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    Clinical Trial Results:
    Instant MSC Product accompanying Autologous Chondron Transplantation (IMPACT) for focal articular cartilage lesions of the knee; feasibility and safety

    Summary
    EudraCT number
    		 2012-001570-29
    Trial protocol
    		 NL  
    Global end of trial date
    10 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Mar 2020
    First version publication date
    19 Mar 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NL4014200012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02037204
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CCMO File nr: NL40142.000.12, METC protocol nr: 12-452
    Sponsors
    Sponsor organisation name
    UMC Utrecht
    Sponsor organisation address
    Heidelberglaan 100, Utrecht, Netherlands, 3584 CX
    Public contact
    Department of Orthopaedics, University Medical Centre Utrecht, +31 887556971, d.saris@umcutrecht.nl
    Scientific contact
    Department of Orthopaedics, University Medical Centre Utrecht, +31 887556971, d.saris@umcutrecht.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to examine clinical safety and feasibility of the IMPACT therapy.
    Protection of trial subjects
    This study was conducted according to the principle of the Declaration of Helsinki (Tokyo, 2004) and in accordance with the Medical Research Involving Human Subjects Act (WMO). An Independan data monitoring committee was involved. As this is a phase I/II monocenter study in relatively healthy patients, an independent safety officer was appointed to monitor the safety in terms of AE occurrence for the first six patients prior to starting the study. This safety officer was an independent physician with knowledge in the field. This safety officer looked into all clinical patient data, including operation and clinical reports. An independent knowledgeable investigator about the disease indication also looked at the data in terms of data quality, main outcomes and statistical analysis. Both investigators report on the first six patients within two months after inclusion of the sixth patient. The study proceeded after the conclusion of both investigators that it was safe to continue. The independent safety officer and investigator continued to monitor the study with reports at twelve months and at final follow-up (18 months).
    Background therapy
    		 All patients received a mini-arthrotomy with macroscopic inspection of the knee joint. All patients received treatments that are part of the standard surgery protocol.
    Evidence for comparator
    		 Articular cartilage defects in the knee have poor intrinsic healing capacity and may lead to functional disability and osteoarthritis. Cartilage cell therapy using autologous chondrocyte implantation has been established as the first advanced treatment therapy medicinal product. Although this technique has achieved good mid-term results, it is a costly and extensive two-stage procedure which is limited by the number of chondrocytes obtained by biopsy and the dedifferentiation resulting from the expansion phase. Therefore, there is a need for improvement. A new cartilage repair technique should aim at decreasing surgical trauma, lowering complexity, improving logistics and cost-effectiveness while retaining or improving clinical outcome. Direct contact between mesenchymal stromal cells (MSCs) and dedifferentiated articular chondrocytes in vitro showed improvement of the chondrogenic phenotype of dedifferentiated articular chondrocytes. In addition, preserving the pericellular matrix of chondrocytes improves cartilage formation. These chondrons (chondrocytes with their pericellular matrix), which we can obtain using a rapid digestion protocol in 40 minutes, have shown improved cartilage formation when combined with allogeneic MSCs. These cells can be mixed with a widely used, commercially available, fibrin cell carrier (Beriplast®) and applied to the cartilage lesion within one surgical procedure, using a minimally invasive and eventually arthroscopic technique. This will reduce patient morbidity and improve patient care through immediate transplantation of a potent cell-based cartilage product.
    Actual start date of recruitment
    03 Sep 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 35
    Worldwide total number of subjects
    35
    EEA total number of subjects
    35
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    35
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were recruited at the outpatient clinic of the department of Orthopaedics of the UMC Utrecht from 10-04-2013 up untill 6-8-2014.

