Allogeneic ABCB5-positive Stem Cells for Treatment of Epidermolysis Bullosa

An Interventional, Multicenter, Single Arm, Phase I/IIa Clinical Trial to Investigate the Efficacy and Safety of Allo-APZ2-EB on Epidermolysis Bullosa (EB)

The aim of this clinical trial is to investigate the efficacy (by monitoring overall improvement of EB symptoms) and safety (by monitoring adverse events) of three doses of allo-APZ2-EB administered intravenously to patients with recessive dystrophic epidermolysis bullosa (RDEB).

Study Overview

• Status: Completed
• Conditions: Recessive Dystrophic Epidermolysis Bullosa
• Intervention / Treatment: Biological: allo-APZ2-EB

Detailed Description

This is an interventional, single arm, non-randomized, open label, phase I/IIa clinical trial to investigate the efficacy and safety of the IMP allo-APZ2-EB in patients with RDEB.

Patients will undergo treatment with the IMP (three repeated intravenous applications) and will be followed up for efficacy for 12 weeks. To assess long-term safety of allo-APZ2-EB one follow-up visit at Month 12 and one follow-up visit at Month 24 post IMP applications is included.

Determination of the EB linked symptoms and quality of life will be assessed by using the EBDASI score, the iscorEB, the change in pain and itch perception, and patient's quality of life in EB. The wound healing process will be documented by photography.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria, 5020
    • EB-Haus Austria; Salzburger Landeskliniken (SALK); Paracelsus Medizinische Privatuniversität Salzburg (PMU)
• France
  • Paris, France, 75010
    • Hôpital Saint-Louis; Département de dermatologie
• Germany
  • Freiburg, Germany, 79104
    • Department of Dermatology, Medical Center-University of Freiburg
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • King's College London; St John's Institute of Dermatology;
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital; Dermatology Department
• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota, Masonic Cancer Center and Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 55 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients aged between 0 and ≤55 years;

Staggered design for patient enrollment:

1. at least 3 adult patients (safety assessment 2 weeks after last treatment of third patient),
2. at least 3 patients ≥12 to <18 years (safety assessment 2 weeks after first treatment of third patient),
3. at least 3 patients ≥5 to <12 years (safety assessment 2 weeks after first treatment of third patient), and
4. at least 3 patients ≥12 months to <5 years;
5. patients 0 to <12 months (only in the UK);

2. Diagnosed with RDEB (combined diagnosis by genotype assessment [mutation analysis] and correlating phenotype assessment [wound assessment]), patients must have a negative immunofluorescence test result on salt-split skin against proteins of the basement membrane at Visit 1 (existing test results will be accepted);

3. Patient is eligible to participate in this clinical trial based on general health condition at the investigator's discretion;

US only:

Patient is eligible to participate in this clinical trial based on general health condition assessed by specific lab values (Hematology: Absolute neutrophil count >1000/mm3 and platelet count >150,000/mcL; Coagulation: PT and PTT <2x the upper limit of normal for age; Hepatic: AST and ALT <2x the upper limit of normal for age; Renal: Creatinine <2x the upper limit of normal for age; Pulmonary: Oxygen saturation >92% on room air and without supplemental oxygen requirement);

4. Patient/legal representative understands the nature of the procedure and are providing written informed consent prior to any clinical trial procedure;

