Allogeneic ABCB5-positive Stem Cells for Treatment of DFU Malum Perforans

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 surface area reduction of Diabetic Foot Ulcers) and safety (by monitoring adverse events) of two doses of the allogeneic investigational medicinal product allo-APZ2-DFU topically administered to the wound matrix of patients with diabetic neuropathic ulcer.

Detailed Description
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This is an interventional, single arm, phase I/IIa clinical trial to investigate the efficacy and safety of allogeneic ABCB5-positive mesenchymal stem cells (MSCs) on wound healing in patients with diabetic neuropathic ulcer. Allogeneic MSCs will be isolated ex vivo and will be expanded in vitro. The Investigational medicinal product (IMP) containing the ABCB5-positive MSCs will then be applied two times (at Visit 3 and six weeks later, at Visit 10) on the wound surface of DFU. Patients are followed up for efficacy for a period of three months starting after the first IMP application which allows to distinguish actual wound healing from transient wound coverage. The wound healing process will be documented by standardized photography. The wound size reduction evaluation will start two weeks after the first IMP application. The quality of the wound healing process will be assessed on the basis of formation of granulation tissue, epithelialization and wound exudation. Pain will be assessed using a numerical rating scale and quality of life will be investigated with standardized and validated questionnaires. To assess long-term safety of allo-APZ2-DFU three follow-up visits at Months 6, 9 and 12 after the first IMP application are included.

Official Title
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An Interventional, Multicenter, Single Arm, Phase I/IIa Clinical Trial to Investigate the Efficacy and Safety of Allo-APZ2-DFU on Wound Healing of Diabetic Neuropathic Ulcer (DFU)

Conditions
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Diabetic Neuropathic Ulcer

