Allogeneic ABCB5-positive Dermal Mesenchymal Stromal Cells for Treatment of CVU (Phase IIb)

Study Overview
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Brief Summary
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The aim of this clinical trial is to investigate the efficacy (by monitoring the wound size reduction of CVUs) and safety (by monitoring adverse events [AEs]) of three dose groups of the investigational medicinal product (IMP) allo-APZ2-CVU, topically administered on target wounds of patients with CVU compared to placebo.

Detailed Description
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This is a randomized, placebo-controlled, double-blind, dose-ranging, multicenter, phase IIb clinical trial to investigate the efficacy and safety of the IMP allo-APZ2-CVU on wound healing in patients with therapy-resistant CVU. The allogeneic IMP allo-APZ2-CVU contains skin-derived ABCB5-positive dermal mesenchymal stromal cells isolated from skin tissue of healthy donors and stored in a donor cell bank. Patients will be randomized to be treated with allo-APZ2-CVU (dose 1, dose 2, dose 3) or placebo (50 patients per dose group). The patients will undergo treatment with the IMP on Day 0 (V3) and will be followed up for efficacy for 18 weeks (V4 until V14). Two safety follow-up visits will be performed at Month 6 (V15) and Month 10 (V16). The wound healing process will be documented by standardized photography. The wound size measurement will start at the first Screening Visit (V1) and will be measured at each following on-site visit. Pain will be assessed using a numerical rating scale and quality of life will be investigated with standardized and validated questionnaires.

Official Title
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A Randomized, Placebo-Controlled, Double-blind, Dose-Ranging, Multicenter, Phase IIb Clinical Trial to Investigate the Efficacy and Safety of Allo-APZ2-CVU on Wound Healing of Therapy-Resistant Chronic Venous Ulcer (CVU)

Conditions
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Skin Ulcer Venous Stasis Chronic

Intervention / Treatment
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* Biological: allo-APZ2-CVU
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients at least 18 years old; Chronic venous leg ulcer (as defined by the current AWMF guidelines: therapy-resistant ulcer that shows no tendency to heal within 3 months despite of optimal phlebological therapies or has not fully healed within 12 months) at lower leg and/or ankle region and has not been present longer than 15 years, diagnosed by doppler or duplex sonography, ankle brachial index (ABI, 0.9-1.3), physical examination and dermatological review; Wound size of target ulcer between 1 and 50 cm² measured by a standardized photography at the screening visit; If patients have 2 or more ulcers at the same extremity, the target ulcer has to be separated by a minimum bridge of 1 cm of epithelialized skin from other ulcers (the largest ulcer should be the target ulcer, if not decided otherwise at discretion of the investigator; the target ulcer is defined at Visit 1); Body mass index between 15 and 50 kg/m²; Patients understand the nature of the procedure and are providing written informed consent prior to any clinical trial procedure; Women of childbearing potential must have a negative blood pregnancy test at Visit 1; Women of childbearing potential and their partner must be willing to use highly effective contraceptive methods during the course of the clinical trial. Exclusion Criteria: Evidence of the ulcer extending to the underlying muscle, tendon, or bone; Diabetes mellitus that has to be confirmed by blood test (Hemoglobin A1c >7.5%); Peripheral Artery Disease including claudication with need of treatment; Acute deep vein thrombosis (maximum 30 days from diagnosis) or a still untreated deep vein thrombosis; Unable to tolerate leg ulcer compression bandage; Infection of the target ulcer requiring treatment as judged clinically; All diagnosed disorders, unrelated to CVU, that are influencing wound healing of the target wound at investigator's discretion; Current use of medications that influence wound healing: systemic immunosuppressives, cytotoxic medicinal products, and systemic steroids (above Cushing-threshold level); Patient who, in the opinion of the investigator, for any reason are unable or unwilling to complete the trial per protocol (e.g. alcohol or substance abuse, not mobile, short life expectancy) or there is evidence of any other medical condition (such as psychiatric illness, physical examination, or laboratory findings) that may interfere with the planned treatment, affect the patient's compliance, or place the patient at high risk of complications related to the treatment; Any malignancy within the past 5 years, excluding successfully treated carcinoma in situ, basal cell carcinoma or squamous cell carcinoma of the skin without evidence of metastases; Pregnant or lactating women; Any known allergies to components of the IMP; Prior surgical procedures such as bypass or mesh-graft treatment at target leg within 2 months prior to Visit 1 at target leg; Patients with significant ulcer healing or wound size enlargement of more than 25% at Visit 2 compared to Visit 1; Treatment of target ulcer with active wound care agents (e.g. Iruxol®N), which have not been paused 14 days before IMP application; Current or previous (within 30 days of enrollment) treatment with another IMP, or participation and/or under follow-up in another clinical trial; Previous participation in this clinical trial (except for screening failures due to an inclusion or exclusion criterion); Employees of the sponsor, or employees or relatives of the investigator.

