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    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-003524-75
    A.3Full 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.3.1Title 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.3.2Name or abbreviated title of the trial where available
    BMMSCproctitis
    A.4.1Sponsor's protocol code numberLUMC-MDLZ-MSCIBD03
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLeiden University Medical Center
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLeiden University Medical Center
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University Medical Center/ Principal Investigator
    B.5.2Functional name of contact pointA.E. van der Meulen - de Jong
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 ZA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715266913
    B.5.6E-mailae.meulen@lumc.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMesenchymal stromal cells
    D.3.2Product code MSC
    D.3.4Pharmaceutical form Suspension for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPGastroenteral use
    Submucosal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNn.a.
    D.3.9.1CAS number n.a.
    D.3.9.2Current sponsor codeFreshly harvested_BMMSC_P3
    D.3.9.3Other descriptive nameMESENCHYMAL CELLS
    D.3.9.4EV Substance CodeSUB181188
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Ulcerative Colitis
    Colitis Ulcerosa
    E.1.1.1Medical condition in easily understood language
    Chronic inflammatory bowel disease (ulcerative colitis)
    Chronische inflammatoire darmziekte (colitis ulcerosa)
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10045365
    E.1.2Term Ulcerative colitis
    E.1.2System Organ Class 100000004856
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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.4Principal 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.5.1Primary 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.5.1.1Timepoint(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.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other 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.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    Week 24
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 12
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state14
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-12-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-27
    P. End of Trial
    P.End of Trial StatusOngoing
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