Safety and Effectiveness Study to Evaluate NOVOCART® 3D Plus Compared to the Microfracture to Treat Articular Cartilage Defects of the Knee (N3D)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Tetec AG
Sponsor:
Information provided by (Responsible Party):
Tetec AG
ClinicalTrials.gov Identifier:
NCT01656902
First received: July 20, 2012
Last updated: February 10, 2014
Last verified: February 2014
  Purpose

For the cartilage cell product NOVOCART® 3D plus, which is used in the study described here, the company TETEC AG obtained an expanded production authorization from the medication monitoring authorities in compliance with Section 13, Para. 1 of the Medicinal Products Act in 2003. This entitles TETEC AG to produce the pharmaceutical product and already distribute it. More than 6000 patients were already successfully treated with NOVOCART® 3D in Europe since 2003. In order to obtain a general market authorization for NOVOCART® 3D plus, this control group study is conducted, in which the superiority of the safety and effectiveness of carrier-bound Autologous Chondrocyte Transplantation with NOVOCART® 3D plus compared to the standard of care microfracture surgery needs to be proven. This study further aims at developing and validating known and new biologic markers for the quality and clinical efficacy of the product as requested in the context of identity, purity and potency characteristics of the medicinal/investigational product.

The patients will receive one of the therapeutic procedures in the study. The treatment procedure which will be used will be decided by a previously specified random process. This type of study meets the high quality requirements of the statutorily specified safety and quality regulations which are also referred to as "Good Clinical Practice" (GCP). The probability of the patient being allocated to one of the two treatments is 2:1; that is, an approx. 67% probability of therapy with NOVOCART® 3D plus and an approx. 33% probability of therapy with microfracture. Neither the patient, nor the investigator will be able to influence the treatment assignment.

Patients will be screened for eligibility at the Screening Visit. Each patient will remain in the study for 36 months post-implant for the effectiveness assessments, and then an additional two years to complete the planned post-market phase. Each patient will be in the study for up to five years.

Cells and tissues collected from this study will be used in other in vitro-controlled experiments aimed at developing and validating known and novel biologic markers to quantify cell quality in the context of identity, purity and potency. Prognostic values of these biologic markers will be examined by correlating them with clinical data collected in this study.


Condition Intervention Phase
Traumatic Articular Cartilage Defects in the Knee Joint
Drug: NOVOCART® 3D plus
Procedure: Microfracture
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Prospective Randomized Controlled Multicenter Phase-III Clinical Study to Evaluate the Safety and Effectiveness of NOVOCART® 3D Plus Compared to the Standard Procedure Microfracture in the Treatment of Articular Cartilage Defects of the Knee

Further study details as provided by Tetec AG:

Primary Outcome Measures:
  • Subjective IKDC score [ Time Frame: Baseline assessment to 36-month follow-up assessment ] [ Designated as safety issue: No ]

    The primary endpoint is the change from baseline in the "2000 International Knee Documentation Committee" (IKDC) subjective score to 36-month visit.

    The IKDC will be recorded for NOVOCART® 3D plus and microfracture patients at baseline visit 1 and at the 6 weeks, 3-, 6-, 12-, 24-, 36-, 48,- and 60-month follow-up assessments.



Secondary Outcome Measures:
  • Subjective IKDC score [ Time Frame: Baseline assessment to 24-month follow-up assessment ] [ Designated as safety issue: No ]

    In addition to the primary endpoint, another secondary efficacy endpoint is the change from baseline in the subjective IKDC score to 24-month visit. A sequentially rejecting, hierarchical test procedure will be employed to test this secondary endpoint after the test primary efficacy variable was passed.

    The IKDC will be recorded for NOVOCART® 3D plus and microfracture patients at baseline visit 1 and at the 6 weeks, 3-, 6-, 12-, 24-, 36-, 48,- and 60-month follow-up assessments.


  • IKDC objective physician score [ Time Frame: Baseline assessment to 36-month follow-up assessment ] [ Designated as safety issue: No ]

    The IKDC objective physician score will be recorded for both arms at baseline visit 1 and at the 6 weeks, 3-, 6-, 12-, 24-, 36-, 48,- and 60-month follow-up assessments. A sequentially rejecting, hierarchical test procedure will be employed to test these secondary endpoints in the a-priori defined order given here after the test primary efficacy variable was passed.