Intervention / Treatment
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* Biological: allo-APZ2-DFU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged 18 to 85 years; Patients with an existing diagnosis of diabetic mellitus Type 2, evaluated by blood test [HbA1c] < 11%) at the Screening visit (Visit 1). The HbA1c value at visit 1 should not vary more than 1.5% (absolute range) compared to a HbA1c value that was previously measured 1 to 6 months before visit 1; The presence of diabetic neuropathic ulcers malum perforans (Grade I and II according to Wagner) at plantar site of the foot diagnosed by ABI ≥0.7, without claudication, or TcPO2 >40 mmHg or doppler ultrasonography (at the discretion of the investigator) to exclude significant arterial diseases and critical limb ischemia, and a diabetic neuropathy test using a 128 Hz vibration tuning fork according to Rydel-Seiffer (as described by Guideline Nationale Versorgungsleitlinie - Neuropathie bei Diabetes im Erwachsenenalter). If the ABI is >1.3, an additional doppler ultrasonography must be performed to exclude a PAOD masked by media sclerosis; At Screening Visit 1 and 2 the wound surface area of the target ulcer should be between 1 and 50 cm2 measured by using a scaled measuring sensor in combination with digital image analysis; The ulcer's surface area should be (mostly) free from callus or necrotic tissue; If patients are suffering from two or more ulcers at the same extremity, the target ulcer has to be separated by a minimum bridge of 1 cm of healthy tissue from other ulcers; Patients are willing and able to wear therapeutic shoes that are especially designed for patients with a diabetic neuropathic foot; Body mass index (BMI) between 20 and 45 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 must be willing to use highly effective contraceptive methods during the course of the clinical trial. Exclusion Criteria: Presence of acute Charcot foot; Clinical signs of active osteomyelitis in the last three months; Active wet gangrenous tissue; Infection of the target ulcer requiring treatment as judged clinically; Presence of an ulcer Grade ≥3 according to Wagner on the same foot as target ulcer; Patients who are currently receiving dialysis; Peripheral arterial occlusive disease (PAOD) including claudication with need of treatment; Ulcers due to non-diabetic etiology; Prior surgical procedures such as bypass or mesh-graft treatment within 2 months prior to IMP application; Acute deep vein thrombosis (maximum 30 days from diagnosis) or a still untreated deep vein thrombosis; Any chronic dermatological disorders diagnosed at the investigator's discretion; Skin disorders, unrelated to the ulcer, that are present adjacent to the target wound; Treatment of target wound with active wound care agents (e.g. iruxol, local antibiotics or silver dressings), which have not been stopped 14 days before IMP application; 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; Current use of steroid medication above Cushing threshold dose (>7.5 mg/d prednisone or equivalent); Known abuse of alcohol, drugs, or medicinal products; Patients anticipated to be unwilling or unable to comply with the requirements of the protocol; Pregnant or lactating women; Patients infected with the human immunodeficiency virus (HIV 1&2); Any known allergies to components of the IMP or concomitant medication; Current or previous (within 30 days of enrollment) treatment with another IMP, or participation and/or under follow-up in another clinical trial; Evidence of any other medical conditions (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; Employees of the sponsor, or employees or relatives of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Intervention Model: Single Group Assignment
Interventional Model Description: Single Group Assignment Interventional, single arm, multicenter, phase I/IIa clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: allo-APZ2-DFU<br>Application of IMP on patients wound | Biological: allo-APZ2-DFU<br>* Suspension of ABCB5-positive mesenchymal stem cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of wound surface area reduction | Percentage of wound surface area reduction at Week 12, or last available post-baseline measurement of weeks 4, 6 or 8, if the Week 12 measurement is missing (last observation carried forward [LOCF]). | Week 12, or last available post-baseline measurement of weeks 4, 6 or 8 if the Week 12 measurement is missing. | 
| Assessment of adverse event (AE) occurrence | All AEs occurring during the clinical trial will be registered, documented and evaluated. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of wound surface area reduction | Percentage of wound surface area reduction will be evaluated. | Weeks 2, 4, 6, 8 and 12 (without LOCF) | 
| Percentage of invisible and visible wound surface area reduction | Percentage of invisible and visible wound surface area reduction will be evaluated. | Weeks 2, 4, 6, 8 and 12 (without LOCF) | 
| Absolute wound surface area reduction | Absolute wound surface area reduction will be evaluated. | Weeks 2, 4, 6, 8 and 12 (without LOCF) | 
| Absolute invisible and visible wound surface area reduction | Absolute invisible and visible wound surface area reduction will be evaluated. | Weeks 2, 4, 6, 8 and 12 (without LOCF) | 
| Assessment of wound infection | Wound infection will be evaluated. | Days 1 and 2, Weeks 1, 2, 4, 6, 6.1, 6.2, 6.3, 8 and 12 | 
| Time to first complete wound closure | Time to first complete wound closure will be evaluated. | A priori specification not possible; between baseline and week 12 post baseline | 
| Proportion of patients achieving complete wound closure | Proportion of patients achieving complete wound closure will be evaluated. | Weeks 2, 4, 6, 8 and 12 | 
| Time to first 30% reduction of wound surface area | Time to first 30% reduction of wound surface area will be evaluated. | A priori specification not possible; between baseline and week 12 post baseline | 
| Proportion of patients achieving 30% reduction of wound surface area | Proportion of patients achieving 30% reduction of wound surface area will be evaluated. | Weeks 2, 4, 6, 8 and 12 | 
| Assessment of wound exudation, epithelialization and formation of granulation tissue | Wound exudation, epithelialization and formation of granulation tissue will be evaluated. | Day 0 and Week 6.1 prior IMP-application, at Weeks 1, 2, 4, 6, 8 and 12 | 
| Time to amputation at target leg until Week 12 | Time to amputation at target leg until week 12 will be evaluated. | A priori specification not possible; between baseline and week 12 post baseline | 
| Pain assessment as per numerical rating scale (NRS) | Pain assessment as per numerical rating scale (NRS) will be evaluated. | At both Screening Visits, at Days 0, 1 and 2 and at Weeks 1, 2, 4, 6, 6.1, 6.2, 6.3, 8 and 12 | 
| Assessment of Quality of life (QoL) using the short form 36 (SF-36) questionnaire | Quality of life (QoL) using the short form 36 (SF-36) questionnaire will be evaluated. | Screening Visit 1, Visit 3, at Weeks 4 and 12 | 
| Assessment of Dermatology-specific QoL based on the Dermatology Life Quality Index (DLQI) questionnaire | Dermatology-specific QoL based on the Dermatology Life Quality Index (DLQI) questionnaire will be evaluated. | Screening Visit 1, Visit 3, at Weeks 4 and 12 | 
| Physical examination and vital signs | Physical examination and vital signs will be evaluated. | Week 6.1 and Week 12 | 
| Time to amputation of target leg until month 12 | Time to amputation of target leg until month 12 will be evaluated. | A priori specification not possible; between baseline and month 12 post baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetic neuropathic ulcer, ABCB5, allogeneic, mesenchymal stem cells, skin ulcer, advanced therapy medicinal product, somatic cell therapy, phase I/IIa, Diabetic Foot Ulcer