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    Summary
    EudraCT Number:2017-000725-12
    Sponsor's Protocol Code Number:Cx601-0303
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-02-28
    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 ConcernedGermany - PEI
    A.2EudraCT number2017-000725-12
    A.3Full title of the trial
    A phase III, randomized, double blind, parallel group, placebo controlled, international, multicentre study to assess efficacy and safety of Cx601, adult allogeneic expanded adipose-derived stem cells (eASC), for the treatment of complex perianal fistula(s) in patients with Crohn’s disease over a period of 24 weeks and a follow-up period up to 52 weeks. ADMIRE-CD II study.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical research study of an investigational new drug to treat perianal fistulas in patients with Crohn’s disease (CD).
    A.4.1Sponsor's protocol code numberCx601-0303
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03279081
    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 SponsorTiGenix, S.A.U.
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTiGenix S.A.U.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTiGenix, S.A.U.
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressC/ Marconi 1. Parque Tecnológico de Madrid
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28760
    B.5.3.4CountrySpain
    B.5.4Telephone number+3491804 92 64
    B.5.5Fax number+3491804 92 63
    B.5.6E-mailinmaculada.gilaberte@takeda.com
    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 Yes
    D.2.1.1.1Trade name Alofisel
    D.2.1.1.2Name of the Marketing Authorisation holderTakeda Pharma A/S, Dybendal Alle 10, 2630 Taastrup, Denmark
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/667
    D.3 Description of the IMP
    D.3.1Product nameAllogenic eASCs 5 million cells/ml suspension for injection CX601
    D.3.2Product code Cx601
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntralesional use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnap
    D.3.9.2Current sponsor codeAllogenic eASCs
    D.3.9.3Other descriptive nameExpanded human allogenic mesenchymal adult stem cells extracted from adipose tissue (eASCs)
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5000000
    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) No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntralesional use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Perianal fistulising Crohn´s disease
    E.1.1.1Medical condition in easily understood language
    Treatment for perianal fistulising Crohn´s disease
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10002156
    E.1.2Term Anal fistula
    E.1.2System Organ Class 10017947 - Gastrointestinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the Combined Remission of complex perianal fistula(s), defined as the clinical assessment at Week 24 of closure of all treated external openings that were draining at baseline despite gentle finger compression, and absence of collections >2 cm (in at least 2 dimensions) confirmed by blinded central MRI assessment at Week 24.
    E.2.2Secondary objectives of the trial
    - To evaluate the efficacy of Cx601 as compared to placebo in clinical remission at Week 24 and in time to clinical remission (weeks).
    - To evaluate the efficacy and safety of Cx601 as compared to placebo in other clinical and time-to-event related endpoints at Weeks 24 and 52
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    (1) Signed informed consent
    (2) Subjects of either gender ≥ 18 years and ≤75 years of age
    (3) Subjects with CD diagnosed at least 6 months prior to Screening visit in accordance with accepted clinical, endoscopic, histological and/or radiological criteria
    (4) Presence of complex perianal fistula(s) with a maximum of 2 internal openings and a maximum of 3 external openings based on assessment; a central reading of a locally performed contrast enhanced (gadolinium) pelvic MRI will be perfomed to confirm location of the fistula and potential associated perianal abscess(es). Fistula(s) must have been draining for at least 6 weeks prior to Screening visit. Actively draining simple subcutaneous fistula(s), at the time of Screening visit, are not allowed in this study. A complex perianal fistula is defined as a fistula that meets one or more of the following criteria :
    • High inter-sphincteric, high trans-sphincteric, extra-sphincteric or supra-sphincteric
    • Presence of ≥ 2 external openings
    • Associated perianal abscess(es). Note: Abscesses that are larger than 2 cm in at least 2 dimensions on MRI must be confirmed to have been drained adequately by the surgeon during the preparation curettage in order to be eligible.
