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    EudraCT Number:2017-002491-10
    Sponsor's Protocol Code Number:Alofisel-4001
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-11-27
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedCzechia - SUKL
    A.2EudraCT number2017-002491-10
    A.3Full title of the trial
    Postauthorization Safety Study of the Long-Term Safety and Efficacy of Repeat Administration of Darvadstrocel in Patients With Crohn’s Disease and Complex Perianal Fistula
    Poregistrační studie bezpečnosti hodnotící dlouhodobou bezpečnost a účinnost opakovaného podávání přípravku darvadstrocel u pacientů s Crohnovou nemocí a komplexní perianální píštělí
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Postauthorization Safety Study of Darvadstrocel Repeat Administration
    A.4.1Sponsor's protocol code numberAlofisel-4001
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1237-8388
    A.5.4Other Identifiers
    Name:EUPAS numberNumber:EUPAS31439
    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 SponsorTakeda Development Center Americas, Inc.
    B.1.3.4CountryUnited States
    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 supportTakeda Development Center Americas, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Development Center Americas, Inc.
    B.5.2Functional name of contact pointClinical Science
    B.5.3 Address:
    B.5.3.1Street Address95 Hayden Avenue
    B.5.3.2Town/ cityLexington
    B.5.3.3Post code02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018576004183
    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. name Alofisel
    D. 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 nameCx601
    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 INNDarvadstrocel
    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.3.9.4EV Substance CodeSUB190583
    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. cell therapy medicinal product Yes
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    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 assess the long-term safety of repeat administration of darvadstrocel in subjects with CD and complex perianal fistula by evaluation of AEs, serious adverse events (SAEs), adverse events of special interest (AESIs), and special situation reports (SSRs).
    E.2.2Secondary objectives of the trial
    To evaluate the long-term efficacy of repeat administration of darvadstrocel in subjects with CD and complex perianal fistula.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
    2. The subject signs and dates a written, informed consent form (ICF) and any required privacy authorization before the initiation of any study procedures.
    3. The subject is male or female and aged 18 years or older.
    4. The subject has complex perianal fistula(s) with a maximum of 2 internal openings and a maximum of 3 external openings based on clinical assessment and a reading of a locally performed contrast enhanced (gadolinium) pelvic MRI. Fistula(s) must have been draining for at least 6 weeks prior to baseline visit. A complex perianal fistula is defined as a fistula that meets 1 or more of the following criteria:
    a) High inter-sphincteric, high trans-sphincteric, extra-sphincteric or suprasphincteric.
    b) Presence of ≥2 external openings.
    c) 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. The subject has already received treatment with darvadstrocel for a complex perianal fistula at least 6 months prior to baseline visit for retreatment, and their physician has planned a repeat treatment administration for the original tract (full remission not obtained or relapse of fistula draining) or for a new complex perianal fistula tract.
    6. The subject has controlled or mildly active CD (defined as patient reported outcomes measure derived from Crohn’s Disease Activity Index [CDAI] patient reported outcome score-2 [PRO-2] score <14).
    7. A male subject who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use barrier method of contraception (eg, condom with or without spermicide) from signing of informed consent and until 1 year after repeat administration.
    8. A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to use a highly effective/effective method of contraception from signing of informed consent and until 1 year after repeat administration.
    E.4Principal exclusion criteria
    1. The subject has lack of clinical response to prior treatment with darvadstrocel, where clinical response is defined as closure of at least 50% of all treated external fistula openings that were draining at baseline despite gentle finger compression or in the case of a unique fistula, a partial closure of the fistula.
    2. The subject has a history of hypersensitivity or allergies to darvadstrocel or related compounds.
    3. The subject has a history of hypersensitivity or allergies to penicillin or aminoglycosides; Dulbecco modified eagle medium; bovine serum; local anesthetics or gadolinium.
    4. The subject is currently participating in a double-blind clinical study with darvadstrocel. Subjects participating in the ongoing INSPIRE registry (Alofisel-5003) study would need to withdraw from that study in order to enroll in this study.
    5. The subject is currently receiving or has received any other IMP within the last 3 months or at least 5 times the respective elimination half-life time, whichever is longer, before signing the ICF.
    6. The subject has known or suspected COVID-19 by the investigator within the past 2 months (additional testing may be performed at the discretion of the investigator). Positive antibody
    testing for COVID without other evidence of current or recent active infection does not exclude participation.
    a) Subjects who were in screening at the time that COVID-19–related factors resulted in discontinuation may also be rescreened with approval of the sponsor or designee.
    7. The subject has major alterations in any of the following laboratory tests:
    a) Serum creatinine levels >1.5 times the upper limit of normal(ULN).
    b) Total bilirubin >1.5 × ULN.
    c) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3.0 × ULN.
    d) Hemoglobin <10.0 g/dL.
    e) Platelets <75.0 × 109/L.
    f) Albumin <3.0 g/dL.
    8. The subject has an increased risk for surgical procedure.
    9. The subjects has a known chronically active hepatopathy of any origin, including cirrhosis and subjects with persistent positive hepatitis B surface antigen and quantitative hepatitis B virus polymerase chain reaction (PCR) or positive serology for hepatitis C virus (HCV) and quantitative HCV PCR within 6 months before the baseline visit.
    10. If female, the subject is pregnant or breastfeeding, or intending to become pregnant before participating in this study, during the study, or intending to donate ova during such time period.
    11. If male, the subject intends to donate sperm during this study.
    12. The subject has a contraindication to MRI scan (eg, due to the presence of pacemaker, hip replacement, severe claustrophobia, or renal insufficiency as defined by local clinical guidelines).
    13. The subject has a contraindication to the anesthetic procedure.
    14. The subject has severe rectal and/or anal stenosis that would make it impossible to follow the surgery procedure.
    15. The subject has severe proctitis (rectal ulcers >0.5 cm) that would make it impossible to follow the surgery procedure.
    16. The subject has any prior invasive malignancy diagnosed within the last 3 years before baseline visit. Subjects with basal cell carcinoma of the skin completely resected outside the perineal region can be included.
    17. The subject has a current or recent (within 6 months before the baseline visit) history of severe, progressive, and/or uncontrolled hepatic, hematologic, gastrointestinal (other than CD), renal, endocrine, pulmonary, cardiac, neurologic, or psychiatric disease that may result in subject’s increased risk from study participation and/or lack of compliance with study procedures.
    18. The subject has had major surgery of the gastrointestinal tract within 6 months before baseline or any minor surgery of the gastrointestinal tract 3 months before baseline.
    19. The subject has had local major perianal surgery and/or treatment with darvadstrocel within 6 months before baseline. The abscess drainage, cleaning surgery, or seton placement are not considered as "local major surgery" in this protocol.
    20. The subject does not wish to or cannot comply with study procedures.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study will include assessment of the following safety parameters:
    - Incidence of treatment-emergent adverse events
    - Incidence of treatment-emergent SAEs
    - SSRs (pregnancy)
    - Specific AESIs, including:
    – Immunogenicity/alloimmune reactions
    – Hypersensitivity
    – Transmission of infectious agents
    – Tumorgenicity, applying to malignant tumors only.
    – Ectopic tissue formation
    – Medication errors
    E.5.1.1Timepoint(s) of evaluation of this end point
    Subjects will be assessed before repeat administration at the baseline and preparatory visit, and at Weeks 6 (±8 days), 24 (±15 days), 52 (±15 days), 104 (±30 days), and 156 (±30 days) following repeat administration. The Week 6 assessment will be primarily to capture immunogenicity/donor-specific antibody (DSA)/soluble factors.
    Blood samples for central laboratory tests will be collected at baseline, Weeks 24 (±15 days), 156 (±30 days), and the
    early termination visit. Blood samples for DSA levels and exploratory immunogenicity testing will be collected at the
    baseline visit and at Weeks 6 (±8 days), 24 (±15 days), and 156 (±30 days). Blood samples for these tests will be
    analyzed in batches as the study progresses, and available results will be provided with the interim reports.
    E.5.2Secondary end point(s)
    Efficacy will be assessed by evaluating the following endpoints:
    - Proportion of subjects who achieve combined remission of perianal fistula(s) at Weeks 24 and 156 after darvadstrocel administration, where combined remission is defined as:
    - The closure of all treated external openings that were draining at baseline (ie, baseline visit), despite gentle finger compression,
    > Absence of collection(s) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by central MRI assessment.

