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    EudraCT Number:2009-015680-14
    Sponsor's Protocol Code Number:allo bmMSCs CD fistula
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-07-27
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2009-015680-14
    A.3Full title of the trial
    Allogeneic Bone Marrow Derived Mesenchymal Stem Cells
    for the Treatment of Fistulas in Patients with
    Refractory Perianal Crohn’s Disease
    A.3.2Name or abbreviated title of the trial where available
    allo bmMSCs CD fistula
    A.4.1Sponsor's protocol code numberallo bmMSCs CD fistula
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLeiden University Medical Center
    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 support
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameBone Marrow Derived Mesenchymal Stem cells (MSCs)
    D.3.2Product code NA
    D.3.4Pharmaceutical form Injection*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntralesional use
    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) Information not present in EudraCT
    D. cell therapy medicinal product Yes
    D. therapy medical product No
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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
    single or multiple draining perianal fistulas as a result of Crohn's Disease
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10011401
    E.1.2Term Crohn's disease
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To assess the safety (incidence of intervention related [serious] adverse events) and tolerability of the surgical intervention alone or the surgical intervent with local administration of different doses of allogeneic MSCs in fistula tracts of patients with refractory CD.
    2. To document the efficacy of different doses of allogeneic bmMSCs in the induction of response for active fistulizing CD.
    E.2.2Secondary objectives of the trial
    At 12 weeks
    1. To assess changes in the Crohn’s Disease Activity Index (CDAI), the Perianal Disease Activity Index (PDAI) and the adapted Vaizey fecal incontinence score before and after MSC treatment;
    2. To compare endoscopic changes before and after local bmMSC treatment using the Crohn’s Disease Endoscopic Index of Severity (CDEIS) and simplified endoscopic activity score for Crohn’s disease (SES-CD);
    3. To evaluate the effect of local treatment with autologous bmMSCs on the quality of life of patients with fistulizing CD using the short Inflammatory Bowel Disease Questionnaire (sIBDQ) and Short Form (SF)-36 score;
    4. To summarize the changes from baseline compared to 12 weeks in serum CRP.

    At 12 and 24 weeks
    5. To assess the incidence of surgical intervention and infections.

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    a) Men and women  18 years of age;
    b) Patient must have had CD (for at least 3 months from the time of initial diagnosis). The diagnosis of CD must have been confirmed by endoscopic and histologic evidence;
    c) CDAI score of <250 at screening and baseline;
    d) Peri-anal fistulas must be refractory to conventional medical therapy. Which means that at some time during the course of the disease, patient must have received both steroids and immunosuppressive agents (for example, azathioprine, 6-mercaptopurine, methotrexate, or infliximab) which did not result in an adequate response to treatment;
    e) Patients with previous surgical attempts to eradicate perianal fistulas are eligible for inclusion as are patients with setons in situ. Setons will be removed during the surgical procedure.
    f) Patients included in the study might be receiving 5-aminosalicylic acid (5-ASA), steroids, azathioprine, 6-mercaptopurine (6-MP), methotrexate, or any similar drug at the time of enrolment and is allowed to have a history of infliximab treatment, provided the following conditions are fulfilled at screening:
     The dose of 5-ASA (both oral and rectal) must have been stable for at least 4 weeks prior to enrolment.
     The dose of steroids must be stable for at least 4 weeks prior to enrolment.
     The dose of immunosuppressants (for example azathioprine, 6MP, or methotrexate) must have been stable for at least 8 weeks prior to enrolment and the patient on therapy for at least three months prior to enrolment.
     The last dose of infliximab or other anti-TNF drug is > 8 weeks prior to enrolment;
    g) No need for immediate surgery (obstruction, strictures or abscess);
    h) If female and of child-bearing age, patient must be non-pregnant, non-breastfeeding, and use adequate contraception;
    i) Patient is willing to participate in the study and has signed the informed consent. Consent must be obtained prior to any study procedure.
    E.4Principal exclusion criteria
    a) Patients with evidence of acute peri-anal infection, presence of peri-anal abscesses larger than 2 cm, and anal or rectal stricture;
    b) Patients with evidence of any infections needing antibiotic treatment.
    c) Rectovaginal fistulas, or complex peri-anal fistulas with more than two internal openings;
    d) Patients suffering from renal- or hepatic failure.
    e) Use of any investigational drug within 1 month prior to screening or within 5 half-lives of the investigational agent, whichever is longer;
    f) Patient is allergic to gadolinium (MRI contrast agent);
    g) Patient with severe renal insufficiency defined as patients with a glomerular filtration rate (GFR) below 60 mL/min/1.73 m2. GFR = 186.3 x (serum creatinine)-1.154 x (age in years)-0.203 x 1.212 (if patient is black) x 0.742 (if female);
    h) Due to the high strength electromagnetic fields that will be used during MRI there is a risk of interference with any metallic implants in the body. The following conditions will disqualify patients from having an MRI and will be excluded from this study:
     electronically, magnetically, and mechanically activated implants
     ferromagnetic or electronically operated stapedial implants
     cardiac pacemakers/carotid sinus pacemaker implant
     hemostatic clips
     metallic splinters in the orbit
     insulin pumps and nerve stimulators
     lead wires or similar wires
     metal intrauterine device
    i) Change in concomitant medication:
     Steroids must be stable for at least 4 weeks prior to enrolment,
     5-ASA should be on a stable dose > 4 weeks prior to enrolment,
     Immunosuppressants (e.g. azathioprine, 6MP or methotrexate) should be on a stable dose > 8 weeks prior to enrolment,
     Infliximab or other anti-TNF antibody therapy should not be administered < 8 weeks prior to enrolment.
    j) Clausterphobia;
    k) Documented HIV infection. Active hepatitis B, hepatitis C or TB;
    l) Patients who currently have or who have had an opportunistic infection (e.g., herpes zoster [shingles], cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB) within 6 months prior to screening;
    m) Serious infections (such as pneumonia or pyelonephritis) in the previous 3 months. Less serious infections (such as acute upper respiratory tract infection [colds] or simple urinary tract infection) need not be considered exclusions at the discretion of the investigator;
    n) 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);
    o) History of lymphoproliferative disease including lymphoma;
    p) Patient is unwilling or unable to comply with the study procedures.
    E.5 End points
    E.5.1Primary end point(s)
    1. Safety will be assessed in terms of the incidence of adverse events and changes in vital signs and routine laboratory measures. Patients will be monitored for adverse events during MSC administration and at each study visit according to WHO criteria.

    2. Patients will undergo MRI at baseline and 12 weeks after bmMSC administration. MRI classifications will be assessed by a blinded independent radiologist. The reduction in the number of draining fistulas is defined as absence of discharge upon pressure and absence of collections of ≥2 cm directly related to the treated fistulas tracts as measured by MRI.
    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 Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. 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 Yes
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E. description
    surgical approach without intralesional injection of IMP
    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 Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    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
    The end of the study is defined as the last patient’s last visit.
    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
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial 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.1.3Elderly (>=65 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state21
    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 Decision2010-03-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-05-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-12-17
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