care 
compared with baseline Reference Ulcer area assessed during study visits using a digital 3D imaging 
device. 
- 
Secondary endpoints: 
. 
Reference Ulcer area (ASSE, W000, W001, W002, W003, W004, W006 and W008 visits): relative 
reduction of Reference Ulcer area after each visit on top of standard of care compared with baseline 
Reference Ulcer area. 
. 
Linear advance of the wound margin towards the wound centre (ASSE, W000, W001, W002, W003, 
W004, W006 and W008 visits) (Gilman, 1990) to measure healing progress at each visit on top of 
standard of care compared with baseline Reference Ulcer area 
. 
Reference Ulcer volume (ASSE, W000, W001, W002, W003, W004, W006 and W008 visits): 
relative reduction of Reference Ulcer volume at each visit on top of standard of care compared with 
baseline Reference Ulcer volume. 
. 
Pain assessment (W000, W004, W006 visits): change in intensity and in the characteristics compared 
with baseline (W000), using a questionnaire including a Visual Analog Scale (VAS). 
. 
Analgesic drug consumption: dose and/or duration (patient using analgesic drug for Venous Leg 
Ulcer (VLU) during the study) 
. 
Safety measurements: 
. 
Physical examination (ASSE, W000, W001, W002, W003, W004, W006, W008). 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
Name of the sponsor: 
ILKOS THERAPEUTIC INC  
 
Individual 
Study 
Table 
Referring to Part of the 
Dossier 
(For National Authority Use only) 
Name of Finished Product: 
 
 
Volume: 
 
 
Name of Active Ingredient: 
S42909 
 
Page: 
 
. 
6 or 12-leads electrocardiogram (within 5 calendar days prior to W000, W001, W002, W003, W004, 
W006, W008). 
. 
Laboratory assessments (within 5 calendar days prior to W000, W001, W002, W003 (INR only, if 
applicable), W004, W006, W008). 
. 
Adverse events (from ASSE to W008). 
Other measurements  
- 
Pharmacokinetic measurements 
The concentrations of S42909 and its metabolites (S45015, S45236 and S55113) in plasma will be assayed 
according to validated methods.  
- 
Genomics assessment (W000) (optional): 
. 
To evaluate potential associations between polymorphisms in relevant genes and the 
pharmacokinetics of S42909. 
. 
To identify subgroups of participants with genetic susceptibility to develop non healing venous leg 
ulcer or to identify novel genes that may play a critical role in the treatment response. 
- 
Non genomic biomarkers assessment (optional): 
Plasma and serum samples for assessment of non genomic biomarkers related to venous leg ulcer healing, 
underlying chronic venous disease and response to S42909 treatment will be collected at the W000 and W004 
visits. 
 
Statistical methods:  
Study Outcome 
Study outcome analyses will be carried out on the RS (Randomised Set). 
Main efficacy analysis: Detection of an overall dose-response effect 
The objective of the main analysis will be to detect the existence of a dose-response relationship according to 
the ulcer area reduction expressed as the relative change from baseline to W004 (%) and using the MCP-Mod 
Method. 
Study participants (disposition, baseline characteristics and follow-up) and Safety analysis: 
The doses 0 mg (placebo), 100 mg, 200 mg, 400 mg, 800 mg and 1200 mg will be assessed in the study and 
the following set of 7 candidate models: M = (Linear, Emax (2), Sigmoïd Emax, Logistic, Exponential (2)) 
will be considered for the main analysis. 
For each model in M, optimal contrasts will be defined in order to evaluate the global relevance of model. 
Then, a test of contrast will be performed on each model to detect the existence of dose-response relationship 
with control of the Family Wise Error Rate. The model with the minimum p-value (the one with the strongest 
statistical test and greater than an appropriate critical value q) will be chosen as the “best” fit model. 
As secondary analysis, after reassessment of the parameters of the model selected in the main analysis and 
considering an hypothesis of clinically relevant difference that is equal to 6.5% (as compared to placebo), a 
dose window for the Minimal Effective Dose (MED) will be estimated. 
Pharmacokinetic analysis 
A population PK analysis will be performed in order to describe the pharmacokinetics of S42909 and its 
metabolites in participants suffering from active venous leg ulcers, to quantify and qualify the sources of PK 
variability (i.e., covariate analysis), and to provide individual secondary PK parameter estimates (e.g., 
exposure, terminal half-life). 
To further investigate any potential PK/PD relationship, the correlation between S42909 and its metabolites 
PK and the potential biological markers and clinical outcome (mainly on improving healing of Venous Leg 
Ulcers and pain related to venous leg ulcers) will be explored. If relevant, population PK/PD analysis will be 
performed. In addition, the correlation between drug exposure and any evidence of safety signal will be 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
Table of contents 
Table of contents ...................................................................................................................... 11 
1. ADMINISTRATIVE STRUCTURE OF THE STUDY ................................................. 21 
2. BACKGROUND INFORMATION ................................................................................. 21 
3. STUDY OBJECTIVES AND PURPOSE ........................................................................ 26 
3.1. Primary objective ............................................................................................................ 27 
3.2. Secondary objectives ...................................................................................................... 27 
3.3. Additional objectives ...................................................................................................... 27 
4. STUDY DESIGN ............................................................................................................... 28 
4.1. Endpoint(s) ...................................................................................................................... 28 
4.1.1. Primary Efficacy Endpoint ........................................................................................... 28 
4.1.2. Secondary Endpoints .................................................................................................... 28 
4.1.3. Other Endpoints ............................................................................................................ 29 
4.2. Experimental design ....................................................................................................... 29 
4.2.1. Study plan ..................................................................................................................... 29 
4.2.2. Investigation schedule .................................................................................................. 33 
4.3. Measures to minimise bias .............................................................................................. 36 
4.4. Study products and blinding systems.............................................................................. 36 
4.4.1. Products administered .................................................................................................. 36 
4.4.2. Treatment management ................................................................................................ 38 
4.4.3. Management of blinding systems ................................................................................. 39 
4.5. Discontinuation of the study ........................................................................................... 40 
4.5.1. Premature discontinuation of the study ........................................................................ 40 
4.5.2. Discontinuation of the study in the event of objective reached .................................... 40 
4.6. Source data ...................................................................................................................... 40 
5. SELECTION AND WITHDRAWAL OF PARTICIPANTS ........................................ 40 
5.1. Selection criteria ............................................................................................................. 40 
5.1.1. Demographic characteristics ........................................................................................ 40 
5.1.2. Medical and therapeutic criteria ................................................................................... 40 
5.1.3. Informed consent .......................................................................................................... 41 
5.2. Non-selection criteria ...................................................................................................... 41 
5.2.1. General criteria ............................................................................................................. 41 
5.2.2. Medical and therapeutic criteria ................................................................................... 42 
5.3. Inclusion criteria ............................................................................................................. 44 
5.4. Exclusion criteria ............................................................................................................ 44 
5.5. Additional information recorded at the selection/inclusion visit .................................... 45 
5.6. Participant withdrawal .................................................................................................... 45 
5.6.1. Withdrawal criteria ....................................................................................................... 45 
5.6.2. Procedure ...................................................................................................................... 46 
5.6.3. Lost to follow-up .......................................................................................................... 46 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
6. TREATMENT OF PARTICIPANTS .............................................................................. 47 
6.1. IMPs administered .......................................................................................................... 47 
6.2. IMPs dispensing .............................................................................................................. 48 
6.3. Previous and concomitant treatments ............................................................................. 50 
6.4. IMP compliance .............................................................................................................. 51 
6.5. Arrangements after the discontinuation of the IMP ........................................................ 51 
7. ASSESSMENT OF EFFICACY ...................................................................................... 51 
7.1. Efficacy measurements ................................................................................................... 51 
7.2. Methods and measurement times .................................................................................... 52 
8. SAFETY MEASUREMENTS .......................................................................................... 54 
8.1. Safety measurements ...................................................................................................... 54 
8.2. Methods and measurement times .................................................................................... 54 
8.3. Adverse events ................................................................................................................ 56 
8.3.1. Definitions .................................................................................................................... 56 
8.3.1.1. 
Adverse events ......................................................................................................... 56 
8.3.1.2. 
Serious adverse events ............................................................................................. 57 
8.3.1.3. 
Adverse events of special interest ............................................................................ 57 
8.3.1.4. 
Overdose .................................................................................................................. 58 
8.3.1.5. 
Events requiring an immediate notification (ERIN) ................................................ 58 
8.3.2. Responsibilities of the investigator .............................................................................. 58 
8.3.2.1. 
Time frame for AE reporting ................................................................................... 58 
8.3.2.2. 
Evaluation of seriousness, intensity and causality ................................................... 59 
8.3.2.3. 
Documentation of the event ..................................................................................... 60 
8.3.2.4. 
Follow-up of adverse events .................................................................................... 60 
8.3.2.5. 
Special situations (pregnancy, overdoses, intake of IMP by a person around 
the participant) ......................................................................................................... 60 
8.3.2.6. 
Recording Methods in the e-CRF ............................................................................ 61 
8.3.2.7. 
Procedure for an event requiring an immediate notification ................................... 61 
8.3.3. Responsibilities of the sponsor ..................................................................................... 62 
9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY 
OR SAFETY ...................................................................................................................... 62 
9.1. Measurement of drug concentration ............................................................................... 62 
9.1.1. Collection of blood samples ......................................................................................... 63 
9.1.2. Storage and shipment of samples ................................................................................. 64 
9.2. Assessment of non genomic biomarkers relating to healing (biorepository) ................. 64 
9.2.1. Collection of blood samples ......................................................................................... 64 
9.2.2. Optional assessment ..................................................................................................... 64 
9.2.2.1. 
Sampling and storage ............................................................................................... 65 
9.2.2.2. 
Labelling and transfer .............................................................................................. 65 
9.2.2.3. 
Non genomic biomarkers assessment ...................................................................... 65 
9.2.2.4. 
Transfer of analytical results.................................................................................... 65 
9.3. Optional assessment - genomic ....................................................................................... 65 
9.3.1. Collection of blood samples ......................................................................................... 67 
9.3.2. Sampling and storage ................................................................................................... 67 
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9.3.3. Labelling ....................................................................................................................... 67 
9.3.4. Assay ............................................................................................................................ 67 
10. 
STATISTICS ................................................................................................................. 67 
10.1. Statistical analysis ........................................................................................................... 67 
10.1.1. Evaluation criteria ........................................................................................................ 68 
10.1.2. Statistical elements ....................................................................................................... 68 
10.1.3. Analysis sets ................................................................................................................. 68 
10.1.4. Statistical methodology ................................................................................................ 69 
10.2. Determination of sample size ......................................................................................... 71 
11. 
DIRECT ACCESS TO SOURCE DATA / DOCUMENTS ...................................... 73 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 73 
12.1. Study monitoring ............................................................................................................ 73 
12.1.1. Before the study ............................................................................................................ 73 
12.1.2. During the study ........................................................................................................... 73 
12.2. Computerised medical file .............................................................................................. 73 
12.3. Audit - Inspection ........................................................................................................... 74 
13. 
ETHICS ......................................................................................................................... 75 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) .................................. 75 
13.2. Study conduct ................................................................................................................. 75 
13.3. Participant information and informed consent ................................................................ 75 
13.4. Modification of the information and consent form ......................................................... 76 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................... 76 
14.1. Study data ....................................................................................................................... 76 
14.2. Data management ........................................................................................................... 77 
14.3. Archiving ........................................................................................................................ 78 
15. 
INSURANCE ................................................................................................................. 78 
16. 
OWNERSHIP OF THE RESULTS - PUBLICATION POLICY ............................ 78 
17. 
ADMINISTRATIVE CLAUSES ................................................................................. 79 
17.1. Concerning the sponsor and the investigator .................................................................. 79 
17.1.1. Persons to inform .......................................................................................................... 79 
17.1.2. Substantial protocol amendment and amended protocol .............................................. 79 
17.1.3. Final study report .......................................................................................................... 80 
17.2. Concerning the sponsor .................................................................................................. 80 
17.3. Concerning the investigator ............................................................................................ 80 
17.3.1. Confidentiality - Use of information ............................................................................ 80 
17.3.2. Organisation of the centre ............................................................................................ 81 
17.3.3. Documentation supplied to the sponsor ....................................................................... 81 
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18. 
REFERENCES .............................................................................................................. 82 
19. 
APPENDICES ............................................................................................................... 86 
 
 
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Amended Clinical study protocol n° 4 - Final version 
List of tables 
Table (4.1) 1 – Endpoints ......................................................................................................... 28 
Table (4.2.2) 1 - Investigation schedule ................................................................................... 34 
Table (4.2.2) 2 - Pharmacokinetic Investigation Schedule ...................................................... 35 
Table (4.4.1) 1 - Description of the IMPs ................................................................................ 37 
Table (4.4.1) 2 - Description of packaging for Selection and IMP treatment period ............... 37 
 
 
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Amended Clinical study protocol n° 4 - Final version 
List of figures 
Figure (4.2.1) 1 - Study plan .................................................................................................... 33 
Figure (10.2) 1 - Dose-response models .................................................................................. 72 
 
 
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Amended Clinical study protocol n° 4 - Final version 
List of appendices 
Appendix 1: World Medical Association Declaration of Helsinki .......................................... 88 
Appendix 2: Duplex ultrasonography ...................................................................................... 94 
Appendix 3: Venous Leg Ulcer ................................................................................................ 98 
Appendix 4: Revised CEAP Classification ............................................................................ 100 
Appendix 5: Ankle Brachial Pressure Index .......................................................................... 103 
Appendix 6: Ulcer Infection ................................................................................................... 106 
Appendix 7: Renal Failure Classification .............................................................................. 108 
Appendix 8: Heart Failure Classification ............................................................................... 110 
Appendix 9: Questionnaire for Pain Assessment ................................................................... 112 
Appendix 10: Clinical Assessment of Leg Ulcer ................................................................... 115 
Appendix 11: Examples of Standard Meals ........................................................................... 117 
Appendix 12: Ankle Brachial Pressure Index Form .............................................................. 119 
 
 
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List of abbreviations 
ABPI 
: Ankle Brachial Pressure Index 
ADME 
: Absorption Distribution Metabolism Elimination 
AE 
: Adverse Event 
ALT 
: ALanine AminoTransferase 
Anti HCV 
Anti Hepatite C virus 
AST 
: ASpartate AminoTransferase 
ASSE 
: Selection visit 
BCRP 
: Breast Cancer Resistance Protein 
β-HCG 
: β-Human Chronic Gonadotropine 
bid 
: bis in die (twice a day) 
BMI 
: Body Mass Index 
BUN 
: blood urea nitrogen 
CEAP 
: Clincial, Ethiological, Anatomic and Physiopathologic 
Cl 
: Chlore 
cm 
: Centimetre 
cm/mV 
: Centimetre per millivolt 
Cmax 
: Maximum Concentration 
CPK 
: Creatine Phosphokinase 
CRF 
: Case Report Form 
CRP 
: C-Reactive Protein 
CRO 
: Contract Research Organisation 
CSU 
: Clinical Supply Unit 
CV 
: Curriculum Vitae 
CVD 
: Chronic Venous Disease 
CVI 
: Chronic Venous Insufficiency 
CWD 
: Continuous Wave Doppler 
CYP 
: Cytochrome P 
D 
: Day 
3 D 
: three-dimensional 
DDI 
drug-drug interaction 
DNA 
: Deoxyribonucleic acid  
e.g. 
: exempli gratia (for example) 
ECG 
: ElectroCardioGram 
e-CRF 
: Electronic Case Report Form 
EDTA 
 EthyleneDiamineTetraacetic Acid 
eGFR 
Estimated Glomerular Filtration Rate 
ERIN 
: Event Requiring Immediate Notification 
EWMA 
: European Wound Management Association 
FAS 
: Full Analysis Set 
FGF-β1 
: Fibroblast Growth Factor 
FSH 
: Follicle Stimulating Hormone 
FWER 
: Family Wise Error Rate 
g 
: Gram 
g/dL 
: Gram per decilitre 
GCP 
: Good Clinical Practice 
GGT 
: Gamma-Glutamyl Transferase (Gamma-Glutamyl Transpeptidase) 
h 
: Hour 
Hb 
: Hemoglobin 
HbA1c 
: Glycosylated Hemoglobin 
Hbs 
: Surface antigen of Hepatitis B virus 
HCG 
: Human Chorionic Gonadotrophin 
HDL 
: High-Density Lipoprotein 
HFHC 
: High Fat High Calorie 
Hg 
: Mercury 
HIV 
: Human Immunodeficiency Virus 
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HPMC-AS 
: HydroPropyl Methyl Cellulose 
HR 
: Heart Rate 
HUVEC 
: Human Umbilical Vein Endothelial Cells 
i.e. 
: id est (that is) 
I.E.C.  
: Independent Ethics Committee 
IRB.  
: Institutional Review Board 
I.R.I.S. 
: Institut de Recherches Internationales Servier 
ICAM 
: IntraCellular Adhesion Molecule 
ICH 
: International Conference on Harmonisation 
IMP 
: Investigational Medicinal Product (test drug / placebo) 
INR 
International Normalized Ratio 
IWRS 
: Interactive Web Response System 
K 
: Potassium 
Kcal 
: Kilocalory 
K/DOQI 
: Kidney Disease Outcomes Quality Initiative 
kg 
: Kilogram 
LDL 
: Low-Density Lipoprotein 
MCH 
: Mean Corpuscular Haemoglobin 
MCHC 
: Mean Corpuscular Haemoglobin Concentration 
MCP 
: Monocyte Chemo-attractant Protein  
MCP-Mod 
: Multiple Comparisons and Modeling 
MCV 
: Mean Corpuscular Volume 
MDRD 
: Modification of Diet in Renal Disease 
MED 
: Minimal Effective Dose 
MedDRA 
: Medical Dictionary for Regulatory Activities 
mg 
: Milligram 
min 
: Minute 
ml 
: Milliliter 
mm 
: Millimeter 
mm/s 
: Minimeter per seconde 
mmHg 
: Millimeter of mercury 
MMP 
: Matrix Metalloproteinase 
Na 
: Sodium 
NA 
: Not Applicable 
NADPH 
: Nicotinamide Adenine Dinucleotide Phosphate 
NKF 
: National Kidney Foundation 
NOSF 
: Nano-Oligosaccharide Factor 
NSAIDs 
: NonSteroidal Anti-inflammatory Drugs 
NYHA 
: New York Heart Association 
PAI 
: Plasminogen Activator Inhibitor 
Pcr 
: Plasma Creatinine 
PD 
: PharmacoDynamics 
PK 
: PharmacoKinetics 
p.o 
: Per os 
PPS 
: Per Protocol Set 
QTc 
: 
QT interval corrected for heart rate 
QTcF 
QTc calculated using Fridericia formula 
ROC 
: Receiver Operating Characteristic 
ROS 
: Reactive Oxygen Species 
RS 
: Randomised Set 
RT 
: Room Temperatur 
RU 
: Reference Ulcer 
SAE 
: Serious Adverse Event 
SGOT 
: Serum glutamic oxaloacetic transaminase 
SGPT 
: Serum glutamic pyruvic transaminase 
SNP 
: Single Nucleotide Polymorphisms 
SS 
: Safety Set 
TGF-β 
: Transforming Growth Factor 
tmax 
: time corresponding to Cmax 
TNF 
: Tumor Necrosis Factor 
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TU 
: Therapeutic Units 
UGT 
: UDP-Glucuronyl transferase 
ULN 
: Upper Limit of Normal reference range 
VAS 
: Visual Analog Scale 
VCAM 
: Vascular Cell Adhesion Molecule 
VEGF 
: Vascular Endothelial Growth Factor 
VLU 
: Venous Leg Ulcer 
WHO-DD 
: World Health Organization, Drug Dictionary 
WMA 
: World Medical Association 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
1. ADMINISTRATIVE STRUCTURE OF THE STUDY 
Non sponsor parties, sponsor parties and CRO responsible for local management of the study 
are described in a separate document entitled Administrative part of clinical study protocol. 
The list of investigators for each country is given in separate documents attached to the 
protocol and entitled "List of investigators” for Austria, Canada, Czech Republic, Germany, 
Denmark, Italy, Slovakia, Spain, and the United States of America. 
2. BACKGROUND INFORMATION 
Venous disease is considered as extremely common and a major cause for seeking medical 
assistance in Western countries ((Fowkes, 2001); (Beebe-Dimmer, 2005)) costing society 
more than ten million Euros/year per million people (Carpentier , 2004). Several studies based 
on the Clinical, Etiological, Anatomic and Physiopathologic (CEAP) classification have 
shown that a large portion of the general population suffers from symptoms related to venous 
insufficiency in the lower limbs ((Criqui, 2003); (Jawien, 2003); (Chiesa, 2005)). 
Epidemiological surveys have suggested that 15% to 20% of the general population have 
early symptoms, indicative of the disease onset, but without any visible or detectable sign of 
chronic venous disease (C0s on the CEAP classification) (Andreozzi, 2006).  
A more recent epidemiologic study, the Vein Consult Program (VCP), aimed to collect global 
epidemiological data on chronic venous disorders (CVD) based on the CEAP classification. 
The range of CVD is from no visible or palpable signs of venous disease (C0) to leg ulcers 
(C6). Having enrolled 91 545 patients worldwide followed by 6232 general practitioners, 
results showed that the CVD prevalence is high worldwide: 19,7% of C0s (patients reporting 
symptoms but without objective signs), 21,7% of C1, 17,9% of C2 and 24,3% from C3 to C6, 
with C0s to C3 stages predominant whatever the country, and confirmed that CVD affects  
significant part of the populations worldwide (Rabe, 2012). 
Patients with chronic venous insufficiency are prone to develop venous leg ulcers in the ankle 
and the lower leg (Valencia, 2001). 
The annual prevalence of venous leg ulcer is estimated to be between 1.65% and 1.74% in 
adults aged 65 years and older (Margolis, 2002) and this is expected to grow substantially 
during the next several decades. In Europe, the prevalence of leg ulcers varies between 0.2 to 
1% of the general population ((Ruckley, 2000). Leg ulcer is associated with aging with peak 
prevalence between 60 and 80 years old (Brem, 2003). In addition, recent studies have shown 
that one percent of the population developed at least one episode of venous ulcer during a life-
time with a higher prevalence in the elderly (Ramelet, 2008). 
Chronic wounds result in high morbidity as treatment of leg ulcers requires frequent visits to 
dispense topical dressings, debridement, compression therapy and skingraft and may needs 
hospitalisation for complications, mostly leg infections. Despite attempts to improve ulcer 
healing, this pathology represents an unresolved clinical problem as healing may be slow or 
never be achieved in a subset of patients. In addition, leg ulcer is characterized by a high 
incidence rate of recurrent ulcerations reported to be 37% and 48%, 3 and 5 years respectively 
after wound healing (Brem, 2004). 
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Chronic venous disease is the result of a multi-factorial pathological process that finally leads 
to venous stasis and profound deterioration of the microcirculation (Bergan, 2006).  
Several modifications in the microcirculation are observed in patients suffering from venous 
disease. These modifications are initially characterised by a capillary dilatation secondary to 
raised blood pressure in the microvascular bed and microedema formation leading to 
worsened skin nutrition. With the evolution of the pathology, a reduced number of functional 
capillaries are observed due to microthrombosis and/or trapping of white cells, and lymphatic 
microangiopathy that is characterised by destruction of the micro lymphatic network (Scurr, 
1994). 
The disruption of the microcirculation induces a cascade of events which may explain ulcer 
formation: 1) development of oedema responsible for parenchymal cells ischemia by limiting 
the diffusion of oxygen and nutriments; 2) extravasation and degradation of red blood cells 
leading to hemosiderin deposition; 3) formation of pericapillary fibrin cuff; 4) accumulation 
and adhesion of leukocytes in the dermal matrix and release of toxic metabolites (TNFα), 
proteolytic enzymes (MMPs), and growth factors (TGF-β and its receptor endoglin, FGF-β1, 
VEGF) ((Korthuis, 2000); (Perrin, 2011); (Raffetto, 2011)). 
Vascular Endothelial Growth Factor (VEGF), a potent angiogenic factor, enhances 
endothelial proliferation and the vascular permeability in the same time with inducing the 
expression of adhesion molecules such as ICAM-1, VCAM-1 and E-selectin ((Kim, 2001), 
(Verbeuren, 2000)). 
The importance of matrix metalloproteinases (MMPs) has also been discussed due to their 
involvement in both inflammatory reaction and cutaneous tissue remodeling. Recent studies 
showed an increased expression of MMP2 in liposclerotic skin (Tarlton, 1999)  
Venous hypertension is responsible for the progression of the inflammatory cascade. An 
inflammatory process is triggered when there is an increased adhesion of circulating 
leukocytes to the vascular endothelium ((Jacob, 2002); (Howlader, 2003); (Kappelmayer, 
2004)) leading to the release of inflammatory mediators. Leukocyte involvement in the 
process of chronic venous disease (CVD) is supported by the hypothesis of “leukocyte 
trapping”. It refers to the leukocyte adhesion to the endothelium and its migration through the 
altered endothelium of venous wall and venous valve, possibly leading to valve incompetence 
and reflux (Bergan, 2007). 
Leukocyte activation is followed by synthesis and release of many inflamatory molecules 
such as leukotrienes, prostaglandins, bradykinin, free oxygen radicals and cytokines. 
Cytokines act to regulate and perpetuate the inflammatory reaction and thus leading to 
delayed re-epithelisation and liposlerotic skin remodelling.  
In addition, prolonged inflammation generates reactive oxygen species (ROS) by 
inflammatory cells and vascular cells through the NADPH oxidase pathway. Mechanical 
stress also promotes the inflammatory response by increasing the expression of other pro-
inflammatory molecules, such as monocyte chemo-attractant protein-1 (MCP-1), endothelin-1 
and ICAM-1 and secondarily exacerbates ischemia of the surrounding tissue. 
The combination of all these pathophysiological factors leads to cellular and tissue 
dysfunction resulting in dermal changes such as skin fibrosis and ulceration. 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
S42909 is a synthetic benzo (b) pyran-4-one derivative proposed for the treatment of venous 
and mixed leg ulcers. 
Data available on pharmacology, safety and toxicology on S42909 are detailed in the 
brochure for clinical investigators. Non-clinical pharmacological studies carried out with 
S42909 show that it could be a potential new medicine in the treatment of chronic venous 
disease. By correcting the microcirculatory disturbances related to venous disease, S42909 
may represent a powerful leg ulcer treatment. 
Pharmacological properties of S42909 may be summarised as follows: 
Mechanism of action: S42909 is an inhibitor of leukocyte adhesion to human endothelial 
cells stimulated with TNF-α, via an inhibition of cell surface adhesion molecules (E-selectin 
and VCAM-1) expression.   
S42909 reduces the oxidative stress through the inhibition of the vascular NADPH oxidase 
activity. It also decreases the expression of the markers of endothelial cell dysfunction (PAI-
1) in HUVEC (human umbilical vein endothelial cells) and MMP-2 activity in venous smooth 
muscle cells from varicose veins. S42909 shares its pharmacology properties with two of its 
glucuronides, S45015 and S45236. 
 Microcirculation: 
S42909 inhibits hyperpermeability and leukocyte adhesion to endothelial cells 
induced by ischemia/reperfusion in the microcirculation of the hamster cheek pouch. 
It protects the microcirculation against ischemic damage and presents an anti-oedema 
activity in mice and dogs. 
 Venous reactivity: 
In rabbits, S42909 prevents the vasodilatation in a pathological model and reinforces 
the saphenous vein constriction in response to noradrenaline. 
 Lymphatic vessels: 
In rats, S42909 reinforces the contractility of the mesenteric lymphatic vessels which 
should result in an increase in lymphatic flow. 
 Healing of ischemia-reperfusion ulceration: 
In a rat model of cutaneous ulcer, S42909 significantly reduces the intensity of 
ulceration at macro- and microscopic levels and decreases time to heal. 
Pharmacokinetics and metabolism in humans 
In clinical and non-clinical studies, the absolute bioavailability of S42909 is low after oral 
administration; however, the rate and extent of absorption was markedly improved by using 
several different absorbtion-enhancing formulations. 
After single oral administration of S42909 (Formulation R, formulation to be used in this 
study), tmax is observed between 3.0 and 4.5 h. UGT-mediated metabolism occurs in the 
intestine and/or the liver leading to two mono-glucuronides (S45015, S45236) and a di-
glucuronide (S55113). The non-clinical data regarding metabolism and drug elimination was 
confirmed in the human excretion-balance study (PKH-42909-005) in which the majority of 
the radioactivity was recovered in faeces (94% of the dose) and less than 0.1% of the 
radioactivity was excreted in urine. S42909 and its three metabolites suffice to account for the 
total radioactivity in plasma. The highest Cmax and exposures are reached for S45236. 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
Overall, after single oral administration of S42909 (in fasting conditions) in young healthy 
male volunteers, the data suggest a more than proportional increase in exposure with the dose 
for both S42909 and S45015 and less than the proportional with the dose for S45236.  
After repeated oral administration of S42909, steady-state is reached by Day 4, with no 
accumulation of the parent drug after 10 days of repeated administration of S42909 at 600, 
1200 and 1800 mg (with standard meals). Food intake (High Fat High Calorie (HFHC) or 
standard breakfast) increases Cmax and exposure for S42909 and S45015. S45236 Cmax and 
exposure are decreased at 600 mg after a HFHC breakfast. 
Results of one combined study (PKH-42909-003) investigating the S42909 drug-drug 
interactions with a CYP2C9 substrate (warfarin) and with a CYP3A4 substrate (midazolam) 
showed that S42909 at the dose of 210 mg q.d does not interact with the elimination of 
warfarin or midazolam, in accordance with circulating concentrations much lower than Ki and 
supporting a low risk of drug-drug interaction with S42909. 
Safety data in clinical studies 
Overall, 278 subjects have been enrolled into the S42909 clinical studies; out of these, 203 
have received at least one administration of S42909.  
S42909 was administered in doses ranging from: 
• 105 mg to 840 mg in oral single dose administration and 210 mg to 630 mg in oral 
repeated dose administration for periods between 5 and up to 14 days, in the Gelucire® 
44/14 formulation (currently discontinued), 
• 600 mg/day to 2100 mg/day in single oral dose administration and repeated dose 
administration with the newly developed formulation for 10 days. 
Overall, S42909 was well tolerated up to the dose of 1800 mg in oral single dose and 
1200 mg in oral repeated dose administration. There were no clinically relevant abnormalities 
concerning biologic and hematologic parameters, physical examination, vital signs or on ECG 
tracings. 
The majority of the reported Treatment Related Emergent Adverse Events were mild or 
moderate, mainly diarrhoea probably due to the laxative effect of main excipient a cellulosic 
derivative. 
During the conduct of the CL1-42909-013 dose-escalation study, diarrheic episodes were 
reported in several subjects starting from the daily dose of 1200 mg of S42909. The episodes 
increased in frequency, duration and severity when escalating the dose and at the same dose 
when passing from single dose administration to repeated dose administration. Typically, the 
episodes were mild to moderate in intensity occurring rapidly after study drug intake and 
resolved spontaneously the same day. 
The tolerability of S42909 in a b.i.d. schedule of administration was investigated and allowed 
to reduce the frequency of the diarrhoea. 
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S42909 
Amended Clinical study protocol n° 4 - Final version 
Study design and population  
This study will be a parallel group, dose-finding study. 204 participants with an active venous 
leg ulcer (CEAP C6 classification) occuring in the presence of documented pure venous 
disease in a limb with 0.8 ≤ Ankle Brachial Pressure Index (ABPI) ≤ 1.3 and no other 
significant medical disease preventing the use of high compression therapy (Position 
Document EWMA, 2003) will be included.  
The participants will be randomised into one dose group or placebo group. The placebo arm 
will allow the evaluation of the effect of treatment in addition to the standard existing therapy. 
Participants will be treated on top of the standard of care in all treatment arms with 
compression and local wound care. Compression therapy is the current standard treatment for 
venous ulcers. Compression is directed at lowering venous hyperpressure. Numerous studies 
have confirmed that the proportion of complete ulcer healing is improved when high 
compression is used (O'Meara, 2012). To apply uniform standard care procedures, high 
compression stockings (approximately 45 mmHg working pressure) with individually 
adapted-sizes will be provided to all participants selected in the study. 
Justification of the treatments, doses to be administrated 
The dose selection was based on the safety and pharmacokinetic data from Phase 1 studies. 
Considering the variability in exposure of the parent compound and its metabolites and in 
order to avoid overlap of exposure between dose groups a factor 2 between two consecutive 
doses has been chosen (except for the last step). Consequently the doses to be investigated in 
this study will be 100, 200, 400, 800 and 1200 mg of S42909 per day. 
The highest dose of S42909 to be administrated during this study will be 1200 mg/day as this 
dose was administrated in the CL1-42909-013 study and showed a good tolerability after 
single and repeated administration. At this dose level no safety concerns were raised. Mild to 
moderate intermittent diarrhoeic episodes have been reported which stopped after 6 days of 
administration. 
Taking into account the positive food effect on drug absorption (CL1-42909-013), the IMP 
treatment will be taken at the end of the meals. 
Participants will start a 14-days placebo selection treatment period to check their compliance 
with the IMP treatment and compression stockings, then start a 6-weeks IMP treatment being 
randomised equally in each treatment group (one dose or placebo) taking into account 
stratification factors. Finally, the participants will be followed-up during 2 weeks after the last 
intake of study treatment.  
Patients will be assigned to one of the six treatment arms by an algorithm of randomisation 
meant to ensure balanced allocation in all respective arms of treatment. Participants in the 
optional PK will be randomised too, in order to ensure balanced allocation in all arms of 
treatment. Standard wound care treatment and baseline ulcer characteristics generally have a 
significant effect on progression of healing. Therefore it is planned to consider the following 
stratification factors: 
 