    - Proportion of subjects who achieve clinical remission at Weeks 6, 24, 52, 104, and 156 after darvadstrocel administration.
    > Clinical remission is defined as closure of all treated external fistula openings that were draining at baseline despite gentle finger compression.

    - Proportion of subjects who achieve clinical response at Weeks 6, 24, 52, 104, and 156 after darvadstrocel administration.
    > Clinical response is defined as closure of at least 50% of all treated external fistula openings that were draining at baseline despite gentle finger compression.

    - Proportion of subjects with relapse from Week 24 combined remission, where relapse is defined as:
    - Reopening of any of the treated fistula(s) external openings with active drainage as clinically assessed that were in combined remission at Week 24,
    - The development of a collection >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by centrally read MRI assessment.
    - Time to reopening of any of the treated external openings with active drainage as clinically assessed, measured in days relative to Week 24.
    - Proportion of subjects with new perianal abscess in treated fistula.
    - Change from baseline to Weeks 6, 24, 52, 104, and 156 after darvadstrocel administration in scores of discharge and pain items of Perianal Disease Activity Index (PDAI) score.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Subjects will be assessed before repeat administration at the baseline and preparatory visit, and at Weeks 6 (±8 days),
    24 (±15 days), 52 (±15 days), 104 (±30 days), and 156 (±30 days) following repeat administration.
    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 Yes
    E.6.13.1Other scope of the trial description
    To assess the effect of darvadstrocel on microbiome diversity (optional).
    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. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 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 No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months10
    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: 42
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 50
    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 post-trial medication will be provided.
    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 Decision2020-03-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-04
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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