    (5) Clinically controlled, non active or mildly active CD, during the last six months prior to Screening visit with:
    1. a PRO-2 score < 14 at Screening, AND
    2. a colonoscopy documenting the absence of ulcers larger than 0.5 cm in the colonic mucosa: If colonoscopy data are not available within 6 months prior to Screening: a SES-CD ≤ 6 with absence of rectal ulcers larger than 0.5 cm must be documented in a colonoscopy performed at Screening before randomization. If colonoscopy data are available within 6 months prior to Screening, the following must be documented, otherwise a new colonoscopy (as above) will be mandatory: the absence of ulcers larger than 0.5 cm in the colonic mucosa AND the improvement or no worsening in abdominal pain and/or in the diarrhea, sustained for one week or more, since the last colonoscopy was performed in the clinical records until Screening visit AND no hemoglobin decrease > 2.0 g/dL or an unexplained rising C-reactive protein (CRP), > 5.0 mg/L to a concentration above the referenced ULN (unless the rise is due to a known process other than luminal Crohn’s Disease), since the last colonoscopy was performed as compared to results during the Screening visit AND no initiation or intensification of treatment with corticosteroids, immunosuppressants or mAbs dose regimen since the last endoscopy up to Screening visit.
    (6) Subjects whose perianal fistulas were previously treated and have shown an inadequate response (absence of closure of part or all fistula tracts, or new fistula during induction treatment) or a loss of response (fistula relapse during maintenance treatment after initial fistula closure) while they were receiving either an immunosuppressive agent or TNF-α antagonist or vedolizumab or ustekinumab, or having documented intolerance (occurrence, at any time, of an unacceptable level of treatment-related side effects that makes necessary treatment discontinuation) to any of these treatments administered at least at approved or recommended doses during the minimum period mentioned:
    -Immunosuppressive agents
    -TNFα antagonists
    - Anti-integrin
    - Anti-IL-12/23
    (7) Women of childbearing potential (WCBP) must have negative serum pregnancy test at Screening (sensitive to 25 IU human chorionic gonadotropin [hCG]). Both WCBP or male patients participating in this study, with a WCBP as partner, must agree to use an adequate method of contraception during the entire duration of the study. An adequate method of contraception is defined as complete, non-periodic sexual abstinence (refraining from heterosexual intercourse), single-barrier method, vasectomy, adequate hormonal contraception (to have started at least 7 days prior to Screening visit), or an intra-uterine device (to have been in place for at least 2 months prior to Screening visit).
    E.4Principal exclusion criteria
    (1) Concomitant rectovaginal or rectovesical fistula(s).
    (2) Subject naïve to prior specific medical treatment for complex perianal fistula(s) including IS or anti-TNFs.
    (3) Presence of a perianal collection >2 cm in at least two dimensions on the central reading MRI at Screening visit that was not adequately drained as confirmed by the surgeon during the preparation procedure (week -3 to day 0).
    (4) Severe rectal and/or anal stenosis and/or severe proctitis (defined as the presence of large [>0.5 cm] ulcers in the rectum) that make it impossible to follow the Surgery Procedure Manual.
    (5) Subject with diverting stomas.
    (6) Active, uncontrolled infection requiring parenteral antibiotics.
    (7) Subject with ongoing systemic or rectal steroids for CD in the last 2 weeks prior to Preparation visit.
    (8) Subjects with major alteration on any of the following laboratory tests or increased risk for the surgical procedure:
    a. Serum creatinine levels >1.5 times the ULN
    b. Total bilirubin >1.5 times the ULN (unless predominantly non-conjugated due to documented history of Gilbert’s syndrome)
    c. AST/ALT >3.0 times the ULN
    d. Hemoglobin <10.0 g/dL
    e. Platelets <75.0 x 109/L
    f. Albuminemia <3.0 g/dL
    (9) Suspected or documented infectious enterocolitis within 2 weeks prior to Screening visit.
    (10) Any prior invasive malignancy diagnosed within the last 5 years prior to Screening visit. Patients with basal-cell carcinoma of the skin completely resected outside the perineal region can be included.

    (11) Current or recent (within 6 months prior to the Screening visit) history of severe, progressive, and/or uncontrolled hepatic, haematological, gastrointestinal (other than CD), renal, endocrine, pulmonary, cardiac, neurological or psychiatric disease that may result in patients increased risk from study participation and/or lack of compliance with study procedures
    (12) Subjects with primary sclerosing cholangitis
    (13) Subjects with known chronically active hepatopathy of any origin, including cirrhosis and patients with persistent positive HBV surface antigen (HBsAg) and quantitative HBV polymerase chain reaction (PCR), or positive serology for HCV and quantitative HCV PCR within 6 months prior to Screening.