 
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- 1. Country - to account for the variation in wound care from one country to 
another  
- 2. A prognostic factor for healing based on the wound characteristics (wound size 
and duration). 
- 3. Diabetic status (yes/no) 
Efficacy assessment 
The evaluation of therapeutic response in patients with venous leg ulcers is difficult due to the 
long time needed to observe complete wound healing. 
Whereas the complete healing remains the final goal for treating these patients (Guidance 
FDA, 2006), it would be of a great value to clinicians as well as to patients to have a reliable 
estimate of the time to total healing based on early progress in a given treatment regimen. 
This is especially important for chronic leg ulcers where the expected healing time with 
standard care may be 6 months or more. Today, the standard practice for the treatment of 
chronic wounds includes monitoring of the wound size at regular intervals. 
A reliable qualification of the percentage of change in wound area over time is a significant 
prognostic measure of complete healing (Kantor, 2000). A study using a large cohort of 
venous leg ulcer patients has demonstrated that the percentage of change in wound area after 
4 weeks of treatment can be a valid surrogate marker of healing at 12 or 24 weeks of care 
(Gelfand, 2002).  
Consequently, in the current study, the primary efficacy endpoint will be the relative 
reduction of the reference ulcer area after 4 weeks of treatment. In order to establish a dose-
response relationship between S42909 and the relative reduction of ulcer area, the “MCP-
Mod” statistical methodology (Bretz and Al, 2005) will be applied. Based on a set of 
candidate models, the existence of an overall dose-response relationship will be assessed and, 
if observed, the best model will be used, after re-estimation of parameters and convergence, to 
evaluate the dose window able to produce a clinically significant effect. 
Measurements of the ulcer area will be performed using a 3D imaging device and the 
accompanying software. The same equipment will be provided to all centres in order to 
standardize the ulcer measurement methodology: images will be recorded using the same type 
of camera with automatic adjustment of light, focus and color reproduction according to 
distance to the ulcer and measurements will be performed centrally on the provided images. 
The study will be conducted in compliance with the protocol, Good Clinical Practice and the 
applicable regulatory requirements. 
3. STUDY OBJECTIVES AND PURPOSE 
The purpose of this study is to investigate if S42909 at any dose has an effect on healing of 
venous leg ulcer (proof of concept) and to explore the relationship between dose and effect of 
S42909 on venous leg ulcer healing on top of standardized compression and local wound 
care.  
Assessment of efficacy will be performed on the relative reduction of the reference ulcer area 
after 4 weeks of treatment as compared to baseline using a digital 3D imaging device, a 
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surrogate endpoint which is positively correlated with chances to heal after 12 or 24 weeks of 
treatment. 
3.1. Primary objective 
The primary objective of the study is: 
­ To detect the existence of an overall dose-response relationship with S42909 on improving 
healing of venous leg ulcers on top of standard of care (compression and local wound care) 
after 4 weeks of treatment. 
3.2. Secondary objectives 
The secondary objectives of the study are:  
­ To determine a dose window for the Minimal Effective Dose (MED) on improving healing 
of venous leg ulcers. 
­ To explore the effect of S42909 on improving healing of venous leg ulcers on top of 
standard of care (compression and local wound care) after 6 weeks of treatment. 
­ To explore the effect of S42909 on improving pain related to venous leg ulcer over 6 
weeks. 
­ To explore the effect of S42909 on decreasing analgesic drug consumption related to 
venous leg ulcer over 6 weeks. 
­ To assess the safety profile of each tested dose of S42909 (adverse events, laboratory 
parameters, physical examination, body weight, vital signs (blood pressure, heart rate), 6 or 
12-lead electrocardiogram (ECG). and standard urinalysis). 
­ To assess the pharmacokinetics of S42909 and its metabolites in patients after repeated 
administration of S42909. 
3.3. Additional objectives  
­ To assess any potential PK/PD relationship (mainly on improving healing of venous leg 
ulcers and pain related to venous leg ulcer). 
­ Genomic assessment of S42909: 
• To evaluate potential associations between polymorphisms in relevant genes and the 
pharmacokinetics of S42909. 
• To identify subgroups of patients with genomic susceptibility to develop non healing 
venous leg ulcer or to identify novel genes that may play a critical role in the treatment 
response  
­ To collect the blood non genomic biomarkers which can be related to venous leg ulcer 
healing, underlying chronic venous disease, response to S42909 treatment (bio-collection 
in a bio-repository). 
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4. STUDY DESIGN 
4.1. Endpoint(s) 
Table (4.1) 1 – Endpoints 
 
 
Endpoints  
Primary 
 
Relative reduction of Reference Ulcer area after 4 weeks of treatment 
Secondary 
Relative reduction of Reference Ulcer area after each visit 
 
Linear advance of the wound margin towards the wound centre 
 
Reference reduction of Reference Ulcer volume at each visit 
 
Pain assessment by VAS  
 
Analgesic daily dose 
 
Safety assessment 
 
      Adverse event 
 
      Laboratory parameters 
 
      Physical examination, body weight, vital signs 
 
      6 or 12-leads electrocardiogram 
 
 
Exploratory 
 
Pharmacokinetics in plasma 
 
Genomic in blood 
 
Non genomic biomarkers in plasma and serum 
        
4.1.1. Primary Efficacy Endpoint 
­ Relative reduction of Reference Ulcer area after 4 weeks of treatment on top of standard of 
care compared with baseline Reference Ulcer area assessed during study visits using a 
digital 3D imaging device. 
4.1.2. Secondary Endpoints 
­ Reference Ulcer Area using a digital 3D imaging device: Relative reduction of Reference 
Ulcer area after each visit on top of standard of care compared with baseline Reference 
Ulcer area.  
­ Linear advance of the wound margin towards the wound center (Gilman, 1990) to measure 
healing progress at each visit on top of standard of care compared with baseline (see 
section 10 for more details) 
­ Reference Ulcer volume using a digital 3D imaging device: relative reduction of Reference 
Ulcer volume at each visit on top of standard of care compared with baseline Reference 
Ulcer volume. 
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­ Pain assessment (W000, W004, W006): change in intensity and in the characteristics at 
each visit compared with baseline (W000), using a questionnaire including a VAS scale  
­ Analgesic drug consumption (W0, W4, W6): change in daily dose of analgesic taken for 
VLU at each visit compared with baseline (W000) (patient using analgesic drug for VLU 
during the study) 
­ Safety measurements 
o Adverse events occurring during the double-blind period of the study.  
o Assessment of laboratory parameters, physical examination, body weight, 
Vital signs (blood pressure, heart rate), 6 or 12-lead electrocardiogram (ECG).  
4.1.3. Other Endpoints 
­ PK assessment: PK of S42909 and its metabolites will be measured in patients with venous 
leg ulcer at W000, W001, W002, W004 and W006 and will be analysed by population PK 
approach. 
­ Sample collection and storage for genomic exploratory analysis of samples collected at 
W000. 
­ Sample collection and storage for non genomic biomarker analysis of samples collected at 
W000 and W004. 
4.2. Experimental design 
4.2.1. Study plan 
This is a phase IIa, prospective, international, multicentre, randomised, double-blind, placebo-
controlled, parallel group, dose-finding study in patients with venous leg ulcer.  
The study will consist of 3 periods as follows: 
­ A selection period of 14 days of placebo treatment in which participants will be 
investigated for documenting the presence of Chronic Venous Disease and assessment of 
type and size of Reference Leg Ulcer. Their clinical and biological status will be 
documented prior to inclusion. From the selection visit, standard of care will be changed to 
standardized compression and local wound care with sterile saline solution or sterile water 
and “non active” dressings. 
­ A double-blind controlled period of 42 days: 6 weeks of treatment with one dose of 
S42909 or placebo on top of standardized compression and wound local care. 
­ A follow-up period of 2 weeks with standard of care only after the last dose of S42909 
(from W006 to W008). 
An Interactive Web Response System (IWRS) will be set up for participant 
selection/inclusion randomisation and allocations of the therapeutic units pack numbers. 
About 250 patients suffering from chronic venous disease and having at least one active 
venous ulcer matching with the selection criteria (CEAP classification C6 stage) will be 
selected at the selection visit (ASSE) to include 204 participants at W000 visit. 
During the ASSE visit, the underlying chronic venous disease will be documented and 
recorded in the participant medical file according to CEAP classification. To document the 
chronic venous disease, a duplex ultrasonography should have been performed within the 
previous 6 months or will have to be performed during ASSE or the placebo selection period 
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of 14 days to have the results before inclusion and allow verification of compliance with the 
inclusion criteria. If data of the duplex ultrasonography report performed in the previous 6 
months doesn’t permit to fill in the e-CRF and/or to rule out an acute venous thrombosis, a 
duplex ultrasonography must be performed before inclusion. The presence of a peripheral 
arterial component of the disease must be ruled out by measuring and calculating the ankle-
brachial pressure index (ABPI) ideally by continuous waves Doppler, otherwise by duplex 
ultrasonography (see Appendix 5) before applying high level compression (Mosti, 2009).  
During the selection visit (ASSE), one Reference Ulcer (RU) defined as the largest ulcer in 
size that is fitting the area selection criteria will be established for each participant.  
At ASSE visit, the clinical aspect of the RU will be documented by the investigator by 
recording the clinical features of the wound on the clinical assessment document. 
The investigator (or a designated person) will take two 3D pictures of the RU using the digital 
3D devices provided to the site. Only at ASSE, a first picture will be taken before cleansing 
and debridement and a second picture will be taken after cleansing and debridement. In 
addition, only at ASSE, the investigator will take a 3D picture of the leg where the RU is 
located, fully covering the gaiter area. The 3D pictures will be uploaded on a secured website 
and recorded using a standardized procedure. From W000 to W008, 3D pictures will be 
performed only after cleansing and debridement. The same procedure will be used to send the 
pictures to the RU central reviewer. The investigators (or a designated person) will be trained 
to use the device. 
The investigator or a designee will use a transparent sheet that will be provided to trace the 
RU outlines and measure the RU area at the selection visit after cleansing and debridement. 
The investigator or designated person will record the measured RU area of this outline and 
check that the area is fitting the selection criteria. The selection will be based on the 
investigator’s RU area measurement and the compliance with the selection/non selection 
criteria. 
The participants successfully selected will start the selection period and will be switched from 
their current pharmacological and/or local treatment (if any) for venous leg ulcer to 
standardized compression stockings provided to the sites and local wound care with sterile 
saline solution or sterile water, “non-active” dressings (see section 4.4.1). They will be given 
the placebo selection treatment for a period of fourteen days. Prior to first dispensation 
supply, the participants will be trained on the use of stockings. 
The RU area will also be centrally measured by the CRO within the 3 working days following 
the selection visit and the measurement will be sent back to the investigator. The picture 
performed at selection after cleansing and debridement will be the reference for measurement 
of changes between the selection (ASSE) and inclusion (W000) pictures. 
Following the selection, an independent expert will review centrally the clinical aspect of RU. 
The expert will give an opinion on the RU selection by reviewing the clinical aspect of the 
RU. The review will be based on the clinical analysis of the two 3D pictures taken by the 
investigator (or a designated person) at selection visit (before and after cleansing and 
debridement). In addition, the expert will also review the 3D picture of the leg where the RU 
is located, taken at the selection visit. The expert will confirm the selection if RU clinical 
pictures are consistent with a venous aetiology, or give a recommendation for study 
continuation. In case of doubt on the venous aetiology of the ulcer, the expert can send the 
picture to another expert for double review. 
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If the central measurement of the RU area is not fitting the RU area selection criteria and/or if 
the RU clinical aspect is not suitable for the study according to the independent expert, the 
participant who has been selected must be withdrawn before inclusion in the double-blind 
phase of the study. 
Three (or four) working days before the inclusion visit (W000) at the latest, the participants 
will come to the site for a RU picture: after wound cleansing and debridement, the 
investigator (or a designated person) will take a 3D picture of the RU using the digital 3D 
imaging device provided to the site and upload this picture on the same day to a secured 
website for central review. As the local wound care is done at the same time, he will also 
perform RU clinical assessment, and pain will be assessed by VAS during W000 visit.  
In case of persistent doubt after double review of the picture taken at selection, the 
independent expert will recheck the features of the RU and its venous aetiology with the help 
of the 3D picture taken before the inclusion visit. The result of the independent expert review 
will be given within three working days. If the doubt persists at the review of the picture taken 
at inclusion, the patient will not be included.  
The CRO in charge of the central reading of pictures will perform RU area measurement 
before W000 and send it back to the investigator within 3 working days together with the 
central RU area measured at ASSE and the change between ASSE and W000 area 
measurements.  
At the end of the placebo selection period, participants will return to the investigator site for 
inclusion visit and randomisation (W000).  
At W000, the investigator will check that the RU area measured centrally at ASSE is 
consistent with his/her measurement, that independent experts validation is done, and will re 
check the selection criteria.  
­ If the central measurement of ASSE RU area is not fitting the selection criteria, the 
participant will not be included.  
­ If the central measurement of ASSE RU area confirm the RU area selection criteria, the 
investigator will check that the participant complies with the inclusion criteria, the 
recommendations for compression (stockings wearing ≥ 80% of the time according to 
diary information) and is compliant with placebo selection treatment (between 80 and 
120%). The relative change of RU area compared with the RU area measured at ASSE 
visit must be less or equal to 20% in order for the participant to be eligible for inclusion. 
This relative change calculated centrally will be used to check the compliance with the 
inclusion criteria.  
­ Patients found to be eligible for randomisation will have a 3D picture of the RU on the day 
of W000, taken after randomisation and after wound bed preparation. This picture (W000-
B) will be the baseline measure for comparison with all subsequent pictures taken at 
following visits. 
All participants found to be eligible for inclusion will be randomised to one of the following 
six groups - S42909 100, 200, 400, 800 or 1200 mg per day - or placebo. The randomisation 
will be performed using a centralised, dynamic, balanced with 1:1:1:1:1:1 ratio, stratified 
randomisation according to the country, a combined prognosis criterion (age and size of ulcer, 
using the RU area measured centrally at W000), and diabetic status (yes/no) by the IWRS. 
For stratification purposes, will be considered diabetic patients  those with an already 
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confirmed diagnosis of diabetes as well as previously unknown diabetic patients  with a 
fasting blood sugar ≥7mmol/L and/or an elevated HbA1c value between 6.5 and 8% on pre- 
inclusion laboratory results. 
The participants will enter a 6-week ambulatory IMP treatment period on top of standard of 
care (standardized compression and local wound care with sterile saline solution or sterile 
water and “non-active” dressing) followed by a 2-weeks follow-up period with standard of 
care only. During this period the participants will return to the investigator’s site for 
intermediate visits after one week (W001), two weeks (W002), three weeks (W003), four 
weeks (W004), six weeks (W006) and eight weeks (W008). Participants will continue to 
receive standardized compression therapy and local wound care (sterile saline solution or 
sterile water and “non-active” dressing) until the end of the study (W008). At W000, W004 
and W006 visits, pain assessment will be performed at the beginning of the visit using a 
questionnaire with VAS. At each visit, the clinical features of the RU will be recorded and a 
3D picture of the RU will be taken after wound bed preparation. All 3D pictures will be 
recorded and uploaded for central review, measurement of ulcer area, perimeter and volume 
for the primary and secondary endpoints of the study. 
Four PK samples will be taken at W000, W004 and W006 visits and one predose PK sample 
will be taken at W001 and W002 visits in all participants. The participants who agreed to 
participate in the optional PK analysis in participating centres (7 patients per dose group) will 
have 9 PK samples collected over 12 hours at W000 visit and 13 PK samples collected over 
24 hours at the W004 visit instead of the 4 PK samples. 
At each visit general compliance with standardized compression will be checked and size of 
the stockings will be adjusted, if needed. The participant should be explained that the 
standardized compression stockings should be worn everyday and used according to the 
recommendations given by the investigator.  
­ If complete healing of the reference ulcer is observed during the study conduct but other 
ulcers are still open, the participant will keep the same standardized compression until 
complete healing of all ulcers is observed or until the end of the study and will continue to 
take IMP treatment until W006 visit.  
­ If complete healing of all ulcers (including the reference ulcer) is observed, the participant 
will keep the same standardized compression until the end of the study or be switched to a 
compression for leg ulcer recurrence prevention (> 18 mmHg) if the participant refuses 
(this type of compression will not be provided to the sites). The participant will continue to 
take the study drug until W006. 
The end-of-study visit is scheduled to take place at W008 or, in case of prematurely 
withdrawn participants as soon as possible, after stopping the use of standardized 
compression, or after the last IMP intake. In case of premature withdrawal, the next expected 
visit will be performed. If the next expected visit is W003, biochemistry and haematology 
should be added to the assessments to be performed during this visit.   
An electronic case report form (e-CRF) will be used for data capture during the study. 
The study plan is shown in Figure (4.2.1) 1. 
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Figure (4.2.1) 1 - Study plan 
- 
Treatment periods-  
 
 
Group A 
S42909 dose 100 mg, p.o., 50 mg bid    N=34 
 
Group B 
S42909 dose 200 mg, p.o., 100 mg bid   N=34 
Placebo 
Group C 
 
S42909 dose 400 mg, p.o., 200mg bid    N=34 
 
Group D 
 
S42909 dose 800 mg, p.o., 400 mg bid   N=34 
 
Group E 
 
S42909 dose 1200mg, p.o., 600mg bid   N=34 
 
Group F 
 
Placebo, p.o., bid                                      N=34 
On top of standard of care (standardized compression and local wound care) 
Study periods 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ASSE  
 
   W000 
    visit  
 
W001  
visit 
W002  
Visit 
W003  
 visit 
W004 visit 
Primary 
End-point 
      W 006 
visit 
    W008 visit 
 
 
 
4.2.2. Investigation schedule 
Table (4.2.2) 1 describes the measurement of efficacy and safety assessed during the study. 
Placebo selection 
period 
Double-blind controlled treatment period 
Follow-up period 
Inclusion / 
randomisation 
14 Days after ASSE 
RU picture 
3 or 4 working days before 
W000 
Last dose of 
treatment 
End of study 
Selection 
RU picture 
 
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Table (4.2.2) 1 - Investigation schedule 
 
Selection Inclusion 
Treatment period 
End of 
Study 
 
ASSE 
W000 
W001 
W002 
W003 
 
W004 
W006 
W008 
Visits Time windows 
D –14  
 
D0 
±2 days 
D0 
+7 days 
±2 days 
D0 
+14 days  
 ±2 days 
D0 
+21 days  
 ±2 days 
D0 
+28 days 
 ±2 days 
D0 
+42 days 
±4 days 
D0 
+56 days 
 ±4 days 
Informed consent 
X 
 
 
 
 
 
 
 
Selection / non-selection criteria 
Inclusion / non-inclusion criteria 
X 
 
X 
 
 
 
 
 
 
Previous treatment 
X 
 
 
 
 
 
 
 
Medical / surgical history 
X 
X(1) 
 
 
 
 
 
 
Concomitant treatments 
CEAP classification 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CVD imaging (duplex ultrasonography (2) 
ABPI measurement (Doppler ultrasound) 
IWRS connexion (3) 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Treatments 
 
 
 
 
 
 
 
 
Treatment dispensing 
X 
X 
 
X 
 
X 
 
 
Local wound care 
X 
X 
X 
X 
X 
X 
X 
X 
Standardized 
compression 
education 
Standardized compression dispensing 
X 
X 
X 
 
 
 
 
 
 
 
Leg measurements 
X 
X(4) 
X(4) 
X(4) 
X(4) 
X(4) 
X(4) 
 
Treatment Compliance 
 
X 
X 
X 
X 
X 
X 
 
Compliance stocking wearing (diary) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Efficacy measurements 
 
 
 
 
 
 
 
 
3D Picture 
X (5) 
X (6) 
X 
X 
X 
X 
X 
X 
Reference 
Ulcer 
area 
measurement 
(investigator) 
X 
 
 
 
 
 
 
 
Reference 
Ulcer 
area 
measurement 
(central) 
X (5) 
X (6) 
X 
X 
X 
X 
X 
X 
Reference Ulcer features Validation 
(Independent expert) 
X 
X (7) 
 
 
 
 
 
 
Pain assessment by VAS (8) 
 
X 
 
 
 
X 
X 
 
Analgesic drug – consumption 
 
X 
 
 
 
X 
X 
 
Clinical assessment of RU 
X  
X (9) 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Safety measurements 
 
 
 
 
 
 
 
 
Adverse events 
X (10) 
X (10) 
X 
X 
X 
X 
X 
X 
β-HCG 
(women 
with 
childbearing 
potential) (11) 
Prescription(16) Results(16) 
 
 
 
X 
 
X 
FSH (menopausal women) 
Prescription(16) Results(16) 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (HR, SBP, DBP, body 
temperature)  
X 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
X 
 
X 
 
 
X 
X 
Height (for BMI calculation)  
X 
 
 
 
 
 
 
 
ECG 6 or 12-lead (12) 
Prescription(16) Results(16) 
X 
X 
X 
X 
X 
X 
Biochemistry and haematology (13) 
Prescription(16) Results(16) 
X 
X 
 
X 
X 
X 
INR(17) 
Standard urinalysis (dipstick) 
Prescription(16) 
Prescription(16) 
Results(16) 
Results(16) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Other assessments 
 
 
 
 
 
 
 
 
Blood sampling for PK (14) 
 
X 
X 
X 
 
X 
X 
 
Blood sampling for genomic 
 
 
X (15) 
 
 
 
 
 
 
Blood 
sampling 
for 
non 
genomic 
biomarkers (biorepository) 
 
 
X (15) 
 
 
 
X (15) 
 
 
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(1) events occurring before the first intake of the test drug and not associated with a procedure scheduled in the study protocol (duplex, blood 
sampling, etc.), a withdrawal of treatment related to the conditions of the protocol, a product other than the IMP, taken as part of the protocol 
will be recorded in the medical history (see section 8.3.2.6 Recording methods). 
(2) if no duplex ultrasonography available within 6 months prior to selection and or/ insufficient data to fill in the e-CRF and /or suspicious of 
acute Venous Thrombosis (at ASSE or during the selection period).  
(3)IWRS connections to obtain patient number (ASSE), randomisation of patient & allocation of TU (W000), reallocation of TUs (W002; W004) 
and in case of premature withdrawal (withdrawal visit).  
(4) check that the size allocated at selection is still applicable according to the leg measurements. If the size has changed, adequate compression 
stockings size will be supplied. 
(5) To be done and uploaded to central review on the day of ASSE visit to receive the central RU area measurement within 3 working days. 
(6) To be done and uploaded to central review 3 or 4 working days prior to W000 visit at the latest to receive the central RU area measurement 
before W000. Additionally, patients found to be eligible for randomisation will have a baseline 3D picture of the RU (W-000B) on the day of 
W000, taken after randomisation and after wound bed preparation and before the 1st dose of IMP is administered.  
(7) in case of doubt on venous aetiology of the RU after the double check of the picture taken at ASSE. 
 (8) Pain assessment should be performed at the beginning of the visit, before RU clinical assessment and care of the RU. 
 (9) The RU clinical assessment will be performed when the participant comes for the picture 3 or 4 working days before W000. 
(10) Events occurring between the signing of the consent form and the inclusion visit (inclusion visit included) and associated with a procedure 
scheduled in the study protocol (Doppler, duplex ultrasonography, blood sampling, etc.), or a withdrawal of treatment related to the conditions of 
the protocol, or a product other than the IMP taken as part of the protocol will be recorded on an Adverse Event form (see section 8.3.2.6 
Recording methods). 
 (11) Depending on the local regulation, pregnancy tests can be repeated throughout the treatment period. 
(12) ECG must be done before blood sampling. 
(13) In fasting condition for 10 hours.  
(14) Four PK samples will be taken at W000, W004 and W006 visits and one predose PK sample will be taken at W001, W002 visits in all 
participants. The participants who agreed to participate in the optional PK analysis in participating centres will have 9 PK samples collected 
over 12 hours at W000 visit and 13 PK samples collected over 24 hours at W004 visit instead of the 4 PK samples and will be assigned to a dose 
group by the IWRS.  
(15) Before the IMP intake and after specific consent collected for these optional samplings. 
(16) β-HCG, FSH, biochemistry, HbA1c (if a result from previous 3 months is not available), haematology, urinalysis and ECG prescribed at 
ASSE visit: they should be collected within the 5 calendar days prior to W000 visit, with the results available to be checked at W000 visit (at the 
latest) before randomisation.  
(17) INR to be followed at each visit (or more often if judged necessary by the investigator) if patient is under anticoagulant therapy with 
warfarin or phenprocoumon.  
 
   
The maximum total volume of blood collected per participant during the study will be around 
304 ml for the mandatory study and around 410 ml in case of optional pharmacokinetic 
analysis, genomic and non genomic biomarkers sampling. 
Table (4.2.2) 2 - Pharmacokinetic Investigation Schedule 
Time relative to the 
first administration on 
the visit day 
Pre-
dose 
0h 
1h 
2h 
3h 
End of 
visit (2) 
4h 
5h 
6h 
8h 
12h 
(4) 
13h 
14h 
15h 
24h 
IMP intake at the end 
of the meal 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
PK Blood sampling for 
all participants: 
W000, W004, 
W006 (3) 
X(1) 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
PK Blood sampling for 
all participants: 
W001, W002 
X(1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Blood sampling 
over 12-hours for 
participants having 
agreed to this optional 
PK analysis: W000 
X(1) 
 
X 
X 
X 
NA 
X 
X 
X 
X 
X(1) 
 
 
 
 
PK Blood sampling 
over 24-hours for 
participants having 
agreed to this optional 
PK analysis: W004  
X(1) 
 
X 
X 
X 
NA 
X 
X 
X 
X 
X(1) 
X(5) 
X(5) 
X(5) 
X (1),(5) 
(1) PK sampling before meal and IMP administration. 
(2) Blood sampling will be performed in all patients at the end of the study visit, just before leaving or at T4h if possible. 
(3) Except at W000 and W004 for patients participating to the optional PK blood sampling over 12 hours and 24 hours 
respectively. 
(4) Could be adjusted to a maximum of 2 hours before, to accommodate a more convenient dinner time. 
(5) PK sampling schedule for H13, H14, H15 and H24 is relative to the evening IMP administration (respectively 1, 2, 3 and 12h 
after evening IMP administration). 
NA: Not Applicable 
         
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For further practical details, methods of measurement are provided in sections 7, 8 and 9. 
4.3. Measures to minimise bias 
The following measures are taken to avoid or minimise bias: 
­ This is a double-blind study. 
­ All treatments will be identical to protect the blinding for the participants and the 
investigators. 
- All tablets of S42909 or its placebo will be identical in form and appearance 
- Packaging and labelling of all treatment groups will be identical 
- The number of tablets will be identical for all groups 
­ Participants will be distributed within each group of treatment equally by a centralised, 
dynamic, balanced with 1:1:1:1:1:1 ratio, stratified randomisation according to the country, 
a combined prognosis criteria for venous ulcer healing, and diabetic status.  
­ Participants in the optional PK analysis will be distributed across treatment arms 
The combined prognosis criteria (size and age of ulcer) are: 
A : ≤ 10 cm² and ≤ 6 months 
B : > 10 cm² or > 6 months  
­ At the inclusion visit, a centralized randomisation using the IWRS will randomly assign 
the participants to one of the six treatment groups. The randomisation algorithm will be 
built by CRO IWRS according to an adaptive randomisation by minimisation. 
­ The pictures of the ulcers will be performed by the same 3D imaging device in all centres. 
The investigators (or designee) will be trained in the use of the device.  
­ The area, perimeter and volume measurements of the reference venous leg ulcer will be 
performed centrally by a CRO following the same measurement methodology for all 
patients during the entire study. CRO experts in charge of the central reading will be all 
trained on that methodology. The use of the 3D imaging device and software standardize 
the reference ulcer measurement methodology. 
4.4. Study products and blinding systems 
4.4.1. Products administered 
­ Study drug: 
During the selection period (from ASSE to W000), the participant will receive placebo 
selection oral treatment. 
During the double-blind treatment period (from W000 to W006), the participant will be 
treated with one of the 5 oral doses of S42909 or placebo. 
At W006, the participants will stop the IMP treatment until the end of the follow-up period 
(W008). The standardized compression with the local wound care applied during the study 
will be continued. 
The tablets of placebo and S42909 (dosages 50 and 200 mg) will have identical appearance. 
The regimen will be 3 tablets twice a day taken at the end of the meals (3 tablets taken in the 
morning and 3 tablets in the evening) with a glass of water (250 ml). 3 tablets twice a day are 
necessary to reach each of the 5 doses used in the study and keep the blind for all participants. 
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On the day of the study visit, the participant will not take his/her morning study drug 
treatment before the study visit to ensure that pharmacokinetic samples are taken before next 
dose. He/she will take the study drug during the visit after pre-dose PK sampling and at the 
end of the breakfast. 
Table (4.4.1) 1 provides a description of the IMP(s). 
Table (4.4.1) 1 - Description of the IMPs 
 
 
50 mg S42909 
200 mg S42909 
Placebo 
Pharmaceutical form 
Film-coated tablet 
Film-coated tablet 
Film-coated tablet 
Unit dosage 
50 mg of S42909-1 
200 mg of S42909-1 
- 
Appearance, colour 
Oblong, red 
Oblong, red 
Oblong, red 
Composition* 
Lactose monohydrate 
 
Lactose monohydrate 
* only excipients to have a recognized action 
     
Table (4.4.1) 2 provides a description of the packaging of the IMP(s). 
Table (4.4.1) 2 - Description of packaging for Selection and IMP treatment period 
 
Number of units of the pharmaceutical 
form per primary packaging 
 
18 tablets per blister (6 rows of 3 tablets) 
Number of primary packaging per 
secondary packaging 
 
6 blisters per sachet 
Number of secondary packaging per 
participant and per treatment period  
Selection period 
1 kit (i.e. small box) with 1 sachet per participant 
 
Double-blind controlled period 
 
W000-W002: 1 kit (i.e. small box) with 1 sachet per participant 
W002-W004: 1 kit (i.e. small box) with 1 sachet per participant 
W004-W006: 1 kit (i.e. small box) with 1 sachet per participant 
 