    The change from baseline to the 36-month visit in the IKDC objective physician score and from baseline to the 24-month visit will be evaluated.


  • IKDC objective physician score [ Time Frame: Baseline assessment to 24-month follow-up assessment ] [ Designated as safety issue: No ]

    The IKDC objective physician score will be recorded for both arms at baseline visit 1 and at the 6 weeks, 3-, 6-, 12-, 24-, 36-, 48,- and 60-month follow-up assessments. A sequentially rejecting, hierarchical test procedure will be employed to test these secondary endpoints in the a-priori defined order given here after the test primary efficacy variable was passed.

    The change from baseline to the 36-month visit in the IKDC objective physician score and from baseline to the 24-month visit will be evaluated.


  • Knee Injury and Osteoarthritis Outcome Score (KOOS) [ Time Frame: Baseline assessment to 36-month follow-up assessment ] [ Designated as safety issue: No ]

    The KOOS will be recorded for both arms at baseline visit 1 and at the 6 weeks, 3-, 6-, 12-, 24-, 36-, 48,- and 60-month follow-up assessments.

    A sequentially rejecting, hierarchical test procedure will be employed to test these secondary endpoints in the a-priori defined order given here after the test primary efficacy variable was passed. The change from baseline to 36-month visit in the Knee Injury and Osteoarthritis Outcome Score (KOOS) and from baseline to 24-month visit will be evaluated.


  • Knee Injury and Osteoarthritis Outcome Score (KOOS) [ Time Frame: Baseline assessment to 24-month follow-up assessment ] [ Designated as safety issue: No ]

    The KOOS will be recorded for both arms at baseline visit 1 and at the 6 weeks, 3-, 6-, 12-, 24-, 36-, 48,- and 60-month follow-up assessments.

    A sequentially rejecting, hierarchical test procedure will be employed to test these secondary endpoints in the a-priori defined order given here after the test primary efficacy variable was passed. The change from baseline to 36-month visit in the Knee Injury and Osteoarthritis Outcome Score (KOOS) and from baseline to 24-month visit will be evaluated.


  • MOCART Score (MRI) [ Time Frame: Baseline assessment to the 36-month assessment ] [ Designated as safety issue: No ]

    Another secondary efficacy endpoint is the in vivo performance (grading on quality of cartilage fill) measured by the change from baseline to the 36-month assessment of the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. These assessments will be performed on a subset of patients (64 in each treatment group).

    The MRI will be recorded at 3, 12, 36 and 60 months follow-up visit.


  • Health-related quality of life as measured by the SF-36 survey [ Time Frame: Baseline assessment to 36-month follow-up assessment ] [ Designated as safety issue: No ]
    Another secondary efficacy endpoint is the change from baseline to the 36-month visit in the SF-36 to measure clinical utility and summarize health-related quality-of-life and cost-effectiveness. The SF-36 will be recorded for NOVOCART® 3D plus and microfracture patients at baseline visit 1 and at the 6 weeks, 3-, 6-, 12-, 24-, 36-, 48,- and 60-month follow-up assessments.

  • Health-related quality of life as measured by the SF-36 survey [ Time Frame: Baseline assessment to 24-month follow-up assessment ] [ Designated as safety issue: No ]
    Another secondary efficacy endpoint is the change from baseline to the 36-month visit in the SF-36 to measure clinical utility and summarize health-related quality-of-life and cost-effectiveness. The SF-36 will be recorded for NOVOCART® 3D plus and microfracture patients at baseline visit 1 and at the 6 weeks, 3-, 6-, 12-, 24-, 36-, 48,- and 60-month follow-up assessments.

  • Surgical time (cut-to-suture time) [ Time Frame: Transplantation (24 +-5 days post-arthroscopy) and/or arthroscopy (>= 1 day after screening), depending on the study arm ] [ Designated as safety issue: No ]
    The surgical time will be measured in minutes and recorded for NOVOCART® 3D plus patients at arthroscopy (>= 1 day after screening) and transplantation (24 +-5 days post-arthroscopy); for microfracture patients surgical time will be measured in minutes and recorded at arthroscopy (>= 1 day after screening).

