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    Summary
    EudraCT Number:2011-005798-22
    Sponsor's Protocol Code Number:AAG-G-H-1202
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-04-27
    Trial results View 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 number2011-005798-22
    A.3Full title of the trial
    A Clinical Study to Evaluate the Safety and Effectiveness of NOVOCART® 3D plus Compared to Microfracture in the Treatment of Articular Cartilage Defects of the Knee.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to evaluate the safety and effectiveness of NOVOCART® 3D plus compared to the standard of care (microfracture) in the treatment of cartilage defects of the knee.
    A.4.1Sponsor's protocol code numberAAG-G-H-1202
    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 SponsorTETEC – Tissue Engineering Technologies – AG
    B.1.3.4CountryGermany
    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 supportTETEC – Tissue Engineering Technologies – AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTETEC – Tissue Engineering Technologies – AG
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressAspenhaustraße 18
    B.5.3.2Town/ cityReutlingen
    B.5.3.3Post code72770
    B.5.3.4CountryGermany
    B.5.4Telephone number+4971211626204
    B.5.5Fax number+4971211626249
    B.5.6E-mailN3D@tetec-ag.de
    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 nameNOVOCART® 3D plus
    D.3.2Product code N3D
    D.3.4Pharmaceutical form Living tissue equivalent
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntracartilaginous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNOVOCART® 3D plus
    D.3.9.2Current sponsor codeN3D
    D.3.9.3Other descriptive nameAUTOLOGOUS HUMAN CARTILAGE CELLS
    D.3.9.4EV Substance CodeSUB30803
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0.75 x 1000000 to 4.0 x 1000000
    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 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) 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
    Repair of localized, full-thickness cartilage defects of the femoral condyle (medial, lateral or trochlea) of 2-6cm².
    E.1.1.1Medical condition in easily understood language
    Repair of cartilage defects of the knee.
    E.1.1.2Therapeutic area Body processes [G] - Cell Physiological Phenomena [G04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10052913
    E.1.2Term Cartilage operation
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10007705
    E.1.2Term Cartilage damage
    E.1.2System Organ Class 100000004863
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10057104
    E.1.2Term Cartilage repair
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10064112
    E.1.2Term Cartilage graft
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that the effectiveness of the NOVOCART® 3D plus autologous chondrocyte transplantation system is superior to microfracture for the treatment of articular cartilage defects of the knee by demonstrating superiority of the subjective IKDC score improvement from baseline to the score measured at the 24-month assessment visit.
    E.2.2Secondary objectives of the trial
    • To assess the physician evaluation of the functional effectiveness of NOVOCART® 3D plus.
    • To evaluate health-related quality-of-life improvement.
    • To evaluate cartilage (tissue-structure) regenerative effects of NOVOCART® 3D plus and microfracture
    • To assess surgical parameters.
    • To assess the proportion of treatment failures
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    MR Examination Protocols and Data Handling, KS_N3D_DOK12_5.0, 25.05.2018
    E.3Principal inclusion criteria
    Pre-operative inclusion criteria:
    At visit 1 patients must meet the following inclusion criteria for enrollment; all criteria must be answered with “yes” before the patient is scheduled for arthroscopy:
    1. Patient is ≥ 18 and ≤ 65 years old at screening or (in selected countries only) is a pediatric patient (14 to 17 years old) with closed epiphyseal growth plate (confirmation of closure of the epiphyseal growth plate of the index knee by X-ray or MRI required).
    2. Patient has a localized articular cartilage defect of the femoral condyle or the trochlea of the knee. 2 localized cartilage defects are accepted if the total defect size is ≤ 6 cm2 and the size of each individual lesion is ≥ 2 cm2, both cartilage defects are located at the femoral condyle and/or the trochlea and both cartilage defects are to be treated with NOVOCART® 3D plus or microfracture.