     
The labelling of packages complies with the regulatory requirements of each country involved 
in the study, as well as the recommendations in appendix 13 of the European Guide to Good 
Manufacturing 
Practice 
(http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-
4/2009_06_annex13.pdf) 
and 
with 
US 
recommendations 
(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm0649
71.htm). 
­ Standardized compression and local wound care: 
Standardized compression (compression stockings) will be provided to all participants 
according to the leg measurement chart and will be applied throughout the study (from ASSE 
to W008). The participants will be trained by their investigator to the use of the stockings. 
The compression stocking kit provided consists of two understockings and one overstocking. 
The materials of the compression understocking are polyamide, elastane, and cotton, and the 
materials of the compression overstocking are polyamide, elastodiene, and cotton. The 
understocking is first applied on the leg up to the knee over the dressings protecting the ulcer 
and has to be worn 24/7. The overstocking is then applied over the understocking during the 
day and must be removed during the night.  
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The stockings have to be worn for one day and then be washed to recover the initial 
compression properties. That is why two understockings and one overstocking will be 
provided to each participant. 
The cleansing of the wound should only be done with sterile saline solution or sterile water. 
No antiseptic solution (e.g. Prontosan® –betaine/polyhexanide, Chlorexidine) is allowed 
during the study conduct (from ASSE to W008). 
The debridement should only be mechanical (except wet-to-dry gauze dressings): only Stiefel 
curette and spoon are allowed. Local anaesthetics are allowed for the debridement. Autolytic, 
enzymatic, absorptive dressings, surgical and shaved debridement are not allowed.  
The primary dressings usually used at the site and adequate for the ulcer will be applied 
taking into account that “active” dressings are not allowed during the study (e.g. silver 
dressings, NOSF -nano-OligoSaccharide Factor- dressings, ibuprofen dressings) and that the 
dressing to be applied are: hydrogel for dry wounds, hydrocellular foam dressing for normal 
or exudative wounds and alginate dressing for very exudative wounds, or bleeding wound or  
fibrinous wound. 
4.4.2. Treatment management 
­ IMP management: 
Manufacturing, packaging, labelling and dispatching of the IMP to the sites will be the 
responsibility of Les Laboratoires Servier Industrie - Clinical Supply Unit (CSU) (905 Route 
de Saran, 45520 Gidy, France). 
The investigator and/or the person assigned by him and/or the pharmacist of the healthcare 
institution are responsible for the treatment management (receipt, storage, dispensing, 
accountability). 
IMPs will be stored at controlled temperature according to the specifications given by the 
labelling of the therapeutic units in a dry and secure room with restricted access, under the 
investigator’s or designated person responsibility. 
IMP management will be verified on a regular basis by the study monitor. 
At reception of IMPs, the responsible person must return as soon as possible the 
acknowledgment of receipt, duly completed and signed to the address given on the document 
and contact IWRS to acknowledge therapeutic units receipt as the system will ensure the 
stock accountability and automatic restock. All defects or damaged IMP must be declared to 
IWRS by the dedicated functions. 
The investigator/pharmacist is responsible for the IMP temperature monitoring on a daily 
basis with the recording of Min-Max temperature every working day and the documentation 
in a temperature log sheet. 
In case of temperature deviations the investigator/pharmacist should immediately: 
 Block the concerned IMPs in IWRS and place them in quarantine,  
 Alert the monitor or the local project manager if the monitor is absent, forward 
him/her all required information and follow the instructions received. 
Furthermore the investigator/pharmacist must put in place an adequate action plan once the 
first temperature deviation occurs in order to avoid recurrence. 
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The IMP boxes will be allocated by strictly following the instructions included in IWRS 
manual and IWRS connections will be performed at ASSE, W000, W002, W004 visits (for 
the description of dispensing methods, refer to section 6.2 (Treatment dispensing). 
The investigator and/or the pharmacist of the healthcare institution should only use the 
treatment provided for the participants involved in the study. The participants must return all 
unused study drugs to the site.  
The investigator and/or the pharmacist of the medical institution and/or a designated person 
from their study team must complete in real time all documents provided by the sponsor 
concerning treatment management  
 IMP receipt, allocation and dispensing to the participants and study drugs 
returned by the participants will be completed in a therapeutic unit tracking form 
or equivalent form in the centre. Therapeutic unit tracking form (or equivalent 
form in the centre) is the source document to be completed.  
 IMP dispensing and return will also be recorded in the e-CRF. 
The detachable portion of the label on the IMP box must be affixed on a treatment label 
collection form by the investigator or the pharmacist when the IMP box is given to the 
participant. 
The investigator will notify the monitor of all complaints set out by a participant within 24 
hours (change of taste, appearance…). 
Remaining IMPs at site will be collected by the study monitor and returned to a storage or 
destruction site. A tracking form for the recovery and destruction of the IMPs must be 
completed and attached to the remaining IMPs sent for destruction. 
In the event of anticipated return of IMPs to the sponsor (batch recall), the sponsor will 
prepare an information letter intended for the investigator and/or pharmacist of the medical 
institution. This letter will be sent to each study centre by the person locally responsible for 
the study. On receipt of the letter, the investigator and/or the pharmacist will identify the 
participants in possession of the IMP at the moment the incident becomes known, by using, 
among other tools, the therapeutic unit tracking form, and will contact them immediately. 
­ Standardized compression management 
Stockings receipt, allocation and dispensing to the participants will be managed by the 
investigator (or a delegated person). 
4.4.3. Management of blinding systems 
The blind for any study participant should only be broken by the investigator or authorised 
person if it is absolutely necessary to ascertain the type of treatment given. 
The circumstances under which the blind may be broken are: 
 When the knowledge of the treatment allocation will influence the participant 
management. For example, after overdose of study treatment, or 
 When the outcome of a life-threatening medical emergency depends on knowing 
which treatment the participant has received. 
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In the cases where the study treatment blind needs to be broken by the investigators for an 
imperative justified medical reason, a centralised decoding system integrated to IWRS is 
adopted for the study. No sealed envelopes will be used. 
The centralised decoding procedure will be performed by the investigators or an authorised 
person by contacting the IWRS. The system will be available 24 hours a day, 7 days a week. 
The procedure to be followed is detailed in the IWRS manual. If IWRS is not available, the 
helpdesk of the IWRS will be contacted by phone to solve connection issues to allow the 
unblinding with the IWRS system. Additionally, decoding will be possible by calling the 
Servier Emergency Phone Number (+33 1 55 72 60 00) available 24 hours a day, 7 days a 
week. 
4.5. Discontinuation of the study 
4.5.1. Premature discontinuation of the study 
The study can be prematurely discontinued if significant safety concerns are detected at any 
time during the study, if new scientific knowledge emerges or if other conditions arise which 
would place the subjects at undue risk if they were to continue in the study. 
After having informed the investigator//coordinator, the sponsor or the investigator/ 
coordinator or the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) or 
the Competent Authorities may terminate the study before its scheduled term. Two copies of 
the written confirmation will be dated and signed by the coordinators. The IRB/IECs and 
Competent Authorities will be informed according to local regulations. 
4.5.2. Discontinuation of the study in the event of objective reached 
Not applicable 
4.6. Source data  
ECG printouts, e-copy of the 3D pictures and central RU measurement reports, the duplex 
ultrasonography report, the questionnaire for ulcer clinical assessment, the pain assessment 
with VAS, the participant diary will be considered as source document. 
5. SELECTION AND WITHDRAWAL OF PARTICIPANTS 
5.1. Selection criteria  
5.1.1. Demographic characteristics 
1. Caucasian (defined for this study as having 2 Caucasian parents), men or women : 
 A pregnancy test (β-HCG analysis) will be required for women of child-bearing 
potential. Menopausal women will be confirmed by an FSH > 30U/L  
76. Age ≥ 18 years old. 
77. 18.5 kg/m2 ≤ BMI ≤ 45.0 kg/m2 (= Weight (kg) / height² (m²)). 
5.1.2. Medical and therapeutic criteria 
4. Patients with chronic venous disease documented by imaging (duplex ultrasonography – 
See Appendix 2) to detect a venous disorder in both the sub- and extra-fascial venous 
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systems. The examination performed within 6 months before selection can be used for 
documentation in the e-CRF. If data of the report don’t permit to complete the e-CRF and 
in case of suspicion of acute venous thrombosis, a duplex ultrasonography must be 
performed before inclusion (during the selection period and before inclusion (W000)). 
78. Patients with at least one active venous leg ulcer localised in the gaiter area (CEAP C6) 
diagnosed or reoccurred for more than 6 weeks and less than 2 years at selection and 3 cm 
away from other ulcers (See Appendix 3 - Ulcer definition and Appendix 4 - CEAP 
classification). Patients with bilateral ulcerations or multiple ulcerations on one or both 
legs are eligible for selection.  
6. Size of Reference Ulcer (defined as the largest ulcer in size that is fitting the area selection 
criteria) should be ≥ 5 cm2 and ≤ 100 cm2 (measured by transparent sheet and confirmed 
with the digital 3D imaging device). 
7. Ankle Brachial Pressure Index ≥ 0.8 and ≤ 1.3 measured by Doppler ultrasound (See 
Appendix 5). 
8. Ulcer not circumferential. 
9. Ankle circumference between 19 and 32 cm and circumference below the knee between 
28 and 49 cm to be in the range of the compression measurement chart. 
10. Participant able to swallow the tablets, put on and remove the compression stockings. 
11. Participant able to read and complete the diary. 
12. Participant vasectomized or willing to avoid sperm donation for the duration of first 
dosing to 3 months after the last dose taken.  
13. Participant willing to use highly effective contraceptive measures adequate to prevent the 
participant or the participant’s partner from becoming pregnant (i.e. not menopausal, non-
hysterectomised, non-surgically sterilised women) throughout the study and for 3 months 
after completion of study treatment. Highly effective methods of birth control refer to 
those which result in a low failure rate (i.e. less than 1% per year), when used 
consistently and correctly, such as combined hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, implantable), some 
intra uterine devices (IUDs), intrauterine hormone-releasing system (IUS), true sexual 
abstinence (when this is in line with the preferred and usual lifestyle of the participant). 
The investigator must inform the participants about the risks of not using an effective 
method of birth control during the course of the study. 
 Non menopausal woman means that the time since last menstrual period is < 1 year, 
in a woman of appropriate age.  
 Surgically sterilised is defined as having had a bilateral tubal ligation, hysterectomy 
or bilateral oophorectomy. 
5.1.3. 
Informed consent 
14. Obtained as described in section 13.3 of the protocol. 
5.2. Non-selection criteria 
5.2.1. 
General criteria 
15. Unlikely or unwilling to be compliant to standardized compression recommendation, 
study medication and visits, previous records of poor compliance to compression 
stockings. 
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16. Known pregnancy, breastfeeding. 
79. Participation in a clinical study involving another study drug, a compression bandage or 
local care treatment (i.e. dressings) if less than 6 weeks from the end of participation in 
the previous study or from receiving the last treatment of the previous study. Participation 
in another clinical study is not allowed during the participation in this study.  
80. Participant already randomised in the study  
19. Subject is either an immediate family member of a participating investigator, study 
coordinator, employee of investigator or is a member of the staff conducting the study (in 
order to avoid any assessment bias). 
20.  History of excessive consumption of drugs or alcohol abuse (>30 units/week for men and 
>25 units/week for women) or participant at risk of acute alcohol poisoning. 1 unit of 
alcohol is defined as half a pint (280 ml) of beer or cider, 1 glass (125 ml) of wine, 1 
glass (70 ml) of sherry or port, a single shot (25 ml) of gin, brandy or rum, 2 glasses 
(250 ml) of low alcohol wine, 3 half pints (840 ml) of low alcohol beer. 
5.2.2. 
Medical and therapeutic criteria 
Concerning leg ulcer: 
21. Ulcer bed with black necrotic tissue.  
22. Infected ulcer that requires local or systemic antibiotherapy (See Appendix 6 – Ulcer 
Infection). 
23. Ulcer of more than 2 cm in depth or ulcers involving or exposing underlying structures 
(tendon, ligament or bone). 
24. Recent history of lower extremity deep venous thrombosis within the last 3 months. 
25. Other non-venous leg ulcers or other associated skin conditions such as: vasculitis, 
malignancies, burns, post-surgery, pressure ulcers, diabetic foot, connective tissue 
disorders such as lupus, systemic sclerosis, cellulitis, ulcers due to sickle-cell disease. 
26. Asymptomatic and symptomatic peripheral occlusive arterial disease with an ABPI < 0.8 
or > 1.3 in the affected leg. 
27. Planned surgery and venous procedures (including vein stripping, foam sclerotherapy or 
any endovenous procedure) on the leg with the Reference venous leg ulcer during the 
study period. 
28. Concomitant disease (within the past 3 months before selection) that could significantly 
affect the healing process during the study. 
29. Known participants with inappropriate nutritional status (serum albumin <20 g/l). 
30. Participants unable to walk or with severe ankle dysfunction (ankylose) leading to muscle 
pump alteration. 
31. Any clinically relevant abnormality detected during the physical examination performed 
at the selection visit. 
81. Inadequately controlled type 1 and type 2 diabetes, treated or not treated, with an HbA1c 
> 8% either from the result of a test done within the 3 months before selection or from a 
result discovered at the laboratory test done within the 5 calendar days prior to the W000 
visit.  
33. Known severe renal impairment (estimated GFR <30 ml/min) at ASSE visit, calculated 
with MDRD formula (See Appendix 7). 
34. Known acute or chronic hepatic disease. 
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35. Known major cardiovascular events (acute coronary syndrome including unstable angina 
and myocardial infarction, stroke) within 6 months prior to the study or congestive heart 
failure New York Heart Association (NYHA) Class III-IV within 6 months prior to the 
study (See Appendix 8 – Heart failure classification). 
36. Participant with pacemaker or clinically significant arrhythmia.  
37. Presence of malignancy or recurrence of cancer within the past 5 years (except for basal 
cell carcinoma treated by local excision). 
38. Presence of malabsorption disease (Crohn’s disease), inflammatory bowel disease, 
Gilbert syndrome, history of chronic diarrhoea,  
39. History of clinically significant psychiatric disease or any affective disorders likely to 
preclude participation in the study. 
40. History of epilepsy, organic brain disease. 
41. Any chronic or acutely infectious disease up to 2 weeks prior to selection. 
42. Blood donation or frequent blood sampling up to 90 days prior to screening for the study. 
43. History of severe allergies or multiple adverse drug reactions. 
44. Haematology and biochemistry with clinically significant abnormalities and that could in 
the opinion of investigator preclude study participation. 
45. Clinically significant anaemia (i.e. Hb <10 g/dL). 
46. Known carriers of HbS antigen or anti HCV or anti-HIV antibodies. 
47. Clinically significant co-morbidities that may interfere with the study (morbid obesity, 
significant chronic oedema from other origin than chronic venous disease: renal failure or 
decompensated cardiac insufficiency (stage 3 or 4 NYHA classification) or hepatic 
failure or persistent lymphoedema…). 
48. Criterion deleted  
Concerning contra-indications to the treatment 
49. History of hypersensitivity reaction due to intolerance or allergy to any of study 
medication excipients and material of compression stockings. 
50. Contra-indication to lower limb compression with an applied pressure of approximately 
45 mmHg 
51. Contra-indication to the compression stocking wearing other than the ones previously 
listed, including but not limited to: oozing skin disease, blue phlebitis (Phlegmasia 
coerulea dolens) and septic phlebitis, sensitivity disorder in extremities and neuropathy 
disorder, primary chronic polyarthritis. 
52. Grossly oedematous leg (ankle perimeter > 32 cm unable to fit with stockings sizes) or 
participants with abnormal shape of leg that does not allow proper compression therapy 
according to compression stockings recommendations. 
Concerning concomitant medications 
53. Participants who are undergoing treatments known to affect healing within the month 
prior to selection: pentoxifylline, immunosuppressive drugs, immunomodulators, 
cytotoxic chemotherapy or oral corticosteroids.  
54. Topical corticosteroids application on and around the ulcer within 15 days prior to 
selection. 
55. Acetylsalicylic acid treatment started within the last 6 weeks prior to the selection or 
during the study. Acetylsalicylic acid is allowed if started more than 6 weeks before the 
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selection and remaining stable until the end of the study (i.e.: acetylsalicylic acid at 
antiaggregant dose ≤ 350 mg daily). 
56. Participants treated with drugs known to be BCRP substrates such as methotrexate, 
mitoxantrone, irinotecan, imatinib, lapatinib, topotecan, rosuvastatin, sulfasalazin. 
57. Participants who have been exposed to venoactive drugs within the month prior to the 
selection. 
82. Participants treated with oral anticoagulant treatments known to be BCRP substrates such 
as acenocoumarol, fluindione, apixaban, rivaroxaban. 
59. Participants on oral or parenteral antibiotherapy. Long-term, low dose prophylactic 
antibiotherapy started at least one month prior to the selection is however acceptable if 
there is no change in the treatment during the study. 
60. NSAIDs on long-term chronic treatment within the last month, except if taken less than 
one week within the last month.  
61. History of major abdominal surgery which in the investigator’s opinion could interfere 
with the absorption, metabolism of the drug (e.g. gastro-intestinal resection, intestinal 
anastomosis or shunt). 
5.3. Inclusion criteria 
83. Still eligible as per requirement of Selection/Non-selection criteria (except for RU area at 
inclusion which should be ≥ 4.5 cm2 and ≤ 100 cm2). 
84. Presence of venous disease characterized by imaging methods (duplex ultrasonography) 
to detect a venous disorder of both sub- and extra-fascial venous systems and to rule out a 
venous thrombosis. The disorder may be a combination of different manifestations such 
as venous reflux, venous dilation, thickening of venous wall, etc. The results of the 
examinations should be available for the inclusion visit.  
64. No clinically significant change in ulcer healing process confirmed by central reading 
(size and clinical features if applicable). 
5.4. Exclusion criteria 
65. Tablet compliance < 80% or > 120 % during the placebo selection period. 
66. Compliance with the standardized compression regimen < 80% during the placebo 
selection period. 
67. Clinically significant change in the reference ulcer examination between selection and 
inclusion showing unstable evolution or complications (i.e. by infection, erosion) of the 
healing process.  
68. Clinically significant change in ulcer healing process showing a change in reference ulcer 
area of more than 20% between selection and inclusion assessed by the central reviewer. 
69. Laboratory results or examinations performed to confirm the diagnosis not available. 
85. Clinically significant abnormalities in laboratory tests (haematology, biochemistry) 
sampled within the 5 calendar days prior to W000 visit, with results available at W000 
visit (at the latest) before randomisation: 
- Serum albumin <20 g/l 
- eGFR <30 ml/min calculated with MDRD formula (see Appendix 7) 
- AST or ALT > 3ULN (Upper Limit of normal laboratory range)  
- GGT > 3 ULN 
- Total bilirubin > 2 ULN 
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- Clinically significant anaemia (i.e. Hb <10 g/dL) 
- HbA1c > 8% in an available result from the previous 3 months in a known 
diabetic patient or discovered between selection and inclusion (HbA1c > 8% in the 
laboratory test done within the 5 calendar days prior to the W000 visit). 
Note: If a patient is discovered with hyperglycaemia (fasting blood sugar ≥7 
mmol/L) and/or with an elevated HbA1c ≥ 6.5% but ≤ 8% between selection and 
inclusion, the patient can be included in the study and will be stratified as a 
diabetic. 
71. Positive pregnancy test performed within the 5 calendar days prior to W000 visit, or 
results not available. 
72. Any adverse event that might compromise the participant’s safety in the study or any 
study evaluation. 
73. Any new concomitant medication or surgical procedures that could interfere with the 
study.  
74. Not willing to respect the drug or alcohol abuse criteria for the duration of the study. 
75. Clinically significant abnormalities, or marked prolongation of QT/QTc interval in ECG 
performed within the 5 calendar days prior to W000 visit (QTcF interval  >450 ms, 
confirmed by a repeated ECG, with measurements validated by a cardiologist)   
To be eligible for participation in the study, participants will be required to meet all inclusion 
criteria and should not meet any of the exclusion criteria. Participants will be then included in 
the double-blind period of the study and randomised to a treatment group. 
5.5. Additional information recorded at the selection/inclusion visit 
If not already present at the selection visit, the participant will be scheduled for a full set of 
investigations including imaging and functional diagnostic tests to document the pre-existence 
of venous disease (duplex ultrasonography …). The results not available at the selection visit 
need to be available and reviewed before the inclusion visit. The ethnic origin of participants 
will also be collected to confirm that participants are Caucasian. 
5.6. Participant withdrawal 
5.6.1. 
Withdrawal criteria 
Information to be collected during the last visit of these participants is given in section 5.6.2. 
These follow-up modalities are used to ensure the efficacy and safety evaluation of all 
participants who received the IMP. 
The reasons for premature discontinuation of IMP are: 
­ Adverse events or any condition that would jeopardise participants’ safety and is 
incompatible with continuation of the IMP according to the judgement of the investigator. 
These include:  
- ALT or AST increase > 3 times the ULN value, after 2 consecutive tests 
performed 7 days apart. 
- Total bilirubin increase > 2 times the ULN value, after 2 consecutive tests 
performed 7 days apart. 
- CPK increase > 5 times the ULN value, after 2 consecutive tests performed 7 
days apart. 
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- Clinically significant anaemia defined by an haemoglobin level < 10g/dL and a 
decrease ≥ 1.5 g/dL in men and ≥ 1 g/dL in women compared to previous value. 
- QTcF > 500 ms, or QTcF > 480 ms with increase in QTcF > 60 ms as 
compared with QTcF at selection period, confirmed by a repeated ECG, with 
measurements validated by a cardiologist. 
- Clinically significant adverse event related to the cardiovascular system for which, 
in the judgement of the investigator, continuation of the IMP could constitute a 
risk for the safety of the participant. 
- Severe uncontrolled diarrhoea with risk of dehydration. 
- Major deviation to the protocol or any medical condition incompatible with 
continuation of the IMP treatment (including pregnancy) or preventing the 
analysis of the primary endpoint (e.g. non-compliance with standardized 
compression regimen or with protocol requirements or study-related procedures).  
- Any medical event requiring administration of an unauthorised concomitant 
treatment (see section 6.3). 
- Non-medical reason (e.g. withdrawal of participant’s consent), which should be 
carefully documented. 
- Lost to follow-up (see section 5.6.3). 
5.6.2. 
Procedure 
­ The investigator must record in the medical file and in the electronic case report form, the 
reason and the time for the premature discontinuation of treatment / for the withdrawal 
from the study, the main assessment criteria, and the medical follow-up data.  
­ If there are several reasons, the investigator must indicate the main reason. An end-of-
study visit should always be suggested to the participant and when it should be scheduled 
(at the same time as the date of discontinuation of treatment, at the theoretical end-of-study 
date…). 
­ In the case of premature withdrawal from the study due to an adverse event (event 
requiring immediate notification or not), the investigator must make every effort to collect 
the information related to the outcome of the event. If necessary, the information will be 
collected afterwards (see section 8.3.2.4). This information is recorded in that part of the 
electronic case report form which concerns adverse events. If the investigator cannot 
collect the information from a visit, he must collect it from the physician ensuring the 
follow-up of the participant. 
­ If the study is stopped / IMP is discontinued as a result of an event requiring immediate 
notification, the procedure described in section 8.3.1.5 is to be implemented. 
­ Treatment discontinuation or withdrawal from the study is to be documented by 
completing the appropriate page in the e-CRF. The investigator or a designated person 
must connect to the IWRS to perform the withdrawal visit in case of treatment 
discontinuation or withdrawal of the participant from the study. 
The dispositions to be taken after the IMP discontinuation are described in section 6.5. 
5.6.3. 
Lost to follow-up 
When the investigator has no news of the participant, he/she must make every effort to 
contact him/her or a person around him/her (phone calls, letters including registered 
ones…etc.), to establish the reason for the discontinuation of the IMP and to suggest the 
participant comes to an end-of-study visit. If all these attempts to contact the participant fail, 
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the investigator can then declare the participant “lost to follow-up”. The investigator should 
document all these attempts in the corresponding medical file. 
6. TREATMENT OF PARTICIPANTS 
6.1. IMPs administered 
There are three periods in the study 
­ Placebo selection period of 14 days ± 2 days: 
During this period, the participants will take orally 3 placebo tablets twice a day at the end of 
the meals with a glass of water (250 ml): 3 placebo tablets in the morning at the end of the 
breakfast and 3 placebo tablets in the evening at the end of the dinner. 
In addition, all participants will be provided with standardized compression (compression 
stockings) adapted to their leg size. The adequate size of the stockings will be chosen 
according to leg measurements and the leg measurement chart. If applicable, the participant 
will discontinue his/her usual compression treatment. 
The stockings kit consists of two understockings and one overstocking. The understocking is 
applied on the leg up to the knee over the dressings protecting the ulcer. The overstocking is 
applied over the understocking. The participant has to wear both during the day and must 
remove the overstocking during the night, keeping the understocking which has to be worn 
24/7 over the dressings protecting the ulcer. The stockings have to be worn one day and then 
washed to recover the initial compression properties. Two understockings and one 
overstocking with the same size will be provided to the participants. So, the participants will 
be able to wear one understocking over the night while the used overstocking and the other 
understocking are washed and dried overnight to be used the following day. The investigator 
may dispense additional compression stocking kits (of the same size) to the patients if needed 
to maintain daily compliance with compression therapy. 
The participant has to complete a diary on the days he/she is wearing the compression 
stockings. 
­ Randomised double-blind active treatment period of 42 days ± 4 days, from W000 to 
W006: 
At W000, after verification of the participant’s inclusion criteria and compliance with 
selection treatment and compression, the participant will be randomly assigned to one of the 
six treatment arms. 
During this period, the participants will take orally 3 tablets twice a day at the end of the 
meals with a glass of water (250 ml or 8 ounces): 3 tablets in the morning at the end of 
breakfast and 3 tablets in the evening at the end of dinner of S42909 (a total of 100, 200, 400, 
800 or 1200 mg daily) or placebo. Tablets of 0, 50 and 200 mg of strength of S42909 will be 
used to reach each dose. The packaging will ensure that the 3 tablets to be taken by the 
participant for each intake will be on one line. This will be clearly explained in the 
participant’s diary. 
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The measurements of the leg will be done at each visit and the stockings size will be 
confirmed or changed according to these measurements. 
On the day of visits W000, W001, W002, W004 and W006, the participant will omit the 
morning IMP intake and will come to the study visit under fasting condition (10 hours). The 
participant will take the assigned IMP treatment with a glass of water (250 ml or 8 ounces) 
during the study visit after the predose PK sampling and at the end of breakfast.  
­ Follow-up period of 14 days ± 4 days, from W006 (at D0 + 42 days ± 4 days) to W008: 
On the day of the W006 visit, the participant will omit the morning IMP intake and will come 
to the study visit under fasting condition (10 hours). The participant will take the morning 
IMP intake during the study visit at the end of the breakfast with a glass of water (250 ml or 8 
ounces), will the stop taking the IMP treatment and give the TU box back to the investigator. 
During this period, participants will continue with standardized compression therapy and the 
local wound care up to end of study visit (W008).  
After the end-of-study visit, the investigator will decide on continuation of leg ulcer treatment 
according to the centre’s standard of care. 
6.2. IMPs dispensing 
Therapeutic unit (TU) will be identified by a 6-digit number for identification, tracking and 
stock management purposes.  
The randomisation and allocation of the therapeutic unit numbers to each participant will be 
managed centrally by the CRO responsible for the IWRS. All procedures will be detailed in 
the IWRS manual. 
IMP treatment will be dispensed by the investigator or the pharmacist or a designated person, 
according to the local organisation, as follows: 
- 
At the selection visit (ASSE): 14-days placebo selection period.  
The investigator will connect to IWRS at the selection visit to register the participant, create a 
participant’s number and register the selection. Then, the system will allocate a selection kit 
number. The box corresponding to the kit number will be dispensed to the participant. 
Moreover, the participants will be provided with 1 stocking kit (containing 2 understockings 
and 1 overstocking) of the adequate size. The adequate size of the stockings will be chosen 
according to leg measurements and the leg measurement chart.  
- 
At the inclusion visit (W000):  
After verification of the participant’s inclusion criteria and compliance with selection 
treatment and compression, the investigator will connect to the IWRS. The system will 
allocate to the participant the therapeutic unit (TU) number corresponding to the treatment 
group randomised (placebo or S42909 100, 200, 400, 800 or 1200 mg). The TU box 
corresponding to the TU number will be given to the participant and will correspond to 2 
weeks of treatment. As the participant must omit the morning IMP intake before the study 
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visit, he/she will take the new treatment assigned during the study visit after predose PK 
sampling and at the end of breakfast. 
The measurements of the participant’s leg will be checked and if the stocking size has 
changed, 1 new stocking kit will be provided to the participant according to the leg 
measurement chart. 
- 
At the W001 visit: 
The participant will come to the visit and bring back the TU box allocated at W000. He/she 
will take the treatment at the centre on the day of this visit after predose PK sampling and at 
the end of breakfast. The drug accountability of the remaining tablets will be performed only 
if the participant withdraws from the study at this visit.  
The participant will continue until W002 with the same TU box. IWRS will not be contacted 
at W001 visit. 
As the participant must omit the morning IMP intake before the study visit, he/she will take 
the IMP treatment during the study visit after predose PK sampling and at the end of 
breakfast. 
The measurements of the participant’s leg will be checked and if the stocking size has 
changed, 1 new stocking kit will be provided to the participant according to the leg 
measurement chart. 
- 
At the W002 visit: 
The TU box allocated at W000 visit will be retrieved from the participant and the drug 
accountability of the remaining tablets will be performed.  
At the end of the visit, IWRS will be contacted and a new TU number will be allocated. The 
box corresponding to the TU number will be given to the participant and will correspond to 2 
weeks of treatment. As the participant must omit the morning IMP intake before the study 
visit, he/she will take the treatment from the new TU box assigned during the study visit, after 
predose PK sampling and at the end of breakfast. 
The measurements of the participant’s leg will be checked and if the stocking size has 
changed, 1 new stocking kit will be provided to the participant according to the leg 
measurement chart. 
- At the W003 visit: 
The participant will come to the visit with the TU box allocated at W002. The drug 
accountability of the remaining tablets will be performed only if the participant withdraws 
from the study at this visit.  
The participant will continue until W004 with the same TU box. IWRS will not be contacted 
at W003 visit. 
The measurements of the participant’s leg will be checked and if the stocking size has 
changed, 1 new stocking kit will be provided to the participant according to the leg 
measurement chart. 
- 
At the W004 visit: 
The TU box allocated at W002 visit will be retrieved from the participant and the drug 
accountability of the remaining tablets will be performed.  
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At the end of the visit, IWRS will be contacted and a new TU number will be allocated. The 
box corresponding to the TU number will be given to the participant and will correspond to 2 
weeks of treatment. 
As the participant must omit the morning IMP intake before the study visit, he/she will take 
the treatment from the new TU box assigned during the study visit, after predose PK sampling 
and at the end of breakfast. 
The measurements of the participant’s leg will be checked and if the stocking size has 
changed, 1 new stocking kit will be provided to the participant according to the leg 
measurement chart. 
- 
At the W006 visit: 
The TU box allocated at W004 visit will be retrieved from the participant and the drug 
accountability of the remaining tablets will be performed.  
The IMP treatment will be stopped at this visit with the morning dose taken after PK predose 
at site and the participant will enter the follow-up period where he/she will continue wearing 
the compression stockings until the end of the study. The measurements of the participant’s 
leg will be checked at this visit and if the stocking size has changed, 1 new stocking kit will 
be provided to the participant according to the leg measurement chart. 
For each participant, the IMP will only be dispensed during the study. At the last visit of the 
study, the investigator will propose a treatment adapted to the nature of the clinical state of 
the participant. 
6.3. Previous and concomitant treatments 
The previous treatments will be recorded within the 6 months prior to the selection for 
treatment involved in the studied disease and within the 6 weeks prior to the selection for 
other treatments. 
The following treatments will be forbidden because they are known to interact significantly 
with wound healing or may interact with the IMP treatment: 
­ Topical corticosteroid application on and around the ulcer within 15 days prior to selection 
and during the study 
­ Oral corticosteroids within the month prior to selection and during the study  
­ Immunomodulators, immunosuppressants, cytotoxic chemotherapy within the month prior 
to selection and during the study 
­ Pentoxifylline within the month prior to selection and during the study 
­ Acetylsalicylic acid treatment started within the last 6 weeks prior to the selection or 
during the study. Acetylsalicylic acid is allowed at antiaggregant dose and at long term ≤ 
350 mg daily (coronary disease).  
­ Drugs known to be BCRP substrates during the study such as methotrexate, 
mitoxantrone,irinotecan, imatinib, lapatinib, topotecan, rosuvastatin, sulfasalazin. 
­ Oral anticoagulant treatments known to be BCRP substrates such as acenocoumarol, 
fluindione, apixaban, rivaroxaban. Anticoagulant if prescribed during the study. 
­ Venoactive drugs within the month prior to selection and during the study 
­ Participants on oral or parenteral antibiotherapy. Long-term, low dose prophylactic 
antibiotherapy started at least one month before the selection is however acceptable if there 
is no change in the treatment during the study. 
­ Local antibiotherapy on the surface of RU, during the study. 
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­ Oral and parenteral antibiotherapy during the study, except if less than or equal to 7 days.  
­ NSAIDs on long-term chronic treatment within one month prior to the selection, except if 
taken less than one week within the last month. NSAIDs are not allowed during the study 
except if taken once and not longer than 3 consecutive days. 
6.4. IMP compliance 
The dates of the first and last therapeutic unit intake, any treatment interruption if any, will be 
recorded in the e-CRF.  
The number of tablets dispensed and the number of tablets returned by the participant are to 
be counted by the investigator or a designated person from his/her team and recorded in the 
electronic case report form. If the participant does not bring back his TU box and diary, the 
number of tablets taken and number of days when stockings have been applied will be 
estimated by the investigator by questioning the participant. If the information becomes 
available at a next visit, the data should be corrected.  
The compliance will be assessed at W000, W002, W004 and W006 as therapeutic unit boxes 
are allocated for 2 weeks of treatment. 
The compliance will be calculated on the basis of the ratio between the number of tablets 
actually taken (and number of days for stockings) and the theoretical number of tablets (or 
days) required by the number of treatment days.  
If the compliance is unsatisfactory during the study (e.g. less than 80% or higher than 120%), 
the participant should be questioned to identify the reason for this and the study objectives 
should be reminded. Particular importance should be given to possible occurrence of adverse 
event. 
The investigator should particularly assess the compliance of treatment and stockings at 
W000 visit to check the related non-inclusion criteria.  
The compliance of stockings should also be assessed at each visit. Each participant must 
record the days he/she is wearing the stockings in a diary provided by the investigator and this 
number of days will be recorded in the e-CRF. If the compliance of stockings is less than 
80%, the participant must be retrained and motivated. 
6.5. Arrangements after the discontinuation of the IMP 
After the discontinuation of the IMP, the participant will have access to appropriate medical 
care by his physician.  
The treatment chosen after the end of the study or study withdrawal will be prescribed by 
his/her physician according to the centre standard of care. The study drug is not licensed and 
will not be available outside of the scope of the study. 
7. ASSESSMENT OF EFFICACY 
7.1. Efficacy measurements 
Efficacy measurements performed during the study are indicated in Table (4.2.2) 1. 
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- Reference Ulcer area 
At the selection visit (ASSE), the eligibility will be determined on the Reference Ulcer (RU) 
area based on the measurements performed by the investigator. This measurement will also be 
done centrally on the 3D picture taken by the investigator (or a delegated person) at the 
selection visit (ASSE). The latest will determine the final eligibility in case of discrepancy 
between the investigator and the central measurement. 
For the inclusion visit (W000), the RU area measurement will be performed centrally on a 3D 
picture taken 3 (or 4) working days before W000 visit. Additionally, patients found to be 
eligible for randomisation will have a 3D picture of the RU on the day of W000, after 
randomisation, for baseline measurements. 
At W001, W002, W003, W004, W006 and W008, the RU area measurement will be 
performed centrally on a 3D picture of RU taken and uploaded by the investigator (or a 
delegated person) during the study visits. 
- Reference Ulcer perimeter  
The perimeter will be measured centrally at each study visit (ASSE, W000, W001, W002, 
W003, W004, W006 and W008) on the 3D picture of RU performed and uploaded by the 
investigator (or a delegated person). The perimeter measured will be used to calculate the 
linear advance of the wound margin towards the wound centre. 
- Reference Ulcer volume 
The volume will be measured centrally at each study visit (ASSE, W000, W001, W002, 
W003, W004, W006 and W008) on the 3D picture of RU performed and uploaded by the 
investigator (or a delegated person). 
- Pain assessment 
The pain related to the leg ulcer will be assessed at W000, W004 and W006 visits using a 
questionnaire which includes a VAS scale (See Appendix 9: Questionnaire for pain 
assessment).  
- Analgesic drug consumption  
Analgesic drug consumption related to the leg ulcer will be assessed at W000, W004 and 
W006 with the help of the concomitant treatment form. This assessment will be done in term 
of daily dose and duration. 
- Clinical assessment 
A clinical assessment of the RU will be performed at ASSE, W000, W001, W002, W003, 
W004, W006 and W008 visits by the investigator (See Appendix 10 - Clinical Assessment of 
Leg Ulcer). 
7.2. Methods and measurement times 
- Reference Ulcer area, volume and perimeter measurements: 
The 3D pictures of RU will be taken and uploaded to a secured website at each visit after 
wound cleansing by the investigator (or a delegated person) (except at the selection visit with 
two pictures: one before cleansing and debridement and another one after cleansing and 
debridement). 
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The RU area will be measured by the investigator at selection by tracing the RU outlines 
using a transparent sheet after wound cleansing and debridement. In addition, two 3D pictures 
will be taken and uploaded by the investigator (or a delegated person) at the ASSE visit for 
the central measurement by the CRO for the efficacy analysis. The CRO will send the two 
pictures to the independent expert with an alert system. The central measurement of RU area 
will be sent back to the investigator and if the central measurement is not fitting the selection 
criteria, the participant will be withdrawn before inclusion. 
Three (or four) working days before inclusion visit (W000), the participants will come to the 
site for a RU picture. The investigator (or a delegated person) will upload the image on a 
secured website on the same day. The CRO in charge of the central reading will receive the 
picture, perform RU area measurement, and send it back to the investigator within the three 
following working days and before the inclusion visit.  
The CRO will also send to the investigator the central RU area measured on the picture taken 
3 (or 4) working days before W000 and the calculation of the change between ASSE and 
W000 area measurements.  
At selection, an independent expert will check the feature of RU. The expert will give an 
opinion on the RU by reviewing the clinical aspect of RU on the 3D pictures. The expert will 
confirm the selection or not if RU clinical pictures are consistent with a venous aetiology or 
give a recommendation for study continuation. If a doubt exists on the venous aetiology of the 
RU, another expert will give a second opinion on the picture. If the doubt of the venous origin 
of the RU persists, the expert in charge of the review of the picture at selection will review the 
picture taken at inclusion. If the doubt still persists at the review of the picture taken at 
inclusion, the patient will not be included. 
At the inclusion visit (W000), these measurements will be used by the investigator to check if 
the RU area was in the range of inclusion criteria and if the change in the RU area between 
ASSE and W000 is less or equal to 20% for inclusion. 
Area Change W0-ASSE= │Reference Ulcer Area W000 – Reference Ulcer Area ASSE│ / RU 
Area ASSE. (Reference Ulcer Area ASSE is the one after cleansing and debridement). 
Patients found to be eligible for randomisation will also have a 3D picture of the RU on the 
day of W000 (taken after randomisation) that will be uploaded by the investigator (or a 
delegated person) on the secured website to send these pictures to the central reviewer.  
At W001, W002, W003, W004, W006 and W008, the investigator (or a delegated person) 
will upload the 3D pictures of RU on the secured website to send these pictures to the central 
reviewer. 
In addition to the RU area measurement, the CRO in charge of the central measurement will 
perform volume and perimeter measurements at each visit on the 3D picture. These measures 
will be used for the efficacy criteria. 
- Pain assessment  
The questionnaire with the VAS will be provided by I.R.I.S and completed at the beginning of 
W000, W004 and W006 visits, before RU clinical assessment and local care of the RU. The 
participant will draw a vertical line on the scale to reflect his perception on the intensity of the 
pain since the last visit. The investigator will measure the exact distance from 0 to the line 
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drawn by the participant and report the corresponding measurement in millimetres in the e-
CRF together with documenting the answers to all the questions.  
- Reference Ulcer clinical assessment 
The form for RU clinical assessment will be completed after the pain assessment and will be 
reported in the e-CRF at each study visit: ASSE, W000, W001, W002, W003, W004, W006 
and W008. 
- 
Analgesic drug consumption: 
Analgesic intake follow-up related to VLU: will be evaluated and reported in the e-CRF at 
W000, W004 and W006 visits and will be addressed to patient using analgesic drug linked to 
VLU. 
8. SAFETY MEASUREMENTS 
8.1. Safety measurements 
Safety measurements performed during the study are indicated in Table (4.2.2) 1. 
- Recording of any adverse event occurring during the study using the collection methods 
detailed in section 8.3. 
- Physical examination, body weight measurement, vital signs, 6 or 12-lead 
electrocardiogram (ECG), standard urinalysis and laboratory assessments.  
8.2. Methods and measurement times 
- Physical examination 
Physical examination will be a clinical exam carried out by the investigator at all visits in 
order to assess participant’s condition before deciding to keep the participant in the study. The 
abnormalities of the physical examination will be reported and evaluated by the physician as 
clinically significant or not. Any clinically significant changes during the study should be 
recorded as an adverse event. 
- Weight 
The participant’s weight will be determined at selection (ASSE), inclusion (W000), W002, 
W006 and W008. It should be measured under the same conditions (i.e. same scale, empty 
bladder, before breakfast, being only lightly dressed).  
The participant’s height will be measured at the selection visit for participant’s BMI 
calculation. 
- Vital signs 
Blood pressure and heart rate will be measured at all visits, they should always be measured 
under the same conditions for each participant during the study (one measure after 10 minutes 
in the sitting position). Body temperature will be recorded at all visits for on-site safety. 
- Standard electrocardiogram 
A standard electrocardiogram ECG (6 or 12-lead) will be performed within the 5 calendar 
days prior to W000 visit, with results available at W000 visit (at the latest) before 
randomisation, to check that there are no clinically significant abnormalities. If the 
investigator does not have the expertise to read ECG tracings and/or in case of abnormalities, 
the ECG should be verified by a cardiologist prior to the inclusion of the participant in the 
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study. The ECG will be performed after 15 minutes at rest with the participant in supine 
position. It will be recorded at speed 50 mm/s with 2 cm/mV amplification and with at least 3 
QRS complexes by lead.  
The 6 or 12-lead ECG will be repeated at all subsequent visits. If the investigator does not 
have the expertise to read ECG tracings and/or in case of abnormalities, the ECGs should be 
verified by a cardiologist. Any clinically significant abnormality discovered must be recorded 
as an adverse event in the e-CRF. The following parameters are to be recorded: rhythm, heart 
rate, PR interval, QRS duration, QTc duration and RR interval [QTc calculated using 
Fridericia formula (QTcF = QT / ³√RR)] 
In order to avoid the possible artefacts in the ECG interpretation (e.g. hysteresis effect in 
which an increase in HR is followed more slowly by an adaptation of QT duration and 
consequently lead to an alteration of QT-RR relationship), it is recommended to follow the 
below recommendations:  
 To allow the subject to be reclining at rest for at least 15 minutes prior to ECG 
acquisition and in this time no emotional stimulation of the subject is allowed (TV, 
vital sign acquisition, blood sampling) as they might have an impact on heart rate. 
 To perform blood sampling after the ECG recording when the same time points are 
needed for blood sampling and ECG acquisition. 
- Laboratory assessments 
Local laboratories will be responsible for analysing the biochemistry and haematology 
samples, FSH, β-HCG. The laboratory will send a laboratory report to the investigator who 
will be responsible for the clinical assessment of the results and data entry in the e-CRF. Any 
clinically significant abnormal laboratory value should be recorded as an adverse event in the 
e-CRF. The investigator should follow up all clinically relevant changes until recovery. 
 Biochemistry (within the 5 calendar days prior to W000 with results available at 
W000 at the latest, W001, W002, W004, W006 and W008 visits): AST (SGOT), 
ALT (SGPT), CPK, alkaline phosphatase, GGT, total bilirubin, total protein, 
albumin, Calcium, Urea, Creatinine, CRP, glucose, Na, K and Cl. The analyses will 
be done under fasting condition (10 hours). Within the 5 calendar days prior to W000 
with results available at W000 at the latest, a test for HbA1c must be done for all 
patients except known diabetics  with a result ≤  8% obtained in the 3 months before 
the selection visit.  
 Fasting Lipids (within the 5 calendar days prior to W000 with results available at 
W000 at the latest, W001, W002, W004, W006 and W008 visits): Triglycerides, 
HDL, LDL, and total cholesterol. The analysis will be done under fasting condition 
(10 hours). 
 Haematology (within the 5 calendar days prior to W000 with results available at 
W000 at the latest, W001, W002, W004, W006 and W008 visits): haemoglobin, 
haematocrit, red blood cells, MCV, MCH, MCHC, platelets, white blood cells, 
lymphocytes, monocytes, eosinophils, basophils and neutrophils (white blood cells, 
lymphocytes, monocytes, eosinophils, basophils and neutrophils must be assayed in 
absolute value and entered in the e-CRF in this unit).  For patients under warfarin or 
phenprocoumon, International Normalized Ratio (INR) will be performed at each 
visit (including W003) or more often if judged necessary by the investigator. 
 
