Assessment of Efficacy and Safety of 3 Different Doses of co.Don Chondrosphere to Treat Large Cartilage Defects

Study Overview
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Brief Summary
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This is a prospective, randomised, open label, multicentre Phase II clinical trial to investigate the efficacy and safety of the treatment of large defects with 3 different doses of the autologous chondrocyte transplantation product co.don chondrosphere® (ACT3D-CS) in subjects with cartilage defects of the knee. After screening visit patients were booked for arthroscopy and had their cells harvesting from healthy cartilage. After the arthroscopy the patients were randomised in one of the three dose-groups. The cells are cultivated for 8-10 weeks in vitro to develope 3-dimensional spheroids, that are transplanted in an open knee procedure (treatment surgery)into the defect. Patients of all dose groups subsequently followed the same rehabilitation program and had post-surgery visits. The 12-month-visit is defined as final assessment. Then patients have follow-up assessments up to 60 months.

Detailed Description
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see above

Official Title
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Prospective, Randomised, Open Label, Multicentre Phase II Clinical Trial to Investigate the Efficacy and Safety of the Treatment of Large Cartilage Knee Defects(4-10 cm²) With 3 Diff. Doses of the ACT Product co.Don Chondrosphere®

Conditions
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Large Articular Cartilage Lesions of the Femoral, Condyle, Trochlea, Tibia or Retropatellar

