Clinical Trials Register

Summary
EudraCT Number:	2017-000235-14
Sponsor's Protocol Code Number:	allo-APZ2-PAOD-II-01
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-01-16
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

Czechia - SUKL

A.2

EudraCT number

2017-000235-14

A.3

Full title of the trial

A RANDOMISED, PLACEBO-CONTROLLED, DOUBLE-BLIND, INTERVENTIONAL, MULTICENTER, PHASE I/IIA CLINICAL TRIAL TO INVESTIGATE THE EFFICACY AND SAFETY OF ALLO-APZ2-PAOD FOR THE TREATMENT OF PERIPHERAL ARTERIAL OCCLUSIVE DISEASE (PAOD)

RANDOMIZOVANÁ, PLACEBEM KONTROLOVANÁ, DVOJITĚ ZASLEPENÁ, INTERVENČNÍ, MULTICENTRICKÁ, KLINICKÁ STUDIE FÁZE I/IIA ZA ÚČELEM ZJIŠTĚNÍ ÚČINNOSTI A BEZPEČNOSTI PŘÍPRAVKU ALLO-APZ2-PAOD K LÉČBĚ ISCHEMICKÉ CHOROBY DOLNÍCH KONČETIN (ICHDK)

A.3.1

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

Clinical trial to investigate how efficacious and safe the investigated medicinal product named allo-APZ2-PAOD is in terms of wound healing in patients with non healing wounds on due to peripheral arterial occlusive disease.

Klinické hodnocení k vyhodnocení efektivity a bezpečnosti hodnoceného přípravku allo-APZ2-PAOD z hlediska léčby pacientů s nehojícími se ránami na noze z důvodu ischemické choroby dolných končetin.

A.4.1

Sponsor's protocol code number

allo-APZ2-PAOD-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-PAOD
D.3.2	Product code	allo-APZ2-PAOD
D.3.4	Pharmaceutical form	Suspension for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	n.a.
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection in pre-filled syringe
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

peripheral arterial occlusive disease

E.1.1.1

Medical condition in easily understood language

Peripheral arterial occlusive disease is a chronic vascular disease in which the arteries supplying the extremities are narrowing or closing. The lack of blood supply can lead to non-healing wounds.

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10062585
E.1.2	Term	Peripheral arterial occlusive disease
E.1.2	System Organ Class	10047065 - Vascular disorders

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 PAOD-related clinically relevant ulcers) and safety (by monitoring adverse events [AEs]) of one dose of allo-APZ2-PAOD administered intramuscularly into an affected lower leg of patients with PAOD.

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 45 to 85 years;
2. Patients having PAOD clinically confirmed (maximal systolic ankle pressures ≤ 70 mmHg or systolic toe pressures ≤ 50 mmHg or transcutaneous partial oxygen pressures (tcp02) ≤ 30 mmHg in supine position) as Rutherford category 5 in at least one lower extremity;
3. Angiography results (DSA, CTA or MRA) for the localization of the high-grade obstruction of an artery of the affected leg (≥ 70 %) that is the leading cause for the ulceration are present and not older than 6 months;
4. One or more clinically relevant and quantifiable ulcer(s) below the ankle with a minimum size of 0.5 cm² per ulcer and a maximum wound size of 20 cm² for all ulcers together;
5. Positive vote of the Advisory Board on the suitability of the wound(s) for enrolment, based on the wound photographs;
6. Patients not eligible for surgical/interventional reconstruction due to technical limitations or comorbidity;
7. No evidence of wound healing after standard of care treatment for at least 1 week before screening;
8. In Patients suffering from 2 or more ulcers at the same extremity, these ulcers must be separated by a minimum bridge of 1 cm of epithelialized skin;
9. If patients are hypertensive, they have to be treated with anti-hypertensive medication according to the applicable guideline;
10. Body mass index (BMI) between 20 and 40 kg/m²;
11. Women of childbearing potential must have a negative blood pregnancy test at screening;
12. Women of childbearing potential and their partner must be willing to use highly effective contraceptive methods during the course of the clinical trial;
13. Patients must be able to consent, have been informed of the nature, the scope and the relevance of the study, voluntarily agree to participation and the study’s provisions, and have duly signed the informed consent form (ICF). Subject agrees to comply with the protocol-mandated procedures and visits.