5. Women of childbearing potential must have a negative urine pregnancy test at Visit 1;

6. 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. Tumor diseases or history of tumor disease;
2. Known positive result for human immunodeficiency virus 1 and/or 2;
3. Any known allergies to components of the IMP;
4. Evidence of any other medical conditions (such as psychiatric illness or active infection) based on 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; at investigators discretion;
5. History of prior thrombosis or patients at risk for thrombosis;
6. Clinically significant or unstable concurrent disease or other clinical contraindications (based upon investigator's judgment);
7. Patient/legal representative anticipated to be unwilling or unable to comply with the requirements of the protocol;
8. Pregnant or lactating women;
9. Current or previous (within 30 days of enrollment) treatment with another IMP, or participation and/or under follow-up in another clinical trial;
10. Previous participation in this clinical trial (except for screening failures due to an exclusion criterion);
11. Known abuse of alcohol, drugs, or medicinal products;
12. 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-EB; intravenous infusion, three doses of allo-APZ2-EB (2 x 10^6 cells/kg)	Biological: allo-APZ2-EB; intravenous infusion of allo-APZ2-EB; Other Names: allogeneic ABCB5-positive mesenchymal stem cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall improvement of EB symptoms after 12 weeks (measured by percentage change of a patient's EBDASI score), score), or last available post-baseline measurement if the Week 12 measurement is missing	EBDASI: epidermolysis bullosa disease activity and scarring index; measured in percentage change to baseline score	Week 12 post baseline, or last available post-baseline measurement if the Week 12 measurement is missing (last observation carried forward [LOCF])
Assessment of adverse event (AE) occurrence	All AEs occurring during the clinical trial will be registered, documented and evaluated.	Up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall improvement of EB symptoms after 12 weeks (measured by percentage change of a patient's EBDASI score)	EBDASI: epidermolysis bullosa disease activity and scarring index; measured in percentage change to baseline score	between baseline and week 12 post baseline (without LOCF)
Overall improvement of EB symptoms after 12 weeks (measured by percentage change of patient's iscorEB), or last available post-baseline measurement if the Week 12 measurement is missing	iscorEB: instrument for scoring clinical outcome of research for epidermolysis bullosa; measured in percentage change to baseline score	Week 12 post baseline, or last available post-baseline measurement if the Week 12 measurement is missing (LOCF);
Overall improvement of EB symptoms after 12 weeks (measured by percentage change of patient's iscorEB)	iscorEB: instrument for scoring clinical outcome of research for epidermolysis bullosa; measured in percentage change to baseline score	between baseline and week 12 post baseline (without LOCF)
Overall improvement of EB symptoms at Day 17 (measured by percentage change of a patient's EBDASI score)	EBDASI: epidermolysis bullosa disease activity and scarring index; measured in percentage change to baseline score	between baseline and day 17 post baseline
Overall improvement of EB symptoms at Day 17 (measured by percentage change of a patient's iscorEB)	iscorEB: instrument for scoring clinical outcome of research for epidermolysis bullosa; measured in percentage change to baseline score	between baseline and day 17 post baseline
Overall improvement of EB symptoms at Day 35 (measured by percentage change of a patient's EBDASI score)	EBDASI: epidermolysis bullosa disease activity and scarring index; measured in percentage change to baseline score	between baseline and day 35 post baseline
Overall improvement of EB symptoms at Day 35 (measured by percentage change of a patient's iscorEB)	iscorEB: instrument for scoring clinical outcome of research for epidermolysis bullosa; measured in percentage change to baseline score	between baseline and day 35 post baseline
Inflammation (measured by panel of inflammation markers)	A panel of inflammation markers will be measured and evaluated.	between baseline and day 17, day 35 and week 12 post baseline
Pain assessment as per NRS	Pain assessment as per numerical rating scale (NRS) will be evaluated.	between baseline and day 17, day 35 and week 12 post baseline
Itch assessment as per NRS	Itch assessment as per numerical rating scale (NRS) will be evaluated.	between baseline and day 17, day 35 and week 12 post baseline
Differences in patient's quality of life in EB	Assessment of quality of life data using an EB-specific quality of life questionnaire	between baseline and day 17, day 35 and week 12 post baseline
Physical examination until Week 12;	A full physical examination will be performed and abnormal physical examination results will be evaluated and reported as AEs.	At Screening, baseline, day 17, day 35 and week 12
Vital signs: Body temperature until Week 12;	Body temperature will be evaluated at Screening, baseline, day 17, day 35 and week 12	At Screening, baseline, day 17, day 35 and week 12
Vital signs: Blood pressure until Week 12;	Blood pressure will be evaluated at Screening, baseline, day 17, day 35 and week 12	At Screening, baseline, day 17, day 35 and week 12
Vital signs: Heart rate until Week 12;	Heart rate will be evaluated at Screening, baseline, day 17, day 35 and week 12	At Screening, baseline, day 17, day 35 and week 12
Overall survival at month 24		month 24 post baseline

Collaborators and Investigators

• Sponsor: RHEACELL GmbH & Co. KG
• Collaborators: FGK Clinical Research GmbH; Ticeba GmbH; Granzer Regulatory Consulting & Services
• Investigators: Principal Investigator: Jakub Tolar, MD, PhD, University of Minnesota, Masonic Cancer Center and Medical Center

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.
• Kiritsi D, Dieter K, Niebergall-Roth E, Fluhr S, Daniele C, Esterlechner J, Sadeghi S, Ballikaya S, Erdinger L, Schauer F, Gewert S, Laimer M, Bauer JW, Hovnanian A, Zambruno G, El Hachem M, Bourrat E, Papanikolaou M, Petrof G, Kitzmuller S, Ebens CL, Frank MH, Frank NY, Ganss C, Martinez AE, McGrath JA, Tolar J, Kluth MA. Clinical trial of ABCB5+ mesenchymal stem cells for recessive dystrophic epidermolysis bullosa. JCI Insight. 2021 Nov 22;6(22):e151922. doi: 10.1172/jci.insight.151922.

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2019
• Primary Completion (Actual): November 26, 2021
• Study Completion (Actual): November 26, 2021

Study Registration Dates

• First Submitted: April 24, 2018
• First Submitted That Met QC Criteria: May 7, 2018
• First Posted (Actual): May 18, 2018

Study Record Updates

• Last Update Posted (Actual): October 7, 2022
• Last Update Submitted That Met QC Criteria: October 6, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Congenital Abnormalities; Mesenchymal Stem Cells; Allogeneic; Skin Diseases, Genetic; Epidermolysis Bullosa; ABCB5; Epidermolysis Bullosa Dystrophica; Skin Abnormalities; Somatic Cell Therapy
• Additional Relevant MeSH Terms: Skin Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Skin Diseases, Genetic; Skin Diseases, Vesiculobullous; Skin Abnormalities; Collagen Diseases; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica
• Other Study ID Numbers: allo-APZ2-EB-II-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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