Clinical Trials Register

Summary
EudraCT Number:	2016-004684-40
Sponsor's Protocol Code Number:	N-O_CLI_Study
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-01-22
Trial 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

Poland - Office for Medicinal Products

A.2

EudraCT number

2016-004684-40

A.3

Full title of the trial

Regeneration of ischemic damages in cardiovascular system using Wharton’s jelly as an unlimited source of mesenchymal stem cells for regenerative medicine.
Project of the National Centre for Research and Development (Poland) ‘STRATEGMED II’.
Cardiovascular Clinical Project to Evaluate the Regenerative Capacity of CardioCell in patients with no-option critical limb ischemia (N-O CLI).

Regeneracja uszkodzeń niedokrwiennych układu sercowo-naczyniowego z wykorzystaniem Galarety Whartona jako nieograniczonego źródła terapeutycznego komórek macierzystych (CIRCULATE - Projekt Strategiczny Narodowego Centrum Badań i Rozwoju "STRATEGMED II") Zastosowanie innowacyjnego leku CardioCell w leczeniu pacjentów z krytycznym niedokrwieniem kończyn dolnych.

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

CardioCell evaluation in N-O CLI

Ocena CardioCell w N-O CLI

A.4.1

Sponsor's protocol code number

N-O_CLI_Study

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	Krakowski Szpital Specjalistyczny im. Jana Pawła II
B.1.3.4	Country	Poland
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	Krakowski Szpital Specjalistyczny im. Jana Pawła II
B.4.2	Country	Poland
B.4.1	Name of organisation providing support	Narodowe Centrum Badań i Rozwoju (NCBiR)
B.4.2	Country	Poland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ewa Gąsior
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Prądnicka 80
B.5.3.2	Town/ city	Cracow
B.5.3.3	Post code	31-202
B.5.3.4	Country	Poland
B.5.4	Telephone number	48126142000
B.5.5	Fax number	48126142266
B.5.6	E-mail	e.gasior@szpitaljp2.krakow.pl

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	CardioCell
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarterial use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Wharton's jelly mesenchymal stem cells
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	N/A
D.3.9.3	Other descriptive name	WJ MSC (Wharton's jelly mesenchymal stem cells)
D.3.9.4	EV Substance Code	SUB191586
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30mln WJ MSC/20ml
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	Yes
D.3.11.3.5.1	CAT classification and reference number	EMA/CAT/625295/2016
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
D.8.4	Route of administration of the placebo	Intraarterial use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Critical limb ischemia

Krytyczne niedokrwienie kończyn

E.1.1.1

Medical condition in easily understood language

Critical limb ischemia

Krytyczne niedokrwienie kończyn

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10058069
E.1.2	Term	Critical limb ischemia
E.1.2	System Organ Class	100000004866

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluation of the regeneration ischemia cardiovascular system in critical limb ischemia without the possibility of revascularization (N-O CLI) by treatment with CardioCell.

Ocena zdolności regeneracji uszkodzeń niedokrwiennych układu sercowo-naczyniowego w krytycznym niedokrwieniu kończyn dolnych bez możliwości leczenia rewaskularyzacyjnego (N-O CLI), za pomocą leczenia preparatem CardioCell.

E.2.2

Secondary objectives of the trial

Assess the efectiveness of the use of the product on the basis of the increase walking distance without pain, assessed at thye main hospitalization and at 6 month follow-up beetween two groups (active vs sham).

Ocena skuteczności zastosowania preparatu na podstawie oceny wzrostu dystansu marszu bez bólu, ocenianego podczas głównej hospitalizacji i w obserwacji 6 miesięcznej pomiędzy dwoma grupami (aktywna vs sham).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients able to walk
- Male and female patients, aged 18-80 years
- No-option CLI (definition: exhausted revascularization options including surgery or endovascular treatment) in Rutherford stage 4-5
- In case of bilateral N-O CLI, the limb with shorter claudication distance will be treated
- Presence of adequate inflow (patent iliac and common femoral arteries)
- Run-off through at least one (even partially seen) below-the-knee (BTK) artery
- Signed informed consent

- Pacjenci mogący chodzić,
- Pacjenci płci męskiej i żeńskiej w wieku 18-80 lat
- Pacjenci z krytycznym niedokrwieniem kończyny bez możliwości leczenia rewaskularyzacyjnego, w klasie Rutherford 4-5
- W przypadku obustronnego niedokrwienia kończyn dolnych, w ramach badania klinicznego będzie leczona kończyna o krótszym dystansie chromania
- Zachowany napływ krwi do leczonej kończyny (drożne tętnice biodrowe oraz udowa wspólna)
- Zachowany przepływ krwi przez co najmniej jedną (chociaż częściowo widoczną) tętnicę poniżej kolana (ang. BTK)
- Podpisanie świadomej zgody

E.4

Principal exclusion criteria

- Malignancy
- Moderate or severe immunodeficiency
- Acute or chronic bacterial or viral infectious disease
- Soft tissue disease or local infection in a place of required artery puncture
- Pregnancy or breastfeeding
- Any objective or subjective reason for inability to attend follow-up visits
- Females of childbearing potential, who does not want to use a highly effective method of contraception
- Females of childbearing potential who does not have a menstrual period confirmed and a negative highly sensitive urine or serum pregnancy test
- Participation in any other clinical research study that has not reached the primary efficacy endpoint or otherwise would interfere with the patient’s participation in this project
- Life expectancy < 1 year
- Any concurrent disease or condition that, in the opinion of the investigator, would make the patient unsuitable for participation in the project

