Dose-response Relationship Study of S42909 on Leg Ulcer Healing

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

Detailed Description
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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).

Official Title
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A 10-week Randomized, Double-blind, Placebo-controlled, Prospective, International, Multicentre, Phase IIa Study of S42909 on Leg Ulcer Healing.

Conditions
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Venous Leg Ulcer

Intervention / Treatment
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* Drug: S42909 100 mg
* Drug: S42909 200 mg
* Drug: S42909 400 mg
* Drug: S42909 800 mg
* Drug: S42909 1200 mg
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian (defined for this study as having 2 Caucasian parents), men or women Age ≥ 18 years old 18.5 kg/m2 ≤ BMI ≤ 45.0 kg/m2 (= Weight (kg) / height² (m²)) Patients with chronic venous disease documented by imaging to detect a venous disorder in one or both the sub- and extra-fascial venous systems. The examination performed within 6 months before selection can be used. 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. Patients with bilateral ulcerations or multiple ulcerations on one or both legs are eligible for selection. 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 at the selection visit and ≥ 4.5 cm2 and ≤ 100 cm2 at the inclusion visit (measured by transparent sheet and confirmed with the digital 3D imaging device). Ankle Brachial Pressure Index (ABPI) ≥ 0.8 and ≤ 1.3 measured by Doppler ultrasound. Exclusion Criteria: Unlikely or unwilling to be compliant to standardized compression recommendation, study medication and visits, previous records of poor compliance to compression stockings. Inadequately controlled type 1 and type 2 diabetes with an HbA1c > 8%.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>S42909 dose 100 mg p.o., 50 mg bid | Drug: S42909 100 mg<br>* 50 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals.<br>|
| Experimental: Group B<br>S42909 dose 200 mg p.o., 100 mg bid | Drug: S42909 200 mg<br>* 50 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals.<br>|
| Experimental: Group C<br>S42909 dose 400 mg p.o., 200 mg bid | Drug: S42909 400 mg<br>* 200 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals.<br>|
| Experimental: Group D<br>S42909 dose 800 mg p.o., 400 mg bid | Drug: S42909 800 mg<br>* 200 mg Film-coated tablets per os administration,twice a day taken at the end of the morning and at evening meals.<br>|
| Experimental: Group E<br>S42909 dose 1200 mg p.o., 600 mg bid | Drug: S42909 1200 mg<br>* 200 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals.<br>|
| Placebo Comparator: Group F<br>Placebo p.o. bid | Drug: Placebo Oral Tablet<br>* Matching placebo tablets, per os administration, twice a day taken at the end of the morning and at evening meals.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Reduction of Reference Ulcer Area After 4 Weeks of Treatment on Top of Standard of Care Compared With Baseline Reference Ulcer Area (W000) Assessed During Study Visits | Change of reference Ulcer area measurement in cm^2 from Baseline to Week 4. | Baseline and Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Occurring during the double-blind period of the study | Up to 8 weeks | 
| Assessment of Laboratory Parameters | Biochemistry, Haematology and Fasting Lipids | Up to 8 weeks |