Intervention / Treatment
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* Drug: co.don chondrosphere®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients, age: between 18 and 50 years Defect: isolated ICRS grade III or IV single defect on medial or lateral femoral condyle, trochlea, tibia and retropatellar defects, 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) Defect size: ≥ 4 to 10 cm2 after debridement to healthy cartilage; chondral lesions, including osteochondritis dissecans on femoral condyle, trochlea, tibia,retropatellar defects up to 6 mm in depth. Assessment with MRI at Screening and per estimation during arthroscopy prior to randomization Nearly intact surrounding chondral structure around the defect as well as corresponding joint area Informed consent signed by patient Patient understands strict rehabilitation protocol and follow-up programme and is willing to follow it. 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 topic NSAIDs and/or paracetamol combination preparation 1 week before each visit whereas the use of paracetamol mono-preparation (max 4 g/day) is allowed. However, in the morning of the visit day, no pain medication is allowed. However, in the morning of the visit day, no pain medication is allowed. Other pain medications are allowed during surgical operation and may be taken for a period not exceeding 4 weeks after surgery. Exclusion Criteria: Defects on both knees at the same time Radiological signs of osteoarthritis Any signs of knee instability Valgus or varus malalignment (more than 5° over the mechanical axis) Clinically relevant second cartilage lesion on the same knee More than 50 % resection of a meniscus in the affected knee or incomplete meniscal rim Rheumatoid arthritis, parainfectious or infectious arthritis, and condition after these diseases Pregnancy and planned pregnancy (no MRI possible) Obesity (Body Mass Index >30) Uncontrolled diabetes mellitus Serious illness Poor general health as judged by physician Participation in concurrent clinical trials or previous trials within 3 months of screening Previous treatment with ACT in the affected knee Microfracture performed less than 1 year before screening in the affected knee Alcohol or drug (medication) abuse Meniscal transplant in the affected knee Meniscal suture (in the affected knee) three months prior to baseline Mosaicplasty (Osteoarticular Transplant System, OATS) in the affected knee Having received hyaluronic acid intra-articular injections in the affected knee within the last 3 months of baseline Taking specific osteoarthritis drugs such as chondroitin sulfate, diacerein, n-glucosamine, piascledine, capsaicin within 2 weeks of baseline Corticosteroid treatment by systemic or intra-articular route within the last month of baseline or intramuscular or oral corticosteroids within the last 2 weeks of baseline Chronic use of anticoagulants Any concomitant painful or disabling disease of the spine, hips or lower limbs that would interfere with evaluation of the afflicted knee Any clinically significant or symptomatic vascular or neurological disorder of the lower extremities Any evidence of the following diseases in the affected knee: septic arthritis,inflammatory joint disease, recurrent episodes of pseudogout, Paget's disease of bone, ochronosis, acromegaly, haemochromatosis, Wilson's disease, primary osteochondromatosis, heritable disorders, collagen gene mutation Current diagnosis of osteomyelitis, human immunodeficiency virus (HIV-1, 2) and/or hepatitis C (HCV) infection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: co.don chondrosphere®, 3-7 spheroids/cm2<br>co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group A is 3-7 spheroids/cm2 defect | Drug: co.don chondrosphere®<br>* co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group A is 3-7 spheroids/cm2 defect, in group B 10-30 spheroids/cm2 defect and in group C 40-70 spheroids/cm2 defect<br>* Other names: ACT3D-CS;|
| Active Comparator: co.don chondrosphere®,10-30spheroids/cm2<br>co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group B is 10-30 spheroids/cm2 defect | Drug: co.don chondrosphere®<br>* co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group A is 3-7 spheroids/cm2 defect, in group B 10-30 spheroids/cm2 defect and in group C 40-70 spheroids/cm2 defect<br>* Other names: ACT3D-CS;|
| Active Comparator: co.don chondrosphere®,40-70spheroids/cm2<br>co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group C is 40-70 Spheroids/cm2 defect | Drug: co.don chondrosphere®<br>* co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group A is 3-7 spheroids/cm2 defect, in group B 10-30 spheroids/cm2 defect and in group C 40-70 spheroids/cm2 defect<br>* Other names: ACT3D-CS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of overall KOOS | Change of overall KOOS (Knee Injury and Osteoarthritis Outcome Score) from baseline (Day 0)to final assessment (FA)determined for each dosage group and between the dosage groups. | 12 months after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of overall KOOS | 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 and compared between the dosage groups | 24, 36, 48, 60 months after transplantation | 
| Change of the 5 subscores of the KOOS | 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)) determined for each dosage group and between the dosage groups | 12, 24, 36 ,48, 60 months after transplantation | 
| Assessment of MRIs by the MOCART-Score (MRI Score) | Assessment of MRIs by the MOCART-Score (MRI Score) at 12, 24, 36, 48 and 60 months after transplantation compared between the dosage groups | 12, 24, 36, 48 and 60 months after transplantation | 
| Assessment of cartilage repair using an Arthroscopy and take a biopsy | Arthroscopy and biopsy at 12 months after transplantation, assessment of cartilage repair after ACT3D to be compared for each dosage group and between the dosage groups | 12 months after transplantation | 
| Assessment of the histology from the biopsy by ICRS Visual Histological Assessment Score | Assessment of the ICRS Visual Histological Assessment Score at final assessment (FA, 12 months) determined for each dosage group and compared between the dosage groups | 12 months after transplantation | 
| Assessment of the histology from the biopsy by the Bern Score and additional histological scores | Assessment of the histology from the biopsy by the Bern Score and additional histological assessment scores at final assessment (12 months) determined for each dosage group and compared between the dosage groups | 12 months after transplantation | 
| Change of ICRS/IKDC | 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 | 12, 24, 36, 48 and 60 months after transplantation | 
| Assessment of change of modified Lysholm Score | 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 | 12, 24, 36, 48 and 60 months after transplantation | 
| Days of absence from work (employment) and/or days of inability to follow usual activities | 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 | annual | 
| Frequency and type of adverse events | Frequency and type of adverse events | 3,12, 24, 36, 48, 60 months after transplantation | 
| Measurement of blood pressure, pulse and laboratory parameters | Measurement of the vital signs and physical examination, laboratory parameters at 3 and 12 months after transplantation. | 3, 6, 12, 24, 36, 48, 60 months after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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large cartilage defects, knee joint, femoral condyle, tibia, trochlear, retropatellar