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    Summary
    EudraCT Number:2015-005162-34
    Sponsor's Protocol Code Number:clinical_study_protocol
    National Competent Authority:Croatia - MIZ
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-12-15
    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 ConcernedCroatia - MIZ
    A.2EudraCT number2015-005162-34
    A.3Full title of the trial
    Randomized, multi-center phase II clinical trial for the regeneration of cartilage lesions in the knee using nasal chondrocyte-based tissue (NTEC) or nasal chondrocyte-based cell (N-CAM)-therapies
    Randomisierte, multizentrische klinische Studie Phase II zur Regeneration von Knorpelläsionen im Knie unter Verwendung von auf nasalen Knorpelzellen basierender Gewebe- (N-TEC) oder Zelltherapie (N-CAM)
    Randomizirano, multicentrično kliničko ispitivanje faze II za regeneraciju oštećenja hrskavice u koljenu terapijama temeljenim na tkivu dobivenom iz hondrocita hrskavice nosnog septuma (N-TEC) ili stanicama hondrocita iz hrskavice nosnog septuma (N-CAM).
    Studio clinico randomizzato, multicentrico di fase II per la rigenerazione di lesioni della cartilagine del ginocchio mediante terapia tissutale a base di condrociti nasali (N-TEC) o terapia cellulare a base di condrociti nasali (N-CAM)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized, multi-center phase II clinical trial for the regeneration of cartilage lesions in the knee using nasal chondrocyte-based tissue (N-TEC) or nasal chondrocyte-based cell- (N-CAM) therapies
    Randomisierte (zufällig zu einer Behandlungsgruppe zugeordnete) multizentrische klinische Studie Phase II zur Regeneration (Wiederherstellung) von Knorpelläsionen (Knorpelschäden) im Knie unter Verwendung von auf nasalen Knorpelzellen basierender Gewebe- (N-TEC) oder Zelltherapie (N-CAM)
    Randomizirano, multicentrično kliničko ispitivanje faze II za regeneraciju oštećenja hrskavice u koljenu terapijama temeljenim na tkivu dobivenom iz hondrocita hrskavice nosnog septuma (N-TEC) ili stanicama hondrocita iz hrskavice nosnog septuma (N-CAM)
    Studio clinico randomizzato, multicentrico di fase II per la rigenerazione delle lesioni della cartilagine nel ginocchio mediante una terapia rappresentata da tessuto nasale a base di condrociti isolati (N-TEC) o condrociti nasali su membrana (N-CAM)
    A.3.2Name or abbreviated title of the trial where available
    Nose to Knee II
    Nose to Knee II
    Nose to Knee II
    Nose to Knee II
    A.4.1Sponsor's protocol code numberclinical_study_protocol
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02673950
    A.5.4Other Identifiers
    Name:SNCTPNumber:000001712
    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 SponsorUniversity Hospital Basel
    B.1.3.4CountrySwitzerland
    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 supportEU Horizon 2020
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Basel
    B.5.2Functional name of contact pointMarcus Mumme
    B.5.3 Address:
    B.5.3.1Street AddressHebelstrasse 20
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4031
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+41615565885
    B.5.5Fax number+41612653990
    B.5.6E-mailMarcus.Mumme@usb.ch
    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 nameN-TEC
    D.3.4Pharmaceutical form Implant
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraarticular use
    Implantation
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Yes
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Yes
    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.IMP: 2
    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 nameN-CAM
    D.3.4Pharmaceutical form Implant
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPImplantation
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Yes
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Yes
    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
    Patients must display 1-2 symptomatic, focal cartilage lesion grade IIIIV
    (according to the grading by the International Cartilage Repair
    Society (ICRS)) from 2 to 8 cm2 on the femoral condyle and/or the
    trochlea, have to be between 18-65 years old and must consent in oral
    and written manner in order to be enrolled in the study.
    E.1.1.1Medical condition in easily understood language
    Patients must display 1-2 severe, symptomatic,cartilage lesion from 2
    to 8 cm2 in the knee, have to be between 18-65 years old and must
    consent in order to be enrolled in the study.
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    This proposed phase II trial seeks to primarily define whether a tissue
    therapy for cartilage repair in the knee will improve the clinical efficacy
    for the patient, leading to an increase of at least 10 points in the main
    primary outcome (self-assessed score KOOS) after 24 months as
    compared to the cell therapy group. Comparison between groups will
    allow assessment of whether the tissue therapy is superior to the cell
    therapy.