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 Standard urinalysis will be performed using a dipstick, within the 5 calendar days 
prior to W000 with results available at W000 at the latest, W004, W006 and W008 
visits by the investigator or a delegated person. Urinalysis: pH, proteins, blood, 
leucocytes, bilirubin, ketones bodies, nitrites and glucose. 
 A blood sampling will be performed for β-HCG or FSH analysis (within the 5 
calendar days prior to W000 visit, with results available at W000 visit at the latest) to 
diagnose pregnancy and menopause respectively. β-HCG tests will be repeated at 
W004 and W008 visits for women of child-bearing potential. Depending on the local 
regulation, pregnancy tests can be additionally repeated throughout the treatment 
period (urinary tests which is not to be entered into e-CRF). 
8.3. Adverse events 
All adverse events and other situations relevant to the safety of the participants must be 
followed up and fully and precisely documented in order to ensure that the sponsor has the 
necessary information to continuously assess the benefit-risk balance of the clinical trial. 
The same procedure applies whether the participant receives the test drug or a comparison 
product (placebo, S42909). 
8.3.1. 
Definitions 
8.3.1.1. 
Adverse events 
An adverse event is defined as any untoward medical occurrence in a subject participating in a 
clinical study, whether or not there is a causal relationship with the IMP and/or experimental 
procedures, occurring or detected from the date the participant signs the information and 
consent form, irrespective of the period of the study (periods without administration of the 
IMP (e.g. selection period) are also concerned). 
An adverse event can therefore be: 
- 
any unfavourable and unintended sign, including an abnormal finding from an 
additional examination (lab tests, X-rays, ECG, etc.) which is deemed clinically 
relevant by the investigator, 
- 
any symptom or disease, 
- 
any worsening during the study of a symptom or a disease already present when the 
participant entered the study (increase in frequency and/or intensity), including the 
studied pathology, 
and detected during a study visit or at an additional examination or occurred since the 
previous study visit (including relevant event reported in participant’s diary or safety 
evaluation scale). 
Of note: 
- 
Any hospitalisation for social reasons, educational purpose (e.g. learning of arterial 
hypertension management by the participant) or routine check-up, and the 
hospitalization for PK sampling purposes at W004 (participants having signed the 
consent form for the optional PK analysis) should not be considered as an adverse 
event and should not be reported in the e-CRF. 
- 
The following procedures, whether planned before the study or not, whether leading to 
a hospitalisation or not, should be reported in the specific page “Procedures not 
subsequent to an adverse event” of the e-CRF: 
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 therapeutic procedures related to a non-aggravated medical history (e.g. cataract 
extraction not due to an aggravation of the cataract during the study, haemodialysis 
sessions related to a renal insufficiency not aggravated during the study),  
 prophylactic procedures (e.g. sterilisation, wisdom teeth removal),  
 comfort procedures (e.g. cosmetic surgery),  
 control procedures of a pre-existing condition without aggravation (e.g. colonoscopy 
to control the remission of colon cancer). 
 any hospitalisation to perform the duplex ultrasonography examination 
- 
In the framework of this protocol, local adverse reactions at ulcer site such as pruritus, 
erythema, pain, discomfort, bleeding, etc., are reactions that are expected to occur in 
normal conditions during the healing process and investigators should use their 
clinical judgement to discern whether a specific event is falling into this category or 
not. Expected local adverse reactions should not be reported as adverse events. 
8.3.1.2. 
Serious adverse events 
Any adverse event that at, any dose: 
­ results in death, 
­ is life-threatening(1), 
­ requires inpatient hospitalization or prolongation of existing hospitalization, 
­ is medically significant(2), 
­ results in persistent or significant disability/incapacity(3), 
­ is a congenital anomaly/birth defect(4). 
(1) Life-threatening in this context refers to an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death if it was 
more severe.  
(2) Any event that might not be immediately life-threatening or result in death or hospitalisation, but 
might jeopardise the participant or might require intervention to prevent one of these outcomes (for 
example: oedema or allergic bronchospasm that required intensive treatment at home, blood dyscrasia, 
convulsions that do not result in hospitalisation, or development of drug dependence or drug abuse). 
The investigator should exercise his/her scientific and medical judgement to decide whether or not 
such an event requires expedited reporting to the sponsor. 
(3) Disability/incapacity in this context refers to any event that seriously disrupts the ability of the 
participant to lead a normal life, in other words leads to a persistent or permanent significant change, 
deterioration, injury or perturbation of the participant's body functions or structure, physical activity 
and/or quality of life. 
(4) Congenital anomaly or birth defect refers to the exposure to the IMP before conception (in men or 
women) or during pregnancy that resulted in an adverse outcome in the child. 
8.3.1.3. 
Adverse events of special interest 
Not applicable.  
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8.3.1.4. 
Overdose 
This refers to any intake of a quantity of IMP which is above the maximum dose 
recommended in the study protocol, independently of the occurrence of any adverse event. 
The quantity should be considered per administration or cumulatively regarding the maximum 
dose recommended in the study protocol. For instance, as the study protocol requires two 
daily administrations, one intake of the planned two daily intakes at the same time should be 
considered as overdose. 
8.3.1.5. 
Events requiring an immediate notification (ERIN) 
An event must be notified immediately (i.e. within 24 hours) to the sponsor if it is: 
­ a serious adverse event, 
­ an overdose of the IMP even if asymptomatic,  
­ any intake of the IMP by a person around the participant, 
­ a pregnancy. 
8.3.2. 
Responsibilities of the investigator 
For any adverse event and special situation mentioned above the investigator must: 
­ Note in the participant's medical file the date on which he/she learned of the event (at a 
follow-up visit or a telephone contact with the participant or a third person, …) and any 
other relevant information which he/she has learned of the event,  
­ Report the event to the sponsor using the AE form (in case of ERIN, the reporting should 
be done immediately),  
­ Evaluate the seriousness, intensity and causality, 
­ Document the event with additional useful information,  
­ Ensure the follow-up of the event,  
­ Fulfil his/her regulatory obligations to the Competent Authorities and/or to the IRB/IEC, 
in accordance with local regulations. 
8.3.2.1. 
Time frame for AE reporting 
Any event meeting the above mentioned definitions (see section 8.3.1) must be reported to the 
sponsor on an adverse event form if it occurred: 
­ before the first intake of the test drug, for event associated with any procedure/condition 
required by the study protocol: procedure (duplex ultrasonography, ECG, etc.), change 
or withdrawal of previous/concomitant treatment relating to the conditions of the protocol.  
­ at any time after the first intake of the test drug up to the participant’s last study visit for 
all events,  
­ after the participant’s last study visit: 
 up to 30 calendar days after the participant's last study visit for all ERIN, regardless 
of the supposed role of the research (IMP, or experimental procedure). 
 irrespective of the time of onset after the end of the study in case of serious adverse 
event related to the research (IMP, or experimental procedure). 
Of note, events occurring between the signature of the informed consent and the first 
administration of the test drug for which the investigator does not consider an association with 
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any procedure/condition required by the study protocol must be reported as medical history in 
the dedicated form of the e-CRF. 
All other adverse events 
 
     
       
 
 to be reported as Medical history 
 
 
 
 
 
 
 
 
 
Adverse Events associated
with: 
- 
A procedure scheduled in 
the study protocol, 
- 
A change or withdrawal 
of previous / concomitant 
treatment related to the 
conditions 
of 
the 
protocol, 
- 
A product other than the 
test drug, taken as part of 
the protocol. 
 
All adverse 
events 
 
All 
ERIN 
 
All 
SAE 
related 
to 
the research 
(IMP, 
experimental 
procedure) 
 to be 
reported 
as 
Adverse 
Event 
 
 
 
 
 
 
 
 
 
Signing of the  
consent form  
1st administration  
of the 42909 or placebo 
 
Participant's 
last study visit 
 
30 calendar days after 
the participant's last 
study visit 
 
 
 
 
 
 
8.3.2.2. 
Evaluation of seriousness, intensity and causality 
It is important that the investigator gives his/her own opinion regarding the seriousness, the 
intensity of the event as well as the cause-effect relationship between an adverse event and 
the IMP. This evaluation must be assessed by the investigator and reported in the AE form. 
The Seriousness should be evaluated according to international guidances (see definition 
section 8.3.1.2, in accordance with ICH Topic E2A and Directive 2001/20/EC of the 
European 
Parliament 
and 
of 
The 
Council 
of 
4 
April 
and 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm071696.pdf). 
The Intensity should be evaluated according to the following rule: 
­ mild: signs or symptoms, easily tolerated, relieved with symptomatic treatment, 
­ moderate: enough discomfort to cause interference with usual activity, only partially 
relieved with symptomatic treatment, 
­ severe: incapacity in some regular activities, not easily relieved with symptomatic 
treatment. 
The causal relationship to the IMP  must be assessed when reporting the AE in the AE form. 
Only cases ticked "related" by the investigator or judged by the sponsor as having a 
reasonable suspected causal relationship to the test drug (AE linked to the mechanism of 
action of the test drug…) will be considered as suspected Adverse Drug Reaction. In general, 
the expression reasonable causal relationship means to convey that there is evidence or 
arguments to suggest a causal relationship. 
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8.3.2.3. 
Documentation of the event 
The investigator must ensure that all events are well documented. In particular for ERIN, 
he/she should provide the sponsor, as they become available, with anonymized copies of the 
documents which provide additional useful information, such as hospital admission reports, 
reports of further consultations, laboratory test reports, reports of other examinations aiding 
diagnosis (where possible, the results from pre-test drug assessments should be appended for 
comparison with the results obtained under test drug), or the autopsy report, if autopsy is 
performed. 
8.3.2.4. 
Follow-up of adverse events 
The investigator must ensure that follow-up of the participant is appropriate to the nature of 
the event, and that it continues until resolution if deemed necessary. 
Any change in terms of diagnosis, intensity, seriousness, measures taken, causality or 
outcome regarding an adverse event already reported must be written up in a new complete 
evaluation of the event documented on the “Adverse event” page previously created for the 
event in the e-CRF. 
If the adverse event has not resolved at the participant's final visit in the study, the participant 
must be followed up suitably and any information on the outcome of the event will be noted 
on the « Adverse Event » page previously created for the event in the e-CRF. 
If the follow-up of the participant is not done by the investigator him/herself (hospitalisation, 
followed by a specialist or the participant's general practitioner, etc.), the investigator will do 
everything to establish/maintain contact with the person/department in charge of follow-up of 
the participant. 
8.3.2.5. 
Special situations (pregnancy, overdoses, intake of IMP by a person around 
the participant) 
Pregnancy  
If a female participant in the study becomes pregnant, the investigator must: 
­ stop immediately the IMP, 
­ report it on an « Adverse Event » page as well as on the specific paper pregnancy form to 
be notified immediately (ERIN), 
­ contribute to the follow-up of this pregnancy and provide the sponsor with information 
concerning this follow-up  
­ If the partner of a participant becomes pregnant during the course of the study or within 3 
months after completion of study treatment, the pregnancy should not be reported in the e-
CRF. The investigator should immediately contact the sponsor (contact details provided in 
the investigator’s study file) who will inform him/her about the procedure to be followed. 
Overdose of IMP  
­ In case of overdose, the investigator should report it on an “Adverse Event” page to be 
notified immediately (ERIN).  
­ Overdose should be followed-up to ensure that the information is as complete as possible 
with regards to:  
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- dose details (number of units, duration,…) and, if multiple overdose, details regarding 
other medicinal products or substance , 
- context of occurrence, i.e. intentional (suicide attempt, other reason) or accidental 
(error in prescription, administration, dispensing, dosage),  
- related signs and symptoms (“No related adverse events” to be reported otherwise),  
- outcome. 
Intake of IMP by a person around the participant.   
This event should not be reported in the e-CRF. The investigator should immediately contact 
the sponsor (contact details provided in the investigator’s study file) who will inform him/her 
about the procedure to be followed. 
8.3.2.6. 
Recording Methods in the e-CRF 
Adverse events must be documented on the « Adverse Event » page of the e-CRF.  
In case of chronic disease: 
­ if the disease is known when the participant enters in the study, only worsening (increased 
frequency and/or intensity of the episodes/attacks) will be documented as an adverse event,  
­ if the disease is detected during the study and if repeated episodes enable diagnosis of a 
chronic disease, the episodes will be grouped on the « Adverse Event » page previously 
created for the event which will clearly describe the diagnosis. 
In case of gastrointestinal events (such as diarrhoea, loose stools, nausea, flatulence, 
vomiting, dyspepsia, abdominal pain, etc.): 
­ the investigator will specify, in the “description” area of the AE e-CRF form, the 
circumstances of occurrence, localisation, duration and frequency of the event. 
8.3.2.7. 
Procedure for an event requiring an immediate notification  
In case of an event requiring an immediate notification, the investigator must: 
­ Immediately after being informed of this event, fill in the participant's medical file as 
well as the « Adverse Event » page of the e-CRF according to the general instructions 
available in the e-CRF, without waiting for the results of the clinical outcome or of 
additional investigations. When data will be submitted into Inform, an e-mail will be 
immediately and automatically sent to the sponsor. 
­ Provide the sponsor (person designated in the contact details provided in the investigator’s 
study file), as they become available, with anonymized copies of the documents which 
provide additional useful information, 
­ Fulfil his/her regulatory obligations to the Competent Authorities and/or to the IRB/IEC, in 
accordance with local regulations. 
If an adverse event initially judged as non-serious worsens and becomes serious (ERIN), this 
must be reported immediately on an "Adverse event" page of the e-CRF. 
In case the e-CRF is unavailable when the investigator was informed of the ERIN, he/she 
should: 
­ Immediately fill in a paper "Adverse event" page: 
- For a serious event on a paper entitled "Adverse event – Initial information" page,  
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- For an event initially judged as non-serious on a paper entitled "Adverse event – 
Initial information" page, and the worsening leading to seriousness on a paper 
"Adverse event – Additional information" page,  
- Immediately send the pages by fax or e-mail to the person(s) designated in the 
contact details provided in the investigator’s study file. Should a Serious Adverse 
Event or any other reportable event need to be reported outside of the working 
hours, a phone call will be needed in addition to the expected written information 
transmitted by fax or by e-mail. The contact information to be used are the 
following:  
o For European sites: dial the European international prefix followed by 
33.1.55.72.60.00  
o For a Canadian site: dial the ICTR phone number listed in your investigator’s 
study file. 
o For a site in USA: contact the Ilkos medical monitor listed in your 
investigator’s study file. 
o In any case, the investigator can contact the central 24-hour phone line in 
France: 33.1.55.72.60.00 
­ As soon as the e-CRF becomes available, the investigator should enter these data in the 
« Adverse Event » page of the e-CRF.  
8.3.3. 
Responsibilities of the sponsor 
In accordance with international guidances, the assessment of the seriousness and the 
causality of adverse events are usually made by the investigator but falls also under sponsor’s 
duties, who is responsible for ensuring that all suspected unexpected serious adverse reactions 
are reported to Competent Authorities and Ethics Committees.  
The sponsor will review the seriousness of the adverse events and the causality of the serious 
adverse events, whether reported by the investigator or upgraded by the sponsor. The 
causality and the seriousness may be upgraded (but never downgraded). Anonymized copies 
of documents providing useful information such as reports of further consultations, laboratory 
tests reports, reports of other examination aiding diagnosis may be asked for the event 
assessment. If the assessments of the investigator and the sponsor are different, both will be 
reported in the clinical study report. 
Independently of the regulatory obligations of the investigator, the sponsor must report the 
pharmacovigilance data to the appropriate Authorities and to all the investigators involved, 
according to the requirements stated in ICH Good Clinical Practice guidelines and local 
regulations.  
9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY OR 
SAFETY 
9.1. Measurement of drug concentration  
The concentrations of S42909 and its metabolites (S45015, S45236 and S55113) in plasma 
will be analysed according to validated methods by a central CRO (Algorithme Pharma). 
Procedures will be described in separate bio-analytical protocols established by (Algorithme 
Pharma). 
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9.1.1. 
Collection of blood samples 
­ Blood samples (6 ml) will be collected into lithium-heparinised tubes according to the 
tubes provided, each sample being intended for the assay of the parent drug and 
metabolites.  
 In participants participating in the mandatory PK analysis only, a total of 4 
venous blood samples will be collected on the day of W000, W004, W006 study 
visits and one predose venous blood sample will be collected on the day of W001 
and W002 study visits (see Table (4.2.2) 2 - Pharmacokinetic Investigation 
schedule):  
- At W000, W004, W006 visits: prior to breakfast and first study drug intake at the 
end of the breakfast, which will be considered as T0, then 1h, 3h after drug intake 
and just before the participant leaves the site at the end of the study visit.  
- At W001, W002 visits: prior to breakfast and first study drug intake at the end of 
the breakfast. 
 In participants participating in the mandatory and optional PK analyses (see 
Table (4.2.2) 2 - Pharmacokinetic Investigation schedule): 
- a total of 9 venous blood samples will be collected on the day of W000 visit, 
instead of the 4 blood samples listed above: prior to the breakfast and the first 
IMP intake at the end of the breakfast (T0) and 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h 
after first IMP intake. The 12h  timepoint, which will be just prior to the dinner 
and the IMP intake at the end of the meal, can be adjusted to a maximum of 2 
hours earlier to accommodate a more convenient dinner time. 
- at W001, W002 visits: prior to breakfast and first study drug intake at the end of 
the breakfast, which will be considered as T0. 
- a total of 13 venous blood samples will be collected on the day of W004 visit, 
instead of 4 blood samples listed above: prior to the breakfast and the first IMP 
intake at the end of the breakfast (T0) and 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, after 
first IMP intake. The 12h  timepoint, which will be just prior to the dinner and the 
IMP intake at the end of the meal, can be adjusted to a maximum of 2 hours 
earlier to accommodate a more convenient dinner time. PK sampling schedule for 
13h, 14h, 15h and 24h is relative to the evening IMP administration (respectively 
1, 2, 3 and 12h after evening IMP administration).   
- at W006 visit: prior to breakfast and first study drug intake at the end of the 
breakfast, which will be considered as T0, then 1h, 3h after drug intake and just 
before the participant leaves the site at the end of the study visit. 
- participants having signed the consent form for the optional PK analysis will stay 
during 12 hours at W000 and be hospitalized one day and one night at W004 
visits. 
Note: Participation in the CL2-42909-016 study does not imply a mandatory or systematic 
participation in the optional investigations. All voluntary participants will have to sign a 
specific informed consent form. The consent given for this analysis can be withdrawn at any 
moment without compromising the participation in the overall clinical study investigations. In 
addition, in case of consent withdrawal, related samples will be destroyed on a case by cases 
basis. 
On the day of PK samples, well-balanced meals will be taken by the participants, equivalent 
to 600 Kcal for breakfast and 900-1100 Kcal for lunch and dinner with no more than 25% of 
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fat. The participants must consume all contents of their meals on these days. Examples of 
standard breakfast and lunch/dinner are provided in Appendix 11. 
­ Plasma samples handling: 
Blood samples will be centrifuged according to the laboratory manual instructions.  
- After centrifugation, 4 aliquots of at least 0.5ml of clean plasma will be transferred 
into 4 cryovials tubes intended to assay the parent drug (S42909) and its 
metabolites (S45015, S45236 and S55113). Real time of sampling must be noted 
on the relevant page of the e-CRF. 
Tubes will be clearly labelled with indelible ink, with labels provided with the tubes and 
stating for example:  
- Protocol number (CL2-42909-016), Participant number, Treatment number, site 
number 
- Visit, date of the sampling, time (e.g. W000, T12h). 
9.1.2. 
Storage and shipment of samples 
The plasma tubes will be immediately frozen at approximately –20 or -80°C (-4 or -112°F) 
and kept at this temperature until shipment. 
On a mutually agreed date and according to the instructions written in the laboratory manual, 
two aliquots of each plasma sample will be sent by special carrier to the logistical platform in 
an isolated box containing dry ice for storage. Samples will be accompanied with a list of 
contents. 
The shipments will be organised by the logistical platfrom. 
The logistical platform will be in charge of the shipment of the aliquots to the assay centre. 
The remaining two aliquots (safeguard samples) will be sent later on request of the logistical 
platform.  
9.2. Assessment of non genomic biomarkers relating to healing (biorepository) 
9.2.1. 
Collection of blood samples 
Non genomic biomarkers will be measured in plasma and serum (in ante brachial vein). Blood 
samples will be collected in both EDTA and SST tubes for plasma and serum aliquot 
preparation at W000 before first administration of treatment and at W004, in participants 
having given their written informed consent for these optional samplings (See investigational 
schedule (Table (4.2.2) 1). 
9.2.2. 
Optional assessment 
Participation in the CL2-42909-016 study does not imply a mandatory or systematic 
participation in the optional investigations. All voluntary participants will have to sign a 
specific informed consent form. The consent given to this analysis can be withdrawn at any 
moment without compromising the participation in the overall clinical study investigations. In 
addition, in case of consent withdrawal, related samples will be destroyed before any optional 
analysis is completed. 
Non genomic biomarkers related to venous leg ulcer healing should be measured to establish 
a potential correlation between the presence or absence from body fluids and healing success. 
The non genomic biomarkers related to the underlying chronic venous disease, the response to 
S42909 treatment may also be analysed. 
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A biorepository will be establish to hold plasma and serum samples collected from the 
participants having given their written informed consent for these optional samplings, until 
the candidate non genomic biomarkers will be selected for analysis. 
For genomic assessment, see 9.3.Optional assessment-genomics. 
9.2.2.1. 
Sampling and storage  
The management of the samples (centrifugation, aliquoting) and the storage before shipment 
will be done according to the instructions written in the laboratory manual. 
The aliquots will be frozen at approximately –80°C (-112°F) and kept at this temperature until 
shipment.  
On a mutually agreed date and according to the instructions written in the laboratory manual, 
the plasma and serum samples will be sent to the logistical platform in an isolated box 
containing dry ice for storage according to the instructions written in the laboratory manual. 
The logistical platform will store the samples during the study and will organise the shipment 
to the biorepository for long term storage. 
The samples will be stored for a maximum 25 years, after the end of the study or earlier if 
requested, and according to local regulations. 
Samples not stored in the biorepository will be destroyed after analysis or after completion of 
the analytical report, and at the latest before the end of the study. 
9.2.2.2. 
Labelling and transfer  
• Labelling:  
Labelling must allow unique sample and participant identification. Information will be 
detailed in the Logistic platform specifications 
• Transfer:  
The deep frozen samples will be transported by special delivery in dry ice to the biorepository 
or to the responsible laboratory. 
9.2.2.3. 
Non genomic biomarkers assessment  
Not applicable  
9.2.2.4. 
Transfer of analytical results  
Not applicable. 
9.3. Optional assessment - genomic 
The pharmacokinetics and pharmacodynamics of many medicinal products is prone to assess 
between subjects’ variability, which is caused by several factors such as sex, age, weight, 
renal and hepatic functions, and genomics factors. In recent years, a rapid development in our 
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understanding of the influence of genomes between subjects’ differences in drug action has 
occurred.  
Determination of genes influencing the response to a treatment could allow the identification 
of participants having a better response to a given treatment or participants with higher 
susceptibility to develop adverse events related to a treatment. Identification of these genes 
could help provide the most suitable therapy to each participant. 
An optional genotyping analysis will be performed. The objective is mostly to develop the 
knowledge of the impact of genomic on the ADME parameters and on the pharmacodynamics 
of the test drug. 
Sequencing of the human genome, identification of informative genomic biomarkers such as 
single nucleotide polymorphisms (SNP) and development of new technologies such as DNA 
arrays have facilitated the study of the genome in a large scale. The use of these technologies 
facilitates the study of genomics biomarkers associated with the susceptibility to have a 
disease or to respond to a treatment and accelerates the implementation of pharmacogenomics 
studies in drug development. On the other hand, Regulatory Agencies nowadays encourage 
development of genomic studies in order to advance the understanding of relationships 
between genotypes and responses to drugs. 
In order to improve the knowledge of S42909 in human (pharmacokinetics and 
pharmacodynamics), to better understand the mechanism of response to treatment and to 
determine factors related to the response, a genotyping analysis will be performed to try to: 
­ identify genes implicated in the S42909 drug absorption, distribution, metabolism and 
excretion and evaluate associations between polymorphisms of relevant genes and 
pharmacokinetics of S42909 and the response to treatment. 
­ identify genes implicated in the pharmacological target, subgroups of participants with 
genetic susceptibility to develop non-healing venous leg ulcer or to identify novel genes 
that may play a critical role in the treatment response.  
These polymorphisms could be further used as biomarkers of the type of response to 
treatment.  
Candidate genes for genomic studies are those implicated in drug absorption and disposition 
(e.g. pharmacokinetics) and drug effects (e.g. pharmacodynamics, drug efficacy and adverse 
effects).  
The samples will not be used for any investigations not specified in this protocol or for the 
elaboration of a DNA bank. 
There will be no communication of individual results neither to the investigator nor to the 
participant. 
Note: Participation in the CL2-42909-016 study does not imply a mandatory or systematic 
participation in the optional investigations. All voluntary participants will have to sign a 
specific informed consent form. The consent given to this analysis can be withdrawn at any 
moment without compromising the participation in the overall clinical study investigations. In 
addition, in case of consent withdrawal, related samples will be destroyed before any optional 
analysis is completed. 
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9.3.1. 
Collection of blood samples 
A blood sample will be collected in an EDTA aliquot for DNA isolation in participants 
having given their written informed consent for this optional analysis. The samples collection 
will be performed at  the inclusion visit before first administration of treatment (W000) as 
indicated in the investigational schedule (Table (4.2.2) 1) in participants having given their 
written informed consent form for this optional sampling information. 
9.3.2. 
Sampling and storage  
The management of the blood samples and the storage before shipment (if applicable) will be 
done according to the instructions written in the laboratory manual. The aliquots will be 
frozen at approximately –80°C (-112°F) and kept at this temperature until shipment. 
The blood samples will be first sent to the logistical platform in an isolated box containing dry 
ice for storage according to the instructions written in the laboratory manual. 
The logistical platform will store the samples during the study and will organise the shipment 
to the laboratory responsible for the DNA extraction and genomic analysis in an isolated box 
containing dry ice. The shipment for analysis will be organised at the end of the study with 
the agreement of the sponsor. 
After completion of the analysis, remaining aliquots will be sent to the biorepository for long 
term storage. 
The samples will be stored for a maximum of 25 years, after the end of the study or earlier if 
requested and according to local regulations. 
9.3.3. 
Labelling 
Labelling must allow unique sample and participant identification. Information will be 
detailed in the Logistic platform specifications. 
9.3.4. 
Assay  
Genomic biomarkers will be analysed using a Fluidigm Technology platform. Following first 
analysis the samples containing extracted DNA will be stored for a period of up to 25 years 
after the end of the study or earlier if requested and could be used for subsequent analyses. All 
samples will be destroyed after a maximum period of 25 years after the end of the study, or on 
the simple demand of the participant to the investigator. 
Genomic markers will be determined and analysed based on the clinical pharmacokinetic data 
obtained. The genotyping test will be performed on genes thought to be involved in the 
absorption, distribution, metabolism and excretion of S42909. After the first analysis, the 
remaining quantity of the samples will be stored in order to provide the opportunity to 
investigate 
unknown 
polymorphic 
sites 
related 
to 
the 
pharmacokinetics 
and 
pharmacodynamics of S42909, not identified yet at the time of the first analysis. 
10. STATISTICS 
10.1. Statistical analysis 
A Statistical Analysis Plan will be written after finalising the protocol and definitively 
completed before breaking the blind. These specifications will detail the implementation of all 
the planned statistical analyses in accordance with the principal features stated in the protocol. 
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10.1.1. Evaluation criteria 
Efficacy criteria 
- Main criterion: 
- Reference Ulcer area expressed as a relative change from baseline to W004 (%): 
 Main analytical approach: Detection of an overall dose-response effect using the 
MCP-Mod Method (for more details see § 10.1.4, Statistical Methodology). 
 Secondary analytical approach: Determination of dose window for the Minimal 
Effective Dose (MED) using the MCP-Mod Method (for more details see §10.1.4 
Statistical Methodology). 
- Secondary criteria 
- Linear advance of the wound margin towards the wound center:  
p
A
d
∆
=
 
