Articular Cartilage Defect
Conditions
Keywords
Cartilage legions, symptomatic focal cartilage defects, microfracture, MACI, autologous chondrocyte
Brief summary
The objective of this trial is to demonstrate superior efficacy and safety of MACI compared with arthroscopic microfracture in the treatment of patients (aged 18 to 55 years) with symptomatic articular cartilage defects of the knee.
Detailed description
This is a prospective, randomized, open-label, parallel-group, multicenter study designed to investigate the outcome of MACI implant versus arthroscopic microfracture in the treatment of articular cartilage defects in the knee in patients between ages of 18 and 55 years. All patients who meet the eligibility criteria and are considered suitable for inclusion will have a cartilage biopsy taken prior to randomization to study treatment. Eligible patients will then be randomized during the index arthroscopy procedure to receive either MACI implant or microfracture treatment. Patients randomized to treatment with MACI implant will return within approximately 4 to 8 weeks of the index arthroscopy to undergo the chondrocyte implantation procedure via arthrotomy. Patients randomized to microfracture will undergo the procedure during the index arthroscopy. Patients will be assessed post-arthroscopy and post-arthrotomy at intervals during 2 years follow-up. Evaluations include adverse events, functional and pain outcomes, arthroscopic and histologic evaluation and magnetic resonance imaging (MRI).
Interventions
PROCEDUREMicrofracture
Microfracture performed by arthroscopic surgery
Implantation via mini-arthrotomy
Sponsors
Vericel Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Symptomatic, single or multiple full-thickness cartilage defects of the knee with or without bone involvement
Exclusion criteria
* Known history of hypersensitivity to gentamicin, other aminoglycosides, or products of porcine or bovine origin * Severe osteoarthritis of the knee * Inflammatory arthritis, inflammatory joint disease, or uncorrected congenital blood coagulation disorders * Prior knee surgery (within 6 months), excluding surgery to procure a biopsy or a concomitant procedure to prepare the knee for a MACI implant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 104 for the Participant's Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain and Function (Sports and Recreational Activities) Scores. | Baseline and Week 104 | The KOOS is a validated knee-specific instrument developed to assess the patients' opinion of their knee and associated problems. KOOS consists of 5 subscales: Pain, Function in sports and recreational activities, other Symptoms, Function in activities of daily living (ADL), and knee related Quality of life (QOL). A 5-point Likert scale was used to record the response to each item ranging from 0 (no problems) to 4 (extreme problems). Within each subscale, items were added up and normalized to a value between 0 (extreme problems) and 100 (no problems). Subscales are not combined to calculate a total score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Defect Fill by Magnetic Resonance Imaging (MRI) | Week 104 | Number of participants with MRI degree of defect fill \> 50%. Evaluation of MRI data was performed by independent central review blinded to the participant's treatment. Appropriate MRI sequences were used to image cartilage repair tissue. |
| Response Rate Based on KOOS Pain and Function (Sports and Recreational Activities) Scores at Week 104. | Week 104 | A responder is defined as a participant with at least a 10-point improvement in both the KOOS Pain and Function (Sports and Recreational activities) scores from Baseline |
| Histological Evaluation of Structural Repair of Evaluable Biopsies Harvested From the Core of the Index Lesion During Arthroscopy at Week 104 | Week 104 | The mean microscopic International Cartilage Repair Society (ICRS) II overall assessment score was used to assess the histology efficacy endpoint. Scoring of the cartilage repair biopsies was completed using the ICRS II histology scoring system (Mainil-Varlet, 2010, Am J Sports Med) by 2 independent pathologists blinded to the patient's assigned study treatment. This scoring system includes 14 parameters, comprising an overall assessment score reported here, as well as 13 other items related to chondrocyte phenotype, tissue structure, and other factors, each scored on a scale from 0 to 100 representing poor to good quality cartilage. |