    The KOOS score will be used to measure the primary outcome. The
    primary endpoint is the difference in the KOOS at 24 months between
    the two techniques (comparison of the efficacy of the technique). The
    KOOS score, covering the fields of Symptoms, Pain, Activities of daily
    life, Sport activities and Quality of life, is suitable for assessing the
    improvement for the patient. This validated questionnaire is widely
    used to assess efficacy of cartilage repair therapies.
    E.2.2Secondary objectives of the trial
    The stability and integration as well as the morphological properties of
    the graft will be assessed by the MOCART Score.
    The remodeling of the tissue after implantation towards native
    cartilage will be assessed by dGEMRIC evaluation (MRI) from the 24-
    month assessment of the relative ΔR1.
    The KOOS will be recorded for patients at baseline visit 1 or 2 and at
    the 12- and 24-month follow-up assessments. Variations over time will
    be recorded through completion of the questionnaires at enrolment and
    at each follow-up visit (12 and 24 months after treatment).
    Retrospectively data will be analyzed to identify the possibility of
    treatment selection (tissue therapy vs. cell therapy) in relation to the
    time after onset of symptoms (acute vs chronic cartilage lesions) in
    order to determine if one treatment is more beneficial than the other
    (e.g. higher stability, better integration etc.).
    The study will evaluate the safety by the number of SADRs or SUSARs.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patient is ≥18 and ≤65 years old at time of screening.
    • Patient has a localized articular cartilage defect of the femoral
    condyle and/or the trochlea of the knee. 2 localized cartilage defects
    are accepted if the total defect size is ≤ 8 cm2, both cartilage defects
    are located at the femoral condyle and/or the trochlea and both
    cartilage defects are to be treated with N-CAM or N-TEC.
    • Patient has a defect of grade 3 or 4 according to the ICRS
    classification.
    • Patient has a defect size ≥2 and ≤8 cm2 as assessed by
    MRI/arthroscopy.
    • Patient has an opposite intact (≤ICRS Grade 1 ) articulating joint
    surface (no "kissing lesions").
    • Patient has an intact meniscus (maximum 1/3-resection).
    • Patient has a stable knee joint or sufficiently reconstructed
    ligaments. If not, ligament repair has to be done during the operation
    or within 6 weeks of the planned cartilage treatment.
    • Patient has a maximum baseline score of 75/100 in the KOOS
    subjective knee evaluation.
    • Patient is willing and able to give written informed consent to
    participate in the study and to comply with all study requirements,
    including attending all follow-up visits and assessments and to
    complete postoperative rehabilitation regimen.
    E.4Principal exclusion criteria
    • Patient is unable to understand the patient information
    • Patient is unable to undergo magnetic resonance imaging (MRI) or
    is sensitive to gadolinium
    • Patient has had prior surgical treatment of the target knee within 12
    months using mosaicplasty and/or microfracture (Note: prior
    diagnostic arthroscopy with debridement and lavage are acceptable
    within 12 months). Anterior cruciate ligament repair is accepted, if the
    target knee is stable or a primary ACL reconstruction is performed
    within 6 weeks of the planned cartilage treatment.
    • Patient has an onset of symptoms of > 5 years.
    • Patient has a relevant meniscus tear. Partial meniscal removal
    allowed, if not exceeding 1/3. Meniscus suture is not allowed in
    parallel, but if successful, cartilage treatment might be added 12
    months later.
    • Patient has radiologically apparent degenerative joint disease in the
    target knee as determined by Kellgren and Lawrence grade >2.
    • Patient has evidence of joint disease e.g. chronic inflammatory
    arthritis, and/or infectious arthritis.
    • Patient has an unstable knee joint or insufficiently reconstructed
    ligaments. If ligament repair is necessary, the repair has to be
    performed during the operation or within 6 weeks of the planned
    cartilage treatment.
    • Patient has malalignment (no valgus- or varus-deformity) in the
    target knee ≥ 5°. In suspected cases, the mechanical axis must be
    established radiographically through complete leg imaging during
    standing and in a.p. or rather p.a. projection. If alignment surgery is
    necessary, surgery has to be performed within 6 weeks of the planned
    cartilage treatment.
    • Patient has an osteochondral defect (defined as bony substancedefect of >3mm depth). Bone marrow edema is allowed.
    • Any concomitant painful or disabling disease of the spine, hips, or
    lower limbs that would interfere with evaluation of the afflicted knee.
    • Patient has a known systemic connective tissue disease.
    • Patient has a known autoimmune disease.
    • Patient has a known immunological suppressive disorder or is taking
    immunosuppressives.
    • Patient is currently systemically or intra-articularly taking steroids
    and/or has used steroids within the 30 days prior to the planned
    treatment.
    • The patient has a known history of HIV/AIDS. (Protection of staff)
    • The patient has a known history of Treponema pallidum (syphilis).
