Clinical Trials Register

Summary
EudraCT Number:	2017-000234-57
Sponsor's Protocol Code Number:	allo-APZ2-DFU-II-01
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-13
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2017-000234-57

A.3

Full title of the trial

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).

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to investigate the efficacy and safety of allo-APZ2-DFU on wound healing of diabetic neuropathic ulcer.

A.4.1

Sponsor's protocol code number

allo-APZ2-DFU-II-01

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	RHEACELL GmbH & Co. KG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	RHEACELL GmbH & Co. KG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	RHEACELL GmbH & Co. KG
B.5.2	Functional name of contact point	Information Office
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 517
B.5.3.2	Town/ city	Heidelberg
B.5.3.3	Post code	69120
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496221718330
B.5.5	Fax number	+4962217183329
B.5.6	E-mail	office@rheacell.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	allo-APZ2-DFU
D.3.2	Product code	allo-APZ2-DFU
D.3.4	Pharmaceutical form	Cutaneous suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	T202-3
D.3.9.3	Other descriptive name	Allogeneic skin-derived ABCB5-positive mesenchymal stem cells
D.3.10	Strength
D.3.10.1	Concentration unit	million organisms/ml million organisms/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Yes
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Diabetic neuropathic ulcer (DFU)

E.1.1.1

Medical condition in easily understood language

In diabetic patients, impaired wound healing represents a major health problem, leading eventually to a painful non healing wound at the foot called diabetic foot ulcer (DFU).

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10012664
E.1.2	Term	Diabetic foot ulcer
E.1.2	System Organ Class	100000004858

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The aim of this clinical trial is to investigate the efficacy (by monitoring the wound size reduction of DFUs) and safety (by monitoring adverse events) of two doses of allo-APZ2-DFU topically administered to the wound matrix of patients with diabetic neuropathic ulcer.

E.2.2

Secondary objectives of the trial

Not applicable.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients aged 18 to 85 years;
2. 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;
3. The presence of diabetic neuropathic ulcers “malum perforans” (Grade I and II according to Wagner) at plantar side 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;
4. 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;
5. The ulcer’s surface area should be (mostly) free from callus or necrotic tissue;
6. 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;
7. Patients are willing and able to wear therapeutic shoes that are especially designed for patients with a diabetic neuropathic foot;
8. Body mass index (BMI) between 20 and 45 kg/m²;
9. Patients understand the nature of the procedure and are providing written informed consent prior to any clinical trial procedure;
10. Women of childbearing potential must have a negative blood pregnancy test at Visit 1;
11. Women of childbearing potential must be willing to use highly effective contraceptive methods during the course of the clinical trial.

E.4

Principal exclusion criteria

1. Presence of acute Charcot foot;
2. Clinical signs of active osteomyelitis in the last three months;
3. Active wet gangrenous tissue;
4. Infection of the target ulcer requiring treatment as judged clinically;
5. Presence of an ulcer Grade ≥3 according to Wagner on the same foot as target ulcer;
6. Patients who are currently receiving dialysis;
7. Peripheral arterial occlusive disease (PAOD) including claudication with need of treatment;
8. Ulcers due to non-diabetic etiology;
9. Prior surgical procedures such as bypass or mesh-graft treatment within 2 months prior to IMP application;
10. Acute deep vein thrombosis (maximum 30 days from diagnosis) or a still untreated deep vein thrombosis;
11. Any chronic dermatological disorders diagnosed at the investigator’s discretion;
12. Skin disorders, unrelated to the ulcer, that are present adjacent to the target wound;
13. 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;
14. 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;
15. Current use of steroid medication above Cushing threshold dose (>7.5 mg/d prednisone or equivalent);
16. Known abuse of alcohol, drugs, or medicinal products;
17. Patients anticipated to be unwilling or unable to comply with the requirements of the protocol;
18. Pregnant or lactating women;
19. Patients infected with the human immunodeficiency virus (HIV 1&2);
20. Any known allergies to components of the IMP or concomitant medication;
21. Current or previous (within 30 days of enrollment) treatment with another IMP, or participation and/or under follow-up in another clinical trial;
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.

E.5 End points

E.5.1

Primary end point(s)

1. Primary efficacy endpoint: 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]).
2. Primary safety endpoint: Adverse events.

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Week 12, or last available post-baseline measurement of Weeks 4, 6 or 8, if the Week 12 measurement is missing.
2. During all patient visits except screening.

E.5.2

Secondary end point(s)

Secondary efficacy endpoints:
1. Percentage of wound surface area reduction;
2. Percentage of invisible and visible wound surface area reduction;
3. Absolute wound surface area reduction;
4. Absolute invisible and visible wound surface area reduction
5. Assessment of wound infection;
6. Time to first complete wound closure;
7. Proportion of patients achieving complete wound closure;
8. Time to first 30% reduction of wound surface area;
9. Proportion of patients achieving 30% reduction of wound surface area;
10. Assessment of wound exudation, epithelialization and formation of granulation tissue;
11. Time to amputation at target leg until Week 12;
12. Pain assessment as per numerical rating scale (NRS);
13. Assessment of Quality of life (QoL) using the short form 36 (SF-36) questionnaire;
14. Assessment of Dermatology-specific QoL based on the Dermatology Life Quality Index (DLQI) questionnaire.

Secondary safety endpoints:
15. Physical examination and vital signs at Week 6.1 and Week 12;
16. Time to amputation of target leg until Month 12.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Weeks 2, 4, 6, 8, 12, w/o LOCF;
2. Weeks 2, 4, 6, 8, 12, w/o LOCF;
3. Weeks 2, 4, 6, 8, 12, w/o LOCF;
4. Weeks 2, 4, 6, 8, 12, w/o LOCF;
5. Days 1 and 2, Weeks 1, 2, 4, 6, 6.1, 6.2, 6.3, 8, 12;
6. A priori specification not possible; between baseline and week 12;
7. Weeks 2, 4, 6, 8, 12;
8. A priori specification not possible; between baseline and week 12;
9. Weeks 2, 4, 6, 8, 12;
10. Day 0 and Week 6.1 prior IMP-application, Weeks 1, 2, 4, 6, 8, 12;
11. A priori specification not possible; between baseline and month 12;
12. Both Screening Visits, Days 0, 1, 2 and Weeks 1, 2, 4, 6, 6.1, 6.2, 6.3, 8, 12;
13. Screening V1, V3, Weeks 4 and 12;
14. Screening V1, V3, Weeks 4 and 12.
15. Weeks 6.1 and 12;
16. A priori specification not possible; between baseline and month 12.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Safety and efficacy in patients

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After withdrawal patients will receive standard medical care according to individual needs.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-08-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-06-29

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