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    Summary
    EudraCT Number:2020-003193-48
    Sponsor's Protocol Code Number:Darvadstrocel-3004
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2020-10-13
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2020-003193-48
    A.3Full title of the trial
    A Phase 3, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of Darvadstrocel in
    the Treatment of Complex Perianal Fistula in Pediatric Subjects with Crohn’s Disease over a
    Period of 24 Weeks and an Extended Follow-up Period for a Total of up to 52 Weeks.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Study to Evaluate the Efficacy and Safety of Darvadstrocel in the Treatment of Complex Perianal Fistula in Pediatric Subjects with Crohn’s Disease.
    A.3.2Name or abbreviated title of the trial where available
    Darvadstrocel in the Treatment of Complex Perianal Fistula in Pediatric Crohn’s Disease.
    A.4.1Sponsor's protocol code numberDarvadstrocel-3004
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/253/2014
    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 Trial Information
    B.5.3 Address:
    B.5.3.1Street Address95 Hayden Avenue
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number+12247147333
    B.5.5Fax number+16175513742
    B.5.6E-mailsandra-paola.gonzalez@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
    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 nameDarvadstrocel
    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 codeCx601
    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 number120
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Complex Perianal Fistulas in Crohn’s Disease
    E.1.1.1Medical condition in easily understood language
    Crohn's Disease is a condition that damages the bowel wall. Complex perianal fistulas have several abnormal connections and openings, or with passages that go deep inside the body.
    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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10068659
    E.1.2Term Perianal fistula
    E.1.2System Organ Class 100000004856
    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 efficacy of darvadstrocel in combined remission at Week 24 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.
    E.2.2Secondary objectives of the trial
    To evaluate;

    the efficacy of darvadstrocel in clinical remission at Week 24 and Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.

    the efficacy of darvadstrocel in clinical response at Week 24 and Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.

    the efficacy of darvadstrocel in time to clinical remission up to Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.

    the efficacy of darvadstrocel in time to clinical response up to Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.

    the efficacy of darvadstrocel on relapse by Week 52 in pediatric subjects with combined remission at Week 24.

    the safety of darvadstrocel for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years over 52 weeks.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subject eligibility is determined according to the following criteria prior to entry into the study:
    1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.

    2. The subject, or when applicable, the subject’s legally acceptable representative, signs and dates a written, informed consent/pediatric assent form and any required privacy authorization before the initiation of any study procedures.

    3. The subject is male or female aged 4 to <18 years at the time of informed consent/pediatric assent.

    4. The subject has a CD diagnosis based on accepted clinical, endoscopic, histological and/or radiologic criteria at least 6 months before the screening visit.

    5. The subject has complex perianal fistula refractory to at least one of the following treatments:
    immunosuppressants or biologics (anti-TNFs, anti-integrin, anti-interleukin [IL] 12/23).
    Fistula(s) refractory to therapy are defined in this study as follows:

    Immunosuppressants: Inadequate response after 3 months, based on clinical assessment, or more treatment with azathioprine, 6-mercaptopurine or methotrexate.

    Biologics: Inadequate response after 14 weeks (16 weeks for anti-IL 12/23), based on clinical assessment, or more standard treatment for induction and maintenance.

    6. A complex perianal fistula(s) that meets one or more of the following criteria, according to the American Gastroenterological Association (AGA) technical review [26]:
     High intersphincteric, transsphincteric, extrasphincteric, or suprasphincteric.
     Presence of 2-3 external openings (tracts).
     Associated fluid collections.

    This study requires that the subject has complex perianal fistulas with a maximum of 2 internal openings and a maximum of 3 external openings, based on clinical assessment. Darvadstrocel treatment is targeted for fistulas that connect between internal and external openings. A central reading of a locally performed pelvic MRI (with or without gadolinium enhancement) will be performed to confirm the location of the fistula and potential associated perianal abscess(es). Fistulas must have been draining for at least 6 weeks before the screening visit. Subjects with actively draining simple subcutaneous fistulas, at the time of the screening visit, are not allowed in this study.

    7. The subject has inactive or mildly active luminal CD defined by meeting all of the following criteria:
    a. Colonoscopy, flexible sigmoidoscopy or rectoscopy performed either at screening or within the 6 months before screening, demonstrating no rectal ulcers larger than 0.5 cm. A subject who has documented rectal ulcers larger than 0.5 cm within the 6 months before screening but has undergone subsequent treatment may be eligible if there are no rectal ulcers larger than 0.5 cm on a sigmoidoscopy or rectoscopy performed after treatment or at
    the time of screening.
    b. The improvement of, or no worsening in stool frequency, sustained for 1 week or more, in the interval between the colonoscopy, flexible sigmoidoscopy or rectoscopy in inclusion criteria 7(a) and the screening visit.
    c. No initiation or intensification of treatment with corticosteroids, immunosuppressants, or monoclonal antibody dose regimen between the colonoscopy, flexible sigmoidoscopy or rectoscopy in inclusion criteria 7(a) and the screening visit.

    8. 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 the time of signing of informed consent/pediatric assent throughout the duration of the study. The female partner of a male subject should also be advised to use a highly effective method of contraception.