    (Protection of staff)
    • The patient has an active hepatitis B or C infection with verified
    antigens. Patients with a cured hepatitis B or C infection and/or
    verified antibodies are not excluded. (Protection of staff)
    • The patient has at the site of surgery an active systemic or local
    microbial infection, eczematization or inflammable skin alterations
    (including Protozoonosis: Babesiosis, Trypanosomiasis (e.g. Chagas-
    Disease), Leishmaniasis, persistent bacterial infections, such as
    Brucellosis, spotted and typhus fever, other Rickettsiosis, Leprosy,
    Recurrent Fever, Melioidosis or Tularaemia).
    • Patient has a known history of cancer.
    • Patient has a known history of primary hyperparathyroidism,
    hyperthyroidism, reduced kidney function (GFR > 80 ml/min), or prior
    pathological fractures, independent of the genesis.
    • Patient has any degenerative muscular, vascular or neurological
    condition that would interfere with evaluation of outcome measuresincluding but not limited to Parkinson's disease, amyotrophic lateral
    sclerosis (ALS), or multiple sclerosis (MS).
    • Patient has a body mass index (BMI) >30 kg/m2.
    • Patient is pregnant, lactating or anticipates becoming pregnant
    within 24 months after surgery.
    • Patient is currently participating, or has participated in any other
    clinical study within 3 months prior to the screening visit.
    • Patient has known current or recent history of illicit drug or alcohol
    abuse or dependence defined as the continued use of alcohol or drugs
    despite the development of social, legal or health problems.
    • Patient has psychiatric or cognitive impairment that, in the opinion
    of the investigator, would interfere with the patient's ability to comply
    with the study requirements, e.g., Alzheimer's disease.
    • Patient has any other condition, which, in the opinion of the
    investigator, would make the patient unsuitable for the study.
    • Patient is unable to tolerate local anesthesia
    • Any known allergies, especially for porcine collagen, penicillin or
    streptomycin
    • Patient is unwilling and/or unable to give written informed consent
    to participate in the study and to comply with all study requirements,
    including attending all follow-up visits and assessments and to
    complete postoperative rehabilitation regimen.
    Intraoperative Exclusion Criteria:
    • Patient has a total defect size <2 or defect size extends graft size
    and could therefore not be treated in total.
    • Patient has >2 independent cartilage lesions
    • Patient has symptomatic full-thickness (ICRS Grade 3 or 4) of
    patella or tibial plateau.
    E.5 End points
    E.5.1Primary end point(s)
    KOOS score: The primary endpoint is the KOOS subjective score at the
    24-month visit. The difference in the KOOS-score will be compared
    between the two groups (Comparison of Efficacy of Treatment)
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 24 months
    E.5.2Secondary end point(s)
    MOCART Score (MRI): The MRI will be performed at 3, 12, 24 months
    follow-up visits and MOCART scores calculated. (Assessment of
    stability and integration)
    • dGEMRIC evaluation (MRI): The relative delta R1 will be evaluated
    by dGEMRIC and recorded at 3, 12, 24 months follow-up visits and
    referenced to the native cartilage of the treated knee. (Assessment of
    quality of the repair tissue)
    • A further questionnaire (EQ-5d) at 12 and 24 month and an
    additional time point (12 month) for KOOS will allow the more detailed
    analysis of the clinical development of the patient's recovery and
    elucidate changes in the perceived quality of life before and after
    treatment.
    Other outcomes:
    • Retrospective analysis of primary and secondary endpoint data with
    regard to the onset of symptoms to identify a possible selection of
    treatment of acute (onset < 1 years) or chronic (onset >1 years)
    lesions
    Safety:
    • Any AE and SAEs will be recorded regarding event descriptions,
    onset, resolution dates and relationship to the IMP. All SADR or SUSAR
    will be reported to Basel as leading center and the respective
    authorities.
    E.5.2.1Timepoint(s) of evaluation of this end point
    MRI and dGEMRIC will be performed at 3, 12, 24 months follow-up.
    questionnaires will be performed after 12 and 24 months follow-up.
    Retrospective Analysis will be performed at the end of the study.
    AEs will be recorded throughout the study.
    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 Yes
    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 Yes
    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
    two treatment arms (N-TEC and N-CAM)
    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 trial2
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA3
    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
    Croatia
    Germany
    Italy
    Switzerland
    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
    last visit of last Patient in 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 months0
    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 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.1.2.1Number of subjects for this age range: 108
    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 No
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state27
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 81
    F.4.2.2In the whole clinical trial 108
    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 Decision2016-09-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-11
    P. End of Trial
    P.End of Trial StatusOngoing
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