| Change From Baseline at Week 104 in the Remaining 3 Subscales of the KOOS Instrument (Activities of Daily Living, Knee-related Quality of Life, and Other Symptoms) | Baseline and Week 104 | The KOOS is a validated knee-specific instrument developed to assess the patients' opinion of their knee and associated problems. KOOS consists of 5 subscales: Pain, Function in sports and recreational activities, other Symptoms, Function in activities of daily living (ADL), and knee related Quality of life (QOL). A 5-point Likert scale was used to record the response to each item ranging from 0 (no problems) to 4 (extreme problems). Within each subscale, items were added up and normalized to a value between 0 (extreme problems) and 100 (no problems). |
| Participants With Treatment-Emergent Adverse Events | Week 104 | — |
| Treatment Failure | Week 104 | The planned analyses concerning time to treatment failure were not conducted due to the small number of per protocol treatment failure cases. As such, the number of participants with treatment failure is being reported. Patients were considered as a treatment failure if all of the following 5 criteria were met: 1. Patient's global assessment of their knee joint compared to Baseline was the same or worse 2. Physician's global assessment of the patient's knee joint compared to Baseline was the same, worse, or significantly worse. 3. Percent improvement from Baseline in KOOS Pain score was less than 10%. 4. Physician diagnostic evaluation of failure excluded etiologies (eg, meniscal tear) other than failed treatment of the index lesion. 5. The physician decided that surgical re-treatment of the index lesion(s) was required that involved either extensive debridement for lesion expansion, violation of the subchondral bone, or autologous cultured chondrocyte implantation. |
Countries
Czechia, France, Netherlands, Norway, Poland, Sweden, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MACI autologous cultured chondrocytes on porcine collagen membrane | 72 |
| Microfracture Microfracture | 72 |
| Total | 144 |
Baseline characteristics
| Characteristic | Microfracture | Total | MACI |
|---|---|---|---|
| Age, Continuous | 32.9 years STANDARD_DEVIATION 8.78 | 33.8 years STANDARD_DEVIATION 9 | 34.8 years STANDARD_DEVIATION 9.16 |
| Region of Enrollment Czech Republic | 11 participants | 24 participants | 13 participants |
| Region of Enrollment France | 9 participants | 18 participants | 9 participants |
| Region of Enrollment Netherlands | 30 participants | 58 participants | 28 participants |
| Region of Enrollment Norway | 3 participants | 6 participants | 3 participants |
| Region of Enrollment Poland | 14 participants | 28 participants | 14 participants |
| Region of Enrollment Sweden | 1 participants | 2 participants | 1 participants |
| Region of Enrollment United Kingdom | 4 participants | 8 participants | 4 participants |
| Sex: Female, Male Female | 24 Participants | 51 Participants | 27 Participants |
| Sex: Female, Male Male | 48 Participants | 93 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 55 / 72 | 58 / 72 |
| serious Total, serious adverse events | 11 / 72 | 19 / 72 |
Outcome results
Primary
Change From Baseline to Week 104 for the Participant's Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain and Function (Sports and Recreational Activities) Scores.
The KOOS is a validated knee-specific instrument developed to assess the patients' opinion of their knee and associated problems. KOOS consists of 5 subscales: Pain, Function in sports and recreational activities, other Symptoms, Function in activities of daily living (ADL), and knee related Quality of life (QOL). A 5-point Likert scale was used to record the response to each item ranging from 0 (no problems) to 4 (extreme problems). Within each subscale, items were added up and normalized to a value between 0 (extreme problems) and 100 (no problems). Subscales are not combined to calculate a total score.