    3. Patient has a defect size ≥ 2 and ≤ 6 cm2. Note: defect size can be estimated by MRI at visit 1 if no data is available from medical history.
    4. Patient has an intact articulating joint surface (≤ Grade 2 International Cartilage Repair Society [ICRS] classification, no “kissing lesions”). Note: ICRS classification can be estimated by MRI at visit 1 if no data is available from medical history.
    5. Patient has an intact meniscus; a maximum of 50% resection is allowed. Note: status of meniscus can be estimated at visit 1 if no data is available from medical history.
    6. Patient has a stable knee joint or sufficiently reconstructed ligaments. If not, ligament repair must be done before, during or within 6 weeks after cartilage treatment (ACT/microfracture).
    7. Patient has free range of motion of the affected knee joint or ≤ 10° of Extension and flexion loss.
    8. Patient has a defect-grade of III or IV according to the ICRS classification. Note: ICRS classification can be estimated by MRI at visit 1 if not data is available from medical history.
    9. Patient has a baseline score of ≤ 60/100 on the 2000 International Knee Documentation Committee (IKDC) subjective knee evaluation.
    10. 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 postoperative rehabilitation regimen.
    11. Mandatory for France only: Patient benefits of a health insurance regimen.

    Intra-operative inclusion criteria:
    Patients who are eligible for the study according to the inclusion/exclusion criteria assessed at visit 1 will be scheduled for arthroscopy (visit 2). At visit 2, the following inclusion criteria from visit 1 need to be confirmed; all criteria must be answered with “yes” before the patient is randomized into the study:
    1. Patient is not pregnant as confirmed by urine pregnancy test before arthroscopy.
    2. Patient has a localized articular cartilage defect of the femoral condyle or the trochlea of the knee. 2 localized cartilage defects are accepted if the total defect size is ≤ 6 cm2 and the size of each individual lesion is ≥ 2 cm2, both cartilage defects are located at the femoral condyle and/or the trochlea and both cartilage defects are to be treated with NOVOCART® 3D plus or microfracture.
    3. Patient has a defect size ≥ 2 and ≤ 6 cm2 post-debridement.
    4. Patient has an intact articulating joint surface (≤ Grade 2 International Cartilage Repair Society [ICRS] classification;) no “kissing lesions”).
    5. Patient has an intact meniscus; a maximum of 50% resection is allowed (no indication for concurrent meniscus transplant).
    6. Patient has a stable knee joint or sufficiently reconstructed ligaments. If not, ligament repair must be done during or within 6 weeks after cartilage Treatment (ACT/microfracture).
    7. Patient has a defect grade of III or IV according to the ICRS classification.
    E.4Principal exclusion criteria
    Pre-operative exclusion criteria:
    At visit 1 none of the following exclusion criteria must apply to any enrolled patient; all criteria must be answered with “no” before the patient is scheduled for arthroscopy:
    1. Patient is the investigator or any subinvestigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the study.
    2. Patient is unable to undergo magnetic resonance imaging (MRI).
    3. Patient has prior surgical treatment of the target knee using mosaicplasty, autologous chondrocyte transplantation and/or microfracture. Note: prior diagnostic arthroscopies with debridement and lavage are acceptable. Ligament repair is accepted, if performed before, during or within 6 weeks after cartilage treatment (ACT/microfracture).
    4. Patient has radiologically apparent degenerative joint disease in the target knee as determined by Kellgren and Lawrence grade ≥ 2 (see Appendix A).
    5. Patient has chronic inflammatory arthritis and/or infectious arthritis.
    6. Patient has joint space narrowing > 1/3 in the target knee when compared to the other knee or < 3 mm joint space measured on x-ray.
    7. Patient has malalignment (valgus- or varus-deformity) in the target knee. Note: In suspected cases, the mechanical axis must be established radiographically by complete leg imaging in standing position and in a.p. or rather p.a. projection. The Mikulicz line is not allowed to deviate more than 5 mm of the eminentia intercondylaris. If alignment is necessary, surgery has to be performed before, during or within 6 weeks after cartilage treatment (ACT/microfracture).