Where A
∆is the difference in the area (
Baseline
Visit
A
A
−
) and p is the average of the wound 
perimeter (
2
Baseline
visit
p
p
p
+
=
) 
- Reference Ulcer Volume 
- Pain intensity 
- Analgesic drug consumption 
Safety criteria 
- Adverse events 
- Blood biochemistry, haematology, and urinalysis 
- Physical examination and vital signs 
- 6 or 12-lead electrocardiogram (ECG) 
Biomarker criteria 
- Plasma biomarkers 
- Genomic criteria 
The complete list of biomarkers will be subsequently determined. 
10.1.2. Statistical elements 
The type one error of the statistical analyses will be set at 2.5 % in a one tailed situation. 
The following descriptive statistics will be provided depending on the nature of variables: 
Quantitative variable: number of observed values, mean and standard deviation, minimum 
and maximum, median, and if necessary first and third quartiles. 
Qualitative or ordinal variable: number and percentage of patients per class. 
10.1.3. Analysis sets 
Randomised Set (RS) 
This set will correspond to all randomised patients. 
Safety set for double blind period (SS) 
This set will correspond to patients who received at least one dose of study treatment. 
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Full Analysis Set (FAS) 
This set will correspond to randomised patients who received at least one dose of study 
treatment and who have at least one baseline value and one value of reference ulcer area at 
W004. 
Per Protocol Set (PPS) 
This set will correspond to patients of the Full Analysis Set without relevant deviation(s) 
which could affect the evaluation of the primary efficacy criterion. 
Based on the actual deviations, the criteria for exclusion of patients from the different data 
sets will be specified and updated if necessary before breaking the blind. 
10.1.4. Statistical methodology 
Study Outcome 
Study outcome analyses will be carried out on the RS. 
Characteristics of patients including demography, prognostic factors, baseline values of 
assessment criteria will be described by dose and overall. 
Treatment duration, global treatment compliance, status of patients and reason for withdrawal, 
protocol deviations, concomitant treatments will be described by dose and overall. 
Main characteristics of patients will also be described for the SS, the FAS and the PPS. 
Efficacy 
Efficacy analyses will be carried out on the FAS and the PPS. 
- Primary criterion: Reference Ulcer area  
Main analysis: Detection of an overall dose-response effect 
The objective of the main analysis will be to detect the existence of a dose-response 
relationship according to the reference ulcer area reduction expressed as the relative change 
from 
baseline 
to 
W004 
(%) 
and 
using 
the 
MCP-Mod 
Method 
((EMA/CHMP/SAWP/757052/2013, 2014); (Bretz, 2005)). 
The doses 0 mg (placebo), 100 mg, 200 mg, 400 mg, 800 mg and 1200 mg will be assessed in 
the study and the following set of 7 candidate models: M = (Linear, Emax (2), Sigmoïd Emax, 
Logistic, Exponential (2)) considered for the main analysis. 
The models will be defined as follows with some pairs (d*, p*) where d* is a dose and p* is 
the maximal percentage of efficacy related to the concerned dose: 
- 
Linear 
- 
Emax1 (200 mg, 90%) 
- 
Emax2 (400 mg, 70%) 
- 
Sigmoïd Emax (200 mg, 10%) and (1000 mg, 90%) 
- 
Logistic (200 mg, 10%) and (1000 mg, 90%) 
- 
Exponential1 (400 mg, 10%) 
- 
Exponential2 (800 mg, 10%) 
A test of contrast will be performed on each model to detect the existence of dose response 
relationship (“proof of concept”) with control of the Family Wise Error Rate (FWER) at a 
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pre-specified level α. If at least one model is statistically significant, the “best” fit model will 
be selected. 
The “best” fit model will be chosen by the minimum p-value (the one with the strongest 
statistical test and greater than an appropriate critical value q). 
Secondary analyses:  
- Determination of dose window for the Minimal Effective Dose (MED) 
Using the selected model resulting from the main analysis, a dose window of the Minimal 
Effective Dose (MED) will be estimated, considering an hypothesis of a clinically relevant 
effect as compared to placebo of 6.5%. 
The parameters of the selected model in the main analysis will be re-assessed and, if the 
model converges, it will be used to estimate the MED. If the model doesn’t converge, the 
second “best” fit model will be used.  
- Description 
The relative change from baseline of the reference ulcer area will also be described at each 
visit. 
- Secondary criteria 
 Linear advance of the wound margin towards the wound centre 
Description at each visit will be provided. 
 Reference Ulcer Volume 
Descriptive statistics at each visit will be performed. 
 Pain intensity 
Descriptive statistics at each visit will be carried out. 
 Analgesic drug consumption 
Descriptive statistics at each visit will be carried out. 
In addition, relative change of the reference ulcer area, linear advance of the wound margin 
towards the wound centre and reference ulcer volume will be described at each visit in the 
following subgroups: 
- 
Combined prognosis criteria on size and age of the ulcer (≤ 10 cm² and ≤ 6 months / > 
10 cm² or > 6 months) 
- 
Size of the ulcer at baseline ( ≤ 50 cm² / > 50 cm²) 
- 
Diabetes status (yes/no).  
Exploratory data analyses will be conducted as applicable. 
Safety  
Safety analyses will be carried out on the Safety Set by group over the W0-W6 period. 
 Adverse events 
Number of adverse events, number and percentage of patients reporting at least one adverse 
event will be described by System Organ Class (SOC) and Preferred Term. The same analysis 
will be performed for emergent adverse events and serious adverse events. 
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Emergent adverse events will be also described in accordance to the intensity, outcome, 
relationship to the study treatments, and adverse events leading to the study drug withdrawal. 
 Clinical laboratory evaluation 
Laboratory parameters will be described using value at the visit, last value under treatment 
and change from baseline to last value under treatment. 
Moreover, biochemistry, haematology and urinary parameters will be classified according to 
the laboratory reference ranges and alert values for the potentially clinically significant 
abnormal values, and shift tables from baseline to worst event will be presented. 
 Physical Examination and vital signs 
Physical examination and vital signs will be described using value at the visit, last post-
baseline value and change between baseline and last post-baseline value. 
 6 or 12-lead electrocardiogram (ECG) 
ECG parameters and ECG abnormalities will be described at each visit. 
Biomarkers 
The association between healing and plasma biomarkers could be investigated with 
prognostic approaches e.g. regression models, Receiver Operating Characteristic (ROC) 
curve. 
In order to study the association between genomic criteria and efficacy or safety of S42909, 
exploratory analyses using single-marker and multi-marker approaches could be used. 
10.2. Determination of sample size 
Sample size was estimated with a type one error rate set at 2.5% and using the statistic 
function “sampsize” described in the publication “MCP-Mod : An R Package for the Design 
and Analysis of Dose-Finding Studies” edited by B. Bornkamp, J. Pinheiro and F. Bretz 
(2009). 
Considering: 
- a standard deviation of 42%, 
- a minimal relative change of Reference ulcer area at one month (Rmin) of 32.5%, 
- a maximal relative change of Reference ulcer area at one month (Rmax) of 62.5%, 
- a maximal efficacy (Rmax – Rmin) of 30%,  
- six doses: 0 (placebo), 100, 200, 400, 800, 1200 mg, 
- seven candidate models defined by some couples (d*, p*) (dose, maximal percentage 
of efficacy): 
o 
Linear 
o 
Emax1 (200 mg, 90%) 
o 
Emax2 (400 mg, 70%) 
o 
Sigmoïd Emax (200 mg, 10%) and (1000 mg, 90%) 
o 
Logistic (200 mg, 10%) and (1000 mg, 90%) 
o 
Exponential1 (400 mg, 10%) 
o 
Exponential2 (800 mg, 10%), 
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Figure (10.2) 1 - Dose-response models 
 