Time frame: Baseline and Week 104
Population: All randomized patients
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MACI | Change From Baseline to Week 104 for the Participant's Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain and Function (Sports and Recreational Activities) Scores. | Change from Baseline KOOS Pain | 45.45 units on a scale | Standard Deviation 21.08 |
| MACI | Change From Baseline to Week 104 for the Participant's Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain and Function (Sports and Recreational Activities) Scores. | Change from Baseline KOOS Function | 46.04 units on a scale | Standard Deviation 28.35 |
| Microfracture | Change From Baseline to Week 104 for the Participant's Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain and Function (Sports and Recreational Activities) Scores. | Change from Baseline KOOS Pain | 35.23 units on a scale | Standard Deviation 23.91 |
| Microfracture | Change From Baseline to Week 104 for the Participant's Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain and Function (Sports and Recreational Activities) Scores. | Change from Baseline KOOS Function | 35.83 units on a scale | Standard Deviation 31.63 |
Comparison: The changes from Baseline to Week 104 in KOOS Pain and Function (SRA) scores (co-primary efficacy parameter) were analyzed with a multivariate analysis of variance (MANOVA) model, with the last observation carried forward (LOCF) method for handling missing data. Terms included in the model are treatment and center as class variables and baseline KOOS pain and Function (SRA) as continuous covariates.p-value: 0.001MANOVA
Secondary
Assessment of Defect Fill by Magnetic Resonance Imaging (MRI)
Number of participants with MRI degree of defect fill \> 50%. Evaluation of MRI data was performed by independent central review blinded to the participant's treatment. Appropriate MRI sequences were used to image cartilage repair tissue.
Time frame: Week 104
Population: Number of participants with MRI data at Week 104
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MACI | Assessment of Defect Fill by Magnetic Resonance Imaging (MRI) | 58 Participants |
| Microfracture | Assessment of Defect Fill by Magnetic Resonance Imaging (MRI) | 53 Participants |
Comparison: Differences between groups were tested by the Cochran-Mantel-Haenszel row mean score chi-squared test for defect fill.p-value: 0.92Cochran-Mantel-Haenszel
Secondary
Change From Baseline at Week 104 in the Remaining 3 Subscales of the KOOS Instrument (Activities of Daily Living, Knee-related Quality of Life, and Other Symptoms)
The KOOS is a validated knee-specific instrument developed to assess the patients' opinion of their knee and associated problems. KOOS consists of 5 subscales: Pain, Function in sports and recreational activities, other Symptoms, Function in activities of daily living (ADL), and knee related Quality of life (QOL). A 5-point Likert scale was used to record the response to each item ranging from 0 (no problems) to 4 (extreme problems). Within each subscale, items were added up and normalized to a value between 0 (extreme problems) and 100 (no problems).
Time frame: Baseline and Week 104
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MACI | Change From Baseline at Week 104 in the Remaining 3 Subscales of the KOOS Instrument (Activities of Daily Living, Knee-related Quality of Life, and Other Symptoms) | Change from Baseline in Activities of Daily Living | 43.70 units on a scale | Standard Deviation 24.52 |
| MACI | Change From Baseline at Week 104 in the Remaining 3 Subscales of the KOOS Instrument (Activities of Daily Living, Knee-related Quality of Life, and Other Symptoms) | Change from Baseline in KOOS Quality of Life | 37.41 units on a scale | Standard Deviation 27.24 |
| MACI | Change From Baseline at Week 104 in the Remaining 3 Subscales of the KOOS Instrument (Activities of Daily Living, Knee-related Quality of Life, and Other Symptoms) | Change from Baseline in KOOS Other Symptoms | 35.47 units on a scale | Standard Deviation 20.83 |
| Microfracture | Change From Baseline at Week 104 in the Remaining 3 Subscales of the KOOS Instrument (Activities of Daily Living, Knee-related Quality of Life, and Other Symptoms) | Change from Baseline in KOOS Other Symptoms | 27.31 units on a scale | Standard Deviation 24.59 |
| Microfracture | Change From Baseline at Week 104 in the Remaining 3 Subscales of the KOOS Instrument (Activities of Daily Living, Knee-related Quality of Life, and Other Symptoms) | Change from Baseline in Activities of Daily Living | 32.76 units on a scale | Standard Deviation 26.78 |
