Allogeneic ABCB5-positive Stem Cells for Treatment of CVU

An Interventional, Single Arm, Multicenter, Phase I/IIa Clinical Trial to Investigate the Efficacy and Safety of Allo-APZ2-CVU on Wound Healing of Chronic Venous Ulcer (CVU)

The aim of this clinical trial is to investigate the efficacy (by monitoring the wound size reduction of Chronic Venous Ulcers) and safety (by monitoring adverse events) of the medicinal product to be studied after two applications on the wound surface in patients with Chronic Venous Ulcers.

Study Overview

• Status: Completed
• Conditions: Skin Ulcer Venous Stasis Chronic
• Intervention / Treatment: Biological: allo-APZ2-CVU

Detailed Description

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 chronic venous ulcer (CVU). Allogeneic MSCs will be isolated ex vivo and will be expanded in vitro. The IMP incorporating the ABCB5-positive MSCs will then be applied on the wound surface of CVU under local anesthesia (on Day 0 and Week 6.1).

Wound measurements from Visit (V) 2 and V9 will be used to determine the cell amount for the IMP treatments on V3 and V10, respectively.

Patients are followed up for efficacy for 3 months which allows to distinguish actual wound healing from transient wound coverage.

The wound healing process will be documented by standardized photography. The wound size evaluation will start on the day of the first change of wound dressing. 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-CVU three follow-up visits at Months 6, 9 and 12 after the first IMP applications are included.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Bochum, Germany, 44805
    • Venenzentrum der Dermatologischen und Gefäßchirurgischen Kliniken, Kliniken der Ruhr-Universität Bochum im St. Maria Hilf Krankenhaus
  • Erlangen, Germany, 91054
    • Universitätsklinikum Erlangen, Hautklinik
  • Greifswald, Germany, 17475
    • Klinik und Poliklinik für Hautkrankheiten, Universitätsmedizin Greifswald
  • Hamburg, Germany, 20253
    • Klinische Forschung Hamburg GmbH, Dermatologie / Allergologie
  • Kiel, Germany, 24119
    • pro scientia med im Mare Klinikum; Department Klinische Forschung und Entwicklung
  • Münster, Germany, 48149
    • Universitätsklinikum Münster, Klinik für Hautkrankheiten, Allgemeine Dermatologie und Venerologie
  • Schwerin, Germany, 19055
    • Klinische Forschung Schwerin GmbH
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm, Klinik für Dermatologie und Allergologie
  • Würzburg, Germany, 97080
    • Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 33 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients aged 35 to 85 years;
2. Chronic venous leg ulcer (as defined by the current AWMF guidelines: therapy resistant ulcer that shows no improvement within 3 months despite of optimal phlebological therapies or is not healed within 12 months) diagnosed by doppler ultrasonography (DUS), ankle brachial index (ABI, 0.9-1.3), physical examination and dermatological review;
3. Wound size of target ulcer between 1.5 and 100 cm2 measured by a standardized photography at the screening visits (Visit 1 and Visit 2);
4. Wound location below knee;
5. If patients are suffering from 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);
6. Body mass index (BMI) between 20 and 45 kg/m²;
7. Patients understand the nature of the procedure and are providing written informed consent prior to any clinical trial procedure;
8. Women of childbearing potential must have a negative blood pregnancy test at Visit 1
9. 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:

