Clinical Trials Register

Summary
EudraCT Number:	2017-003524-75
Sponsor's Protocol Code Number:	LUMC-MDLZ-MSCIBD03
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-02-19
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

Netherlands - Competent Authority

A.2

EudraCT number

2017-003524-75

A.3

Full title of the trial

Allogeneic Bone Marrow Derived Mesenchymal Stromal Cells for the Treatment of Refractory Proctitis in Ulcerative Colitis

Allogene, uit het beenmerg afkomstige, mesenchymale stromale cellen voor de behandeling van refractaire proctitis bij colitis ulcerosa

A.3.1

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

Mesenchymal Stromal Cells for the treatment of Ulcerative Colitis

Mesenchymale Stamceltherapie bij Colitis Ulcerosa

A.3.2

Name or abbreviated title of the trial where available

BMMSCproctitis

A.4.1

Sponsor's protocol code number

LUMC-MDLZ-MSCIBD03

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	Leiden University Medical Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Leiden University Medical Center
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Leiden University Medical Center/ Principal Investigator
B.5.2	Functional name of contact point	A.E. van der Meulen - de Jong
B.5.3	Address:
B.5.3.1	Street Address	Albinusdreef 2
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 ZA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31715266913
B.5.6	E-mail	ae.meulen@lumc.nl

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	Mesenchymal stromal cells
D.3.2	Product code	MSC
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	Gastroenteral use Submucosal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	n.a.
D.3.9.1	CAS number	n.a.
D.3.9.2	Current sponsor code	Freshly harvested_BMMSC_P3
D.3.9.3	Other descriptive name	MESENCHYMAL CELLS
D.3.9.4	EV Substance Code	SUB181188
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000000
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)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
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

Ulcerative Colitis

Colitis Ulcerosa

E.1.1.1

Medical condition in easily understood language

Chronic inflammatory bowel disease (ulcerative colitis)

Chronische inflammatoire darmziekte (colitis ulcerosa)

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10045365
E.1.2	Term	Ulcerative colitis
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the safety, tolerability and feasibility of endoscopic injected MSCs in the distal colon of patients with refractory proctitis after 6 weeks.

Vaststellen van de veiligheid, verdraagbaarheid en haalbaarheid van endoscopisch geïnjecteerde MSCs in het distale deel van het colon bij patiënten met refractaire proctitis 6 weken na de behandeling.

E.2.2

Secondary objectives of the trial

At 2, 6 and 24 weeks

1. To assess changes in the Mayo Score (appendix C) before and after BMMSC treatment; as an indication of efficacy.

At 2, 6, 12 and 24 weeks

2. To assess changes in patient-reported outcome measures (PROMs) using the mHealth index (appendix D) [71].
3. To summarize the changes in serum c-reactive protein (CRP) and fecal calprotectin.

At 6 and 24 weeks
4. To compare histologic disease activity before and after local BMMSC treatment using the Geboes score (appendix E).
5. To evaluate the effects of this intervention on immunological parameters and local MSC persistence.

At 6, 12, 24 weeks

6. To evaluate the effect of local treatment with allogeneic BMMSCs on the quality of life using the 12-item Short Form Health Survey (SF-36) (appendix F) and the short Inflammatory Bowel Disease Questionnaire (sIBDQ) (appendix G).

Op week 2, 6 en 24
1. Vaststellen van veranderingen in de Mayo Score (appendix C) voor en na behandeling met BMMSC behandeling; als een indicatie voor effectiviteit.
Op week 2, 6, 12 en 24
2. Vaststellen van veranderingen in patient-reported outcome measures (PROMs) door gebruik te maken van de mHealth index (appendix D).
3. Samenvatten van veranderingen in serum c-reactive protein (CRP) en fecaal calprotectin.
Op week 6 en 24
4. Vergelijken van histologische ziekte activiteit voor en na lokale BMMSC behandeling door gebruik te maken van de Geboes score.
5. Evalueren van de effecten van deze interventie op immunologische parameters en persistentie van MSCs in de darm.
Op week 6, 12 en 24
6. Evalueren van de effecten van lokale behandeling met allogene BMMSCs op de kwaliteit van leven door gebruik te maken van de Short Form Health Survey (SF-36) (appendix F) en de Short Inflammatory Bowel Disease Questionnaire (sIBDQ) (appendix G).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