| Microfracture | Change From Baseline at Week 104 in the Remaining 3 Subscales of the KOOS Instrument (Activities of Daily Living, Knee-related Quality of Life, and Other Symptoms) | Change from Baseline in KOOS Quality of Life | 29.93 units on a scale | Standard Deviation 28.11 |
Comparison: Analysis of covariance was conducted with treatment and center as fixed effects and Baseline subscale as covariate, conducted at α = 0.05 level of significance. Last observation carried forward was used for missing data imputation.p-value: <0.001ANCOVA
Comparison: Analysis of covariance was conducted with treatment and center as fixed effects and Baseline subscale as covariate, conducted at α = 0.05 level of significance. Last observation carried forward was used for missing data imputation.p-value: 0.029ANCOVA
Comparison: Analysis of covariance was conducted with treatment and center as fixed effects and Baseline subscale as covariate, conducted at α = 0.05 level of significance. Last observation carried forward was used for missing data imputation.p-value: <0.001ANCOVA
Secondary
Histological Evaluation of Structural Repair of Evaluable Biopsies Harvested From the Core of the Index Lesion During Arthroscopy at Week 104
The mean microscopic International Cartilage Repair Society (ICRS) II overall assessment score was used to assess the histology efficacy endpoint. Scoring of the cartilage repair biopsies was completed using the ICRS II histology scoring system (Mainil-Varlet, 2010, Am J Sports Med) by 2 independent pathologists blinded to the patient's assigned study treatment. This scoring system includes 14 parameters, comprising an overall assessment score reported here, as well as 13 other items related to chondrocyte phenotype, tissue structure, and other factors, each scored on a scale from 0 to 100 representing poor to good quality cartilage.
Time frame: Week 104
Population: includes all subjects with histology follow-up data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MACI | Histological Evaluation of Structural Repair of Evaluable Biopsies Harvested From the Core of the Index Lesion During Arthroscopy at Week 104 | 63.8 units on a scale |
| Microfracture | Histological Evaluation of Structural Repair of Evaluable Biopsies Harvested From the Core of the Index Lesion During Arthroscopy at Week 104 | 62.3 units on a scale |
p-value: 0.717ANOVA
Secondary
Participants With Treatment-Emergent Adverse Events
Time frame: Week 104
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MACI | Participants With Treatment-Emergent Adverse Events | 55 Participants |
| Microfracture | Participants With Treatment-Emergent Adverse Events | 60 Participants |
Secondary
Response Rate Based on KOOS Pain and Function (Sports and Recreational Activities) Scores at Week 104.
A responder is defined as a participant with at least a 10-point improvement in both the KOOS Pain and Function (Sports and Recreational activities) scores from Baseline
Time frame: Week 104
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MACI | Response Rate Based on KOOS Pain and Function (Sports and Recreational Activities) Scores at Week 104. | 63 Participants |
| Microfracture | Response Rate Based on KOOS Pain and Function (Sports and Recreational Activities) Scores at Week 104. | 49 Participants |
Comparison: Differences between groups were tested by the Cochran-Mantel-Haenszel chi-squared test stratified by center for responders.p-value: 0.016Cochran-Mantel-Haenszel
Secondary
Treatment Failure
The planned analyses concerning time to treatment failure were not conducted due to the small number of per protocol treatment failure cases. As such, the number of participants with treatment failure is being reported. Patients were considered as a treatment failure if all of the following 5 criteria were met: 1. Patient's global assessment of their knee joint compared to Baseline was the same or worse 2. Physician's global assessment of the patient's knee joint compared to Baseline was the same, worse, or significantly worse. 3. Percent improvement from Baseline in KOOS Pain score was less than 10%. 4. Physician diagnostic evaluation of failure excluded etiologies (eg, meniscal tear) other than failed treatment of the index lesion. 5. The physician decided that surgical re-treatment of the index lesion(s) was required that involved either extensive debridement for lesion expansion, violation of the subchondral bone, or autologous cultured chondrocyte implantation.
Time frame: Week 104
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MACI | Treatment Failure | 0 Participants |
| Microfracture | Treatment Failure | 2 Participants |