E.4

Principal exclusion criteria

1. Patients with skin lesions of leading venous origin or patients suffering from a vasculitis;
2. Patients with thrombangiitis obliterans;
3. Diabetic patients in whom the leading cause for lesions is microangiopathy or neuropathy;
4. Patients with high grade obstruction (≥ 70 %) in the aorto-iliac segment or the common femoral artery as leading cause for skin lesions;
5. Patients with ulcers at the heel due to immobility;
6. Patients with osteomyelitis at ulceration;
7. Patients medicated with vitamin K antagonist, if treatment cannot be stopped before injection or bridged according to applicable guidelines;
8. Patients medicated with DOACs, if they cannot be withheld for 24 hours before injection;
9. Surgical/interventional reconstruction during 1 week before screening (not applicable if it becomes evident during reconstruction that revascularization is not successful: these patients can be included immediately);
10. Patients for whom major amputation is scheduled on target leg;
11. Patients with uncontrolled hypertension defined as systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg; For these patients a re-screening and inclusion into the study will be possible after blood pressure is controlled;
12. Patients who had a myocardial infarction during 3 months before screening;
13. Patients with uncontrolled infection at any of the relevant ulcers;
14. Patients with uncontrolled acute or chronic infection with systemic symptoms;
15. Known serious disease with life expectancy of less than 1 year;
16. Any chronic dermatological disorders diagnosed at the investigator’s discretion;
17. Skin disorders, unrelated to the ulcer, that are present adjacent to any of the relevant ulcers;
18. Active malignancy or history of malignancy within 5 years prior to study entry;
19. Patients tested positive for human immunodeficiency virus (HIV-1, HIV-2), Hepatitis B or Hepatitis C;
20. Any known allergies to components of the IMP;
21. Current or previous (within 30 days of enrolment) treatment with another IMP, or participation and/or under follow-up in another clinical trial;
22. Current use of glucocorticoid-medication above Cushing threshold dose (>7.5 mg/d prednisone or equivalent) or any other prohibited medication or therapy;
23. Known abuse of alcohol, drugs, or medicinal products;
24. Patients anticipated to be unwilling or unable to comply with the requirements of the protocol;
25. 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;
26. Pregnant or lactating woman;
27. 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: Percent change from baseline to week 12 in total wound size of the target leg. The total wound size of the target leg is calculated as sum of the wound sizes of all relevant ulcers of the target leg.

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 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. Time to total healing of all relevant ulcers at target leg;
2. Percent change in total wound size of the target leg;
3. Absolute change in total wound size of the target leg;
4. Ankle-brachial index (ABI) of target leg;
5. Number of amputated toes at target leg;
6. Time to major amputation at target leg until week 12;
7. Epithelialization assessment of all relevant ulcers of the target leg;
8. Assessment of formation of granulation tissue and wound exudation of all relevant ulcers of the target leg;
9. Assessment of quality of life (QoL) using the short form 36 (SF-36) questionnaire;
10. Pain assessment as per numerical rating scale (NRS).

Secondary safety endpoints:
11. Physical examination and vital signs at week 12;
12. Laboratory assessments at Week 12
13. Time to major amputation.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary efficacy endpoints:
1. A priori specification not possible; between baseline and week 12 post baseline;
2. Baseline, week 1, 2, 4, 6, and 8;
3. Baseline, week 1, 2, 4, 6, 8 and 12;
4. Screening Visit, Baseline, Week 2, 4, 8 and 12;
5. A priori specification not possible; between baseline and week 12 post baseline.
6. A priori specification not possible; between baseline and week 12 post baseline.
7. Day 0 prior IMP-application, week 2, 4, 8 and 12;
8. Day 0 prior IMP-application, week 2, 4, 8 and 12;
9. Day 0 prior IMP-application, week 2, 8 and 12;
10. Day 0 prior IMP-application, week 2, 4, 8 and 12;

Secondary safety endpoints:
11. Week 12;
12. Week 12;
13. A priori specification not possible; between baseline and month 12 post baseline.

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Yes

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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

2019-04-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-27

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-05-15

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