Articular Cartilage Lesion of the Femoral Condyle
Conditions
Keywords
Cartilage, Articular, Femoral, Knee
Brief summary
This is a phase III, multicenter, open-label, randomized controlled trial of ChondroCelect® in an Autologous Chondrocyte Implantation (ACI) procedure compared to the procedure of microfracture (MF) in the repair of symptomatic cartilage lesions of the knee. Eligible patients attended two screening visits and were booked for arthroscopy approximately 2 weeks later. At that time, patients were randomized to either ACI with ChondroCelect® or to MF, a procedure in which the subchondral bone is perforated to allow a bloodcloth to form scar tissue. Patients randomized to MF had the procedure performed at the time of their arthroscopy; those randomized to ACI with ChondroCelect® had their cells harvested during the arthroscopy and then returned to the clinic approximately 4 weeks later for an open knee procedure, during which the ACI procedure using ChondroCelect® was performed. Patients subsequently followed the same rehabilitation program and had follow-up assessments up to 12 months post-surgery. The 12-month visit was the end-of-study visit for the TIG/ACT/01/2000 protocol. Subject to satisfying the eligibility criteria, patients who had participated in the initial 12 month trial could enter the extension trial. The 12-month visit for the initial study was the baseline visit for the extension study. During the extension study, patients have follow-up assessments up to 60 months post-surgery.
Detailed description
see above
Interventions
DRUGChondroCelect implantation
10.000 cells/µl cell suspension for implantation (Autologous Chondrocyte Implantation). ChondroCelect consists of characterised autologous cartilage-forming cells expressing a specific marker profile. The dose depends on the size of the lesion. Recommended dose is 0.8 to 1.0 million cells/cm².
PROCEDUREMicrofracture
A procedure in which the subchondral bone is perforated to allow a bloodcloth to form scar tissue.
Sponsors
TiGenix n.v.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Signed patient informed consent * Symptomatic cartilage single lesion of the femoral condyle * Lesion on femoral condyle between 1 and 5 cm² * Agree to participate actively in a strict rehabilitation protocol and follow-up programme * Agree to only use paracetamol mono-or combination preparation (max 4g/d) and Non-Steroidal Anti Inflammatory Drugs (NSAIDS) during the study and to discontinue this medication 2 weeks before the baseline visit and the follow-up visits. The use of paracetamol mono-preparation (max 4g/d) is allowed up to one week before the baseline visit and the follow-up visits. * Females of childbearing age should use a proven method to prevent pregnancy
Exclusion criteria
* Participation in concurrent trials * Participation in previous trials within 3 months * Subjects with hepatitis, HIV or syphilis * Malignancy * Alcohol or drug (medication) abuse * Poor general health as judged by Investigator * Clinically relevant second cartilage lesion on the patella * Patellofemoral cartilage lesion * Osteochondritis Dissecans (OCD) : recent OCD (within 1 year before baseline), depth of lesion \> 0.5cm, subchondral slerosis * Advanced osteoarthritis (OA) : radiographic atlas of OA grade 2-3 * Known allergy to gentamicin or penicillins (or presence of multiple severe allergies) * Complex ligamentous instability of the knee * Meniscal transplant * Meniscal suture with meniscal arrows (ipsilateral) * Meniscus resection : if \< 1 yr before baseline - lateral meniscus resection or medial meniscus resection of more than 50%. If \> 1 yr before baseline - ipsilateral meniscus resection of more than 50%, controlateral meniscus resection of more than 50% if ipsilateral meniscus is not intact, combination of medial and lateral meniscus resection and one of both \> 50%. * Varus or valgus malalignment of more than 5° * Mosaicplasty * Microfracture performed less than 1 yr before baseline * Having received hyaluronic acid intra-articular injections in the affected knee within the last 6 months of baseline * Taking specific OA drugs such as chondroïtin sulfate, diacerein, n-glucosamine, piascledine, capsaicin within 2 weeks of the baseline visit * Corticosteroïd treatment by systemic or intra-articular route within the last month of baseline or intramuscular or oral corticosteroïds within the last 2 weeks of baseline * Chronic use of anticoagulants * Uncontrolled diabetes * 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 neurologic disorder of the lower extremities * Any evidence of the following diseases in the target joint : septic arthritis, inflammatory joint disease, gout, recurrent episodes of pseudogout, Paget's disease of bone, ochronosis, acromegaly, hemochromatosis, Wilson's disease, primary osteochondromatosis, heritable disorders, collagen gene mutation * Current diagnosis of osteomyelitis * Liver enzymes (SGOT, SGPT, Alkaline Phosphatase) of more then two times the upper limit of normal or any other result that is clinically important according to the Investigator * CRP \> 10 mg/l