  • Length of incision [ Time Frame: Only for verum group at transplantation (24 +-5 days post-arthroscopy) ] [ Designated as safety issue: No ]
    The length of incision will be measured in cm and recorded for NOVOCART® 3D plus patients at transplantation (24 +-5 days post-arthroscopy)

  • Any unanticipated adverse event [ Time Frame: Baseline assessment up to 60-months follow-up assessment ] [ Designated as safety issue: Yes ]

    Event descriptions, onset, resolution dates, relationship to the IP and procedures of any AEs will be recorded. Each event will be categorized by seriousness and intensity to facilitate complete safety reporting throughout the trial.

    While comparisons between treatment groups can be made for each class of AE, there is no statistical hypothesis governing acceptance of this endpoint at the end of the clinical study because of the different AE profiles associated with the two treatment arms.



Estimated Enrollment: 261
Study Start Date: January 2013
Estimated Study Completion Date: June 2019
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: N3D plus
NOVOCART® 3D plus (Autologous Chondrocyte Transplantation System)
Drug: NOVOCART® 3D plus
Other Name: Autologous Chondrocyte Transplantation System
Active Comparator: Microfracture
Microfracture is the standard care surgery.
Procedure: Microfracture
Other Name: Microfracture according to Steadman

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient is ≥18 and ≤65 years old at time of screening.
  • 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, 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..
  • Patient has a defect size ≥2 and ≤6 cm2 post-debridement.
  • Patient has an intact (≤Grade 2 ICRS classification) articulating joint surface (no "kissing lesions").
  • Patient has an intact meniscus (maximum 1/2-resection).
  • Patient has a stable knee joint or sufficiently reconstructed ligaments. If not, ligament repair has to be done within 6 weeks to the planned cartilage treatment (ACT/microfracture).
  • Patient has free range of motion of the affected knee joint or ≤10° of extension and flexion loss.
  • Patient has a defect of grade III or IV according to the ICRS classification.
  • Patient has a maximum baseline score of 60/100 on the 2000 IKDC 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 postoperative rehabilitation regimen.

Preoperative Exclusion Criteria:

  • Patient is the investigator or any subinvestigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol.
  • Patient is unable to undergo magnetic resonance imaging (MRI).
  • Patient has prior surgical treatment of the target knee using mosaicplasty and/or microfracture (Note: prior diagnostic arthroscopy with debridement and lavage are acceptable). Anterior cruciate ligament repair are accepted, if the target knee is stable or a primary ACL reconstruction is performed within 6 weeks to the planned cartilage treatment (ACT/microfracture).
  • Patient has radiologically apparent degenerative joint disease in the target knee as determined by Kellgren and Lawrence grade ≥2.
  • Patient has chronic inflammatory arthritis, and/or infectious arthritis.
  • 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.
  • Patient has an instable knee joint or unsufficiently reconstructed ligaments. If ligament repair is necessary, the repair has to be performed within 6 weeks to the planned cartilage treatment (ACT/microfracture).
  • Patient has malalignment (no valgus- or varus-deformity) in the target knee. 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. 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 within 6 weeks to the planned cartilage treatment (ACT/microfracture).
  • Patient has prior surgical treatment of clinical relevance of the target knee.
  • Patient has an osteochondral defect.
  • Patient has bilateral lower limb pain or low back pain.
  • Patient has a known systemic connective tissue disease.
  • Patient has a known history of diabetes.
  • Patient has a known autoimmune disease.
  • Patient has a known immunological suppressive disorder or is taking immunosuppressants.
  • Patient is currently systemically or intra-articularly taking steroids and/or has used steroids within the last 30 days prior to the planned arthroscopy (tissue harvest/microfracture).
  • The patient has a known history of HIV/AIDS.
  • The patient has a known history of Treponema pallidum (syphilis).
  • 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.
  • 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).
  • Patient has a known history of cancer.
  • Patient is taking indomethacin or other NSAIDs as acute anti-pain and/or anti-inflammatory medication.
  • Patient has a known history of osteoporosis; also patients with primary hyperparathyroidism, hyperthyroidism, chronic renal failure or patients with prior pathological fractures independent of the genesis.
  • 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).
  • Patient has a body mass index (BMI) >35 kg/m2.
  • Patient is a woman who 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.