    Pre-assignment
    Screening details
    		 - Provides written informed consent, is able to understand the content of the study, understands the requirements for follow-up visits and is willing to provide the required information at follow-up visits. - Symptomatic isolated articular cartilage lesion on the femoral condyle or trochlea. - Age >18 and <45 years old

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - Baseline
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 1
    		IMPACT - Baseline
    Started
    35
    Completed
    35
    Period 2
    Period 2 title
    Safety analysis day 1
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - Safety analysis day 1
    Arm description
    		 During one surgical procedure and using a minimally invasive technique autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs are mixed with a fibrin cell carrier (Beriplast®) and applied to the cartilage lesion in the knee.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 2
    		IMPACT - Safety analysis day 1
    Started
    35
    Completed
    35
    Period 3
    Period 3 title
    Safety analysis week 1
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - Safety analysis week 1
    Arm description
    		 During one surgical procedure and using a minimally invasive technique autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs are mixed with a fibrin cell carrier (Beriplast®) and applied to the cartilage lesion in the knee.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 3
    		IMPACT - Safety analysis week 1
    Started
    35
    Completed
    35
    Period 4
    Period 4 title
    Safety analysis week 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - Safety analysis week 2
    Arm description
    		 During one surgical procedure and using a minimally invasive technique autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs are mixed with a fibrin cell carrier (Beriplast®) and applied to the cartilage lesion in the knee.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 4
    		IMPACT - Safety analysis week 2
    Started
    35
    Completed
    35
    Period 5
    Period 5 title
    Safety analysis week 4
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - Safety analysis week 4
    Arm description
    		 During one surgical procedure and using a minimally invasive technique autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs are mixed with a fibrin cell carrier (Beriplast®) and applied to the cartilage lesion in the knee.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 5
    		IMPACT - Safety analysis week 4
    Started
    35
    Completed
    35
    Period 6
    Period 6 title
    Safety analysis week 6
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - Safety analysis week 6
    Arm description
    		 During one surgical procedure and using a minimally invasive technique autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs are mixed with a fibrin cell carrier (Beriplast®) and applied to the cartilage lesion in the knee.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 6
    		IMPACT - Safety analysis week 6
    Started
    35
    Completed
    35
    Period 7
    Period 7 title
    3 months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - 3 months
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 7
    		IMPACT - 3 months
    Started
    35
    Completed
    35
    Period 8
    Period 8 title
    6 months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - 6 months
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 8
    		IMPACT - 6 months
    Started
    35
    Completed
    35
    Period 9
    Period 9 title
    12 months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - 12 months
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 9
    		IMPACT - 12 months
    Started
    35
    Completed
    35
    Period 10
    Period 10 title
    18 months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - 18 months
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 10
    		IMPACT - 18 months
    Started
    35
    Completed
    35
    Period 11
    Period 11 title
    12 months - second look
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - second look
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 11
    		IMPACT - second look
    Started
    35
    Completed
    33
    Not completed
    2
         No consent was provided for this part
    2
    Period 12
    Period 12 title
    12 months - biopsy
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMPACT - biopsy
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    INSTANT MSC PRODUCT ACCOMPANYING AUTOLOGOUS CHONDRON TRANSPLANTATION (IMPACT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intracartilaginous use
    Dosage and administration details
    The surgical procedure started with a mini-arthrotomy, followed by inspection of the articular surfaces of the knee with identification and macroscopic scoring of the isolated articular cartilage lesion. Following this, the defect was debrided to create a stable surgical base and borders. This debrided tissue was transported to the CellTherapyFacility. The cartilage was cut into small pieces and the rapid digestion protocol (RDP) was performed. In parallel with the RDP the cryopreserved allogeneic MSCs were thawed and counted for later combination with the isolated chondrons. Once the cells were added together, they mixed with the fibrinogen component of Beriplast®. When the product was finished it was transported back to the operation theatre and the surgeon applied the Beriplast® loaded with the chondrons and MSCs to the cartilage defect.

    Number of subjects in period 12
    		IMPACT - biopsy
    Started
    33
    Completed
    32
    Not completed
    1
         Lack of efficacy
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 35 35
    Age categorical
    Units: Subjects
    Age continuous
    Inclusion between 18 and 45 years old.
    Units: years
        arithmetic mean (standard deviation)
    		 30 ± 8 -
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 24 24
    Location cartilage defect
    Location of the cartilage defect in the knee.
    Units: Subjects
        Medial femoral condyle
    		 17 17
        Lateral femoral condyle
    		 12 12
        Trochlea
    		 6 6
    Previous surgeries
    Previous surgeries performed in same knee
    Units: Subjects
        Menisectomy
    		 6 6
        Debridement
    		 4 4
        Bone marrow stimulation by microfracture
    		 10 10
        No previous surgeries
    		 15 15
    Cellular mixture
    Autologous chondrons and allogeneic MSCs were combined in a 10:90 ratio (standard yield) or 20:80 ratio (high yield), depending on the amount of chondrons isolated.
    Units: Subjects
        10:90 cellular mixture
    		 17 17
        20:80 cellular mixture
    		 18 18