- 
function “min” of Bretz package (power of each model is greater or equal to 
the nominal power to detect a signal of dose-response relationship), 
27 evaluable participants per group guarantee a nominal power of at least 80% to detect a 
signal of dose-response relationship (proof-of-concept). 
After 1000 data simulations based on above hypotheses, with a true dose-response 
relationship supposed to be a logistic model (defined by the couples (200 mg, 10%) and 
(1000 mg, 90%)) and 27 participants by dose, the empiric power to detect a signal of dose-
response relationship (main objective) is about 90%. 
In this case, for the secondary objective, the empiric power to determine the Minimal 
Effective Dose with a clinically relevant difference of 6.5% of healing rate at one month (as 
compared to placebo) is about 87.5%. 
Other simulated data with a true dose-response relationship supposed to be an Emax model or 
an Exponential model lead to an empiric power to detect a signal of dose-response 
relationship (proof-of-concept) of about 80% and to an empiric power to determine the 
Minimal Effective Dose with a clinically relevant difference of 6.5% of healing rate at one 
month (as compared to placebo) of at least 70% for an Emax model, at least 65% for an 
Exponential model. 
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Taking into account an exclusion rate from the Randomised Set estimated at 20%, about 34 
participants per treatment group will have to be included. 
11. DIRECT ACCESS TO SOURCE DATA / DOCUMENTS 
The investigator will allow the monitors, the persons responsible for the audit, the 
representatives of the IRB/IEC, and of the Competent Authorities to have direct access to 
source data / documents. 
12. QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. Study monitoring 
12.1.1. Before the study 
The investigator will allow the monitor to visit the site and facilities where the study will take 
place in order to ensure compliance with the protocol requirements. 
Training sessions may be organised for the investigators and/or designated persons.  
12.1.2. During the study 
The investigator will allow the monitor to: 
­ inspect the site, the facilities and the material used for the study, 
­ meet all members of his/her team involved in the study, 
­ consult the documents relevant to the study, 
­ have access to the electronic case report forms (i.e. access to an analogic phone line or 
his/her computer), 
­ check that the electronic case report forms have been filled out correctly, 
­ directly access source documents for comparison of data therein with the data in the 
electronic case report form, 
­ verify that the study is carried out in compliance with the protocol and local regulatory 
requirements. 
The study monitoring will be carried out at regular intervals, depending on the recruitment 
rate and / or the investigation schedule, and scheduled between the investigator and/or 
designated persons and monitor. 
All information dealt with during these visits will be treated as strictly confidential. 
12.2. Computerised medical file 
If computerised medical files are used, and if the computer system allows, no change made in 
the medical files by the investigator should obscure the original information. The record must 
clearly indicate that a change was made and clearly provide a means to locate and read the 
prior information (i.e. audit trail). The investigator will save data at regular intervals. 
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The investigator must guarantee the integrity of the study data in the medical files by 
implementing security measures to prevent unauthorised access to the data and to the 
computer system. 
If the computerised medical files are considered as not validated by the sponsor, the 
investigator undertakes: 
­ at the start of the study, to print the medical files of all participants allowing a reliable 
verification of the study criteria (e.g. medical history/previous treatments/ characteristics of 
the studied disease documented within the period of time defined by the study protocol), 
­ during the study, to print in real time each data entry and each data change. 
The investigator will personally sign, date and give the number of pages on the first or last 
page of each print-out. At each visit by the monitor, the investigator will provide all the print-
outs of the medical files of the participants. The monitor will personally sign and date the first 
(or last) page then initial all pages in each paper print-out. 
If the computer system allows the tracking of the changes made to the medical files, the 
investigator will supply the monitor, at each visit, with a print-out of the medical files of the 
participants and the records of the changes made. Each print-out will be personally dated and 
signed, by the investigator and the monitor on the first page. The number of pages will also be 
indicated by the investigator and the monitor on the first page. 
If the computerised medical files are considered as validated by the sponsor, the investigator 
undertakes to give access to the monitor to the computerised medical files of all participants. 
If the monitor cannot access to the tracking of the changes made to the medical files, the 
investigator will supply the monitor, at each visit, with a print-out of the records of the 
changes made to the medical files of the participants. Each print-out will be personally dated 
and signed, by the investigator and the monitor on the first page. The number of pages will 
also be indicated by the investigator and the monitor on the first page. 
The investigator undertakes to keep: 
­ all medical file print-outs signed and dated by him/her and by the monitor when the 
computer system is considered as not validated by the sponsor,  
­ if the computer system used allows changes to be made, the print-outs of the audit trail 
when the computer system is considered as not validated by the sponsor or when the 
monitor cannot access to the audit trail in the computer system, 
­ all original source-documents (originals of specific examinations, informed consent forms, 
therapeutic unit tracking form, etc.). 
12.3. Audit - Inspection 
The investigator should be informed that an audit may be carried out during or after the end of 
the study. 
The investigator should be informed that the Competent Authorities may also carry out an 
inspection in the facilities of the sponsor and/or the study centre(s). The sponsor will inform 
the investigators concerned immediately upon notification of a pending study centres 
inspection. Likewise, the investigator will inform the sponsor of any pending inspection. 
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The investigator must allow the representatives of the Competent Authorities and persons 
responsible for the audit:  
­ to inspect the site, facilities and material used for the study, 
­ to meet all members of his/her team involved in the study, 
­ to have direct access to study data and source documents, 
­ to consult all of the documents relevant to the study. 
If the computerised medical file is considered as not validated, the investigator undertakes to 
provide all the source-documents and the print-outs of the medical files of the participants 
and, if the computer system used allows, the record of the changes made during the study. 
If the computerised medical file is considered as validated, the investigator undertakes to: 
­ give access to the representatives of the Competent Authorities and persons responsible for 
the audit to the computerised medical files of all participants, 
­ provide the print-outs of the changes made during the study, if the tracking of the changes 
made to the medical files cannot be accessed in the computer. 
13. ETHICS 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) 
The study protocol, the "Participant information and consent form" document, the list of 
investigators document, the insurance documents will be submitted to IRB(s)/IEC(s) by the 
investigator(s) or the national coordinator(s) or the sponsor in accordance with local 
regulations. 
The study will not start in a centre before written approval by corresponding IRB/IEC(s) has 
been obtained, the local regulatory requirements have been complied with, and the signature 
of the clinical study protocol of each contractual party involved has been obtained. 
13.2. Study conduct 
The study will be performed in accordance with the ethical principles stated in the Declaration 
of Helsinki 1964, as revised in Fortaleza, 2013 (see Appendix 1). 
13.3. Participant information and informed consent 
In any case, the participant (and/or his/her legal representative, when required) must be 
informed that he/she is entitled to be informed about the outcome of the study by the 
investigator. 
The investigator or a person designated by him/her is to collect written consent from each 
participant before his/her participation in the study. Prior to this, the investigator or his/her 
delegate must inform each participant of the objectives, benefits, risks and requirements 
imposed by the study, as well as the nature of the IMPs, underlying that the participation of 
the participant is entirely voluntary and he/she can withdraw from the study at any time 
without affecting standard of care he/she receives. 
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The participant will be provided with two information and consent forms in clear, simple 
language: one for the study including the optional PK analysis and one for the optional 
samples for pharmacogenomic and non genomic biomarkers analysis.  
For each information and consent form, two original information and consent forms must be 
completed, dated and signed personally by the participant and by the person responsible for 
collecting the informed consent. 
If the participant is unable to read, an impartial witness should be present during the entire 
informed consent discussion. The participant must give consent orally and, if capable of doing 
so, complete, sign and personally date the information and consent form. The witness must 
then complete, sign and date the form together with the person responsible for collecting the 
informed consent. 
The participant will be given one signed original information and consent form, the second 
original will be kept by the investigator. 
A copy of the information and consent form in the language(s) of the country is given in the 
“Participant information and consent form” document attached to the protocol. 
13.4. Modification of the information and consent form 
Any change to the information and consent form constitutes an amendment to this document 
and must be submitted for approval to the IRB/IEC(s), and if applicable to the Competent 
Authorities. 
A copy of the new version of the information and consent form in the language(s) of the 
country will be given in the amendment to the “Participant Information and consent form”. 
Such amendments may only be implemented after written approval of the IRB/IEC has been 
obtained and compliance with the local regulatory requirements, with the exception of an 
amendment required to eliminate an immediate risk to study participants. 
Each participant affected by the amendment or an independent witness must complete, date 
and sign two originals of the new version of the information and consent form together with 
the person who conducted the informed consent discussion. He/she will receive one signed 
original amendment to the information and consent form. 
14. DATA HANDLING AND RECORD KEEPING 
14.1. Study data 
An electronic data capture system is going to be used for this study. An electronic case report 
form (e-CRF) is designed to record the data required by the protocol and collected by the 
investigator. 
The e-CRF will be produced by I.R.I.S. in compliance with its specifications. The investigator 
or a designated person from his/her team will be trained for the use of the e-CRF by the 
sponsor. 
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Data entry at the investigator’s site will be performed by the investigator or by the designated 
person from his/her team after completion of the participant’s Medical File. 
Upon entry, data will be transmitted via the Internet from the study centre to the study 
database. 
The investigator or the designated person from his/her team agrees to complete the e-CRF, at 
each participant visit, and all other documents provided by the sponsor (e.g. documents 
relating to the IMP management…). 
Data recorded directly in the e-CRF and considered as source data (see section 4.6) must be 
collected immediately in the e-CRF. The other e-CRF forms must be completed within 5 days 
after patient’s visits. 
All corrections of data in the e-CRF must be made by the investigator or by the designated 
person from his/her team using electronic data clarifications according to the provided 
instructions. All data modification will be recorded using the audit trail feature of Inform 
software, including date, reason for modification and identification of the person who has 
made the change. 
In order to ensure confidentiality and security of the data, usernames and passwords will be 
used to restrict system access to authorised personnel only, whether resident within the 
investigator’s sites, the sponsor or third parties. 
Data will be verified in accordance with the monitoring strategy defined for the study. After 
comparing these data to the source documents, the monitor will request correction / 
clarification from the investigator using electronic data clarifications that should be answered 
and closed within 5 days after query issue. 
Data can be frozen during the study after their validation. However the investigator has the 
possibility to modify data if deemed necessary via a request to the sponsor. 
After the last visit of the participant, the investigator or co-investigator must attest the 
authenticity of the data collected in the e-CRF by entering his/her user name and password. 
After the data base lock, the investigator will receive a CD-ROM containing participant data 
of his/her centre for the study file. 
14.2. Data management 
Data are collected via an e-CRF and stored in a secured database. 
For data collected on the e-CRF, the Data & Clinical Logistics of I.R.I.S. is responsible for 
data processing including data validation performed according to a specification manual 
describing the checks to be carried out. As a result of data validation, data may require some 
changes. An electronic data clarification form is sent to the investigator who is required to 
respond to the query and make any necessary changes to the data. 
For data transferred from the logistical platform, central reading centre of the RU 
measurements, the Data & Clinical Logistics of I.R.I.S. is responsible for data transfer: 
centralised laboratory, central reading centre of RU measurements provide electronic transfer 
of computerised data to the Clinical Data Division of I.R.I.S. Data are transferred according to 
a transfer protocol issued by the I.R.I.S. data manager. 
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The Medical Data Department of I.R.I.S. is responsible for data coding including: 
­ medical / surgical history, adverse events and procedures using MedDRA  
­ medications using WHO-DD. 
The coding process is described in a specification manual. 
When data validation is achieved, a blind review of the data is performed according to the 
sponsor standard operating procedure. When the database has been declared to be complete 
and accurate, it will be locked and the IMP codes will be unblinded and made available for 
data analysis. 
14.3. Archiving 
The investigator will keep all information relevant to the study for at least 15 years after the 
end of the study, or more if specified by local regulations. 
At the end of the study, the investigator will be provided with a copy of each participant’s 
data on a CD-ROM support. These data include all data and comments reported in the e-CRF, 
the history of all queries and signatures and the full audit trail reports. 
15. INSURANCE 
I.R.I.S., or any parent company of SERVIER GROUP in charge of the management of 
clinical trials, is insured under the liability insurance program subscribed by ILKOS 
THERAPEUTIC INC to cover its liability as sponsor of clinical trials on a worldwide basis. 
Where an indemnification system and/or a mandatory policy are in place, I.R.I.S. or any 
parent company of SERVIER GROUP will be insured under a local and specific policy in 
strict accordance with any applicable law.  
All relevant insurance documentation is included in the file submitted to any authorities’ 
where approval is required. 
16. OWNERSHIP OF THE RESULTS - PUBLICATION POLICY 
ILKOS THERAPEUTIC INC, acting as the study sponsor, assumes full responsibility relating 
to this function and retains exclusive property rights over the results of the study, which it 
may use as it deems fit.  
As the study is a multicentre one, the first publication must be performed only with data 
collected from several centres and analysed under the responsibility of the Pole of Expertise 
Methodology and Data Valorisation of I.R.I.S. The investigator commits himself not to 
publishing or communicating data collected in only one centre or part of the centres before 
the publication of the complete results of the study, unless prior written agreement from the 
other investigators and ILKOS THERAPEUTIC INC has been provided. 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
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submission. This allows the sponsor to protect proprietary information and to provide 
comments.  
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
Any project of publication and/or communication relative to the study and/or relative to the 
obtained results during the study or after the study end, shall be submitted to the sponsor at 
least 30 days for a publication and 15 days for an abstract before the forecasted date of 
communication and/or submission for a publication. The sponsor shall make comments on the 
project within 15 days for a publication and 7 days for an abstract, of receipt of the project. 
The investigator, who submitted the project, shall take the sponsor's comments into due 
consideration. In any case, should the investigator who submitted the project decide not to 
modify the project according to the sponsor's comments, it shall provide the sponsor with the 
grounds of its decision in writing. 
However, in the case where the sponsor is in the process of filing a patent application on the 
results of the study, the sponsor will be able to delay its authorisation for publication or 
communication of the results of the study until the date of international registration of the 
patent. 
17. ADMINISTRATIVE CLAUSES 
17.1. Concerning the sponsor and the investigator  
17.1.1. Persons to inform 
In accordance with local regulations, the investigator and/or the sponsor will inform, the 
Director of the medical institution, the pharmacist involved in the study and the Director of 
the analysis laboratory. 
With the agreement of the participant, the investigator will inform the participant’s general 
practitioner about his/her patient’s participation in a clinical study. 
17.1.2. Substantial protocol amendment and amended protocol 
If the protocol must be altered after it has been signed, the modification or substantial 
amendment must be discussed and approved by the international study coordinator and the 
sponsor. 
The substantial protocol amendment must be drafted in accordance with the sponsor standard 
operating procedure and an amended protocol must be signed by both parties. Both 
documents must be kept with the initial protocol. 
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All substantial amendments and corresponding amended protocols must be sent by the 
investigator(s) or the coordinator(s) or the sponsor, in accordance with local regulations, to 
the IRB/IEC that examined the initial protocol. They can only be implemented after a 
favourable opinion of the IRB/IEC has been obtained, local regulatory requirements have 
been complied with, and the amended protocol has been signed, with the exception of a 
measure required to eliminate an immediate risk to the study participants. 
When the submission is performed by the investigator or the coordinator, the latter must 
transmit a copy of IRB/IEC’s new written opinion to the sponsor, immediately upon receipt. 
Furthermore, the substantial amendment and amended protocol are to be submitted to the 
Competent Authorities in accordance with local regulations. 
17.1.3. Final study report 
The study report will be drafted by the report writing department in compliance with I.R.I.S. 
standard operating procedure. 
The sponsor’s representative and the international study coordinator must mutually agree on 
the final version. One copy of the final report, must be dated and signed by the international 
study coordinator and the sponsor. 
17.2. Concerning the sponsor 
The sponsor undertakes to: 
­ supply the investigator with adequate and sufficient information concerning the IMP 
administered during the study to enable him/her to carry out the study, 
­ supply the investigator with the Investigator’s Brochure if the test drug is not marketed,  
­ obtain any authorisation to perform the study and/or import licence for the IMP 
administered that may be required by the local authorities before the beginning of the 
study, 
­ provide the international study coordinator annually, or at another frequency defined by the 
local regulations, with a document describing study progress which is to be sent to the 
IRB/IEC(s). 
17.3. Concerning the investigator 
17.3.1. Confidentiality - Use of information 
All documents and information given to the investigator by the sponsor with respect to 
S42909 and study CL2-42909-016  are strictly confidential. 
The investigator expressly agrees that data on his/her professional and clinical experience is 
collected by the sponsor on paper and computer, and stored for its sole use relating to its 
activities as the sponsor of clinical trials, in accordance with GCP.  
He/she has a right to access, modify, and delete his/her own personal data by applying to the 
sponsor. 
The investigator agrees that he/she and the members of his/her team will use the information 
only in the framework of this study, for carrying out the protocol. This agreement is binding 
as long as the confidential information has not been disclosed to the public by the sponsor. 
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The clinical study protocol given to the investigator may be used by him/her or his/her 
colleagues to obtain the informed consent of study participants. The clinical study protocol as 
well as any information extracted from it must not be disclosed to other parties without the 
written authorisation of the sponsor. 
The investigator must not disclose any information without the prior written consent from the 
sponsor, except to the representatives of the Competent Authorities, and only at their request. 
In the latter case, the investigator commits himself to informing the sponsor prior to 
disclosure of information to these authorities. 
A participant screening log and a full identification and enrolment list of each participant will 
be completed and kept by the investigator who should agree to provide access on site to the 
auditor and/or the representatives of the Competent Authorities. The information will be 
treated in compliance with professional secrecy. 
The participant screening log must be completed from the moment the investigator checks 
that a participant could potentially take part in the study (by assessment of participant medical 
history during a visit or by examination of the medical file). 
17.3.2. Organisation of the centre 
Every person to whom the investigator delegates under his/her responsibility a part of the 
follow-up of the study (co-investigator, nurse, etc.) and any other person involved in the study 
for this centre (cardiologist, pharmacist, etc.) must figure be listed in the "Organisation of 
centre" document. 
This document should be filled in at the beginning of the study and updated at any change of a 
person involved in the study in the centre. 
17.3.3. Documentation supplied to the sponsor 
The investigator undertakes before the study begins: 
­ to provide his/her dated and signed English Curriculum Vitae (CV) (maximum 2 pages) or 
to complete in English the CV form provided by the sponsor and to send it to the sponsor, 
together with that of his/her co-investigator(s), 
­ to provide a detailed description of the methods, techniques, and investigational 
equipment, and the reference values for the parameters measured, 
­ to provide any other document required by local regulation (e.g. Food & Drug 
Administration 1572 form), 
­ to send a copy of the IRB/IEC’s opinion with details of its composition and the 
qualifications of its constituent members. 
The CVs of other members of the team involved in the study (if possible in English) will be 
collected during the course of the study (at least members involved in the participant’ medical 
follow-up/study related process decision and persons involved in the measurement of main 
assessment criteria). 
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Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schttenfeld D. The epidemiology of chronic venous insufficiency 
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Bergan JJ. Molecular mechanism in chronic venous insufficiency. Ann Vasc Surg 2007;21:260-266. 
[PE0059054]. 
Bergan JJ. Chronic Venous Disease. New England Journal of Medicine 2006; 355:488-98[ PE0051483] 
Brem H, Tomic-Canic M, Tarnovskaya A, Ehrlich HP, Baskin-Bey E, Gill K, Carasa M, Weinberger S, 
Entero H, Vladeck B. Healing of elderly patients with diabetic foot ulcers, venous stasis ulcers, and pressure 
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Brem H, Kirsner R, Falanga V. Protocol for the successful treatment of venous ulcers. Am J Surg 2004;188:1-
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Bretz F., Pinheiro J., Branson M. Combining Multiple Comparisons and Modelling Techniques in Dose-
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Carpentier PH, Hildegard RM, Biro C, Ponçot-Makinen CO. Prevalence, risk factors, and clinical patterns of 
chronic venous disorders of lower limbs: A population-based study in France. J Vasc Surg 2004;40:650-659. 
[PE0066022]. 
Chiesa R, Marone EM, Limoni C, Volonte M, Schaefer E, Petrini O, et al. Demographic factors and their 
relationship with the presence of CVI signs in Italy: the 24-cities cohort study. Eur J Vasc Endo Vasc 
Surg 2005;30(6):674-680. [PE0066021] 
Clane, S. EWMA Position Document. Understanding Compression Therapy. Medical Education Partnership 
Ltd. 2003.[PE0093898] 
Coleridge-Smith PD. Duplex Ultrasound Investigation of the Veins in Chronic Venous Disease of the Lower 
Limbs – UIP Consensus Document. Part I. Basic Principles. Eur. J. Vasc. Endovas. Surg. 2006;31(1):83-
92.[PE0054807] 
Criqui MH, Denenberg JO, Bergan J, Langer RD and Fronek. A. Chronic venous disease in an ethnically 
diverse population, the San Diego population study. Am. J. Epidemiol 2003;158:448-456. [PE0066122] 
EWMA. Position Document. Understanding Compression Therapy. Medical Education Partnership Ltd. 
2003.[PE0093898] 
Fowkes FGR, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous insufficiency. Angiology 
2001;52:S5-S6. [PE0066124]. 
Gelfand JM, Hoffstad O, Margolis DJ. Surrogate Endpoints for the treatment of Venous Leg Ulcers. The 
Journal of Investigate Dermatology 2002;119(6): 1420-25. [PE0092092] 
Gilman Th. Parameter for Measurement of Wound Closure. Wounds 1990;2(3):95-101. [PE0092263] 
Guidance FDA. Guidance for Industry FDA- Chronic Cutaneous Ulcer and Burn Wounds – Developing 
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Howlader MH, Coleridge-Smith PD. Symptoms of chronic venous disease and association with systemic 
inflammatory markers. J Vasc Surg 2003;38:950-954. [PE0066023]. 
Jacob MP, Cazaubon M, Scemama A, Prie D, Blanchet F, Guillin MC, et al. Plasma matrix metalloproteinase-
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Jawien A, Grzela T, Ochwat A. Prevalence of chronic venous insufficiency in men and women in Poland: 
multicentre cross-sectional study in 40095 patients. Phlebology 2003;18(3):110-121. [PE0066401]. 
Kantor J, Margolis DJ. A multicentre study of percentage change in venous leg ulcer area as a prognostic 
index of healing at 24 weeks. British Journal of Dermatology. 2000;142:960-4. [PE0092093] 
Kappelmayer J, Nagy JrB, Miszti-Blasius K, Hevessy Z, Setiadi H. The emerging value of P-Selectin as 
disease marker. Clin Chem Lab med 2004;42(5):475-486. [PE0066063]. 
Kim I., Moon SO, Kim SH, Kim HJ, Koh Y and Gou, Koh Y. Mechanisms of Signal Transduction: Vascular 
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Korthuis R, Unthank J. Experimental models to investigate inflammatory processes in chronic venous 
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Margolis DJ., Bilker W, Santanna J, Baumgarten M. Venous leg ulcer: Incidence and prevalence in the 
elderly.J AmAcad. Dermatol. 2002;46:381-6[PE0093569] 
Mosti G, Mattaliano V, Polignano R, Masina M. Compression therapy in the treatment of leg ulcers.Acta 
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Valencia 2001 IC., Falabella A, Kirsner RS., and. Eaglstein WH, Miami, Florida. Chronic venous 
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Regulatory references: 
ICH Topic E6 (R2) – Integrated Addendum to Good Clinical Practice (GCP), Step 5, Adopted by CPMP, 15 
December 2016, issued as EMA/CPMP/ICH/135/1995. 
ICH Topic E9 – Statistical Principles for Clinical Trials: Adopted by CPMP, March 1998, issued as 
CPMP/ICH/363/96/step 5. 
ICH Topic E2A – Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, issued 
as CPMP/ICH/377/95. 
Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from 
clinical trials on medicinal products for human use (‘CT-3’), (2011/C 172/01) 
DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 on 
the approximation of the laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). 
Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from 
clinical trials on medicinal products for human use (‘CT-3’) (2011/C 172/01). 
Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance. U.S. Department of Health and 
Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for 
Biologics Evaluation and Research (CBER). April 1996. ICH 
Guidance for Industry E9 Statistical Principles for Clinical Trials. U.S. Department of Health and Human 
Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for 
Biologics Evaluation and Research (CBER). September 1998; ICH 
Guidance for Industry and Investigators Safety Reporting Requirements for INDs and BA/BE Studies. U.S. 
Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and 
Research (CDER). Center for Biologics Evaluation and Research (CBER). December 2012. Drug Safety 
Guidance for Industry. In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies.  FDA 
Draft Guidance October 2017 [PE76967]. 
Guideline on the Investigation of Drug Interactions. European Medicines Agency. 21 June 2012 [PE78267]. 
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19. APPENDICES 
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Appendix 1: Word Medical Association Declaration of Helsinki 
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Appendix 1: World Medical Association Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington DC, USA, 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1.
The World Medical Association (WMA) has developed the Declaration of Helsinki as a
statement of ethical principles for medical research involving human subjects, including
research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs
should be applied with consideration of all other relevant paragraphs.
2.
Consistent with the mandate of the WMA, the Declaration is addressed primarily to
physicians. The WMA encourages others who are involved in medical research
involving human subjects to adopt these principles
General Principles 
3.
The Declaration of Geneva of the WMA binds the physician with the words, “The
health of my patient will be my first consideration,” and the International Code of
Medical Ethics declares that, “A physician shall act in the patient's best interest when
providing medical care.”
4.
It is the duty of the physician to promote and safeguard the health, well-being and rights
of patients, including those who are involved in medical research. The physician's
knowledge and conscience are dedicated to the fulfilment of this duty.
5.
Medical progress is based on research that ultimately must include studies involving
human subjects.
6.
The primary purpose of medical research involving human subjects is to understand the
causes, development and effects of diseases and improve preventive, diagnostic and
therapeutic interventions (methods, procedures and treatments). Even the best proven
interventions must be evaluated continually through research for their safety,
effectiveness, efficiency, accessibility and quality.
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7.
Medical research is subject to ethical standards that promote and ensure respect for all
human subjects and protect their health and rights.
8.
While the primary purpose of medical research is to generate new knowledge, this goal
can never take precedence over the rights and interests of individual research subjects.
9.
It is the duty of physicians who are involved in medical research to protect the life,
health, dignity, integrity, right to self-determination, privacy, and confidentiality of
personal information of research subjects. The responsibility for the protection of
research subjects must always rest with the physician or other health care professionals
and never with the research subjects, even though they have given consent.
10.
Physicians must consider the ethical, legal and regulatory norms and standards for
research involving human subjects in their own countries as well as applicable
international norms and standards. No national or international ethical, legal or
regulatory requirement should reduce or eliminate any of the protections for research
subjects set forth in this Declaration.
11.
Medical research should be conducted in a manner that minimises possible harm to the
environment.
12.
Medical research involving human subjects must be conducted only by individuals with
the appropriate ethics and scientific education, training and qualifications. Research on
patients or healthy volunteers requires the supervision of a competent and appropriately
qualified physician or other health care professional.
13.
Groups that are underrepresented in medical research should be provided appropriate
access to participation in research.
14.
Physicians who combine medical research with medical care should involve their
patients in research only to the extent that this is justified by its potential preventive,
diagnostic or therapeutic value and if the physician has good reason to believe that
participation in the research study will not adversely affect the health of the patients
who serve as research subjects.
15.
Appropriate compensation and treatment for subjects who are harmed as a result of
participating in research must be ensured.
Risk, Burdens and Benefits 
16.
In medical practice and in medical research, most interventions involve risks and
burdens.
Medical research involving human subjects may only be conducted if the importance of
the objective outweighs the risks and burdens to the research subjects.
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17.
All medical research involving human subjects must be preceded by careful assessment
of predictable risks and burdens to the individuals and groups involved in the research
in comparison with foreseeable benefits to them and to other individuals or groups
affected by the condition under investigation.
Measures to minimise the risks must be implemented. The risks must be continuously
monitored, assessed and documented by the researcher.
18.
Physicians may not be involved in a research study involving human subjects unless
they are confident that the risks have been adequately assessed and can be satisfactorily
managed.
When the risks are found to outweigh the potential benefits or when there is conclusive
proof of definitive outcomes, physicians must assess whether to continue, modify or
immediately stop the study.
Vulnerable Groups and Individuals 
19.
Some groups and individuals are particularly vulnerable and may have an increased
likelihood of being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered protection.
20.
Medical research with a vulnerable group is only justified if the research is responsive
to the health needs or priorities of this group and the research cannot be carried out in a
non-vulnerable group. In addition, this group should stand to benefit from the
knowledge, practices or interventions that result from the research.
Scientific Requirements and Research Protocols 
21.
Medical research involving human subjects must conform to generally accepted
scientific principles, be based on a thorough knowledge of the scientific literature, other
relevant sources of information, and adequate laboratory and, as appropriate, animal
experimentation. The welfare of animals used for research must be respected.
22.
The design and performance of each research study involving human subjects must be
clearly described and justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved and
should indicate how the principles in this Declaration have been addressed. The
protocol should include information regarding funding, sponsors, institutional
affiliations, potential conflicts of interest, incentives for subjects and information
regarding provisions for treating and/or compensating subjects who are harmed as a
consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for post-trial
provisions.
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Research Ethics Committees 
23.
The research protocol must be submitted for consideration, comment, guidance and
approval to the concerned research ethics committee before the study begins. This
committee must be transparent in its functioning, must be independent of the researcher,
the sponsor and any other undue influence and must be duly qualified. It must take into
consideration the laws and regulations of the country or countries in which the research
is to be performed as well as applicable international norms and standards but these
must not be allowed to reduce or eliminate any of the protections for research subjects
set forth in this Declaration.
The committee must have the right to monitor on-going studies. The researcher must
provide monitoring information to the committee, especially information about any
serious adverse events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of the study, the researchers
must submit a final report to the committee containing a summary of the study’s
findings and conclusions.
Privacy and Confidentiality 
24.
Every precaution must be taken to protect the privacy of research subjects and the
confidentiality of their personal information.
Informed Consent 
25.
Participation by individuals capable of giving informed consent as subjects in medical
research must be voluntary. Although it may be appropriate to consult family members
or community leaders, no individual capable of giving informed consent may be
enrolled in a research study unless he or she freely agrees.
26.
In medical research involving human subjects capable of giving informed consent, each
potential subject must be adequately informed of the aims, methods, sources of funding,
any possible conflicts of interest, institutional affiliations of the researcher, the
anticipated benefits and potential risks of the study and the discomfort it may entail,
post-study provisions and any other relevant aspects of the study. The potential subject
must be informed of the right to refuse to participate in the study or to withdraw consent
to participate at any time without reprisal. Special attention should be given to the
specific information needs of individual potential subjects as well as to the methods
used to deliver the information.
After ensuring that the potential subject has understood the information, the physician
or another appropriately qualified individual must then seek the potential subject’s
freely-given informed consent, preferably in writing. If the consent cannot be expressed
in writing, the non-written consent must be formally documented and witnessed.
All medical research subjects should be given the option of being informed about the
general outcome and results of the study.
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27.
When seeking informed consent for participation in a research study the physician must
be particularly cautious if the potential subject is in a dependent relationship with the
physician or may consent under duress. In such situations the informed consent must be
sought by an appropriately qualified individual who is completely independent of this
relationship.
28.
For a potential research subject who is incapable of giving informed consent, the
physician must seek informed consent from the legally authorised representative. These
individuals must not be included in a research study that has no likelihood of benefit for
them unless it is intended to promote the health of the group represented by the potential
subject, the research cannot instead be performed with persons capable of providing
informed consent, and the research entails only minimal risk and minimal burden.
29.
When a potential research subject who is deemed incapable of giving informed consent
is able to give assent to decisions about participation in research, the physician must
seek that assent in addition to the consent of the legally authorised representative. The
potential subject’s dissent should be respected.
30.
Research involving subjects who are physically or mentally incapable of giving consent,
for example, unconscious patients, may be done only if the physical or mental condition
that prevents giving informed consent is a necessary characteristic of the research
group. In such circumstances the physician must seek informed consent from the legally
authorised representative. If no such representative is available and if the research
cannot be delayed, the study may proceed without informed consent provided that the
specific reasons for involving subjects with a condition that renders them unable to give
informed consent have been stated in the research protocol and the study has been
approved by a research ethics committee. Consent to remain in the research must be
obtained as soon as possible from the subject or a legally authorised representative.
31.
The physician must fully inform the patient which aspects of their care are related to the
research. The refusal of a patient to participate in a study or the patient’s decision to
withdraw from the study must never adversely affect the patient-physician relationship.
32.
For medical research using identifiable human material or data, such as research on
material or data contained in biobanks or similar repositories, physicians must seek
informed consent for its collection, storage and/or reuse. There may be exceptional
situations where consent would be impossible or impracticable to obtain for such
research. In such situations the research may be done only after consideration and
approval of a research ethics committee.
Use of Placebo 
33.
The benefits, risks, burdens and effectiveness of a new intervention must be tested
against those of the best proven intervention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is
acceptable; or
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Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention 
and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.
In advance of a clinical trial, sponsors, researchers and host country governments should
make provisions for post-trial access for all participants who still need an intervention
identified as beneficial in the trial. This information must also be disclosed to
participants during the informed consent process.
Research Registration and Publication and Dissemination of Results 
35.
Every research study involving human subjects must be registered in a publicly
accessible database before recruitment of the first subject.
36.
Researchers, authors, sponsors, editors and publishers all have ethical obligations with
regard to the publication and dissemination of the results of research. Researchers have
a duty to make publicly available the results of their research on human subjects and are
accountable for the completeness and accuracy of their reports. All parties should
adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as
positive results must be published or otherwise made publicly available. Sources of
funding, institutional affiliations and conflicts of interest must be declared in the
publication. Reports of research not in accordance with the principles of this
Declaration should not be accepted for publication.
Unproven Intervention in Clinical Practice 
In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorised representative, may use an unproven 
intervention if in the physician's judgment it offers hope of saving life, re-establishing health 
or alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded 
and, where appropriate, made publicly available. 
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Appendix 2: Duplex ultrasonography 
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Both legs will be fully investigated (Coleridge Smith, 2006). 
Venous Duplex ultrasonography 
Venous obstruction will be assessed using the duplex ultrasonography performed with a 
superficial probe (7 to 13 Megahertz or MHz), on a participant in supine position, to explore 
the veins listed below (obstruction list). Vein compression, retrograde flow in deep and 
superficial veins using compression of the calf muscles, echography B mode, pulsed wave 
and colour Doppler will be used.  
For venous valve incompetence, the participant will be examined in standing position. Reflux 
will be search on the veins listed below with compression of the calf or valsalva manoeuvre 
for veins above knee, and with compression on the foot for veins below knee. Reflux will be 
considered if retrograde flow lasted > 0.5 second for superficial veins, anterior and posterior 
tibial veins, peroneal veins, perforator veins, and if retrograde flow lasted > 1 second for 
common femoral vein, femoral vein, and popliteal vein. 
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Please, tick the appropriate boxes: 
Right/Left leg 
Not present 
Present 
Reflux 
Great Saphenous Vein above knee 
(0)  
(1)  
Great Saphenous Vein below knee 
(0)  
(1)  
Small Saphenous Vein 
(0)  
(1)  
Non saphenous superficial veins 
(0)  
(1)  
Gastrocnenial, soleal veins 
(0)  
(1)  
Tibial anterior vein 
(0)  
(1)  
Tibial posterior vein 
(0)  
(1)  
Peroneal vein 
(0)  
(1)  
Popliteal vein 
(0)  
(1)  
Femoral vein 
(0)  
(1)  
Common femoral vein 
(0)  
(1)  
Please, tick the appropriate boxes: 
Right/Left leg 
Not present 
Present 
Obstruction 
Great Saphenous Vein above knee 
(0)  
(1)  
Great Saphenous Vein below knee 
(0)  
(1)  
Small saphenous vein 
(0)  
(1)  
Non saphenous superficial veins 
(0)  
(1)  
Gastrocnenial, soleal veins 
(0)  
(1)  
Tibial anterior vein 
(0)  
(1)  
Tibial posterior vein 
(0)  
(1)  
Peroneal vein 
(0)  
(1)  
Popliteal vein 
(0)  
(1)  
Femoral vein 
(0)  
(1)  
Deep femoral vein 
(0)  
(1)  
Common femoral vein 
(0)  
(1)  
Pelvic veins* 
(0)  
(1)  
Internal iliac vein* 
(0)  
(1)  
External iliac vein* 
(0)  
(1)  
Common iliac vein* 
(0)  
(1)  
Inferior vena cava* 
(0)  
(1)  
*If probe for this assessment is available (e.g. convex probe from 3.5 to 5MHz) 
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Arterial Duplex ultrasonography 
Duplex ultrasonography of the artery system will also be performed in the leg affected by the 
reference ulcer in order to check for arteriopathy from iliac to tibial arteries.  
*If probe for this assessment is available (e.g. convex probe from 3.5 to 5MHz) 
** For either Method 1 (planimetry) or Method 2 (velocity measurement) or Method 3 (flow type), please fill in all boxes under the 
heading of that method for which results are available. If results by Methods 2 and 3 are available, please fill them both. 
For information: flow type (waveform) of the arterial curve 
0 = no flow;  1 = trickle flow;  2 = dampened monophasic;  3 = monophasic;  4 = biphasic;  5 = triphasic 
Please, tick the appropriate boxes: 
     Leg affected by the reference ulcer 
          Methods** 
  Method 1       or       Method 2    and/or       Method 3 
     (Planimetry)               (Velocity)   
 (Flow type / Waveform) 
Arteriopathy 
Common iliac artery* 
% stenosis 
   cm/s 
Flow type (0-5) 
Internal iliac artery* 
% stenosis 
   cm/s 
Flow type (0-5) 
External iliac artery* 
% stenosis 
   cm/s 
Flow type (0-5) 
Common femoral artery 
% stenosis             
   cm/s 
Flow type (0-5) 
Internal femoral artery 
% stenosis 
   cm/s 
Flow type (0-5) 
External femoral artery 
% stenosis 
   cm/s 
Flow type (0-5) 
Popliteal artery 
% stenosis 
   cm/s 
Flow type (0-5) 
Tibial anterior artery 
% stenosis 
   cm/s 
Flow type (0-5) 
Tibial posterior artery 
% stenosis 
   cm/s 
Flow type (0-5) 
Peroneal artery 
% stenosis 
   cm/s 
Flow type (0-5) 
Dorsal pedal artery 
% stenosis 
   cm/s 
Flow type (0-5) 
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Appendix 3: Venous Leg Ulcer 
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A leg ulcer is defined as a non-healing ulcer that fails to heal after a period of 6 weeks. 
A venous leg ulcer will be defined as full-thickness defect of skin, most frequently in ankle 
region, that fails to heal spontaneously and is sustained by documented CVD. Typical 
localization for venous ulcers: the gaiter area – from just below the ankle or malleolus up to, 
but not including the knee flexural crease. 
For the study purposes the largest existing venous leg ulcer fitting the selection criteria in a 
participant becomes the Reference Ulcer (RU). All selection/inclusion criteria referring to 
ulcer characteristics take into account RU. 
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Appendix 4: Revised CEAP Classification 
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The CEAP classification (Clinical-Etiology-Anatomy-Pathophysiology) was adopted 
Worldwide to facilitate meaningful communication about CVD and serve as a basis for more 
scientific analysis of management alternatives. 
Clinical classification 
C0: no visible or palpable signs of venous disease 
C1: telangiectasies or reticular veins 
C2: varicose veins 
C3: edema 
C4a: pigmentation or eczema 
C4b: lipodermatosclerosis or atrophie blanche 
C5: healed venous ulcer 
C6: active venous ulcer 
Even if the patient will be C6, other classification from C1 to C5 will have to be defined (e.g. 
a patient could be C1, C3 and C6). 
Each clinical class is further characterized by a subscript for the presence of symptoms (s, 
symptomatic) or absence of symptoms (a, asymptomatic), for example, C2a or C5s. 
Symptoms include heaviness, pain, aching, tightness, skin irritation, muscle cramps, and other 
complaints attributable to venous dysfunction. 
Etiologic classification 
Ec: congenital 
Ep: primary 
Es: secondary (postthrombotic) 
En: no venous cause identified 
(Only Ep, Es and En will have to be defined) 
Anatomic classification 
As: superficial veins 
Ap: perforator veins 
Ad: deep veins 
An: no venous location identified 
(Only As, Ad and An will have to be defined) 
Pathophysiologic classification (basic) 
Pr: reflux 
Po: obstruction 
Pr,o: reflux and obstruction 
Pn: no venous pathophysiology identifiable 
Advanced CEAP: Same as basic CEAP, with addition that any of 18 named venous segments 
can be used as locators for venous pathology 
Superficial veins (will have to be defined) 
Telangiectasies or reticular veins 
Great saphenous vein above knee 
Great saphenous vein below knee 
Small saphenous vein 
Nonsaphenous veins 
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Deep veins (will have to be defined) 
Inferior vena cava 
Common iliac vein 
Internal iliac vein 
External iliac vein 
Pelvic: gonadal, broad ligament veins, other 
Common femoral vein 
Deep femoral vein 
Femoral vein 
Popliteal vein 
Crural: anterior tibial, posterior tibial, peroneal veins 
(all paired) 
Muscular: gastrocnemial, soleal veins, other 
Perforating veins: (will not have to be defined) 
Thigh 
Calf 
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Appendix 5: Ankle Brachial Pressure Index 
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Continuous wave Doppler (CWD) is used to perform the assessment of the Ankle Brachial 
Pressure Index (ABPI) with a probe of 8 MHz (5 MHz for obese patient). The main objective 
is to determine resting ankle systolic pressure and resting brachial systolic pressure (as an 
approximation of central pressure). 
Systolic blood pressure will be measured after 10 minutes of rest on both arms in sitting or 
supine position and on each foot on the following 2 locations: posterior tibial, and anterior 
tibial. Each measurement will be performed twice and tables will have to be completed in a 
specific form (see Appendix 12). 
If CWD is not available, the following procedure will be performed with the Duplex Ultra 
Sonography with a superficial probe (7 to 13 MHz). 
Explain the procedure and reassure the patient and ensure that he/she is lying flat and is 
comfortable, relaxed and rested with no pressure on the proximal vessels.  
1. Measure the brachial systolic blood pressure:  
o Place an appropriately sized cuff around the upper arm  
o Locate the brachial pulse (humeral artery) and apply ultrasound contact gel  
o Angle the Doppler probe and move the probe to obtain the best signal  
o Inflate the cuff until the signal is abolished then deflate the cuff slowly and 
record the pressure at which the signal returns being careful not to move the 
probe from the line of the artery (in case of duplex ultrasonography: signal 
returns must be associated to the systolic curve on the screen) 
o Repeat the procedure for the other arm  
o Use the highest of the two values to calculate the ABPI  
2. Measure the ankle systolic pressure:  
o Place an appropriately sized cuff around the ankle immediately above the 
malleoli having first protected any ulcer that may be present by dressing and 
cling film 
o Examine the foot, locating the anterior tibial pulse and apply contact gel 
(Figure 3) 
 
Figure 3 -  
 
o Continue as for the brachial pressure, recording this pressure in the same way  
Repeat this for the posterior tibial (Figure 4)  
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Figure 4 - The posterior tibial artery lies just behind the medial malleolus. 
Reflux can frequently be heard in the adjacent veins and this can help to locate 
the artery  
 
3. ABPI calculation 
o Use the highest reading obtained to calculate the ABPI for that leg (each 
arterial signal must be present: posterior tibial, anterior tibial, if not, occlusion 
must be excluded by duplex scan) 
o Repeat for the other leg  
o Calculate the ABPI for each leg using the formula below:  
 
Causes of error in ABPI calculations 
Too small cuff size at the ankle: overestimate of the ABPI. 
Repeatedly inflating and deflating: inaccurate pressure reading. 
Inappropriate cuff position, as the pressure recorded is the pressure at the level of the cuff and 
not the pressure at the site of the Doppler probe. 
Bad probe: normally 8MHz when assessing superficial blood vessels (best combination of 
depth of tissue penetration and focus). Obese patient or oedematous legs: 5MHz probe.  
Bad position of the probe: ideally 45 degrees to the skin surface with contact gel in case of 
CWD. 
Participants will be eligible for the study if ABPI measured as above is found to be above or 
equal to 0.8 and below or equal to 1.3 
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Appendix 6: Ulcer Infection 
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Chronic wounds are almost always contaminated with micro-organisms and in small numbers 
they do not necessarily delay healing. Where infection occurs it is most commonly caused by 
bacteria. The criteria used to describe bacterial loading have been loosely defined by EWMA 
as follows: 
- Contamination is the presence of bacteria with no multiplication 
- Colonisation describes multiplication of bacteria with no host response 
- Infection is said to be present when there is invasion of healthy tissue with a host 
response 
Assessment of ulcer infection will be made by clinical means taking into account traditional 
inflammatory signs: redness, swelling, hyperthermia, pain and limited function. Additionally 
the following parameters should be also considered: 
- Increased exudate: substantial increase in the amount of exudate, possibly with 
increased viscosity, change in colour, offensive odour. 
- Friable granulation tissue 
- Slough 
- Changed odour 
- Changed pain 
- Stagnation in the healing process 
- Serological markers of systemic infection, e.g. leucocytosis, increased CRP 
For the purpose of the study, ulcer infection will be graded in 4 different grades taking into 
account the extent of inflammatory signs: 
Grade 1: no signs or symptoms of infection 
Grade 2: in subcutaneous tissue only 
Grade 3: extensive erythema, infection of deeper tissue 
Grade 4: systemic inflammatory response indicating severe infection 
Participants with infection of Grades 2-3-4 will undergo medical management at the 
investigator’s discretion including antibiotherapy, except local antibiotherapy on the surface 
of RU. Should the antibiotics be required for more than 7 days during the same month to 
control the infection the participant will be withdraw from the study. 
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Appendix 7: Renal Failure Classification 
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The Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney 
Foundation (NKF) defines chronic kidney disease as either kidney damage or a decreased 
glomerular filtration rate (GFR) of less than 60 ml/min/1.73 m2 for 3 or more months. 
Whatever the underlying etiology, the destruction of renal mass with irreversible sclerosis and 
loss of nephrons leads to a progressive decline in GFR. The different stages of chronic kidney 
disease form a continuum in time.  
In 2002, K/DOQI published its classification of the stages of chronic kidney disease, as 
follows: 
- Stage 1: Kidney damage with normal or increased GFR (>90 ml/min/1.73 m2) 
- Stage 2: Mild reduction in GFR (60-89 ml/min/1.73 m2) 
- Stage 3: Moderate reduction in GFR (30-59 ml/min/1.73 m2) 
- Stage 4: Severe reduction in GFR (15-29 ml/min/1.73 m2) 
- Stage 5: Kidney failure (GFR < 15 ml/min/1.73 m2 or dialysis) 
Estimation of eGFR 
Estimation of eGFR will be done using the Modification of Diet in Renal Disease (MDRD) 
formula 
For creatinine in mg/dL: 
•
Female patients
eGFR= [186 x Serum creatinine -1.154 x (Age) -0.203] x 0.742 x 0.95
•
Male patients
eGFR= [186 x (Serum creatinine) -1.154 x (Age) -0.203] x 0.95
For creatinine in µmol/L: 
•
Female patients
eGFR= [186 x (Serum creatinine x 0.0113)-1.154 x (Age) -0.203] x 0.742 x 0.95
•
Male patients
eGFR= [186 x (Serum creatinine x 0.0113)-1.154 x (Age) -0.203] x 0.95
The laboratory will automatically calculate estimated eGFR according to the above formulas. 
Participants having eGFR < 30 ml/min/1.73 m2 or participants requiring dialysis are not 
eligible for participating in the study. 
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Appendix 8: Heart Failure Classification 
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Participant’s cardiac function should be assessed prior inclusion. In case of heart failure the 
New York Heart Association (NYHA) functional classification system will be used. This 
system relates symptoms to everyday activities and the participant's quality of life. 
Class 
Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of cardiac 
insufficiency at rest. If any physical activity is undertaken, discomfort is increased 
. 
Patients with heart failure class III and IV are not eligible to participate in the study. 
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Appendix 9: Questionnaire for Pain Assessment 
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Please ask the participant the following questions before cleansing and debridement and tick 
with an X () the response(s) that is/are  the most appropriate based on your impression 
One or several boxe(s) can be checked as appropriate, according to the participant’s 
response: 
1. Do you feel any pain or discomfort (aching, heaviness, fatigue, soreness, burning)
related to your leg ulcer?
 No 
 Yes 
If Yes, how would you characterize the intensity of pain or discomfort since 
your last visit on the following scale (from 0 being no pain to 10 being the worst 
possible pain)?  
Please ask the participant to draw a vertical line on the horizontal axis in accordance with 
the intensity of his pain since his/her last visit. 
No pain          
  Extreme pain 
*I__I__I. I__I cm
 (*Filled in by the 
investigator) 
*In case the VAS is not properly completed, please follow the rules defined on the ruler given
at the beginning of the study. 
0
10 
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2.
How would you characterize your pain or discomfort in relation with your daily
activities?
 None
 Occasional pain or discomfort that does not restrict regular daily
activities 
 Daily pain or discomfort that interferes with, but does not 
prevent, regular daily activities 
 Daily pain or discomfort that limits most regular daily activities 
(None = 0) 
(Mild = 1) 
(Moderate = 2) 
(Severe = 3) 
(*For the investigator 
use) 
3. Is the pain continuous/constant?
 No
 Yes
4. Is the pain mostly related with:
 Dressing change
 Debridement
 Other procedure,
Please specify which procedure(s) (for example, wearing compression stockings, etc…):
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
5. Is the pain or discomfort more predominant during specific periods of the day:
 Night
 Morning
 Afternoon
 Evening
 Same intensity along the whole day
6. Do you need to take medication for control of the pain associated to VLU ?
 No
 Yes
If yes, please specify (analgesic drug consumption):
- 
drug name: __________________________________________________ 
- 
daily dose and number of intakes : 
____________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
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Appendix 10: Clinical Assessment of Leg Ulcer 
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Chronic venous reference ulcer examination 
Localisation of the ulcer 
(At baseline only) 
Ulcer imaging 
Picture taken Y/N 
Observation of new ulceration  Y/N (Except at ASSE) 
Complete healing 
Y/N (Except at ASSE) 
Wound bed % cover 
Granulation tissue 
 Absent      Low (<10%)      Moderate (10 – 50%)      High (>50%) 
Fibrotic tissue 
 Absent      Low (<10%)      Moderate (10 – 50%)      High (>50%) 
Sclerotic tissue 
 Absent      Low (<10%)      Moderate (10 – 50%)      High (>50%) 
Exudate 
High, Moderate or Low 
Increasing of exudate level since last visit Y/N (Except at 
ASSE) 
Colour of the exudate  
(Serous, Haemoserous or Purulent) 
Odour Y/N 
Surrounding skin appearance 
Macerated 
Eczema 
Erythema 
Other (specify) 
Signs of infection 
Infection suspected (requiring systemic antibiotherapy): Y/N 
If Yes, Action taken 
Ulcer treatment 
Wound cleansing Y/N 
Debridement performed Y/N 
(Specify the method) 
Is the patient compliant to compression Y/N 
Local wound dressing: 
Hydrogel, Hydrocellular Foam, Alginate or Other (specify) 
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Appendix 11: Examples of Standard Meals 
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- Example of breakfast (around 600 Kcal): 
1 individual packet of cereal (28 grams or one ounce)
2 slices of wholemeal bread
2 slices of butter or low fat spread
28 g Jam (or one ounce)
250 ml semi skimmed milk
240 ml Orange juice
- Example of lunch/dinner (around 1000 Kcal, well balanced with no more than 25% fat): 
100 g (or 3.5 ounces) beef or lamb or 160 g (or 5.6 ounces) of chicken / 250 g (or 8.8
ounces) of hake filet/ cooked with a small piece of butter
100 g steamed potatoes / mashed potatoes / rice cooked
100 g carrots
100 g green beans
100 g white bread
1 nature yoghurt + 1 apple or 25 g (0.88 ounces) of gruyere
250 ml of orangina or coca-cola or orange juice
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Appendix 12: Ankle Brachial Pressure Index Form 
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Ankle Brachial Pressure Index (ABPI) 
Inclusion criteria: 0.8 ≤ ABPI ≤ 1.3 
Systolic blood pressure will be measured after 10 minutes of rest on both arms in sitting 
postion or supine position and on each foot on the following 2 locations: posterior tibial, and 
anterior tibial, following the procedure detailed in Appendix 5 ‘Ankle Brachial Pressure 
Index’ of the study protocol.  
Each measurement will be performed twice and completed in the following tables.  
Brachial systolic blood pressure  
 
Measure 1 (mmHg) Measure 2 (mmHg) 
Right arm 
Systolic blood pressure 
 
 
Left arm 
Systolic blood pressure 
 
 
 
Ankle systolic blood pressure 
 
Location  
Measure 1 (mmHg) 
Measure 2 (mmHg) 
Right ankle 
Systolic blood pressure 
Posterior Tibial 
 
 
Anterior Tibial 
 
 
Left ankle 
Systolic blood pressure 
Posterior Tibial 
 
 
Anterior Tibial 
 
 
 
Calculation of ABPI  ( Automatic calculation in eCRF) 
 
 
 
= 
ABPI 
Ankle systolic pressure 
(Highest pressure of the ankle vessels for a leg) 
Brachial systolic pressure 
(Highest brachial pressure of the two arms) 
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SAP_001.pdf: 
 
 
Document title 
STATISTICAL ANALYSIS PLAN (SAP) 
 
ATTACHED TO CL2-42909-016 STUDY  
 
 
 
Study title  
Dose-response relationship study of S42909 on leg ulcer 
healing after oral repeated administration in patients with 
active venous leg ulcer. A 10-week randomised, double-
blind, 
placebo-controlled, 
prospective, 
international, 
multicentre, phase IIa study. 
 