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Histomorphometry Safranin-O + Anti-Collagen II Antibody Staining | 12 months post-surgery | Histomorphometry on end point biopsies at 12 months post-surgery. Safranin-O (ratio 0-1)+ anti-Collagen II antibody (ratio 0-1) stain signal expressed as a ratio of the total cartilage surface area (Saf O + anti Coll II divided by total surface = ratio 0-2). Safranin-O stains proteoglycans and anti-Collagen II antibody reflects the presence of Collagen II. |
| Overall Histology Assessment on First Subscale of ICRS II Score | 12 months post-surgery | Overall histology assessment of cartilage repair, first subscale of International Cartilage Repair Society II (ICRS II) score by two blinded independant histopathologists on a visual analogue scale (VAS 0-100mm) from worst (0) to best (100) |
| Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average) | Average change from baseline in Overall KOOS at 12-18 months post-surgery | Overall Knee injury and Osteoarthritis Outcome score (average of 4 KOOS subdomains, Sports not included) at the average of 12-18 months (calculated by averaging change from baseline measurements at 12 and 18 months). Best score = 100; worst score = 0. The analysis was the average of the change from baseline at the 12 and 18 months timepoints. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months | Change from baseline in Overall KOOS at 36 months post-surgery | Overall Knee injury and Osteoarthritis Outcome score (average of 4 KOOS subdomains: Activities of Daily Living, Quality of Life, Symptoms and Stiffness Pain; Sports not included) at 36 months (change from baseline). Best = 100; worst = 0. |
| Number of Treatment Failures at 36 Months | Continuous | Participants with failed treatment - defined as the number of patients who underwent a reintervention of the index lesion - at 36 months. The index lesion is the lesion that was initially treated in the study. |
| Safety: Adverse Events | continuous up to 60 months | Side effects are recorded as the number of patients with adverse events. These events are coded according to the Medical Dictionary for Regulatory Affairs (MedDRA terms). |
Countries
Belgium, Croatia, Germany, Netherlands
Participant flow
Recruitment details
Recruitment by orthopaedic surgeons (medical clinic). Recruitment period: 21 February 2002 to 23 November 2004.
Pre-assignment details
Enrolled patients excluded: Not fulfilling inclusion criteria. Withdrawal of consent.
Participants by arm
| Arm | Count |
|---|---|
| ChondroCelect ChondroCelect is intended for use in autologous cartilage repair and is administered to patients in an Autologous Chondrocyte Implantation procedure (ACI) | 57 |
| Microfracture Microfracture is a surgical technique involving several systematic steps, including debridement to a stable cartilage margin, careful removal of the calcified cartilage layer, and homogeneous placement of microfracture penetrations within the cartilage defect with resultant complete defect fill by a well-anchored mesenchymal clot. | 61 |
| Total | 118 |
Baseline characteristics
| Characteristic | ChondroCelect | Microfracture | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 57 Participants | 61 Participants | 118 Participants |
| Age Continuous | 33.93 years STANDARD_DEVIATION 8.54 | 33.92 years STANDARD_DEVIATION 8.61 | 33.92 years STANDARD_DEVIATION 8.54 |
| Region of Enrollment Belgium | 33 participants | 35 participants | 68 participants |
| Region of Enrollment Croatia | 4 participants | 5 participants | 9 participants |
| Region of Enrollment Germany | 1 participants | 4 participants | 5 participants |
| Region of Enrollment Netherlands | 19 participants | 17 participants | 36 participants |
| Sex: Female, Male Female | 22 Participants | 20 Participants | 42 Participants |
| Sex: Female, Male Male | 35 Participants | 41 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 50 / 51 | 51 / 61 |
| serious Total, serious adverse events | 10 / 51 | 12 / 61 |
Outcome results
Primary
Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average)
Overall Knee injury and Osteoarthritis Outcome score (average of 4 KOOS subdomains, Sports not included) at the average of 12-18 months (calculated by averaging change from baseline measurements at 12 and 18 months). Best score = 100; worst score = 0. The analysis was the average of the change from baseline at the 12 and 18 months timepoints.