a) Men and women ≥ 18 years of age;
b) Patient must have UC confirmed by endoscopic and histologic evidence;
c) Inflammation must be limited to the rectum (up to 15 cm beyond the anal verge), confirmed by endoscopy maximum 3 months before baseline (slight inflammation in other parts of the colon is accepted with a maximum Mayo Score of 1);
d) Moderate to severe proctitis indicated by a Mayo Score of 2 or 3;
e) Proctitis must be refractory to conventional medical therapy. Which means that at some time during the course of the disease, patient must have received rectal 5-ASA therapy and rectal corticosteroid therapy for at least 4 weeks which did not result in an adequate response to treatment;
f) If treated with rectal therapy, therapy must be stopped two weeks before endoscopic implantation of MSCs and only restarted after 6 weeks;
g) If treated with oral 5-ASA therapy, dose must be stable for 4 weeks prior to study entry and remain on same dose during the first 6 weeks after MSC treatment;
h) If treated with oral corticosteroids, dose must be stable for 2 weeks prior to study entry and remain on same dose during the first 6 weeks after MSC treatment;
i) If treated with 6-mercaptopurine, methotrexate, azathioprine, vedolizumab or anti-TNF therapy patients must have been on medication for 3 months and a stable dose for 2 months prior to study entry and remain on same dose during the first 6 weeks after MSC treatment;
j) If female and of child-bearing age, patient must be non-pregnant, non-breastfeeding, and use adequate contraception;
k) Patient is willing to participate in the study and has signed the informed consent.
Consent must be obtained prior to any study procedure.

a) Mannen en vrouwen ≥ 18 jaar.
b) Colitis ulcerosa bevestigt tijdens endoscopie en bij beoordelen histologie.
c) Ontsteking in het rectum (tot maximaal 15 cm boven de anale ring), bewezen bij endoscopie maximaal 3 maanden voor baseline (geringe ontsteking in ondere delen van colon is geaccepteerd tot maximum van Mayo score 1).
d) Matige tot ernstige proctitis (Mayo score 2 of 3).
e) Proticitis moet refractoir zijn voor standaard medicatie. Dit betekent dat patienten tijdens de ziekte behandeld moeten zijn met rectale 5-ASA en corticosteroid therapie voor in ieder geval 4 weken zonder dat dit tot adequaat behandelingsrespons heeft geleid.
f) Als patienten rectale therapie hebben moet dit 2 weken voor de behandeling met mesenchymale stamcellen (MSC) gestopt worden en enkel herstart na 6 weken.
g) Als patienten behandeld worden met orale 5-ASA dan moet de dosering 4 weken voor inclusie in de studie stabiel zijn en op dezelfde dosis blijven tijdens de eerste 6 weken na MSC behandeling.
h) Als patienten behandeld worden met orale corticosteroiden dan moet de dosering 2 weken voor inclusie stabiel zijn en op dezelfde dosis blijven tijdens de eerste 6 weken na MSC behandeling.
i) Als patienten behandeld worden met 6-mercaptopurine, methotrexaat, azathioprine, vedolizumab of anti-TNF therapie dan moeten patienten bij inclusie reeds 3 maanden het betreffende middel gebruiken, deze dosering moet 2 maanden voor inclusie stabiel zijn en deze dosering blijft gelijk tot 6 weken na MSC behandeling.
j) Vrouwen in de vruchtbare leeftijd moeten adequate contraceptie gebruiken, mogen niet zwanger zijn of borstvoeding geven.
k) Patient wil meewerken aan de studie en heeft informed consent getekent. Informed consent moet verkegen worden voordat patient deelneemt aan een studieprocedure.

E.4

Principal exclusion criteria

a) Patients suffering from renal- or hepatic failure;
b) Use of any investigational drug within 1 month prior to screening or within 5 half-lives of the investigational agent, whichever is longer;
c) Positive stool culture for enteric pathogens (salmonella, shigella, and campylobacter), positive C. difficile toxin, or positive stool ova and parasite exam;
d) All active infections requiring treatment;
e) Patients who had tuberculosis or an opportunistic infection (e.g., herpes zoster [shingles], cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis) within 6 months prior to screening;
f) Malignancy within the past 5 years (except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence);
g) Any dysplasia in the colon in the past 5 years;
h) Very severe proctitis; expected to result in hospitalization/ surgery within 3 months;
i) Previous treatment with allogeneic MSCs;
j) Any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study;
k) Patient is unwilling or unable to comply with the study procedures.

a) Patienten met lever- of nierfalen.
b) Gebruik van een ander onderzoeksproduct in de maand voor screening of binnen 5 halfwaarde tijden van het andere onderzoeksproduct.
c) Positieve feces kweek voor darmpathogenen (Salmonella, Shigella of Campylobacter), positieve C. difficile toxin of een positieve feces voor parasieten.
d) Alle actieve infecties die behandeling vereisen.
e) Patienten die tuberculose of een opportunistische infectie (zoals herpes zoster, cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis) hebben gehad in de 6 maanden voor screening.
f) Maligniteit in de afgelopen 5 jaar (behalve een plaveiselcel of basaalcel carcinoom van de huid dat succesvol behandeld is).
g) Dysplasie in de colon in de afgelopen 5 jaar.
h) Ernstige proctitis; met de verwachting dat dit binnen 3 maanden leidt tot ziekenhuisopname of een operatie.
i) Eerdere behandeling met allogene MSCs.
j) Een andere conditie die naar de mening van de onderzoeker de patientn niet geschikt maakt voor inclusie of kan interfereren met de particiaptie van de patient in de studie.
k) De patient wil of kan niet meedoen aan de studieprocedures.