 
Test drug code 
S42909 
 
 
Indication 
Venous leg ulcer 
 
 
Development phase 
IIa 
 
 
Protocol code 
CL2-42909-016 
 
 
EudraCT Number 
2016-004143-36 
 
 
Universal Trial Number 
NA 
 
 
Sponsor 
ILKOS THERAPEUTIC INC. 
 
 
Date of the document 
02 March 2020 
 
 
Version of the document 
1.0 
 
 
 
CONFIDENTIAL 




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Follow up of versions 
Version Release date 
(dd/mm/yyyy) 
Key modifications (*) 
Impact  
1.0 
02/03/2020 
The linear advance of the wound 
margin towards the wound center 
will not be described as a relative 
change from baseline, as the value 
at baseline of the linear advance is 
equal to zero by definition. Only 
value at each visit will be 
provided. 
No impact 
Additional subgroup :  
Size of the ulcer at baseline 
(≤ 20 cm² / > 20 cm²) 
No impact 
Randomised set definition: 
Only patients included will be 
considered. 
2.1 Analysis sets  
MCPMod adjusted on diabetic 
factor and prognosis criteria on 
size and age of the ulcer at baseline 
will be provided as sensitivity 
analysis 
3.4.2.2 Sensitivity analyses 
The primary analysis will be 
repeated in the FAS with patients 
from centers where PK results 
confirm the treatment intake. 
3.4.2.2 Sensitivity analyses 
The number, dose and/or duration 
of analgesic drug for Venous Leg 
Ulcer (VLU) will not be described. 
The analgesic description will be 
done only through the question 
“Need to take medication for 
control of the pain associated with 
VLU?” from the pain questionnaire 
3.4.3 Secondary efficacy 
criteria 
Since ECG are not centralised and 
heart rate is also measured from 
the vital signs, heart rate from 
ECG will not be described  
3.6.3.2 Electrocardiogram 
(*) Main changes as compared to the statistical analyses planned in the protocol for the first 
SAP signed version (1.0). Main changes from the previous signed version for the other SAP 
signed version(s). 
 
 


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Table of contents 
Table of contents ........................................................................................................................ 4 
List of tables ............................................................................................................................... 6 
List of figures ............................................................................................................................. 7 
List of abbreviations ................................................................................................................... 8 
1. INTRODUCTION ............................................................................................................. 10 
1.1. Study objectives .............................................................................................................. 10 
1.2. Study design .................................................................................................................... 10 
1.2.1. Study plan ..................................................................................................................... 11 
1.2.2. Type of randomisation .................................................................................................. 12 
1.3. Determination of sample size ......................................................................................... 12 
2. ANALYSIS SETS / TREATMENT GROUPS ................................................................ 14 
2.1. Analysis sets ................................................................................................................... 14 
2.2. Treatment groups ............................................................................................................ 16 
3. STATISTICAL METHODS ............................................................................................. 17 
3.1. General considerations .................................................................................................... 17 
3.1.1. Descriptive statistics ..................................................................................................... 17 
3.1.2. General definitions ....................................................................................................... 17 
3.2. Disposition and baseline characteristics ......................................................................... 18 
3.2.1. Disposition of patients .................................................................................................. 18 
3.2.2. Protocol deviations ....................................................................................................... 18 
3.2.3. Demographic data and other baseline characteristics ................................................... 18 
3.3. Treatments of patients ..................................................................................................... 19 
3.3.1. Global duration, extent of exposure and treatment compliance ................................... 19 
3.3.2. Concomitant treatments ................................................................................................ 19 
3.4. Efficacy analysis ............................................................................................................. 19 
3.4.1. Statistical hypotheses.................................................................................................... 19 
3.4.2. Primary efficacy criterion ............................................................................................. 19 
3.4.2.1. 
Primary analysis ....................................................................................................... 19 
3.4.2.2. 
Sensitivity analyses .................................................................................................. 22 
3.4.2.3. 
Supplementary analyses ........................................................................................... 22 
3.4.3. Secondary efficacy criteria ........................................................................................... 22 
3.4.4. Subgroups analysis ....................................................................................................... 23 
3.5. Exploratory analysis ....................................................................................................... 23 
3.6. Safety analysis ................................................................................................................ 23 
3.6.1. Adverse events.............................................................................................................. 23 
3.6.2. Clinical laboratory evaluation ...................................................................................... 24 
3.6.3. Vital signs, clinical examination and other observations related to safety ................... 25 
3.6.3.1. 
Vital signs and clinical examination ........................................................................ 25 
3.6.3.2. 
Electrocardiogram .................................................................................................... 25 
3.7. Biomarkers analysis ........................................................................................................ 26 


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4. INTERIM ANALYSIS ...................................................................................................... 27 
5. APPENDICES .................................................................................................................... 28 
5.1. General analytic definitions ............................................................................................ 28 
5.1.1. First and last IMP intake dates ..................................................................................... 28 
5.2. Specific analytic definitions and data handling conventions .......................................... 28 
5.2.1. Disposition and baseline characteristics ....................................................................... 28 
5.2.2. Treatments of patients .................................................................................................. 29 
5.2.3. Efficacy analysis ........................................................................................................... 31 
5.2.4. Safety analysis .............................................................................................................. 32 
5.2.4.1. 
Adverse events ......................................................................................................... 32 
5.3. Statistical methods details ............................................................................................... 32 
5.3.1. MCPMod method for primary analysis ........................................................................ 32 
5.3.2. MCPMod method with covariate-adjusted inferences ................................................. 35 
5.4. Software and programming codes .................................................................................. 36 
6. REFERENCES .................................................................................................................. 37 
 
 
 


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List of tables 
Table (5.3.1) 1 - Dose-response models ................................................................................... 33 
Table (5.3.1) 2 - Dose-response models parameters ................................................................ 33 
 
 
 
 


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List of figures 
Figure (1.2.1) 1 - Study plan .................................................................................................... 11 
Figure (1.3) 1 - Dose response models ..................................................................................... 13 
 


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List of abbreviations 
% 
: percentage 
AE 
: Adverse Event 
ASSE 
: Selection visit 
ATC 
: Anatomical Therapeutic Chemical 
b.i.d. 
: bis in die (twice a day) 
BMI 
: Body Mass Index 
BP 
: Blood Pressure 
Bpm 
: beats per minute (heart rate unit) 
CHMP 
: Committee for Medicinal Products for Human Use 
CI 
: Confidence Interval 
cm 
: centimetre 
CPMP 
: Committee for Proprietary Medicinal Products 
CVD 
: Chronic Venous Disease 
DBP 
: Diastolic Blood Pressure 
e.g. 
: exempla gratia (for example) 
EAE 
: Emergent Adverse Event 
ECG 
: ElectroCardioGram 
e-CRF 
: electronic-Case Report Form 
EMA 
: European Medicines Agency 
FAS 
: Full Analysis Set 
FWER 
: Family Wise Error Rate 
g 
: gram 
G/L 
: Giga (109) per litre 
g/dL 
: Gram per decilitre 
h 
: hour 
HbA1c 
: Glycated Haemoglobin 
HR 
: Heart Rate 
i.e. 
: id est 
I.R.I.S.: 
: Institut de Recherches Internationales Servier 
ICH 
: International Conference on Harmonization 
IMP 
: Investigational Medicinal Product 
IS 
: Included Set 
IU 
: International Unit 
IWRS 
: Interactive Web Response System 
kg 
: kilogram 
L 
: Litre 
LLN 
: Lower Limit of Normal laboratory reference range 
LLS 
: Lower Limit used to define potentially clinically Significant 
abnormal values 
Max 
: Maximum 
MCPMod 
 
Multiple Comparison Procedures and Modeling 
MED 
: Minimal Effective Dose 
MedDRA 
: Medical Dictionary for Regulatory Activities 
mg 
: milligram 
min 
: minute 
Min 
: Minimum 


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mL 
: millilitre 
mm 
: millimetre 
mmHg 
: millimetre of mercury 
ms 
: millisecond 
NA 
: Not Applicable 
NAE 
: Number of Adverse Events 
NEAE 
: Number of Emergent Adverse Events 
ng 
: nanogram 
NPD 
: Number of Protocol Deviations 
o.d. 
: omni die (every day) 
PCSA 
: Potentially Clinically Significant Abnormal value 
PD 
: Pharmacodynamics 
PK 
: Pharmacokinetics 
po 
: per os (orally) 
PPS 
: Per Protocol Set 
PT 
: Preferred Term 
PV 
: PharmacoVigilance 
QTc 
: QT interval corrected for heart rate 
RBC 
: Red Blood Cells 
RS 
: Randomised Set 
RU 
: Reference Ulcer 
s 
: second 
SAE 
: Serious Adverse Event 
SAP 
: Statistical Analysis Plan 
SBP 
: Systolic Blood Pressure 
SD 
: Standard Deviation 
SEAE 
: Serious Emergent Adverse Event 
SOC 
: System Organ Class 
SS 
: Safety Set 
t.i.d. 
: ter in die (three times a day) 
TLG 
: Tables, Listings and Graphs 
TU 
: Therapeutic Unit 
ULN 
: Upper Limit of Normal laboratory reference range 
ULS 
: Upper Limit used to define potentially clinically Significant 
abnormal values 
VAS 
: Visual Analog Scale 
VLU 
: Venous Leg Ulcer 
WHO 
: World Health Organization 
 
 
 


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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) details the planned analyses to be performed, in 
accordance with the main characteristics of the amended study protocol (version N° 4 dated 
05 March 2018). 
The templates for Tables, Listings and Graphs (TLG) are described in a separate document. 
Of note, this SAP does not cover the pharmacokinetic and metabolism profiling and genomic 
assessment and non genomic biomarkers data analyses described in the study protocol. These 
analyses are covered in separate analysis plans. 
1.1. Study objectives 
The purpose of this study is to investigate if S42909 at any dose has an effect on healing of 
venous leg ulcer (VLU) (proof of concept) and to explore the relationship between dose and 
effect of S42909 on venous leg ulcer healing on top of standardized compression and local 
wound care. 
 
The primary objective is to detect the existence of an overall dose-response relationship 
with S42909 on improving healing of venous leg ulcers on top of standard of care 
(compression and local wound care) after 4 weeks of treatment. 
 
The secondary objectives are: 
­ To determine a dose window for the Minimal Effective Dose (MED) on improving healing 
of venous leg ulcers.  
­ To explore the effect of S42909 on improving healing of venous leg ulcers on top of 
standard of care (compression and local wound care) after 6 weeks of treatment.  
­ To explore the effect of S42909 on improving pain related to venous leg ulcer over 
6 weeks. 
­ To explore the effect of S42909 on decreasing analgesic drug consumption related to 
venous leg ulcer over 6 weeks.  
­ To assess the safety profile of each tested dose of S42909 (adverse events, laboratory 
parameters, physical examination, body weight, vital signs (blood pressure, heart rate), 6 or 
12-lead electrocardiogram (ECG) and standard urinalysis).  
­ To assess the pharmacokinetics (PK) of S42909 and its metabolites in patients after 
repeated administration of S42909. 
 
The additional objectives are: 
­ To assess any potential PK/Pharmacodynamics (PD) relationship (mainly on improving 
healing of venous leg ulcers and pain related to venous leg ulcer).  
­ Genomic assessment of S42909. 
­ To collect the blood for non genomic biomarkers which can be related to venous leg ulcer 
healing, underlying chronic venous disease, response to S42909 treatment (bio-collection 
in a bio-repository). 
1.2. Study design 
Study CL2-42909-016 is a Phase IIa, prospective, international, multicentre, randomised, 
double-blind, placebo-controlled, parallel group (S42909: 100, 200, 400, 800 or 1200 mg per 
day and placebo), dose-finding study in patients with venous leg ulcers.  


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1.2.1. 
Study plan 
The study is divided into the following three periods: 
­ A placebo run-in period of 14 days (from the selection visit (ASSE) to the 
inclusion/randomisation visit at week 0 (W000)), in which patients are investigated for 
documenting the presence of Chronic Venous Disease (CVD) and for assessing the type 
and the size of the Reference Leg Ulcer. 
­ A double-blind treatment period of 6 weeks (from visit 0 (W000) to visit 6 (W006)) on top 
of standard of care (standardized compression and local wound care with sterile saline 
solution or sterile water and “non-active” dressing): 
At W000:  
 Patients are randomised to one of the following six groups – S42909: 100, 200, 400, 
800 or 1200 mg per day - or placebo.  
Note that the treatment (S42909 or Placebo) post randomisation is considered as 
Investigational Medicinal Product (IMP). 
 For each group, patients are instructed to take 3 tablets orally (per os administration) 
twice a day at the end of the meals in the morning and in the evening. The appearance 
and taste of the tablets are the same for all IMPs throughout the study.  
 The first IMP intake takes place the day of the inclusion visit (W000). 
­ A follow-up period of 2 weeks without treatment (from visit 6 (W006) to visit 8 (W008)).  
During this period, patients continue to receive the standard of care only. 
The study plan is shown in Figure (1.2.1) 1. 
Figure (1.2.1) 1 - Study plan 
 


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1.2.2. 
Type of randomisation 
The treatment randomisation and allocation are centralised using an Interactive Web 
Response System (IWRS) procedure. The treatment (S42909: 100, 200, 400, 800 or 1200 mg 
per day or placebo) is assigned at the inclusion visit (W000) by a dynamic, balanced with 
1:1:1:1:1:1 ratio, stratified randomisation according to the country, a combined prognosis 
criteria (size and age of ulcer) and diabetic status (yes/no). The randomisation algorithm is 
built according to an adaptive randomisation by minimisation. 
The combined prognosis criteria (size and age of ulcer) for ulcer healing are:  
­ A: ≤ 10 cm² and ≤ 6 months. 
­ B: > 10 cm² or > 6 months. 
 
For the randomisation, the diabetic status is defined by known diabete and/or a fasting blood 
sugar ≥7 mmol/L and/or elevated HbA1c value between 6.5% and 8% on pre-inclusion 
laboratory results. 
 
Participants in the optional 24-hour PK analysis are distributed across treatment arms.  
1.3. Determination of sample size 
Sample size was estimated with a type one error rate set at 2.5% and using the statistic 
function “sampsize” described in the publication “MCPMod: An R Package for the Design 
and Analysis of Dose-Finding Studies” edited by B. Bornkamp, J. Pinheiro and F. Bretz 
(2009). 
Considering: 
­ A standard deviation of 42%. 
­ A minimal relative change of Reference ulcer area at 4 weeks (Rmin) of 32.5%. 
­ A maximal relative change of Reference ulcer area at 4 weeks (Rmax) of 62.5%. 
­ A maximal efficacy (Rmax – Rmin) of 30%. 
­ Six doses: 0 (placebo), 100, 200, 400, 800, 1200 mg per day. 
­ Seven candidate models defined by some couples (d*, p*) (dose, maximal percentage of 
efficacy): 
 Linear. 
 Emax1 (200 mg, 90%). 
 Emax2 (400 mg, 70%). 
 Sigmoïd Emax (200 mg, 10%) and (1000 mg, 90%). 
 Logistic (200 mg, 10%) and (1000 mg, 90%). 
 Exponential1 (400 mg, 10%). 
 Exponential2 (800 mg, 10%). 
Candidate models are presented in Figure (1.3) 1. 


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Figure (1.3) 1 - Dose response models 
 
­ Function “min” of Bretz package (power of each model is greater or equal to the nominal 
power to detect a signal of dose-response relationship).  
 
27 evaluable participants per group guarantee a nominal power of at least 80% to detect a 
signal of dose-response relationship (proof-of-concept). 
 
After 1000 data simulations based on above hypotheses, with a true dose-response 
relationship supposed to be a logistic model (defined by the couples (200 mg, 10%) and 
(1000 mg, 90%)) and 27 participants by dose, the empiric power to detect a signal of 
dose-response relationship (main objective) is about 90%. 
 
Taking into account an exclusion rate from the Randomised Set (RS) estimated at 20%, about 
34 participants per treatment group had to be included. 
 
Based on that exclusion rate, a total of 204 patients was planned to be included in the study.  
Due to recruitment difficulties, 121 patients were finally included in the study. 
 
 


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2. ANALYSIS SETS / TREATMENT GROUPS 
2.1. Analysis sets  
­ Randomised Set (RS): 
All included and randomised patients (i.e. all patients to whom a Therapeutic Unit (TU) was 
randomly assigned using IWRS).  
 
­ Safety set for double blind period (SS): 
All patients having taken at least one dose of IMP. 
Note: Patients for whom no information is available about any IMP intake, will be excluded 
from the Safety Set if they have no post-baseline safety assessment. 
 
­ Full Analysis Set (FAS): 
In accordance with the intention-to-treat principle and Section 5.2.1 of the ICH E9 guideline, 
all randomised patients who received at least one dose of IMP and who have at least one 
baseline value and one value of Reference ulcer (RU) area (primary efficacy criterion) at 
W004.  
 
­ Per Protocol Set (PPS): 
All patients of the Full Analysis Set (FAS) without relevant deviation(s) which could affect 
the evaluation of the IMP effect on the primary efficacy criterion. The deviations are 
categorized in three groups, as follows: 
*  : According to protocol deviation 
**: According to medical review 
¤ : Derived in datasets 
 
More precisely, the PPS includes all patients of the FAS with: 
Before/at inclusion (all Caucasian patients of the FAS) with: 
­ BMI at ASSE between 18.5 and 45 kg/m2 inclusive*. 
­ RU localised in the gaiter area. RU diagnosed or reoccurred for more than 6 weeks and less 
than 2 years at ASSE*. 
­ Size of RU ≥ 5 cm2 and ≤ 100 cm2 in the picture taken at the selection visit (ASSE) (or 
ASSE-R), as measured by 3D imaging device*. 
­ Size of RU ≥ 4.5 cm2 and ≤ 100 cm2 at picture taken before inclusion (W000).¤ 
­ Change in RU area < 20% between picture taken at ASSE (or ASSE-R) and the picture 
taken 3 or 4 days before inclusion (W000) *. 
­ Ankle Brachial Pressure Index ≥ 0.8 and ≤ 1.3 *. 
­ Patients with chronic venous disease documented by Duplex Scan (during the selection 
period, or within 6 months before selection), with a venous reflux in the superficial and/or 
deep veins and/or a venous obstruction in the deep veins*. 
­ Required Laboratory values (authorized). 
 Serum albumin ≥20 g/l*. 
 Hb ≥10 g/dL*. 
 HbA1c ≤ 8% (either from a test done within 3 months before selection or during the 
selection period)*. 
 


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Before/at inclusion (all Caucasian patients of the FAS) without: 
­ Unauthorized diseases**:  
 Presence of malabsorption disease (Crohn’s disease), inflammatory bowel disease, 
Gilbert syndrome, history of chronic diarrhoea. 
 History of lower extremity deep venous thrombosis within the last 3 months. 
 Known major cardiovascular events (acute coronary syndrome including unstable 
angina and myocardial infarction, stroke) within 6 months prior to the study or 
congestive heart failure Class III-IV within 6 months prior to the study. 
­ Unauthorized diseases*: 
 Other non-venous leg ulcers or other associated skin conditions: vasculitis, 
malignancies, burns, post-surgery, pressure ulcers, diabetic foot, connective tissue 
disorders such as lupus, systemic sclerosis, cellulitis, ulcers due to sickle-cell disease . 
 History of major abdominal surgery which in the investigator’s opinion could interfere 
with the absorption, metabolism of the drug (e.g. gastro-intestinal resection, intestinal 
anastomosis or shunt). 
 
­ Unauthorized treatments**: 
 Participants who are undergoing treatments known to affect healing within the month 
prior to selection: pentoxifylline, immunosuppressive drugs, immunomodulators, 
cytotoxic chemotherapy or oral corticosteroids.  
 Topical corticosteroids application on and around the ulcer within 15 days prior to 
selection. 
 Participants who have been exposed to venoactive drugs within the month prior to the 
selection. 
 Participants on oral or parenteral antibiotherapy. Long-term, low dose prophylactic 
antibiotherapy started at least one month prior to the selection is however acceptable if 
there is no change in the treatment during the study.  
­ Planned surgery and venous procedures (including vein stripping, foam sclerotherapy or 
any endovenous procedure) on the leg with the Reference venous leg ulcer during the study 
period **. 
 
During the W000 - W004 period with: 
­ Blind not broken. 
­ Received treatment = planned treatment (IWRS). 
­ Duration of Study Treatment between 26 and 30 days (inclusive). 
­ Compliance with Study Treatment should be between 80% and 120%. 
­ Compliance with compression stockings should be ≥ 80%. 
 
During the W000 - W004 period without: 
­ Unauthorized concomitant treatment**:  
 Topical corticosteroid application on and around the ulcer.  
 Oral corticosteroids.  
 Immunomodulators, immunosuppressants, cytotoxic chemotherapy.  
 Pentoxifylline.  
 Venoactive drugs within the month prior to selection and during the study.  
 Participants on oral or parenteral antibiotherapy. Long-term, low dose prophylactic 
antibiotherapy started at least one month before the selection is however acceptable if 
there is no change in the treatment during the study.  


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 Local antibiotherapy on the surface of RU.  
 Oral and parenteral antibiotherapy during the study, except if less than or equal to 
7 days. 
­ Withdrawal criteria:  
 Clinically significant anemia defined by an haemoglobin level < 10g/dL and a decrease 
≥ 1.5 g/dL in men and ≥ 1 g/dL in women compared to previous value. ¤ 
 
The size of each analysis set and reasons for exclusion of patients will be described. 
 
Listings of patients with their membership, or not, in each analysis set and of excluded 
patients with reasons for exclusion will be provided. 
 
Listing of patients randomised but non included patients will be provided. 
2.2. Treatment groups 
Treatment groups considered for the analyses are S42909 50 mg b.i.d, S42909 100 mg b.i.d, 
S42909 200 mg b.i.d, S42909 400 mg b.i.d, S42909 600 mg and placebo corresponding to 
S42909 100 mg per day, S42909 200 mg per day, S42909 400 mg per day, S42909 800 mg 
per day, S42909 1200 mg per day and placebo.  
They correspond to the randomised treatment over the W000-W006 period except for safety 
analyses for which treatment taken at inclusion visit is considered. 
In the unlikely event of a patient has taken an incorrect Therapeutic Unit (TU) at a particular 
post-W000 visit in the double-blind treatment period, which would result in a switch of 
treatment group, the patient will be considered in the treatment group corresponding to their 
TU(s) taken until the switch. Their data recorded from the switch will be kept in the analyses. 
However, all safety data and IMP administration data of the patients with a switch of 
treatment group will be listed separately. 
 
 


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3. STATISTICAL METHODS 
3.1. General considerations 
3.1.1. 
Descriptive statistics 
For qualitative data, the number of observed values, the number and the percentage of 
patients per class will be presented. Unless otherwise specified in the Tables, Listings and 
Graphs (TLG), no class "Missing" is considered. 
For quantitative data, the number of observed values, the mean, the standard deviation, the 
median, the first and third quartiles, the minimum and the maximum will be presented.  
 
For event, the following will be presented : 
­ Number of patients having experienced the event (n). 
­ Number of events that occurred (for AE analyses only) (NAE). 
­ Number of patients at risk for the event (N). 
­ Global incidence rate (%) calculated as the ratio between the number of patients having 
experienced the event and the number of patients at risk at the beginning of the study. 
3.1.2. 
General definitions 
The following definitions will be considered: 
­ IMP is the treatment intake (S42909 or Placebo) post randomisation. 
­ Analysable value will be defined as any non-missing value. 
­ Baseline value will be defined as the last analysable value prior to the first IMP intake (i.e. 
before or the same date as the first IMP intake date). 
Note: In case of patient included and/or randomised but not treated (i.e. patients with 
treatment duration equal to 0): value at baseline is defined as the last analysable value prior 
or equal to the date of the inclusion visit. 
­ Post-baseline value will be defined as any value recorded at a given timepoint after 
baseline. 
­ Change from baseline will be defined as the arithmetic difference between a post-baseline 
value and the baseline value for a given variable at a given time point. 
­ Relative change from baseline will be defined as : 100 * change from baseline / baseline 
value. 
For safety criteria (except for adverse events), the following definitions will be applied: 
­ A value is considered under treatment if the assessment date is between the first IMP 
intake date (excluded) over the W000 and W006 period and the last IMP intake date "+ 
15 days" (included). 
Note: for all definitions concerning value under treatment ‘+ 15 days’ was calculated 
according to the half-life of the S42909. 
­ High emergent abnormal value under treatment according to the laboratory reference 
ranges is defined as value ≤ ULN (Upper Limit of Normal laboratory reference range) or 
missing at baseline and > ULN under treatment.  
­ Low emergent abnormal value under treatment according to the laboratory reference 
ranges is defined as value ≥ LLN (Lower Limit of Normal laboratory reference range) or 
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­ High emergent abnormal value under treatment according to the cut-offs for PCSA 
(Potentially Clinically Significant Abnormal value) values is defined as value ≤ ULS 
(Upper Limit used to define potentially clinically Significant abnormal values) or missing 
at baseline and > ULS under treatment.  
­ Low emergent abnormal value under treatment according to the cut-offs for PCSA values 
is defined as value ≥ LLS (Lower Limit used to define potentially clinically Significant 
abnormal values) or missing at baseline and < LLS under treatment. 
3.2. Disposition and baseline characteristics  
Disposition of patients and baseline characteristics will be described by randomised treatment 
group, to assess their comparability, and overall (treatment groups pooled). 
Details concerning definitions on the disposition of patients and baseline characteristics are 
provided in Appendix 5.2. and provided in the Specifications document. 
3.2.1. 
Disposition of patients 
Disposition of patients, including reasons for withdrawal, will be summarized during the 
study by randomised treatment, overall and by visit, in the RS). 
3.2.2. 
Protocol deviations 
Protocol deviations before or at inclusion (W000), as well as after inclusion on W000-W004, 
W000-W006 and W000-W008 periods, will be described in the RS, by category of important 
deviations (based on ICH E3 guideline and ICH E3 Q&A). 
If necessary a listing of non-included randomised patients will be provided. 
3.2.3. 
Demographic data and other baseline characteristics 
Demographic data and other baseline characteristics such as life habits, history of the venous 
leg ulcers, venous duplex scan results, compression stocking dispensing(at W000 and at each 
visit), ankle brachial pressure index, baseline value of efficacy criteria (ulcer assements and 
pain intensity), vital signs and ECG parameters at baseline will be described in the RS. 
The main patients’ characteristics will also be described in the FAS and the PPS. 
The QTcF interval at baseline will be also described in classes (≤ 450, ]450; 480], ]480; 500] 
and > 500ms, in accordance with ICH E14 guideline) and the following continuous data will 
also be described in classes: 
Age ([18 ; 64], [65; 84], ≥85 years). 
All previous treatments for venous leg ulcers will be described in the RS, by Anatomical 
Therapeutic Chemical (ATC) code. All medical history other than venous leg ulcers and 
surgical or medical procedures history, will be described in the RS by primary system organ 
class (SOC) and preferred term (PT). 
For compression stocking, compliance on W000-W004 and W000-W006 period will be also 
described in classes (< 80, [80; 120], and > 120%). 
Details concerning this compliance are provided in Appendix 5.2. 


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3.3. Treatments of patients 
Details concerning definitions on extent of exposure, treatment compliance and concomitant 
treatments are provided in Appendix 5.2 and provided in the Specifications document. 
3.3.1. 
Global duration, extent of exposure and treatment compliance 
Global duration (days), extent of exposure (treatment exposure (days) and treatment duration 
(days)) and treatment compliance (%) over the W000-W004 and the W000-W006 period will 
be described in the FAS and the SS. 
Treatment compliance (over the W000-W004 and W000-W006 periods) will be also 
described in classes (< 80, [80; 120], and > 120%). 
3.3.2. 
Concomitant treatments 
All concomitant treatments taken at inclusion, during the treatment period (over the 
W000-W004 and W000-W006 periods) and after the last IMP intake will be described in the 
RS, by ATC code. 
3.4. Efficacy analysis 
General definitions are provided in Section 3.1.2. Details concerning efficacy criteria 
definitions are provided in Appendix 5.2. 
3.4.1. 
Statistical hypotheses 
The statistical hypothesis is based on a multi-contrast test. 
The hypothesis of the test is: 
𝐻0: 𝑐′𝜇= 0   vs   𝐻1: 𝑐′𝜇> 0. 
Where: 
­ µ is a vector of mean response. 
­ 𝑐 is a vector of contrast. 
Due to the use of the MCPMod methodology, the overall Type I error rate across the assumed 
dose-response relationships will be controlled at a one-sided 2.5% level. 
3.4.2. 
Primary efficacy criterion 
Definition: The primary efficacy criterion is defined as relative reduction of Reference Ulcer 
area after 4 weeks of treatment on top of standard of care compared with baseline Reference 
Ulcer area assessed during study visits using a digital 3D imaging device. 
3.4.2.1. 
Primary analysis 
Primary analysis:  the MCPMod method (Multiple Comparison Procedures and Modelling) 
will be applied to the primary efficacy endpoint in the FAS. The MCP-step corresponds to the 
establishing of a dose-response signal (the dose-response curve is not flat) and the Mod-step 
to the estimation of the dose-response curve. 
The MCPMod method was introduced for developing robust dose-response evaluation 
strategies in Phase II trials (Bretz, Pinheiro and Branson, 2005). All details of this method are 
provided in Appendix 5.3.1.  
More specifically, let 
ij
Y be the relative change from baseline at W004 for the patient 𝑗 treated 
at the dose 𝑖 of S42909. 


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We assume that: 
²)
,0
(
~
σ
ε
ε
N
µ
Y
ind
ij
ij
i
ij
+
=
 
Where: 
­ µi = f(di, θ) is the mean response at dose di for the dose response models 
f(. ) parameterized by a vector of parameters θ. 
­ i = 1, … , k where k is the number of doses. 
­ j = 1 … , ni where ni the number of patients at the dose 𝑖. 
­ εij is the error term for patient j within dose group i follows a normal distribution with 
mean 0 and variance σ2. 
 
Dose-finding will be performed using the following set of predefined candidate models of  
f(. ) defined by some couples (d*, p*) (dose per day, percentage of efficacy at this dose): 
­ Linear. 
­ Emax1 (200 mg, 90%). 
­ Emax2 (400 mg, 70%). 
­ Sigmoïd Emax (200 mg, 10%) and (1000 mg, 90%). 
­ Logistic (200 mg, 10%) and (1000 mg, 90%). 
­ Exponential1 (400 mg, 10%). 
­ Exponential2 (800 mg, 10%). 
See Appendix 5.3.1 for more details on each model. 
 
The MCPMod procedure is based on a multi-contrast test. A unique dose-response contrast is 
associated with each dose-response model. This contrast is defined as the contrast that has the 
highest power, i.e., the highest probability of rejecting the associated null hypothesis of no 
effect, under this particular model. The computation of the optimal contrast is explained in 
Appendix 5.3.1. 
 
The significance of the dose-response trend based on each model-specific contrast will be 
assessed using the following 𝑡 statistics: 
∑
∑
=
=
=
k
i
i
mi
k
i
i
mi
m
n
c
S
Y
c
t
1
2
1
.
 
Where : 
­ 
iY
തതതത
 is the empiric mean of the response within dose group di. 
­ m is the number of models. 
­ ni is the number of patients within the dose group di. 


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­ 
∑∑
=
=
−
−
=
k
i
n
j
i
ij
i
k
N
Y
Y
S
1
1
)²
(
²
   
­ cm is the vector of contrasts with
0
1
=
∑
=
k
i
mi
c
 
 
The dose-response tests identify the set of clinically relevant models. A multiplicity 
adjustment is taken into account in the MCP-step. The joint distribution of the m test statistics 
is taken into account to compute an adjusted critical value that defines the threshold for 
statistical significance. 
Under the global null hypothesis of no treatment effect under any model, the test statistics 
follow a central multivariate t distribution with 𝑁−𝑘 degrees of freedom and correlation 
matrix 𝑅. More details for matrix R are given in Appendix 5.3.1. 
To derive the multiplicity-adjusted critical value, denoted by 𝑞, let 𝑇1; … ; 𝑇𝑚,denote the 
random variables that have the same joint distribution as 𝑡1; … ; 𝑡𝑚 under the global null 
hypothesis. The adjusted critical value 𝑞 is found from : 
 
Pr(𝑇𝑚𝑎𝑥>  𝑞) = ∝ 
 
Where α is the pre-specified Family Wise Error Rate (FWER) level equal to 0.025 (one-sided 
test). 
 
