Clinical trial NCT01656902: Phase III Study to Evaluate Safety and Effectiveness of NOVOCART 3D Plus vs. Microfracture in Knee Cartilage Defects
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Traumatic Articular Cartilage Defects in the Knee Joint
Keywords: Autologous Chondrocyte Transplantation
NOVOCART 3D plus
knee joint pain
safety
efficacy
treatment
TETEC
cartilage
ACT
cartilage repair
tissue
MOCART
Lead sponsor: Tetec AG
Sponsor class: INDUSTRY
First posted: 2012-08-03
Enrollment: 263
Sex: ALL
Minimum age (years): 14
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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 randomization 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 24 months post-implant for the effectiveness assessments, and then an additional three 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Subjective IKDC score
timeFrame: Baseline assessment to 24-month follow-up assessment
Secondary outcomes:
measure: IKDC objective physician score
timeFrame: Baseline assessment to 24-month follow-up assessment
measure: Knee Injury and Osteoarthritis Outcome Score (KOOS)
timeFrame: Baseline assessment to 24-month follow-up assessment
measure: MOCART Score (MRI)
timeFrame: Baseline assessment to the 24-month assessment
measure: Health-related quality of life as measured by the SF-36 survey
timeFrame: Baseline assessment to 24-month follow-up assessment
measure: Surgical time (cut-to-suture time)
timeFrame: Transplantation (24 +-5 days post-arthroscopy) and/or arthroscopy (>= 1 day after screening), depending on the study arm
measure: Length of incision
timeFrame: Only for verum group at transplantation (24 +-5 days post-arthroscopy)
measure: Any unanticipated adverse event
timeFrame: Baseline assessment up to 60-months follow-up assessment
measure: Treatment Failure
timeFrame: From completion of study treatment until 60-months follow-up assessment
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Privatklinik Doebling
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno - Ortopedicka klinika
city: Brno
country: Czechia
facility: Urazova nemocnice v Brne - Traumatologie
city: Horovice
country: Czechia
facility: NH Hospital, a.s., Ortopedicke oddeleni nemocnice Horovice
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove - Ortopedicka klinika
city: Pardubice
country: Czechia
facility: Pardubicka nemocnice
city: Praha
country: Czechia
facility: Fakultni nemocnice v Motole
city: Praha
country: Czechia
facility: UVN - Vojenska fakultni nemocnice Praha
city: Boulogne Billancourt
country: France
facility: Hôpital Ambroise Paré - Service de Chirurgie Orthopedique et Traumatologie
city: Montpellier
country: France
facility: Polyclinique Saint-Roch
city: Paris
country: France
facility: Clinique V - Clinique du Sport
city: Saint-Priest-En-Jarez
country: France
facility: CHU de Saint-Etienne Hôpital Nord - Service orthopedie et traumatologie
city: Freiburg im Breisgau
country: Germany
facility: Universitaetsklinikum Freiburg - Klinik fuer Orthopaedie
city: Mannheim
country: Germany
facility: Theresienkrankenhaus
city: Muenchen
country: Germany
facility: Orthopädische Klinik und Poliklinik der LMU München
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Budapest
country: Hungary
facility: Uzsoki utcai Kórház
city: Győr
country: Hungary
facility: Petz Aladár Megyei Oktató Kórház
city: Miskolc
country: Hungary
facility: B-A-Z Megyei Központi Kórház és Egyetemi Oktatókórház
city: Szombathely
country: Hungary
facility: Markusovszky Egyetemi Oktatókórház
city: Tata
country: Hungary
facility: Kastélypark Klinika
city: Riga
country: Latvia
facility: Hospital of Traumatology and Orthopaedics, Trauma Department
city: Riga
country: Latvia
facility: Orto Clinic
city: Kaunas
country: Lithuania
facility: Kaunas clinical hospital
city: Kaunas
country: Lithuania
facility: Hospital of Lithuanian University of Health Sciences Kaunas Clinics
city: Klaipėda
country: Lithuania
facility: Klaipeda university hospital
city: Vilnius
country: Lithuania
facility: JSC "Kardiolita"
city: Vilnius
country: Lithuania
facility: JSC "SK Impeks Medicinos Diagnostikos Centras"
city: Bielsko Biala
country: Poland
facility: Szpital sw. Lukasza BGL Sp z o.o. S.K.A.
city: Czestochowa
country: Poland
facility: Samozdzielny Publiczny Zaklad Opieki Zdrowotnej Miejskiego Szpitala Zespolonego
city: Katowice
country: Poland
facility: Szpital Angelius
city: Piekary Slaskie
country: Poland
facility: Samozdzielny Publiczny Wojewodzki Szpital Chirurgii Urazowej
city: Warszawa
country: Poland
facility: Centrum Medycyny Sportowej
city: Basel
country: Switzerland
facility: Universitätsklinikum Basel
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
Study officials:
affiliation: Universitätsklinikum Regensburg
name: Peter Angele, Prof.
role: PRINCIPAL_INVESTIGATOR
References: