Clinical trial NCT03257098: Allogeneic ABCB5-positive Stem Cells for Treatment of CVU
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Skin Ulcer Venous Stasis Chronic
Keywords: Chronic Venous Ulcer
ABCB5
Allogeneic
Mesenchymal stem cells
varicose ulcer
skin ulcer
advanced therapy medicinal product
somatic cell therapy
phase I/IIa
Lead sponsor: RHEACELL GmbH & Co. KG
Sponsor class: INDUSTRY
Collaborators: name: FGK Clinical Research GmbH
name: Ticeba GmbH
name: Granzer Regulatory Consulting & Services
First posted: 2017-08-22
Enrollment: 31
Sex: ALL
Minimum age (years): 35
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Interventional, single arm, multicenter, phase I/IIa clinical trial
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of wound size reduction
timeFrame: Week 12 post baseline, or last available post-baseline measurement if the Week 12 measurement is missing
measure: Assessment of adverse event (AE) occurrence
timeFrame: Up to 12 months
Secondary outcomes:
measure: Percentage of wound size reduction
timeFrame: Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12 (without LOCF);
measure: Absolute wound size reduction
timeFrame: Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12
measure: Proportion of patients achieving complete wound closure
timeFrame: Weeks 2, 3, 4, 6, 8, 10, 12, and at any time point
measure: Time to first complete wound closure
timeFrame: A priori specification not possible; between baseline and week 12 post baseline
measure: Proportion of patients achieving 30% wound closure
timeFrame: Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, 12, and at any time point
measure: Time to first 30% wound closure
timeFrame: A priori specification not possible; between baseline and week 12 post baseline
measure: Epithelialization
timeFrame: Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12
measure: Assessment of further wound healing parameters: formation of granulation tissue and wound exudation
timeFrame: 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
measure: Pain assessment as per numerical rating scale (NRS)
timeFrame: Days 0, 1 to 3 and 8, Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12
measure: Assessment of quality of life (QoL) using the short form 36 (SF-36) questionnaire
timeFrame: Day 0 and Weeks 4, 8 and 12
measure: Assessment of dermatology-specific quality of life based on the Dermatology Life Quality Index (DLQI) questionnaire
timeFrame: Day 0 and Weeks 4, 8 and 12
measure: Physical examination and vital signs at Week 6.1 and Week 12
timeFrame: Week 6.1 and Week 12
Other outcomes:
Locations:
city: Bochum
country: Germany
facility: Venenzentrum der Dermatologischen und Gefäßchirurgischen Kliniken, Kliniken der Ruhr-Universität Bochum im St. Maria Hilf Krankenhaus
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen, Hautklinik
city: Greifswald
country: Germany
facility: Klinik und Poliklinik für Hautkrankheiten, Universitätsmedizin Greifswald
city: Hamburg
country: Germany
facility: Klinische Forschung Hamburg GmbH, Dermatologie / Allergologie
city: Kiel
country: Germany
facility: pro scientia med im Mare Klinikum; Department Klinische Forschung und Entwicklung
city: Münster
country: Germany
facility: Universitätsklinikum Münster, Klinik für Hautkrankheiten, Allgemeine Dermatologie und Venerologie
city: Schwerin
country: Germany
facility: Klinische Forschung Schwerin GmbH
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm, Klinik für Dermatologie und Allergologie
city: Würzburg
country: Germany
facility: Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg
Study officials:
affiliation: Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Würzburg
name: Andreas Kerstan, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.