The set of clinically relevant dose-response model corresponds to the models associated with 
𝑡𝑖> 𝑞. The adjusted p-value will be calculated according to the value of 𝑞. 
 
Among the set of clinically relevant dose-response models, the best dose-response contrast 
will be identified as the contrast test with the maximum test statistics.  
 
An estimation of parameters of the best model selected will be provided according to the 
observed data as well as a plot of this model.  
If relevant, modelisation will be done even if no dose-response model is significant.  
 
Multiplicity issues: 
The multiplicity issue due to multiple dose-response models is corrected with the computation 
of an adjusted critical value and adjusted p-values. 
 
Missing data handling: missing data will not be imputed. 
 
Statistical elements:  
Finally, the following elements will be provided in summary tables:  
­ Descriptive statistics and 95% CI of the primary criterion in each arm.  
­ The best dose-response selected.  
­ An estimation of parameters of the best model selected.  


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3.4.2.2. 
Sensitivity analyses 
­ The MCPMod method adjusted on diabetes status factor and prognosis criteria on size and 
age of the ulcer factor will be applied to the primary efficacy endpoint in the FAS. 
Details of the MCPMod approach with covariate-adjusted inferences are provided in 
Appendix 5.3.2. 
­ The primary analysis will be repeated in the FAS with patients from centers where PK 
results confirm the treatment intake. 
3.4.2.3. 
Supplementary analyses 
­ To meet the secondary objective, the Minimal Effective Dose (MED) will be estimated 
using the selected model resulting from the primary analysis. 
The MED is defined as: 
𝑀𝐸𝐷= min൫𝑑: 𝑓(𝑑) > 𝑓(𝑑0) + ∆ , 𝐿(𝑑) >  𝑓(𝑑0)൯ 
with Δ is the clinically relevant difference, 𝐿(𝑑) the lower confidence limit of the predicted 
mean value 𝑓(𝑑) at dose d. 
The estimator will be provided considering a hypothesis of a clinically relevant effect as 
compared to placebo of 6.5%. A confidence interval will be provided by bootstrap method.  
­ The primary analysis will be repeated in the PPS. 
­ For RU area, description at each visit and the relative change from baseline to each visit 
will also be provided in FAS and PPS. 
­ Description of the relative change from W006 to W008 of the reference ulcer (RU) area, 
for patients with a non null value at W006, as well as the description of the relative change 
from W004 to W006, for patients with a non null value at W004, will be described in FAS 
and PPS. 
3.4.3. 
Secondary efficacy criteria 
Definition: 
­ Reference Ulcer Volume (using a digital 3D imaging device). 
­ Linear advance of the wound margin towards the wound centre. 
­ Pain intensity (using a questionnaire including a Visual Analog Scale (VAS)). 
­ Analgesic drug consumption (patient using analgesic drug for Venous Leg Ulcer (VLU) 
during the study). 
 
Analyses: 
For all secondary efficacy criteria, descriptive statistics at each concerned visit will be 
performed in the FAS and PPS. 
 
The Reference Ulcer volume, will be described at each visit, on the change from baseline to 
each visit, as well as the description of the change from W004 to W006 and from W006 to 
W008.  
 
Linear advance of the wound margin towards the wound centre will be described at each visit. 
 
Pain intensity will be described at each concerned visit (W000, W004 and W006) and on the 
change from baseline to W004 and W006.  
 


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Analgesic drug consumption will be described through the question “Need to take medication 
for control of the pain associated with VLU?” From the pain questionnaire at each concerned 
visit (W0, W4 and W6). 
3.4.4. 
Subgroups analysis 
In addition, descriptive statistics at each concerned visit of the reference ulcer area, linear 
advance of the wound margin towards the wound centre and reference ulcer volume will be 
performed. 
Except for the  linear advance of the wound margin towards the wound centre, the relative 
change from baseline (change for volume) will also be described. 
These description will be performed in the FAS in the following subgroups:  
­ Combined prognosis criteria on size and age of the ulcer (≤ 10 cm² and ≤ 6 months / 
> 10 cm² or > 6 months) at baseline. 
­ Size of the ulcer at baseline ( ≤ 20 cm² / > 20 cm²). 
­ Size of the ulcer at baseline ( ≤ 50 cm² / > 50 cm²). 
­ Diabetes status (yes/no). 
If a subgroup contains less than 20 patients, only listings will be provided for this subgroup. 
3.5. Exploratory analysis 
Not applicable. 
3.6. Safety analysis 
All safety analyses will be performed in the SS on the taken IMP treatment, by treatment 
group over the W000-W006 period.  
Only for adverse events, in addition, an analysis will be performed on post treatment intake 
(i.e after last treatment intake date + 15 days (excluded)). 
 
General definitions are provided in Section 3.1.2. Specific definitions are provided in 
Appendix 5.2. and provided in the Specifications document. 
3.6.1. 
Adverse events 
Definition: 
­ Treatment Emergent Adverse Events (TEAE) are defined as all adverse events: 
 which occur between the first IMP intake date (included) and the last IMP intake date + 
15 days (included) 
    or 
 which occur before the first IMP intake date and which worsen (in terms of intensity) or 
become serious according to the investigator’s opinion between the first IMP intake 
date (included) and the last IMP intake date + 15 days (included). 
Note: + 15 days is calculated according to the half-life of the S42909. 
 
Of note, in case of multiple information of the same event before the first IMP intake date, the 
information nearest to the first IMP intake date is taken into account. 
 


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The seriousness of the adverse event and the relationship with the IMP are based on the 
investigator’s opinion but often also include the sponsor’s decision to upgrade the seriousness 
and/or relation to the IMP (see TLG for details). 
 
Analyses: 
The number of events, the number and percentage of patients reporting at least one event, 
presented by primary system organ class (SOC) and/or preferred term (PT) (depending of the 
analysis) will be provided for : 
­ Serious AE over the study period  according to the investigator’s or sponsor’s opinion. 
­ Treatment emergent AE (TEAE), TEAE leading to IMP withdrawal, TEAE requiring new 
treatment or increase of ongoing treatment, TEAE requiring surgical or medical procedure, 
TEAE related to IMP, serious TEAE, severe TEAE, non serious TEAE over the treatment 
period (EUDRACT), After treatment AE. 
TEAE will be described according to the seriousness, the intensity, the relationship with the 
IMP, the action taken regarding the IMP, the requirement of added therapy and the outcome. 
The medical concept of diarrhea, i.e. TEAE related to diarrhea, will be analysed through a 
listing. The MedDRA code list to use is the list n°3741 Diarrhoea medical concept M22.0. 
A listing of deaths and ERIN will be provided. 
A Listing of AE occurring after the treatment period will also provided. 
The following information will be taken into account: 
­ For the analyses where the intensity of the adverse event is considered, the worst intensity 
from the day of emergence to the end of the studied period will be taken into account. 
­ For the analyses where the action taken regarding the IMP is considered, all the actions 
taken recorded from the day of emergence to the end of the studied period will be taken 
into account. 
­ For the analysis of recovered emergent adverse events during the treatment period, an EAE 
is considered as recovered "during treatment period" if the associated outcome is 
"recovered" or "recovered with sequelae" and occurs between the first IMP intake date and 
the last IMP intake date + 15 days (included). 
3.6.2. 
Clinical laboratory evaluation 
For all parameters, the dosing of samples come from local laboratories. So no quantitative 
analysis will be performed. In the qualitative analysis, data will be compared to reference 
ranges provided by these local laboratories. 
Definition:  
­ A laboratory value is considered as analysable if non-missing and not flagged in the 
ClinTrial database as "not analysable". 
Analyses: 
For each biochemical and haematological parameter, the following analyses will be 
performed: 
­ Number and percentage of patients with at least one high/low emergent abnormal value 
under treatment, according to the laboratory reference ranges and to the cut-offs for PCSA 
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­ Laboratory parameters classified (number and percentage of patients in each class) 
according to these reference ranges and cut-offs, and using shift tables from baseline to the 
worst (high and/or low) values under treatment. 
Moreover, listings of patients with out-of-range or PCSA analysable values emergent under 
treatment and of non-analysable values excluded from analyses will be provided. 
Urinary parameters will be described in classes (absent, trace, +, ++, +++, ++++) at baseline 
and at each post-baseline visit under treatment. 
3.6.3. 
Vital signs, clinical examination and other observations related to safety 
3.6.3.1. 
Vital signs and clinical examination 
Definition:  
The following vital signs and clinical examination will be analysed during the study: 
­ Weight (kg). 
­ BMI (kg/m²). 
­ Sitting Systolic Blood Pressure (SBP) (mmHg). 
­ Sitting Diastolic Blood Pressure (DBP) (mmHg). 
­ Sitting heart rate (bpm). 
 
Analysis: 
They will be described, in terms of value at baseline, value at each post-baseline visit under 
treatment as well as in terms of change from baseline to last post-baseline visit under 
treatment. 
3.6.3.2. 
Electrocardiogram 
Definition: 
­ All non-missing values are considered as analysable.  
 
The following ECG parameters will be analysed: 
­ Presence of clinically significant ECG abnormalities (yes/no). 
­ PR interval (msec). 
­ QT interval (msec). 
­ RR interval (msec). 
­ Duration of QRS (msec). 
­ QTcF - Fridericia's Correction Formula (msec). 
­ Sinus Rhythm (yes/no). 
 
Emergence of clinically significant ECG during the treatment period:  
­ When no ECG is judged as clinically significant at baseline and the clinical significance 
appears between the first IMP intake date (included) and the last IMP intake date + 15 days 
(included) 
 


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Analyses: 
ECG parameters will be described, in terms of values at baseline, values at each post-baseline 
visit under treatment and last post-baseline values under treatment; as well as, for quantitative 
criteria, in terms of change from baseline to each post-baseline visit under treatment and to 
last post-baseline visit under treatment and in term of emergence of clinically significant 
ECG. 
 
Moreover, values at each visit and changes from baseline of QTcF interval will be described 
in classes, considering thresholds defined in ICH E14 (i.e., ≤ 450, ]450; 480], ]480; 500] and 
> 500 msec for values at each visit and ≤ 30,]30; 60] and > 60 msec for changes from baseline 
to each visit). 
3.7. Biomarkers analysis  
Not applicable. 
 
 


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4. INTERIM ANALYSIS 
Not applicable.  
 
 


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5. APPENDICES 
5.1. General analytic definitions 
Definitions below correspond to calculation rules for first and last IMP intake dates and other 
general definitions. 
  
5.1.1. 
First and last IMP intake dates 
For patients having taken at least one dose of IMP over the period between W000 and W006, 
the dates of first and last IMP intake on the analysis period will be defined as follows: 
­ The date of the first IMP intake at the first visit performed within the analysis period. 
­ The date of the last IMP intake at the last visit performed within the analysis period. 
Note: Visits with both missing first and last IMP intake dates and with number of returned 
tablets equal to number of tablets delivered at the previous visit (or with estimated number of 
tablets taken equal to 0) will not be taken into account. 
After selection of the dates of first and last IMP intake as defined above, if these dates are 
missing or incomplete, substitution rules will be applied to identify baseline value, values 
under treatment and emergent adverse events. 
5.2. Specific analytic definitions and data handling conventions 
5.2.1. 
Disposition and baseline characteristics  
Disease duration and reference ulcer duration 
The disease duration according to the first leg ulcer (days) is defined as: 
Date of selection visit (ASSE) – Date of diagnosis of the first leg ulcer 
 
The reference ulcer duration according to the patient (days): 
Date of selection visit (ASSE) – Date of occurence or recurrence of the reference ulcer 
according to patient 
 
The reference ulcer duration according to the physician (days): 
Date of selection visit (ASSE) – Date of diagnosis or recurrence of the reference ulcer by the 
physician 
 
Reference ulcer duration according to the physician will also be described in classes 
defined as: 
If (disease duration (days)/30.44) ≤ 6 then disease duration in class = ‘≤ 6 months’. 
If (disease duration (days)/30.44) > 6 then disease duration in class = ‘> 6 months’. 
 
The reference ulcer duration according to the physician in classes is used for the subgroup. 
CEAP classification (Clinical-Etiology-Anatomy-Pathophysiology) 
Presence of an obstruction or a reflux in each type of veins (superficial veins and deep veins) 
will be derived with: 
­ Superficial veins will be defined as: 
Telangiectasies or reticular veins; Great saphenous vein above knee; Great saphenous vein 
below knee; Small saphenous vein and Nonsaphenous veins. 


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­ Deep veins will be defined as : 
Inferior vena cava; Common iliac vein; Internal iliac vein; External iliac vein; Pelvic: 
gonadal, broad ligament veins, other; Common femoral vein; Deep femoral vein; Femoral 
vein; Popliteal vein Crural: anterior tibial, posterior tibial, peroneal veins (all paired) and 
Muscular: gastrocnemial, soleal veins, other. 
­ Presence of an obstruction  is defined if the classification in (« Obstruction » or « Reflux 
and obstruction ») is completed. 
­ Presence of a reflux is defined if the classification in (« Reflux» or « Reflux and 
obstruction ») is completed. 
Medical history other than studied disease and surgical or medical procedures history 
The existence of a history (Yes/No) is defined from the presence, or not, of a Primary system 
organ class (SOC) and/or Preferred term (PT). 
No specific medical and surgical histories or medical procedures are defined. 
Previous treatments 
The previous treatments are the treatments for venous leg ulcers taken within 6 months before 
selection, or any previous treatments which could interfere with the IMP or the study 
assessments in the last 6 weeks before the selection with associated stop date strictly inferior 
to the first IMP intake date (W000). 
 
Note: In case of patient included and/or randomised but not treated (i.e. patients with 
treatment duration equal to 0), the previous treatment is defined as any treatment with an 
associated stop date strictly inferior to the date of the inclusion visit. 
Only treatment with an Anatomical Therapeutic Chemical (ATC) classification and/or a 
Preferred name is considered. 
No specific previous treatments are defined. 
The compliance of compression stocking 
The compliance of compression stocking (%) for each period (W000-W004 and W000-W006 
periods) is defined as: 
(Sum of number of days of stockings wearing / Sum of number of days when stockings had to 
be worn) x 100 (for the considered period) 
with:  
­ Number of days of stockings wearing = Number of days of stockings wearing.  
­ Number of days when stockings had to be worn = Last visit date - First visit date, in days 
(for the considered period)  
Note: Compliance is not calculated in case of missing information. 
5.2.2. 
Treatments of patients 
Global duration 
Global duration (days) is defined as: 
Date of the last visit – Date of selection visit + 1 


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Extent of exposure and treatment compliance 
The treatment duration (days) for each period (W000-W004 and W000-W006 periods) is 
defined as: 
Date of the last IMP intake (for the considered period) – Date of the first IMP intake (for the 
considered period) + 1 
Notes:  
­ For patients with no dose of IMP (for the considered period), the duration is null. 
­ For patients with missing or incomplete date of first or/and last IMP intake (for the 
considered period) before substitution, the duration is not calculated.  
 
The treatment exposure (days) for each period (W000-W004 and W000-W006 periods) is 
defined as:  
Treatment duration – Overall duration of interruption 
with the overall duration of interruption defined as: Sum of (Date of IMP restarted – Date of 
last IMP intake before interruption – 1 (*)).  
(*) or the number of days of interruption in case of missing or incomplete date of IMP 
restarted or date of last IMP intake before interruption. 
The treatment compliance (%) for each period (W000-W004 and W000-W006 periods) is 
defined as: 
(Sum of number of tablets taken / Sum of number of tablets to be taken) x 100 (for the 
considered period) 
with:  
­ Number of tablets taken = Estimated number of tablets taken, or if not completed, Number 
of tablets dispensed - Number of tablets returned (for the considered period).  
­ Number of tablets to be taken = The formula is different depending on the concerned 
period because of the following points: 
The last tablets to be taken during the W000-W004 period are the 6 tablets (3 in the morning 
and 3 in the evening) the day before the visit W004, whereas the last tablets to be taken 
during the W000-W006 period are the 3 tablets in the morning of the visit W006 after the PK 
predose sampling at the site. 
Of note that the visit W003 is the only visit to which patients have to take the 3 tablets in the 
morning before the visit W003. For the other visits, the patient have to take the 3 tablets in the 
morning after the PK predosesampling at the site. 
 For the W000-W004 period, number of tablets to be taken:  
For withdrawn patients at W003: 
Number of tablets prescribed per day x [Last visit date - First visit date, in days] + 
Number of tablets prescribed for the morning of the visit W003 
For other patients: 
Number of tablets prescribed per day x [Last visit date - First visit date, in days]  
 For the W000-W006 period, number of tablets to be taken :  
For completers or withdrawn patients at W003: 
Number of tablets prescribed per day x [(Last visit date - First visit date), in days] + 
Number of tablets prescribed the last morning (i.e., 3 tablets) 
For withdrawn patients at other visits than W003: 
Number of tablets prescribed per day x [(Last visit date - First visit date), in days]  
Note: Compliance is not calculated in case of missing information. 
 


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Concomitant treatments 
The existence of a concomitant treatment (Yes/No) is defined from the presence, or not, of 
an Anatomical Therapeutic Chemical (ATC) classification and/or Preferred name. 
The periods considered for the analysis are: 
­ At inclusion for which treatments with start date ≤ inclusion date and stop date ≥ inclusion 
date or missing are taken into account. 
­ During the treatment period for each considered period (W000-W004 and W000-W006) 
for which treatments: 
 with start date ≥ first IMP intake date and < last IMP intake date (for the considered 
period), or 
 with start date ≤ first IMP intake date and stop date ≥ first IMP intake date or missing 
are taken into account. 
­ After the last IMP intake for which treatments: 
 with start date ≥ last IMP intake, or 
 with start date ≤ last IMP intake date and stop date > last IMP intake date or missing 
are taken into account. 
 
Concomitant treatments could be considered in one or several of the possible analysis periods. 
5.2.3. 
Efficacy analysis 
Linear advance of the wound margin 
Computation of linear advance of the wound margin towards the wound center from 
baseline: 
 
 
Where ∆A is the difference in the area (Avisit - Abaseline) and p the average of the wound 
perimeter:  
 
 
Computation of linear advance of the wound margin towards the wound center from 
previous visit:   
 
 
Where ∆A is the difference in the area (Avisit v – Avisit v-1) and p the average of the wound 
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Pain intensity 
Pain intensity is defined as the Visual Analog Scale (VAS) values.  
In case of response “No” to the question “Does the participant feel any pain or discomfort 
related to his/her leg ulcer?” and the VAS value is missing this value will be imputed to zero. 
Diabetic status 
For efficacy analysis, a patient with HbA1c ≥ 6.5%  or a medical history in the following list : 
1689.2 Evidences of diabetes mellitus M220 is considered as diabetic. 
5.2.4. 
Safety analysis 
5.2.4.1. 
Adverse events 
Each medical concept of adverse event coded according to the internal "multiple medical 
concept" process is taken into account as a single adverse event in the statistical analysis. 
The modalities of the adverse event (onset and end dates, intensity, seriousness, action taken, 
additional therapy, relationship, outcome...) replicated by default to each medical concept are 
also taken into account in the statistical analyses. 
5.3. Statistical methods details 
5.3.1. 
MCPMod method for primary analysis 
The MCPMod method is presented in details in the following paragraph. 
Let 
ij
Y be the relative change from baseline at W004 for the patient 𝑗 treated at the dose 𝑖 of 
S42909. 
We assume that: 
²)
,0
(
~
σ
ε
ε
N
µ
Y
ind
ij
ij
i
ij
+
=
 
Where: 
­ µi = f(di, θ) is the mean response at dose di for the dose response models 
f(. ) parameterized by a vector of parameters θ. 
­ i = 1, … , k where k is the number of dose. 
­ j = 1 … , ni where ni the number of patients at the dose 𝑖. 
­ εij is the error term for patient j within dose group i. εij follows a normal distribution with 
mean 0 and variance σ2. 
Dose-finding will be performed using a set of candidate models of  f(. ). The candidate 
models are set up using the hypothesized dose-response functions as follows: 
 
f(d, θ) = 𝑎+ 𝑏𝑔(𝑑, θ0) 
 
where g(. ) is the standardized form of the dose-response function with θ0 denoting the vector 
of initial values of the model parameters or guesstimates that are derived from the expected 
shape of the dose-response relationship. Further, 𝑎 is the location parameter, and 𝑏 is the scale 
parameter. 
 
Dose response models are defined in the Table (5.3.1) 1. 


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Table (5.3.1) 1 - Dose-response models 
Model 
f(𝑑, θ) 
g(𝑑, θ0) 
Linear 
𝐸0 + δ𝑑 
𝑑 
Emax 
𝐸0 +
𝐸𝑚𝑎𝑥𝑑
𝐸𝐷50 + 𝑑 
𝑑
𝐸𝐷50 + 𝑑 
Sigmoïd Emax 
𝐸0 +
𝐸𝑚𝑎𝑥𝑑ℎ
𝐸𝐷50
ℎ+ 𝑑ℎ 
𝑑ℎ
𝐸𝐷50
ℎ+ 𝑑ℎ 
Exponential 
𝐸0 + 𝐸1(exp ൬𝑑
δ൰−1) 
exp ൬𝑑
δ൰−1 
Logistic 
𝐸0 +
𝐸𝑚𝑎𝑥
(1 + exp ൬𝐸𝐷50 −𝑑
δ
൰)
 
1
(1 + exp ൬𝐸𝐷50 −𝑑
δ
൰)
 
In this study, dose-finding will be performed using the following set of 𝑚 candidate models 
of  f(. ) defined by some couples (d*, p*) (dose, percentage of efficacy at this dose): 
­ Linear. 
­ Emax1 (200 mg, 90%). 
­ Emax2 (400 mg, 70%). 
­ Sigmoïd Emax (200 mg, 10%) and (1000 mg, 90%). 
­ Logistic (200 mg, 10%) and (1000 mg, 90%). 
­ Exponential1 (400 mg, 10%). 
­ Exponential2 (800 mg, 10%). 
 
The parameter values for each candidate model corresponding at the set of candidate models 
are mentionned in the Table (5.3.1) 2. 
Table (5.3.1) 2 - Dose-response models parameters 
Candidate model 
Parameter values (𝜃) 
Linear 
𝐸0 = 32.5, δ = 0.025 
Emax 1 
𝐸0 = 32.5, 𝐸𝑚𝑎𝑥= 30.6, 𝐸𝐷50 = 22.2 
Emax 2 
𝐸0 = 32.5, 𝐸𝑚𝑎𝑥 = 34.3, 𝐸𝐷50 = 171.4 
Sigmoïd Emax 
𝐸0 = 32.5, 𝐸𝑚𝑎𝑥 = 32, 𝐸𝐷50 = 447.2, ℎ = 2.7 
Logistic 
𝐸0 = 31.3, 𝐸𝑚𝑎𝑥 = 32.3, 𝐸𝐷50 = 600,  
ℎ = 182.1 
Exponential 1 
𝐸0 = 32.5, 𝐸1 = 1.95, δ = 428.9 
Exponential 2 
𝐸0 = 32.5, 𝐸1 = 0.03, δ = 174.4 
Optimal contrasts 
The MCPMod procedure is based on a multi-contrast test. A unique dose-response contrast is 
associated with each dose-response model. This contrast is defined as the contrast that has the 
highest power, i.e., the highest probability of rejecting the associated null hypothesis of no 
effect, under this particular model. The standardized version of the model is used and the 
predicted effects is computed under this standardized model: 
 
𝑢𝑖𝑗= 𝑔𝑖൫𝑑𝑗, 𝜃0൯ 


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Where:  
­ j = 0, … , m, with m the number of candidate model. 
­ i the dose. 
 
The predicted effects can be computed using the initial values defined in the Table (5.3.1) 1. 
The optimal constrast is calculated from the predicted effects by centering and normalizing 
this vector.  
The coefficients of the optimal constrast for each model are defined with the following 
formula: 
𝑐𝑖𝑗=
𝑢𝑖𝑗−
1
𝑚+ 1 ∑
𝑢𝑖𝑙
𝑚
𝑙=0
ට∑
(𝑢𝑖𝑗− 
1
𝑚+ 1 ∑
𝑢𝑖𝑙
𝑚
𝑙=0
)2
𝑚
𝑙=0
, 𝑗= 0, … , 𝑚 
Where  
­ j = 0, … , m, with m the number of candidate model 
­ i the dose 
 
Dose-reponse tests 
The significance of the dose-response trend based on each model-specific contrast will be 
assessed using the following 𝑡 statistics: 
∑
∑
=
=
=
k
i
i
mi
k
i
i
mi
m
n
c
S
Y
c
t
1
2
1
.
 
where 
­ 
iY
തതതത
 is the empiric mean of the response within dose group di. 
­ m is the number of model. 
­ ni is the number of patients within the dose group di. 
­ 
∑∑
=
=
−
−
=
k
i
n
j
i
ij
i
k
N
Y
Y
S
1
1
)²
(
²
   
­ cm is the vector of contrasts with
0
1
=
∑
=
k
i
mi
c
 
The dose-response tests identify the set of clinically relevant models. A multiplicity 
adjustment is taken into account in MCP. The joint distribution of the m test statistics is taken 
into account to compute an adjusted critical value that defines the threshold for statistical 
significance. 
Under the global null hypothesis of no treatment effect under any model, the test statistics 
follow a central multivariate t distribution with 𝑁−𝑘 degrees of freedom and correlation 
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The correlation between the test statistics 
it  and 
jt is given by: 
𝜌𝑖𝑗=
∑
𝑐𝑖𝑙𝑐𝑗𝑙
𝑚
𝑙=0
ඥ∑
𝑐𝑖𝑙2
𝑚
𝑙=0
∑
𝑐𝑗𝑙2
𝑚
𝑙=0
 
To derive the multiplicity-adjusted critical value, denoted by 𝑞, let 𝑇1; … ; 𝑇𝑚,denote the 
random variables that have the same joint distribution as 𝑡1; … ; 𝑡𝑚 under the global null 
hypothesis. The adjusted critical value 𝑞 is found from:  
 
Pr(𝑇𝑚𝑎𝑥>  𝑞) = ∝ 
 
where α is the pre-specified Family Wise Error Rate (FWER) level equal to 0.025 (one-sided 
test). 
 
The set of clinically relevant dose-response model corresponds to the models associated with 
𝑡𝑖> 𝑞. Adjusted p-value will be calculated according to the value of 𝑞. 
 
Among the set of clinically relevant dose-response models, the best dose-response contrast 
will be identified as the contrast test with the maximum test statistic.  
 
An estimation of parameters of the best model selected will be provided as well as a plot of 
this model.  
 
5.3.2. 
MCPMod method with covariate-adjusted inferences 
The MCPMod method was originally introduced for developing robust dose-response 
evaluation strategies in Phase II trials with simple primary analyses, e.g., analyses without 
covariate adjustment (Bretz, Pinheiro and Branson, 2005).  The original method was later 
extended in multiple directions. Pinheiro et al. (2013) demonstrated how a generalized version 
of the MCPMod approach can be set up to enable covariate-adjusted inferences in the primary 
analysis. 
 
The general MCPMod method proposed in Pinheiro et al. (2013) will be applied to the  
primary endpoint in the FAS. This endpoint is assumed to be normally distributed and will be 
analyzed using an analysis of covariance (ANCOVA) model adjusted for two stratification 
factors (combined prognosis criteria and diabetic status).   
 
The general MCPMod method will be applied to the seven pre-defined dose-response models 
(see definition in Table (5.3.2) 1) with the 6 doses.  The models will be denoted by 𝑓𝑖(𝑑, 𝛽), 
𝑖= 1 … ,7, where 𝑑 is the dose and 𝛽 is a vector of model parameters, and the doses will be 
denoted by 𝑑1, … , 𝑑6. 
 
The method will be implemented as follows.  As the very first step, initial values of the model 
parameters will be selected for the pre-defined models.  The column vector of initial values 
for the 𝑖th model will be denoted by 𝑏𝑖, 𝑖= 1 … ,7.  Let 𝜇𝑖 denote the column vector of mean 
effects computed from the 𝑖th model using these initial values of the model parameters, i.e., 
𝜇𝑖𝑗= 𝑓𝑖(𝑑𝑗, 𝑏𝑖), 𝑖= 1 … ,7, 𝑗= 1 … ,6. 
 


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The ANCOVA model without an intercept adjusted for the two stratification factors will be 
fitted to the data.  Let 𝜇̂𝑗 denote the covariate-adjusted mean effect in the 𝑗th dose group, 
𝑗= 1 … ,6, and let 𝜇̂ denote the column vector of covariate-adjusted mean effects.  Also, let 𝑆 
denote the covariance matrix for these mean effects estimated from the ANCOVA model.   
 
The optimal dose-response contrasts will be found by computing the following set of vectors: 
𝑐𝑖= 𝑆−1 ቆ𝜇𝑖−𝜇𝑖
′𝑆−1𝐼
𝐼′𝑆−1𝐼ቇ, 
where the prime denotes transposition and 𝐼 is a column vector of 6 ones, i.e., 𝐼′ =
(1 1 1 1 1 1).  After that each vector is normalized, i.e., 𝑐𝑖= 𝑐𝑖/|𝑐𝑖|.  The resulting column 
vector 𝑐𝑖 is the optimal dose-response contrast for the 𝑖th model, 𝑖= 1 … ,7.   
 
Let 𝐶 denote the contrast matrix created from the model-specific optimal contrasts and define 
the matrix 𝐷 as 𝐷= 𝐶′𝑆𝐶.  This matrix is the covariance matrix for the optimal contrasts.   
The test statistic for assessing the significance of the optimal contrast based on the 𝑖th model 
is given by 
𝑡𝑖= 𝑐𝑖
′𝜇̂
𝑐𝑖
′𝑆𝑐𝑖
, 𝑖= 1 … ,7. 
 
These test statistics follow a multivariate 𝑡 distribution with an infinite degrees of freedom 
and correlation matrix 𝐴−1𝐷𝐴−1, where 𝐴= ඥdiag 𝐷, i.e., 𝐴 is a diagonal matrix constructed 
by finding the diagonal elements of 𝐷 and computing the square root.  
  
The set of significant dose-response models is selected by comparing each test statistic to an 
adjusted critical value 𝑞.  This critical value is found from the joint distribution of the test 
statistic under the global null distribution of no dose-response effect for any of the seven pre-
defined models.  In other words,  
𝑃(max (𝑡1, … , 𝑡7) ≥𝑞) = 𝛼, 
where 𝛼 is a one-sided Type I error rate (𝛼= 0.025).   
 
If the set of significant dose-response models is non-empty, the best dose-response model is 
chosen as the model corresponding to the most significant test statistic.  Let 𝑘 denote the 
index of the best dose-response model.  
 
Once the best dose-response model is identified, it is fitted to the covariate-adjusted mean 
effects using the method of weighted least squares (WLS), i.e., the model is fitted by 
minimizing the following WLS criterion 
(𝜇̂ −𝑓𝑘(𝑑, 𝛽))′𝑆−1(𝜇̂ −𝑓𝑘(𝑑, 𝛽)) 
with respect to the vector of model parameters 𝛽.   
 
If relevant, modelisation will be done even if no dose-response model is significant.  
5.4. Software and programming codes 
MCPMod analyses and the MED determination will be performed with the “DoseFinding” 
package using the R software. Seed parameter will be set at 1234. 
Others statistical analyses will be performed using SAS®/PC Software version 9.2.  
 
 


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6. REFERENCES 
Guideline 
ICHIC
H E14 
ICH E14 - The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic drugs - Adopted by CHMP, May 2005, issued as CHMP/ICH/2/04. 
ICHErr
eur ! 
Source 
du 
renvoi 
introuv
able. 
ICH E3 - Structure and Content of Clinical Study Reports - Adopted by CPMP, December 1995, issued as 
CPMP/ICH/137/95/step 5. 
ICHIC
H E3 
Q&A 
ICH E3 Q&A - Structure and Content of Clinical Study Reports - Questions & Answers (R1) - July 2012, 
issued as EMA/CHMP/ICH/435606/2012. 
ICHErr
eur ! 
Source 
du 
renvoi 
introuv
able. 
ICH E9 - Statistical Principles for Clinical Trials - Adopted by CPMP, March 1998, issued as 
CPMP/ICH/363/96/step 5. 
 
Qualification Opinion of MCPMod as an efficient statistical methodology for model-based design and 
analysis of Phase II dose finding studies under model uncertainty - Adopted by CHMP, 23 January 2014, 
issued as EMA/CHMP/SAWP/757052/2013 
Bibliography 
Bretz JC, Pinheiro J and Branson M. “Combining Multiple Comparisons and Modelling Techniques in Dose-
Response Studies”, September 2005, BIOMETRICS 61, 738-748. 
Bornkamp B, Pinheiro J and Bretz F. MCPMod: An R Package for the Design and Analysis of Dose-Finding 
Studies, Journal of Statistical Software, February 2009, Volume 29, Issue 7. 
Pinheiro J., Bornkamp B., Glimm E., Bretz F. (2013). Model-based dose finding under model uncertainty using 
general parametric models. Statistics in Medicine. 33, 1646-1661. 
R Development Core Team. R: A Language and Environment for Statistical Computing. R Foundation for 
Statistical Computing, Vienna, Austria 2011. URL http://www.R-project.org/, ISBN 3-900051-07-0.