Venous Leg Ulcer
Conditions
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).
Interventions
DRUGS42909 100 mg
50 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals.
DRUGS42909 200 mg
50 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals.
DRUGS42909 400 mg
200 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals.
DRUGS42909 800 mg
200 mg Film-coated tablets per os administration,twice a day taken at the end of the morning and at evening meals.
DRUGS42909 1200 mg
200 mg Film-coated tablets per os administration, twice a day taken at the end of the morning and at evening meals.
DRUGPlacebo Oral Tablet
Matching placebo tablets, per os administration, twice a day taken at the end of the morning and at evening meals.
Sponsors
Ilkos Therapeutic Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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%.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline and Week 4 | Change of reference Ulcer area measurement in cm\^2 from Baseline to Week 4. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | Up to 8 weeks | Occurring during the double-blind period of the study |
| Assessment of Laboratory Parameters | Up to 8 weeks | Biochemistry, Haematology and Fasting Lipids |
Countries
Argentina, Austria, Brazil, Canada, Czechia, Hungary, Italy, Poland, Slovakia, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A S42909 dose 100 mg p.o., 50 mg bid
S42909 100 mg: 50 mg Film-coated tablets taken orally, twice a day taken at the end of the morning and at evening meals. | 21 |
| Group B S42909 dose 200 mg p.o., 100 mg bid
S42909 200 mg: 50 mg Film-coated tablets taken orally, twice a day taken at the end of the morning and at evening meals. | 22 |
| Group C S42909 dose 400 mg p.o., 200 mg bid
S42909 400 mg: 200 mg Film-coated tablets taken orally, twice a day taken at the end of the morning and at evening meals. | 20 |
| Group D S42909 dose 800 mg p.o., 400 mg bid
S42909 800 mg: 200 mg Film-coated tablets taken orally,twice a day taken at the end of the morning and at evening meals. | 19 |
| Group E S42909 dose 1200 mg p.o., 600 mg bid
S42909 1200 mg: 200 mg Film-coated tablets taken orally, twice a day taken at the end of the morning and at evening meals. | 19 |
| Group F Placebo p.o. bid
Placebo Oral Tablet: Matching placebo tablets taken orally, twice a day taken at the end of the morning and at evening meals. | 20 |
| Total | 121 |
Baseline characteristics
| Characteristic | Total | Group A | Group B | Group C | Group D | Group E | Group F |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 64 Participants | 12 Participants | 10 Participants | 8 Participants | 15 Participants | 10 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 57 Participants | 9 Participants | 12 Participants | 12 Participants | 4 Participants | 9 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 121 Participants | 21 Participants | 22 Participants | 20 Participants | 19 Participants | 19 Participants | 20 Participants |
| Region of Enrollment Argentina | 11 participants | 0 participants | 4 participants | 1 participants | 2 participants | 2 participants | 2 participants |
| Region of Enrollment Austria | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Region of Enrollment Brazil | 13 participants | 3 participants | 3 participants | 2 participants | 2 participants | 1 participants | 2 participants |
| Region of Enrollment Canada | 2 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Czechia | 26 participants | 4 participants | 4 participants | 4 participants | 5 participants | 4 participants | 5 participants |
| Region of Enrollment Hungary | 8 participants | 2 participants | 2 participants | 1 participants | 0 participants | 2 participants | 1 participants |
| Region of Enrollment Italy | 13 participants | 2 participants | 2 participants | 2 participants | 3 participants | 2 participants | 2 participants |
| Region of Enrollment Poland | 2 participants | 1 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Region of Enrollment Slovakia | 26 participants | 5 participants | 4 participants | 6 participants | 4 participants | 3 participants | 4 participants |
| Region of Enrollment Spain | 11 participants | 2 participants | 2 participants | 1 participants | 1 participants | 3 participants | 2 participants |
| Region of Enrollment United States | 8 participants | 1 participants | 1 participants | 2 participants | 1 participants | 2 participants | 1 participants |
| Sex: Female, Male Female | 66 Participants | 10 Participants | 9 Participants | 10 Participants | 13 Participants | 14 Participants | 10 Participants |
| Sex: Female, Male Male | 55 Participants | 11 Participants | 13 Participants | 10 Participants | 6 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 22 | 0 / 20 | 0 / 19 | 0 / 19 | 0 / 20 |
| other Total, other adverse events | 4 / 21 | 6 / 22 | 8 / 20 | 6 / 19 | 8 / 19 | 6 / 20 |
| serious Total, serious adverse events | 2 / 21 | 0 / 22 | 1 / 20 | 1 / 19 | 0 / 19 | 0 / 20 |
Outcome results
Primary
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.
Time frame: Baseline and Week 4
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group A | 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 | -52.85 cm2 | Standard Deviation 37.79 |
| Group B | 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 | -46.42 cm2 | Standard Deviation 33.3 |
| Group C | 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 | -31.07 cm2 | Standard Deviation 38.73 |
| Group D | 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 | -43.33 cm2 | Standard Deviation 28.37 |
| Group E | 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 | -41.10 cm2 | Standard Deviation 33.99 |
| Group F | 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 | -41.23 cm2 | Standard Deviation 43.71 |
Secondary
Adverse Events
Occurring during the double-blind period of the study
Time frame: Up to 8 weeks
Secondary
Assessment of Laboratory Parameters
Biochemistry, Haematology and Fasting Lipids
Time frame: Up to 8 weeks