- Nowotwór złośliwy
- Umiarkowane lub ciężkie upośledzenie odporności
- Ostre lub przewlekłe, bakteryjne lub wirusowe choroby zakaźne
- Choroby tkanek miękkich lub lokalne zakażenia w miejscu wymaganych nakłuć tętnicy
- Ciąża lub karmienie piersią
- Wszelkie obiektywne lub subiektywne przyczyny braku możliwości udziału w wizytach kontrolnych
- Kobiety w wieku rozrodczym, które nie wyrażają zgody na korzystanie z bardzo skutecznych metod antykoncepcji
- Kobiety w wieku rozrodczym bez potwierdzenia negatywnego wyniku testu ciążowego z moczu lub z krwi
- Udział w innych badaniach klinicznych, które nie osiągnęły punktu końcowego lub mogą kolidować z udziałem pacjenta w badaniu
- Przewidywana długość życia < 1 rok
- Współistniejąca choroba lub dolegliwość, która zdaniem badacza, wyklucza pacjenta z udziału w badaniu

E.5 End points

E.5.1

Primary end point(s)

Change in pain-free walking distance (6M FU vs index evaluation) between two groups (active vs placebo therapy).

Wzrost dystansu marszu bez bólu, oceniany podczas głównej hospitalizacji i w obserwacji 6 miesięcznej pomiędzy dwoma grupami (aktywna vs sham).

E.5.1.1

Timepoint(s) of evaluation of this end point

6 and 12 months Follow-up

6 i 12 miesięczna wizyta kontrolna

E.5.2

Secondary end point(s)

1. Amputation-free survival period evaluation of treated leg at 6 month and 1 year FU.
2. Ulcer-free survival (in patients without ulceration at baseline evaluation) and ulcer-extension free survival (in patients with ulceration in the beginning of the trial) of treated leg in period evaluation at 6 month and 1 year FU.
3. Change in tissue oxygen/CO2 tension, assessed by NIRS method at each trial evaluation point.
4. An improvement of tissue perfusion assessed in MRI at each trial evaluation point.
5. Change in transcutaneous pressure of O2 (tcpO2) between two groups (active vs placebo therapy) at each trial evaluation point.
6. Change in ABI score at each trial evaluation point.
7. Quality of life improvement, assessed by SF-36 v2 questionnaire or other dedicated for investigated population at each trial evaluation point.

1. Czas przeżycia bez amputacji, oceniany w 6 i 12 miesiącu FU.
2. Czas przeżycia bez owrzodzenia, (u pacjentów u których wyjściowo nie obserwowano owrzodzeń), oraz czas przeżycia bez progresji owrzodzeń (u pacjentów u których wyjściowo były obserwowane owrzodzenia) oceniany w 6 i 12 miesiącu FU.
3. Zmiana stężenia tkankowego tlenu, oceniana metodą NIRS wyjściowo oraz na wszystkich wizytach kontrolnych.
4. Poprawa perfuzji tkanek oceniona w MRI wyjściowo i na wszystkich wizytach kontrolnych.
5. Zwiększenie przezskórnego stężenia O2 (TO2) ocenianego wyjściowo i na każdej wizycie kontrolnej pomiędzy dwoma grupami (aktywna vs sham).
6. Zmiana wartości wskaźnika kostkowo-ramiennego (ang. ABI) ocenianego wyjściowo i na każdej wizycie kontrolnej.
7. Poprawa jakości życia, oceniona za pomocą kwestionariusza SF-36 lub innego dedykowanego dla badanej populacji wyjściowo i na każdej wizycie kontrolnej.

E.5.2.1

Timepoint(s) of evaluation of this end point

3, 6 and 12 months follow-up

3, 6 i 12 miesięczna wizyta kontrolna

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

Yes

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)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Information not present in EudraCT

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

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

Ostatnia wizyta ostatniego pacjenta

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:

115

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

115

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

Yes

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

115

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)

In the case of confirmation of the efficacy and safety of the investigational product, the sponsor of the study and the manufacturer of the product CardioCell will make every effort to be able to provide the preparation CardioCell to each patient who was randomized to the placebo group, and expresses the wish receiving such a treatment.

W przypadku potwierdzenia skuteczności oraz bezpieczeństwa badanego produktu, sponsor badania oraz wytwórca produktu CardioCell dołożą wszelkich starań, żeby możliwe było podanie preparatu CardioCell każdemu pacjentowi, który został zrandomizowany do grupy placebo i wraża ochotę otrzymania takiego leczenia.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Krakowski Szpital Specjalistyczny im. Jana Pawła II, Zakład Medycyny Nuklearnej
G.4.3.4	Network Country	Poland
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Krakowski Szpital Specjalistyczny im. Jana Pawła II, Zakład Radiologii i Diagnostyki Obrazowej
G.4.3.4	Network Country	Poland
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	Krakowski Szpital Specjalistyczny im. Jana Pawła II, Laboratorium Analityczne
G.4.3.4	Network Country	Poland

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-04-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-09-28

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