Traumatic Articular Cartilage Defects in the Knee Joint Clinical Trial
— N3DOfficial 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
| Verified date | October 2021 |
| Source | Tetec AG |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
In this phase 3 clinical trial, a second generation ACI (autologous chondrocyte implantation technique) is compared to standard of care therapy (microfracture) to treat traumatic cartilage defects of the knee for efficacy and safety. The investigated study treatment NOVOCART 3D plus is a biphasic biological scaffold which contains cultivated chondrocytes derived from the patient in a previous tissue harvest procedure. Allocation to the study treatment is done by randomization in a ration of 2:1 in favor to ACI (investigational product). Follow-up data for efficacy is collected for 2 years: follow-up visits are performed 6 weeks, 3 months, 6 months, 12 months, 18 months and 24 months after treatment; additional data for safety will be collected for up to 5 years: 36, 48, and 60 months after treatment. The study involves knee surgery (by arthroscopy, or mini-arthrotomically for implantation surgery), and blood withdrawal for safety within the first year after treatment. Initial imaging is required at baseline. Optional MRI imaging and biomarker collection is done as substudy at specific sites only.
| Status | Completed |
| Enrollment | 263 |
| Est. completion date | February 28, 2023 |
| Est. primary completion date | March 6, 2020 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 14 Years to 65 Years |
| Eligibility | Inclusion Criteria: 1. Patient is between 18 and 65 years old at screening OR (in selected countries only) is a pediatric patient (14-17 years old) with closed epiphyseal growth plate (confirmation of closure of 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 is between 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 (not higher than Grade 2 International Cartilage Repair Society 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. Exclusion Criteria (pre-operative): 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 smaller than 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) higher than 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. Intra-operative Inclusion Criteria: 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 up to 6 cm2 and the size of each individual lesion is at least 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 of 2 to 6 cm2 post-debridement. 4. Patient has an intact articulating joint surface (at least (or higher) Grade 2 International Cartilage Repair Society 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. |
| Country | Name | City | State |
|---|---|---|---|
| Austria | Privatklinik Doebling | Vienna | |
| Czechia | Fakultni nemocnice Brno - Ortopedicka klinika | Brno | |
| Czechia | Urazova nemocnice v Brne - Traumatologie | Brno | |
| Czechia | NH Hospital, a.s., Ortopedicke oddeleni nemocnice Horovice | Horovice | |
| Czechia | Fakultni nemocnice Hradec Kralove - Ortopedicka klinika | Hradec Kralove | |
| Czechia | Pardubicka nemocnice | Pardubice | |
| Czechia | Fakultni nemocnice v Motole | Praha | |
| Czechia | UVN - Vojenska fakultni nemocnice Praha | Praha | |
| France | Hôpital Ambroise Paré - Service de Chirurgie Orthopedique et Traumatologie | Boulogne Billancourt | |
| France | Polyclinique Saint-Roch | Montpellier | |
| France | Clinique V - Clinique du Sport | Paris | |
| France | CHU de Saint-Etienne Hôpital Nord - Service orthopedie et traumatologie | Saint-Priest-En-Jarez | |
| Germany | Universitaetsklinikum Freiburg - Klinik fuer Orthopaedie | Freiburg im Breisgau | |
| Germany | Theresienkrankenhaus | Mannheim | |
| Germany | Orthopädische Klinik und Poliklinik der LMU München | Muenchen | |
| Germany | Universitätsklinikum Regensburg | Regensburg | |
| Hungary | Uzsoki utcai Kórház | Budapest | |
| Hungary | Petz Aladár Megyei Oktató Kórház | Gyor | |
| Hungary | B-A-Z Megyei Központi Kórház és Egyetemi Oktatókórház | Miskolc | |
| Hungary | Markusovszky Egyetemi Oktatókórház | Szombathely | |
| Hungary | Kastélypark Klinika | Tata | |
| Latvia | Hospital of Traumatology and Orthopaedics, Trauma Department | Riga | |
| Latvia | Orto Clinic | Riga | |
| Lithuania | Hospital of Lithuanian University of Health Sciences Kaunas Clinics | Kaunas | |
| Lithuania | Kaunas clinical hospital | Kaunas | |
| Lithuania | Klaipeda university hospital | Klaipeda | |
| Lithuania | JSC "Kardiolita" | Vilnius | |
| Lithuania | JSC "SK Impeks Medicinos Diagnostikos Centras" | Vilnius | |
| Poland | Szpital sw. Lukasza BGL Sp z o.o. S.K.A. | Bielsko Biala | |
| Poland | Samozdzielny Publiczny Zaklad Opieki Zdrowotnej Miejskiego Szpitala Zespolonego | Czestochowa | |
| Poland | Szpital Angelius | Katowice | |
| Poland | Samozdzielny Publiczny Wojewodzki Szpital Chirurgii Urazowej | Piekary Slaskie | |
| Poland | Centrum Medycyny Sportowej | Warszawa | |
| Switzerland | Universitätsklinikum Basel | Basel | |
| United Kingdom | Royal Devon and Exeter Hospital | Exeter |
| Lead Sponsor | Collaborator |
|---|---|
| Tetec AG |
Austria, Czechia, France, Germany, Hungary, Latvia, Lithuania, Poland, Switzerland, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Subjective IKDC score | The primary endpoint is the change from baseline in the "2000 International Knee Documentation Committee" (IKDC) subjective score to 24-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. |
Baseline assessment to 24-month follow-up assessment | |
| Secondary | IKDC objective physician score | 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 24-month visit in the IKDC objective physician score and from baseline to the 24-month visit will be evaluated. |
Baseline assessment to 24-month follow-up assessment | |
| Secondary | Knee Injury and Osteoarthritis Outcome Score (KOOS) | 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 24-month visit in the Knee Injury and Osteoarthritis Outcome Score (KOOS) and from baseline to 24-month visit will be evaluated. |
Baseline assessment to 24-month follow-up assessment | |
| Secondary | MOCART Score (MRI) | 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 NOVOCART and 32 in microfracture arm).
The MRI will be recorded at 3, 12, 24 and 60 months follow-up visit. |
Baseline assessment to the 24-month assessment | |
| Secondary | Health-related quality of life as measured by the SF-36 survey | Another secondary efficacy endpoint is the 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. 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. | Baseline assessment to 24-month follow-up assessment | |
| Secondary | Surgical time (cut-to-suture time) | 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). | Transplantation (24 +-5 days post-arthroscopy) and/or arthroscopy (>= 1 day after screening), depending on the study arm | |
| Secondary | Length of incision | The length of incision will be measured in cm and recorded for NOVOCART® 3D plus patients at transplantation (24 +-5 days post-arthroscopy) | Only for verum group at transplantation (24 +-5 days post-arthroscopy) | |
| Secondary | Any unanticipated adverse event | 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. |
Baseline assessment up to 60-months follow-up assessment | |
| Secondary | Treatment Failure | Any event related to a diagnosed failure of the study treatment | From completion of study treatment until 60-months follow-up assessment |