Intraoperative Exclusion Criteria:

  • Patient has a defect size <2 or >6 cm2 post-debridement.
  • Patient has >2 independent cartilage lesions of a total defect size of >6 cm2 that are not located at the femoral condyle and/or the trochlea in one knee that need to be treated with NOVOCART® 3D plus or microfracture.
  • Patient is indicated for concurrent meniscus transplant.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01656902

Contacts
Contact: Silvia Rombach +49 7121 514 87 790 rombach@tetec-ag.de
Contact: Felix Michnacs +49 7121 514 87 78 felix.michnacs@tetec-ag.de

Locations
Austria
Medizinische Universität Wien Recruiting
Wien, Austria, 1090
Contact: Patrick Platzer, Prof.    +43 (0)4 04 00 59 01    patrick.platzer@meduniwien.ac.at   
Principal Investigator: Patrick Platzer, Prof.         
Sub-Investigator: Christian Albrecht, Dr.         
Germany
Theresienkrankenhaus Recruiting
Mannheim, Germany, 68165
Contact: Gerald Mannheim, Prof.    +49 (0)6 21 42 44 254    g.zimmermann@theresienkrankenhaus.de   
Principal Investigator: Gerald Zimmermann, Prof.         
Sub-Investigator: Florian Schwoebel, Dr.         
Sub-Investigator: Timo Markl, Dr.         
Orthopädische Klinik und Poliklinik der LMU München Recruiting
Muenchen, Germany, 81377
Contact: Peter Müller, Prof.    +49 (0)8 97 09 53 781    peter.mueller@med.uni-muenchen.de   
Principal Investigator: Peter Müller, Prof.         
Sub-Investigator: Matthias Pietschmann, Dr.         
Sub-Investigator: Tobias Düll, Dr.         
Sub-Investigator: Joerg Hausdorf, Dr.         
Universitätsklinikum Regensburg Recruiting
Regensburg, Germany, 93042
Contact: Peter Angele, Prof.    +49 (0)9 41 94 46 803    peter.angele@klinik.uni-r.de   
Principal Investigator: Peter Angele, Prof.         
Sub-Investigator: Johannes Zellner, Dr.         
Sub-Investigator: Werner Krutsch, Dr.         
Sub-Investigator: Christian Pfeifer, Dr.         
Berufsgenossenschaftliche Unfallklinik Tübingen Recruiting
Tübingen, Germany, 72076
Contact: Wilhelm Loewe, Dr.    +49 (0)7 07 16 06 11 66    wloewe@bgu-tuebingen.de   
Principal Investigator: Wilhelm Loewe, Dr.         
Sub-Investigator: Markus Gühring, Dr.         
Sub-Investigator: Christoph Gonser, Dr.         
Sub-Investigator: Atesch Ateschrang, Dr.         
Switzerland
Universitätsklinikum Basel Recruiting
Basel, Switzerland, 4031
Contact: Geert Pagenstert, Dr.    +41 (0)6 12 65 25 25    gpagenstert@uhbs.ch   
Principal Investigator: Geert Pagenstert, Dr.         
Sub-Investigator: Jochen Paul, Dr.         
United Kingdom
The Royal Orthopaedic Hospital Not yet recruiting
Birmingham, United Kingdom, B31 2AP
Contact: Dr. Kirti Moholkar, Dr.    +44 (0)121 685 4161    kirti.moholkar@nhs.net   
Principal Investigator: Kirti Moholkar, Dr         
Royal Devon and Exeter Hospital Not yet recruiting
Exeter, United Kingdom, EX2 5DW
Contact: Peter Schranz, Dr.    +44 (0)139 240 3576      
Principal Investigator: Peter Schranz, Dr         
Sub-Investigator: Vipul Mandalia, Dr.         
Sponsors and Collaborators
Tetec AG
Investigators
Principal Investigator: Peter Angele, Prof. Universitätsklinikum Regensburg
  More Information

No publications provided

Responsible Party: Tetec AG
ClinicalTrials.gov Identifier: NCT01656902     History of Changes
Other Study ID Numbers: AAG-G-H-1202
Study First Received: July 20, 2012
Last Updated: February 10, 2014
Health Authority: Germany: Paul-Ehrlich-Institut
Austria: Agency for Health and Food Safety
Switzerland: Swissmedic
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Tetec AG:
Autologous Chondrocyte Transplantation
NOVOCART 3D plus
knee joint pain
safety
efficacy
treatment
TETEC
cartilage
ACT
cartilage repair
tissue
MOCART

Additional relevant MeSH terms:
Cartilage Diseases
Musculoskeletal Diseases
Connective Tissue Diseases

ClinicalTrials.gov processed this record on September 22, 2014