Prospective, randomised, open label, multicentre Phase II clinical trial to investigate the efficacy and safety of the treatment of large defects (4-10 cm2) with 3 different doses of the autologous chondrocyte transplantation product co.don chondrosphere® (ACT3D-CS) in subjects with cartilage defects of the knee

INTERVENTION: Product Name: co.don chondrosphere Pharmaceutical Form: Living tissue equivalent Other descriptive name: Viable autologous human cartilage‐forming chondrocytes Concentration type: range Concentration number: 3 sph./cm2defect‐7 sph./cm2defect Product Name: co.don chondrosphere Pharmaceutical Form: Living tissue equivalent Other descriptive name: Viable autologous human cartilage‐forming chondrocytes Concentration type: range Concentration number: 10 sph./cm2defect‐30 sph./cm2defect Product Name: co.don chondrosphere Pharmaceutical Form: Living tissue equivalent Other descriptive name: Viable autologous human cartilage‐forming chondrocytes Concentration type: range Concentration number: 40 sph./cm2defect‐70 sph./cm2defect CONDITION: Cartilage defects of knee joints, osteochondral defects ; MedDRA version: 18.0 Level: LLT Classification code 10007713 Term: Cartilage tear in knee System Organ Class: 10022117 ‐ Injury, poisoning and procedural complications ; MedDRA version: 18.0 Level: LLT Classification code 10007702 Term: Cartilage biopsy System Organ Class: 100000004848 ; MedDRA version: 18.0 Level: LLT Classification code 10003423 Term: Articular cartilage disorder System Organ Class: 100000004859 ; MedDRA version: 18.0 Level: PT Classification code 10052913 Term: Cartilage operation System Organ Class: 10042613 ‐ Surgical and medical procedures ; MedDRA version: 18.0 Level: LLT Classification code 10007705 Term: Cartilage damage System Organ Class: 10022117 ‐ Injury, poisoning and procedural complications ; MedDRA version: 18.0 Level: HLT Classification code 10007709 Term: Cartilage disorders System Organ Class: 100000004859 ; MedDRA version: 18.0 Level: LLT Classification code 10057104 Term: Cartilage repair System Organ Class: 10042613 ‐ Surgical and medical procedures ; MedDRA version: 18.0 Level: PT Classification code 10007710 Term: Cartilage injury System Organ Class: 10022117 ‐ Injury, poisoning and procedural complications ; MedDRA version: 18.0 Level: PT Classification code 10064112 Term: Cartilage graft System Organ Class: 10042613 ‐ Surgical and medical procedures Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: General Objectives:; Assessment of the short‐term and long‐term efficacy and safety of 3 different doses of the three‐dimensional autologous chondrocyte transplantation product ACT3D‐CS for the treatment of cartilage defects (= 4‐10 cm2) of knee joints.; ; The health economic outcomes are mainly intended to be assessed and evaluated as a basis for future negotiations with health insurances, health care providers and development of newly implemented procedural codes within the German DRG (Diagnosis Related Groups) system for ACT3D‐CS. ; Health economic data within the phase II study will be collected and assessed, where different doses of ACT3D‐CS will be applied. ; ; Primary Objectives:; Change of overall KOOS (Knee Injury and Osteoarthritis Outcome Score) from baseline (Day 0) to final assessment (FA) at 12 months after transplantation determined for each dosage group and between the dosage groups Primary end point(s): Change of overall KOOS (Knee Injury and Osteoarthritis Outcome Score) from baseline (Day 0’) to final assessment (FA) at 12 months after transplantation determined for each dosage group and between the dosage groups. Secondary Objective: see protocol Timepoint(s) of evaluation of this end point: 2014 INCLUSION CRITERIA: 1. Male or female patients, age: between 18 and 50 years 2. Defect: isolated ICRS grade III or IV single defect on medial or lateral femoral condyle, trochlea, tibia and retropatellar defect, also OCD (in case of OCD: Bone grafting up to the level of the original bone lamella must be performed if bone loss exceeds 3 mm in depth) 3. Defect size: = 4 to 10 cm2 after debridement to healthy cartilage up to 6 mm in depth. Assessment with MRI at Screening and per estimation during arthroscopy prior to randomization 4. Nearly intact surrounding chondral structure around the defect as well as corresponding joint area 5. Informed consent signed by patient 6. Patient understands strict rehabilitation protocol and follow‐up programme and is willing to follow it. 7. In case of pain, patient agrees to use only paracetamol mono‐ (max 4 g/day) or combination preparation and oral and/or topic NSAIDs during the trial and to discontinue the use of oral and/or t SECONDARY OUTCOME: Secondary end point(s): Change of overall KOOS from baseline (Day 0) to 24, 36, 48 and 60 months (follow‐up, FU) after transplantation determined for each dosage group; ; Change of overall KOOS from baseline (Day 0) to, 24, 36, 48 and 60 months (follow‐up, FU) after transplantation compared between the dosage groups; ; Change of overall KOOS from Day 0’ (day before transplantation) to 12, 24, 36, 48 and 60 months (follow‐up, FU) after transplantation determined for each dosage group and compared between the dosage groups; ; Change of the 5 subscores of the KOOS (Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec), knee related Quality of life (QoL)) from baseline (Day 0 = day before arthroscopy) to 12, 24, 36, 48 and 60 months (follow‐up, FU) after transplantation determined for each dosage group and between the dosage groups ; ; Change of the 5 subscores of the KOOS (Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec), knee related Quality of life (QoL)) from Day 0’ (day before transplantation) to 12, 24, 36, 48 and 60 months (follow‐up, FU) after transplantation determined for each dosage group and between the dosage groups; ; MOCART (MRI Score) at 12,24, 36, 48 and 60 months after transplantation compared between the dosage groups; ; Arthroscopy and biopsy at 12 months after transplantation, assessment of cartilage repair after ACT3D‐CS to be compared for each dosage group and between the dosage groups; ; ICRS Visual Histological Assessment Score at final assessment (FA, 12 months) determined for each dosage group and compared between the dosage groups; ; Bern Score and additional histological assessment scores at final assessment (12 months) determined for each dosage group and compared between the dosage groups; ; Change of ICRS/IKDC from baseline (Day 0) to 12, 24, 36, 48 and 60 months after transplantation determined for each dosage group and compared between the dosage groups; ; Change of ICRS/IKDC from Day 0’ (day before transplantation) to 12, 24, 36, 48 and 60 months after transplantation determined for each dosage group and compared between the dosage groups; ; Change of modified Lysholm Score from baseline (Day 0) to 12, 24, 36, 48 and 60 months after transplantation determined for each dosage group and compared between the dosage the groups ; ; Change of modified Lysholm Score from Day 0’ (day before transplantation) to 12, 24, 36, 48 and 60 months after transplantation determined for each dosage group and compared between the dosage groups; ; Days of absence from work (employment) and/or days of inability to follow usual activities during the last year or since the last visit, respectively, and time point when patient was back to work and/or to follow usual activities Timepoint(s) of evaluation of this end point: 2018