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
Interventional Model Description: Randomized, placebo-controlled, double-blind, dose-ranging, interventional, multicenter, phase IIb clinical trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: allo-APZ2-CVU (dose group 1: 1 x 10e6 cells/cm²)<br>Application of IMP on patients wound | Biological: allo-APZ2-CVU<br>* Suspension of ABCB5-positive dermal mesenchymal stromal cells. One topical application with a syringe.<br>* Other names: Skin-derived ABCB5-positive dermal mesenchymal stromal cells;|
| Placebo Comparator: Placebo<br>Application of IMP on patients wound | Drug: Placebo<br>* One topical application with a syringe<br>|
| Experimental: allo-APZ2-CVU (dose group 2: 3 x 10e6 cells/cm²)<br>Application of IMP on patients wound | Biological: allo-APZ2-CVU<br>* Suspension of ABCB5-positive dermal mesenchymal stromal cells. One topical application with a syringe.<br>* Other names: Skin-derived ABCB5-positive dermal mesenchymal stromal cells;|
| Experimental: allo-APZ2-CVU (dose group 3: 6 x 10e6 cells/cm²)<br>Application of IMP on patients wound | Biological: allo-APZ2-CVU<br>* Suspension of ABCB5-positive dermal mesenchymal stromal cells. One topical application with a syringe.<br>* Other names: Skin-derived ABCB5-positive dermal mesenchymal stromal cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete wound closure at Week 18 already persisting for at least two weeks | Complete wound closure at Week 18 already persisting for at least two weeks will be evaluated. | Week 18 | 
| Assessment of adverse event (AE) occurrence | All AEs occurring during the clinical trial will be registered, documented and evaluated. | Up to 10 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wound size change in percent at each post-baseline follow-up visit | Wound size change in percent at each post-baseline follow-up visit will be evaluated. | Day 1-2, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, Month 6 and 10 | 
| Time to complete wound closure | Time to complete wound closure will be evaluated. | Day 1-2, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, Month 6 and 10 | 
| Complete wound closures at each post-baseline follow-up visit | Complete wound closures at each post-baseline follow-up visit will be evaluated. | Day 1-2, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, Month 6 and 10 | 
| Duration of wound closure | Duration of wound closure will be evaluated. | Day 1-2, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, Month 6 and 10 | 
| Recurrence of the wound | Recurrence of the wound will be evaluated. | Day 1-2, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, Month 6 and 10 | 
| Quality of wound healing (wound exudate) at each post-baseline follow-up visit | The Quality of wound healing will be assessed at each post-baseline follow-up visit on the basis of the amount and type of wound exudate. | Day 1-2, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, Month 6 and 10 | 
| Quality of wound healing (granulation tissue together with epithelialization) at each post-baseline follow-up visit | The Quality of wound healing will be assessed at each post-baseline follow-up visit on the basis of the formation of granulation tissue together with epithelialization. | Day 1-2, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, Month 6 and 10 | 
| Quality of wound healing (scar formation) at each post-baseline follow-up visit | The Quality of wound healing will be assessed at each post-baseline follow-up visit on the basis of the questions regarding scar formation. | Day 1-2, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, Month 6 and 10 | 
| Assessment of Quality of Life using the Wound-Quality of Life Questionnaire at V8, V11, V14 | Quality of Life using the Wound-Quality of Life Questionnaire at V8, V11, V14 will be evaluated. | Week 6, 12, 18 | 
| Pain assessment as per numerical rating scale on each post-baseline efficacy follow-up visit | Pain assessment as per numerical rating scale on each post-baseline efficacy follow-up visit will be evaluated. | Day 1-2, Week 1, 2, 4, 6, 8, 10, 12, 14, 16, Month 6 and 10 | 
| Physical examination and vital signs at V14 | A physical body examination (e.g. general appearance, thyroid, head, lungs and thorax, ears, cardiovascular system, eyes, abdomen, nose-mouth-throat, musculoskeletal system, skin, extremities, lymph nodes, neurological system) will be performed and abnormal physical examination results will be evaluated and reported as AEs. | Week 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Venous Ulcer, ABCB5, Allogeneic, Dermal mesenchymal stromal cells, varicose ulcer, skin ulcer, advanced therapy medicinal product, somatic cell therapy, phase IIb