    9. A female subject of childbearing potential* who is sexually active with a nonsterilized male partner agrees to use a highly effective method of contraception* from the time of signing of informed consent/pediatric assent throughout the duration of the study.
    *Definitions and highly effective methods of contraception are defined in Section 9.1.10 and reporting responsibilities are defined in Section 9.1.11.
    E.4Principal exclusion criteria
    Any subject who meets any of the following criteria will not qualify for entry into the study:
    1. The subject has received any investigational compound within 12 weeks/84 days before screening.
    2. The subject has received darvadstrocel/eASC in a previous clinical study or as a therapeutic agent.
    3. The subject is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling), or may consent under duress.
    4. The subject weighs <10 kg at screening.
    5. The subject has, in the judgment of the investigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at screening.
    6. The subject has a history of hypersensitivity or allergies to darvadstrocel or any of its excipients.
    7. The subject takes or is required to take excluded medications listed in Table 7.a.
    8. The subject has concomitant perianal fistula(s) with only internal or external opening(s).
    9. The subject has concomitant internal fistula(s) such as ileo-vesical, rectovaginal or ileo-colonic fistula(s).
    10. The subject has an abscess or collections >2 cm, unless resolved in the preparation procedure.
    11. The subject has rectal and/or anal stenosis, and/or active proctitis, which would restrict the surgical procedure.
    12. The subject underwent surgery for the fistula other than drainage or seton placement.
    13. The subject has diverting stomas.
    14. The subject has ongoing systemic corticosteroid treatment or has been treated with systemic corticosteroids within 4 weeks before screening.
    15. The subject requires new treatment with immunosuppressants/anti-TNF agents during the screening period.
    16. 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.
    -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.
    17. The subject requires surgery in the perianal region for reasons other than fistulas at the time of screening or foreseen either during the study and/or during the 24 weeks after treatment administration.
    18. The subject has a serum creatinine ≥2 × upper limit of normal (ULN).
    19. The subject has hepatic impairment defined by both of the following laboratory ranges:
    a) Total bilirubin ≥1.5 × ULN.
    b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥2 × ULN.
    20. The subject has known history of abuse of alcohol or other addictive substances in the 6 months before screening.
    21. The subject has malignant tumor or a prior history of any malignant tumor, including any type of fistula carcinoma.
    22. The subject has current or recent (within 3 months before the screening) history of abnormal, severe, progressive, uncontrolled hepatic, hematologic, gastrointestinal (except CD), endocrine, pulmonary, cardiac, neurological, psychiatric, or cerebral disease.
    23. The subject has either congenital or acquired immunodeficiencies, including subjects known to be HIV carriers or subjects with, in the judgment of the investigator, are suspected to have monogenic inflammatory bowel disease.
    24. The subject has a known clinically significant 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, or positive serology for hepatitis C virus (IgG) and quantitative hepatitis C virus polymerase chain reaction at the screening visit.
    25. The subject has known allergies or hypersensitivity to antibiotics (including benzylpenicillin/streptomycin, gentamicin [used in the darvadstrocel manufacturing process]) human serum albumin; Dulbecco Modified Eagle’s Medium, material of bovine origin, or local anesthetics.
    26. The subject has previously received a bone marrow transplant.
    27. The subject has a contraindication to MRI scan, gadolinium (MRI contrast) or other planned study procedures.
    28. The subject has a contraindication to the anesthetic procedure.
    29. The subject had major surgery or severe trauma within 6 months before the screening visit.
    30. A female subject who is pregnant or is lactating or intending to become pregnant before participating in this study or during the study; or intending to donate ova during such time period.
    31. If male, the subject intends to donate sperm during the course of this study.
    32. The subject does not wish to or cannot comply with study procedures.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint-Efficacy endpoint
    Proportion of subjects who achieve combined remission at Week 24, 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 collections(s) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by central magnetic resonance imaging (MRI) assessment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 24
    E.5.2Secondary end point(s)
    Secondary Endpoints-
    Efficacy at Week 24
    1. Proportion of subjects who achieve clinical remission at Week 24, where clinical remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression.
    2. Proportion of subjects with clinical response at Week 24, 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.

    Efficacy at Week 52
    1. Proportion of subjects who achieve clinical remission at Week 52, where clinical remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression.
    2. Time to clinical remission (weeks) assessed at each clinic visit up to Week 52. This is defined as the time from treatment start to first visit at which clinical remission is observed before Week 52; where clinical remission is said to occur if a clinical assessment shows closure of all treated external openings that were draining at baseline despite gentle finger compression.
    3. Proportion of subjects with clinical response at Week 52, 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.
    4. Time to clinical response (weeks) assessed at each clinic visit up to Week 52. This is defined as the time from treatment start to first visit at which clinical response is observed before Week 52; where clinical response is said to occur if a clinical assessment shows closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression.
    5. Proportion of subjects with relapse by Week 52, in subjects with combined remission at Week 24, where relapse is defined as reopening of any of the treated fistula(s) external openings with active drainage as clinically assessed in subjects who were in combined remission at Week 24.

    Safety Endpoints
    1. Incidence of AEs.
    2. Incidence of SAEs.
    3. Incidence of adverse events of special interest (AESIs).
    4. Vital signs.
    5. Laboratory parameters (biochemistry, hematology, and urinalysis).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 24 and week 52
    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 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Israel
    Japan
    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
    LPLV
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    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 Yes
    F.1.1Number of subjects for this age range: 20
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 8
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 12
    F.1.2Adults (18-64 years) No
    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 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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 16
    F.4.2.2In the whole clinical trial 20
    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)
    None
    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 Decision2021-01-27
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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