    8. Patient has prior surgical treatment of clinical relevance of the target knee.
    9. Patient has an osteochondral defect.
    10. Patient has bilateral lower limb pain or low back pain.
    11. Patient has a known systemic connective tissue disease.
    12. Patient has a current uncontrolled diabetes.
    13. Patient has a known history of autoimmune disease.
    14. Patient has a known history of immunological suppressive disorder or is taking immunosuppressants.
    15. Patient is currently systemically or intra-articularly taking steroids and/or has used steroids within the last 30 days prior to screening visit 1.
    16. The patient has a history of HIV/AIDS.
    17. The patient has a history of syphilis (Treponema pallidum).
    18. The patient has an active hepatitis B or C infection with verified antigens. Note: Patients with a cured hepatitis B or C infection and/or verified antibodies are not excluded.
    19. 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, like Brucellosis, spotted and typhus fever, other Rickettsiosis, Leprosy, Recurrent Fever, Melioidosis or Tularaemia).
    20. Patient has a known history of cancer within the past 5 years.
    21. Patient has a known history of osteoporosis; also patients with primary hyperparathyroidism or hyperthyroidism without satisfactory treatment, chronic renal failure or patients with prior pathological fractures independent of the genesis are excluded.
    22. Patient has any degenerative muscular or neurological condition that would interfere with evaluation of outcome measures including but not limited to Parkinson’s disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).
    23. Patient has a body mass index (BMI) >35 kg/m2.
    24. Patient is a woman who is pregnant or lactating. Note: contraception is indicated for female patients of childbearing potential until the day of cartilage treatment. Female patients who are unwilling to practice a medically acceptable method of birth control until the day of cartilage treatment cannot be included.
    25. Patient is currently participating, or has participated in any other clinical study within 3 months prior to the screening visit.
    26. Patient has known current or recent history of illicit drug or alcohol abuse or dependence
    27. 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.
    28. Patient has any other condition, which, in the opinion of the investigator, would make the patient unsuitable for the study.
    29. Patient has a history of HTLV.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the patient’s functional outcome as measured by the change in the 2000 IKDC subjective knee score from baseline to the 24-month follow-up assessment.

    E.5.1.1Timepoint(s) of evaluation of this end point
    From baseline to the 24-month follow-up assessment.
    E.5.2Secondary end point(s)
    • Change from baseline to the 24-month visit in the IKDC objective physician score.
    • Change from baseline to the 24-month visit in the Knee Injury and Osteoarthritis Outcome Score (KOOS); individual KOOS subscores and KOOS5 (Composite score including all 5 subscores) will be assessed. Proportion of treatment failures at month 24
    • Change from baseline to the 24-month visit in the SF-36 to measure clinical utility and summarize health-related quality-of-life and cost-effectiveness.
    • In vivo performance measured by the 24-month assessment of the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score and T2 mapping. These assessments will be performed on a subset of patients (64 in the NOVOCART® 3D plus group and 32 in the microfracture group) as described in section 7.3.3 and in the attached radiological study protocol
    • Surgical time (cut-to-suture time).
    • Length of incision (NOVOCART® 3D plus group only).
    • Proportion of treatment failures at month 24 (see section 7.2.7)
    E.5.2.1Timepoint(s) of evaluation of this end point
    See E.5.2.
    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) 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Surgical procedure: microfracture
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    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
    Austria
    Czech Republic
    France
    Germany
    Hungary
    Latvia
    Lithuania
    Poland
    Switzerland
    United Kingdom
    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 patient, last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    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 years10
    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: 6
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 229
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 26
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 231
    F.4.2.2In the whole clinical trial 261
    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)
    Standard treatment and care for the condition
    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 Decision2012-11-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-08-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-02-28
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