1. Evidence of the ulcer extending to the underlying muscle, tendon, or bone;
2. Current use of systemic steroid medication above Cushing threshold dose (>7.5 mg/d prednisone or equivalent);
3. Diabetes mellitus that has to be evaluated by blood test (Haemoglobin A1c [HbA1c] >7.5%);
4. Peripheral Artery Disease (PAD) including claudication with need of treatment;
5. Acute deep vein thrombosis (maximum 30 days from diagnosis) or a still untreated deep vein thrombosis;
6. Unable to tolerate leg ulcer compression bandage;
7. Infection of the target ulcer requiring treatment as judged clinically;
8. Any chronic dermatological disorders diagnosed at the investigator's discretion;
9. Skin disorders, unrelated to the ulcer, that are present adjacent to the target wound;
10. Current use of medications that influence wound healing: systemic immunosuppressives, cytotoxic medicinal products, and systemic steroids (above Cushing-threshold level);
11. Known abuse of alcohol, drugs, or medicinal products;
12. Cancerous or pre-cancerous lesions adjacent to the target wound;
13. Patients anticipated to be unwilling or unable to comply with the requirements of the protocol;
14. Pregnant or lactating women;
15. Systemic infectious disease diagnosed by serology testing human immunodeficiency virus (HIV˗1, HIV-2);
16. Any known allergies to components of the IMP;
17. Prior surgical procedures such as bypass or mesh-graft treatment within 2 months prior to Visit 1;
18. Patients with significant ulcer healing or wound size enlargement of more than 25% at Visit 2 compared to Visit 1;
19. Treatment of target ulcer with active wound care agents (e.g. iruxol, local antibiotics or silver dressings), which have not been paused 14 days before IMP application;
20. Current or previous (within 30 days of enrollment) treatment with another IMP, or participation and/or under follow-up in another clinical trial;
21. Previous participation in this clinical trial (except for screening failures due to an inclusion or exclusion criterion);
22. 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;
23. Employees of the sponsor, or employees or relatives of the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: allo-APZ2-CVU; Application of IMP on patients wound	Biological: allo-APZ2-CVU; Suspension of ABCB5-positive mesenchymal stem cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of wound size reduction	Percentage of wound size reduction at Week 12, or last available post-baseline measurement of Weeks 6, 8 or 10 if the Week 12 measurement is missing (last observation carried forward [LOCF]).	Week 12 post baseline, or last available post-baseline measurement 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	Time Frame
Percentage of wound size reduction	Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12 (without LOCF);
Absolute wound size reduction	Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12
Proportion of patients achieving complete wound closure	Weeks 2, 3, 4, 6, 8, 10, 12, and at any time point
Time to first complete wound closure	A priori specification not possible; between baseline and week 12 post baseline
Proportion of patients achieving 30% wound closure	Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, 12, and at any time point
Time to first 30% wound closure	A priori specification not possible; between baseline and week 12 post baseline
Epithelialization	Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12
Assessment of further wound healing parameters: formation of granulation tissue and wound exudation	Visit 3 and Visit 10 before IMP application, Days 1 to 3 and 8, Weeks 2, 3, 4, 6, 6.2, 8, 10, and 12
Pain assessment as per numerical rating scale (NRS)	Days 0, 1 to 3 and 8, Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12
Assessment of quality of life (QoL) using the short form 36 (SF-36) questionnaire	Day 0 and Weeks 4, 8 and 12
Assessment of dermatology-specific quality of life based on the Dermatology Life Quality Index (DLQI) questionnaire	Day 0 and Weeks 4, 8 and 12
Physical examination and vital signs at Week 6.1 and Week 12	Week 6.1 and Week 12

Collaborators and Investigators

• Sponsor: RHEACELL GmbH & Co. KG
• Collaborators: FGK Clinical Research GmbH; Ticeba GmbH; Granzer Regulatory Consulting & Services
• Investigators: Principal Investigator: Andreas Kerstan, Dr., Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Würzburg

Publications and helpful links

General Publications

• Kerstan A, Niebergall-Roth E, Esterlechner J, Schroder HM, Gasser M, Waaga-Gasser AM, Goebeler M, Rak K, Schrufer P, Endres S, Hagenbusch P, Kraft K, Dieter K, Ballikaya S, Stemler N, Sadeghi S, Tappenbeck N, Murphy GF, Orgill DP, Frank NY, Ganss C, Scharffetter-Kochanek K, Frank MH, Kluth MA. Ex vivo-expanded highly pure ABCB5+ mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data. Cytotherapy. 2021 Feb;23(2):165-175. doi: 10.1016/j.jcyt.2020.08.012. Epub 2020 Oct 1.

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2017
• Primary Completion (Actual): June 25, 2020
• Study Completion (Actual): June 25, 2020

Study Registration Dates

• First Submitted: August 17, 2017
• First Submitted That Met QC Criteria: August 17, 2017
• First Posted (Actual): August 22, 2017

Study Record Updates

• Last Update Posted (Actual): September 10, 2020
• Last Update Submitted That Met QC Criteria: September 9, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Allogeneic; Mesenchymal stem cells; varicose ulcer; Chronic Venous Ulcer; ABCB5; skin ulcer; advanced therapy medicinal product; somatic cell therapy; phase I/IIa
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Leg Ulcer; Varicose Veins; Ulcer; Varicose Ulcer; Skin Ulcer
• Other Study ID Numbers: allo-APZ2-CVU-II-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No