    (14) Congenital or acquired immunodeficiencies, including subjects known to be HIV carriers
    (15) Known allergies or hypersensitivity to penicillin or aminoglycosides; DMEM; bovine serum; local anaesthetics or gadolinium (MRI contrast).
    (16) Contraindication to MRI scan (e.g., due to the presence of pacemaker, hip replacement or severe claustrophobia).
    (17) Severe trauma within 6 months prior to Screening visit.
    (18) Pregnant or breastfeeding women.
    (19) Subjects who do not wish to or cannot comply with study procedures.
    (20) Subjects currently receiving, or having received any investigational drug within 3 months prior to Screening visit.
    (21) Subjects previously treated with Cx601 or other allogeneic stem-cell therapy cannot be enrolled into this clinical study.
    (22) Any major surgery of the GI tract (including one or more segments of the colon or terminal ileum) within 6 months prior to screening or any minor surgery of the GI tract within 3 months prior to screening.
    (23) Subjects who had local perianal surgery other than drainage for the fistula within 6 months prior to the Screening visit, or those who may need surgery in the perianal region for reasons other than fistulas at the time of inclusion in the study.
    (24) Contraindication to the anaesthetic procedure.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects who achieve combined remission at Week 24 after IMP administration, where combined remission is defined as:
    - The closure of all treated external openings that were draining at baseline despite gentle finger compression
    AND
    - Absence of collection(s) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by blinded central MRI assessment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at week 24
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Enpoints
    - Proportion of subjects who achieve clinical remission at Week 24 after IMP administration, where clinical remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression.
    - Time to clinical remission (weeks) assessed at Week 24, defined as the time from treatment start to first visit with closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. Subjects who do not achieve clinical remission by Week 24 will be censored at that visit.

    Other Secondary Efficacy Endpoints
    - Proportion of subjects who achieve clinical response at Week 24 after IMP administration, where clinical response is defined as closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression.
    - Time to clinical response (weeks) assessed at Week 24, defined as the time from treatment start to first visit with closure of at least 50% of all treated external openings that were draining at baseline, despite gentle finger compression, as clinically assessed. Subjects who do not achieve clinical response by Week 24 will be censored at that visit.
    - Proportion of subjects who achieve combined remission at Week 52 after IMP administration, where combined remission is defined as:
    a) The closure of all treated external openings that were draining at baseline despite gentle finger compression,
    AND
    b) Absence of collection(s) >2 cm (in at least 2 dimensions) confirmed by blinded central MRI assessment.
    - Proportion of subjects who achieve clinical remission at Week 52 after IMP administration, where clinical remission is defined as closure of all treated external openings that were draining at baseline despite gentle finger compression.
    - Proportion of subjects who achieve clinical response at Week 52 after IMP administration, where clinical response is defined as closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression.
    - Time to clinical remission (weeks) assessed at Week 52, defined as the time from treatment start to first visit with closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. Subjects who do not achieve clinical remission by Week 52 will be censored at that visit.
    - Time to clinical response (weeks) assessed at Week 52, defined as the time from treatment start to first visit with closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. Subjects who do not achieve clinical response by Week 52 will be censored at that visit.
    - Proportion of subjects with a relapse from Week 24 combined remission response, where a relapse is defined as:
    a) Reopening of any of the treated fistula(s) external openings with active drainage as clinically assessed in subjects who were in combined remission,
    OR
    b) The development of a perianal fluid collection >2 cm of the treated perianal fistulas confirmed by centrally read magnetic resonance imaging (MRI) assessment.

    Safety Endpoints
    - Incidence of treatment-emergent AEs (TEAEs)
    - Incidence of treatment-emergent SAEs.
    - Incidence of adverse events of special interest (AESIs).
    - Vital signs.
    - Laboratory parameters

    E.5.2.1Timepoint(s) of evaluation of this end point
    at 24 and 52 weeks after the treatment
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Canada
    Czech Republic
    France
    Hungary
    Israel
    Italy
    Poland
    Spain
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months3
    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.1.2.1Number of subjects for this age range: 462
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 92
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 332
    F.4.2.2In the whole clinical trial 554
    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)
    No plans are foreseen.
    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 Decision2019-07-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-17
    P. End of Trial
    P.End of Trial StatusOngoing
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