Time frame: Average change from baseline in Overall KOOS at 12-18 months post-surgery
Population: FAS (with LOCF for treatment failures)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| ChondroCelect | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average) | Change in oKOOS | 16.18 points on a scale (0-100) | Standard Error 2.42 |
| ChondroCelect | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average) | Baseline value | 56.30 points on a scale (0-100) | Standard Error 13.61 |
| ChondroCelect | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average) | Value at 12 months | 73.26 points on a scale (0-100) | Standard Error 14.66 |
| ChondroCelect | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average) | Value at 18 months | 74.73 points on a scale (0-100) | Standard Error 17.01 |
| Microfracture | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average) | Value at 18 months | 75.04 points on a scale (0-100) | Standard Error 14.5 |
| Microfracture | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average) | Change in oKOOS | 14.37 points on a scale (0-100) | Standard Error 2.35 |
| Microfracture | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average) | Value at 12 months | 73.10 points on a scale (0-100) | Standard Error 16.01 |
| Microfracture | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average) | Baseline value | 59.53 points on a scale (0-100) | Standard Error 14.95 |
95% CI: [-3.28, 6.9]ANCOVA
Primary
Histomorphometry Safranin-O + Anti-Collagen II Antibody Staining
Histomorphometry on end point biopsies at 12 months post-surgery. Safranin-O (ratio 0-1)+ anti-Collagen II antibody (ratio 0-1) stain signal expressed as a ratio of the total cartilage surface area (Saf O + anti Coll II divided by total surface = ratio 0-2). Safranin-O stains proteoglycans and anti-Collagen II antibody reflects the presence of Collagen II.
Time frame: 12 months post-surgery
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ChondroCelect | Histomorphometry Safranin-O + Anti-Collagen II Antibody Staining | 1.01 Ratio | Standard Error 0.08 |
| Microfracture | Histomorphometry Safranin-O + Anti-Collagen II Antibody Staining | 0.75 Ratio | Standard Error 0.08 |
Comparison: Test for superiorityp-value: 0.003ANCOVA
Primary
Overall Histology Assessment on First Subscale of ICRS II Score
Overall histology assessment of cartilage repair, first subscale of International Cartilage Repair Society II (ICRS II) score by two blinded independant histopathologists on a visual analogue scale (VAS 0-100mm) from worst (0) to best (100)
Time frame: 12 months post-surgery
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ChondroCelect | Overall Histology Assessment on First Subscale of ICRS II Score | 55.11 Points on a scale | Standard Error 3.98 |
| Microfracture | Overall Histology Assessment on First Subscale of ICRS II Score | 44.20 Points on a scale | Standard Error 3.74 |
Comparison: Test for superiorityp-value: 0.01ANCOVA
Secondary
Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months
Overall Knee injury and Osteoarthritis Outcome score (average of 4 KOOS subdomains: Activities of Daily Living, Quality of Life, Symptoms and Stiffness Pain; Sports not included) at 36 months (change from baseline). Best = 100; worst = 0.
Time frame: Change from baseline in Overall KOOS at 36 months post-surgery
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ChondroCelect | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months | Change in oKOOS | 21.25 Units on a scale | Standard Error 3.6 |
| ChondroCelect | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months | Baseline value | 56.30 Units on a scale | Standard Error 1.91 |
| ChondroCelect | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months | Value at 36 month | 78.46 Units on a scale | Standard Error 18.7 |
| Microfracture | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months | Change in oKOOS | 15.83 Units on a scale | Standard Error 3.48 |
| Microfracture | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months | Baseline value | 59.46 Units on a scale | Standard Error 1.98 |
| Microfracture | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months | Value at 36 month | 74.47 Units on a scale | Standard Error 18.6 |
Secondary
Number of Treatment Failures at 36 Months
Participants with failed treatment - defined as the number of patients who underwent a reintervention of the index lesion - at 36 months. The index lesion is the lesion that was initially treated in the study.
Time frame: Continuous
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ChondroCelect | Number of Treatment Failures at 36 Months | 2 Participants |
| Microfracture | Number of Treatment Failures at 36 Months | 7 Participants |
Secondary
Safety: Adverse Events
Side effects are recorded as the number of patients with adverse events. These events are coded according to the Medical Dictionary for Regulatory Affairs (MedDRA terms).
Time frame: continuous up to 60 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ChondroCelect | Safety: Adverse Events | 51 participants |
| Microfracture | Safety: Adverse Events | 61 participants |
Post Hoc
Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 60 Months
Patient-administered instrument to assess the patients opinion about their knee and associated problems. It consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life QOL. The last week is taken into consideration when answering questions. Standardized answer options are given (5 Likert boxes) and each question gets a score from 0 to 4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale. The result can be plotted as an outcome profile.
Time frame: 60 months
Population: FAS population with imputation for treatment failures by LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ChondroCelect | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 60 Months | 21.17 units on a scale | Standard Error 2.89 |
| Microfracture | Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 60 Months | 14.07 units on a scale | Standard Error 2.54 |
Post Hoc
Number of Treatment Failures at 60 Months Post-surgery
Participants with failed treatment - defined as the number of patients who underwent a reintervention of the index lesion - at 60 months. The index lesion is the lesion that was initially treated in the study.
Time frame: 60 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ChondroCelect | Number of Treatment Failures at 60 Months Post-surgery | 7 participants |
| Microfracture | Number of Treatment Failures at 60 Months Post-surgery | 10 participants |