E.5 End points

E.5.1

Primary end point(s)

Local MSC therapy in patients with UP will be found safe when no SAEs, related to endoscopic MSC therapy, are reported in the 14 patients treated with MSC therapy after 6 weeks. Evaluation of tolerability will be based upon AE monitoring, measurements of vital signs as well as the patient’s and investigator’s global judgment of tolerability. The therapy will be found tolerable when >80% of the patients after the treatment procedure and at week 6 will define the adverse events and procedure as tolerable. Evaluation of the feasibility will be based upon practical problems and complaints that are encountered in the execution of the study. The therapy will be found feasible when there are <20% practical dropouts.

Lokale MSC therapie in patienten met ulceratieve proctittis wordt veilig bevonden wanneer er geen SAEs zijn opgetreden die gerelateerd zijn aan endoscopische MSC therapie in alle studiepatienten na 6 weken. Evaluatie van de verdraagbaarheid wordt gebaseerd op de AEs, vitale parameters en het oordeel van de onderzoekers en patienten over de verdraagbaarheid. De therapie wordt verdraagbaar genoemd wanneer 80% van de patienten de behandeling op week 6 'verdraagbaar' noemt. Evaluatie van de haalbaarheid wordt gebaseerd op practische problemen en klachten die worden verzameld gedurende de uitvoering van de studie. De therapie wordt haalbaar genoemd wanneer er minder dan 20% praktische dropouts zijn.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 6.
After the first 7 patients there will be an interim analyses. The results will be reviewed by the DSMB.

Week 6.
Na de eerste behandelgroep (7 patienten) zal er een interim analyse plaats vinden. De resultaten worden bekeken door de DSMB.

E.5.2

Secondary end point(s)

At 2, 6 and 24 weeks

1. To assess changes in the Mayo Score (appendix C) before and after BMMSC treatment; as an indication of efficacy.

At 2, 6, 12 and 24 weeks

2. To assess changes in patient-reported outcome measures (PROMs) using the mHealth index (appendix D) [71].
3. To summarize the changes in serum c-reactive protein (CRP) and fecal calprotectin.

At 6 and 24 weeks
4. To compare histologic disease activity before and after local BMMSC treatment using the Geboes score (appendix E).
5. To evaluate the effects of this intervention on immunological parameters and local MSC persistence.

At 6, 12, 24 weeks

6. To evaluate the effect of local treatment with allogeneic BMMSCs on the quality of life using the Short Form Health Survey (SF-36) (appendix F) and the short Inflammatory Bowel Disease Questionnaire (sIBDQ) (appendix G).

Op week 2, 6 en 24
1. Vaststellen van veranderingen in de Mayo Score (appendix C) voor en na behandeling met BMMSC behandeling; als een indicatie voor effectiviteit.

Op week 2, 6, 12 en 24
2. Vaststellen van veranderingen in patient-reported outcome measures (PROMs) door gebruik te maken van de mHealth index (appendix D).
3. Samenvatten van veranderingen in serum c-reactive protein (CRP) en fecaal calprotectin.

Op week 6 en 24
4. Vergelijken van histologische ziekte activiteit voor en na lokale BMMSC behandeling door gebruik te maken van de Geboes score.
5. Evalueren van de effecten van deze interventie op immunologische parameters en persistentie van MSCs in de darm.

Op week 6, 12 en 24
6. Evalueren van de effecten van lokale behandeling met allogene BMMSCs op de kwaliteit van leven door gebruik te maken van de Short Form Health Survey (SF-36) (appendix F) en de Short Inflammatory Bowel Disease Questionnaire (sIBDQ) (appendix G).

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 2, 6, 12 and 24

Week 2, 6, 12 en 24

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)

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)

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

Yes

E.8.1.7.1

Other trial design description

Eerste zeven patienten worden behandeld met zelfde dosis, volgende zevende met dubbele dosis

First seven patients will be treated with the same dose, next seven patients with double dose

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

Yes

E.8.4

The trial involves multiple sites in the 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

Week 24

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)

Follow up of patients up to one year after treatment (through contacting by phone).

Vervolgen van patienten tot 1 jaar na de behandeling (via telefonisch contact).

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

2017-12-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-27

P. End of Trial
P.	End of Trial Status	Ongoing

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