    End points

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    End points reporting groups
    Reporting group title
    IMPACT - Baseline
    Reporting group description
    		 -
    Reporting group title
    IMPACT - Safety analysis day 1
    Reporting group description
    		 During one surgical procedure and using a minimally invasive technique autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs are mixed with a fibrin cell carrier (Beriplast®) and applied to the cartilage lesion in the knee.
    Reporting group title
    IMPACT - Safety analysis week 1
    Reporting group description
    		 During one surgical procedure and using a minimally invasive technique autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs are mixed with a fibrin cell carrier (Beriplast®) and applied to the cartilage lesion in the knee.
    Reporting group title
    IMPACT - Safety analysis week 2
    Reporting group description
    		 During one surgical procedure and using a minimally invasive technique autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs are mixed with a fibrin cell carrier (Beriplast®) and applied to the cartilage lesion in the knee.
    Reporting group title
    IMPACT - Safety analysis week 4
    Reporting group description
    		 During one surgical procedure and using a minimally invasive technique autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs are mixed with a fibrin cell carrier (Beriplast®) and applied to the cartilage lesion in the knee.
    Reporting group title
    IMPACT - Safety analysis week 6
    Reporting group description
    		 During one surgical procedure and using a minimally invasive technique autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs are mixed with a fibrin cell carrier (Beriplast®) and applied to the cartilage lesion in the knee.
    Reporting group title
    IMPACT - 3 months
    Reporting group description
    		 -
    Reporting group title
    IMPACT - 6 months
    Reporting group description
    		 -
    Reporting group title
    IMPACT - 12 months
    Reporting group description
    		 -
    Reporting group title
    IMPACT - 18 months
    Reporting group description
    		 -
    Reporting group title
    IMPACT - second look
    Reporting group description
    		 -
    Reporting group title
    IMPACT - biopsy
    Reporting group description
    		 -

    Primary: Change in C-reactive protein between day 1 to week 6

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    End point title
    		 Change in C-reactive protein between day 1 to week 6 [1]
    End point description
    All patients were monitored for inflammation and signs of a foreign body response by an independent physician (rheumatologist) using blood analysis including serum C-reactive protein.
    End point type
    Primary
    End point timeframe
    At day 1, week 1, week 2, week 4 and week 6.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A clinical immune/rheumatologist independent of the design and surgical treatment team performed the clinical monitoring. No signs of a foreign body response were identified by the independent rheumatologist. Levels were monitored and supposed to remain low after typical post-surgical procedure responses.
    End point values
    		 IMPACT - Safety analysis day 1 IMPACT - Safety analysis week 1 IMPACT - Safety analysis week 2 IMPACT - Safety analysis week 4 IMPACT - Safety analysis week 6
    Number of subjects analysed
    35
    35
    35
    35
    35
    Units: milligram(s)/litre
    arithmetic mean (full range (min-max))
        C-reactive protein count
    20.3 (1.6 to 103)
    6.5 (0.8 to 59)
    5.1 (0.5 to 32)
    2.8 (0.5 to 12)
    3 (0.5 to 21)
    No statistical analyses for this end point

    Primary: Change in erythrocyte sedimentation rate between day 1 to week 6

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    End point title
    		 Change in erythrocyte sedimentation rate between day 1 to week 6 [2]
    End point description
    All patients were monitored for inflammation and signs of a foreign body response by an independent physician (rheumatologist) using blood analysis including
    End point type
    Primary
    End point timeframe
    At day 1, week 1, week 2, week 4 and week 6.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A clinical immune/rheumatologist independent of the design and surgical treatment team performed the clinical monitoring. No signs of a foreign body response were identified by the independent rheumatologist. Levels were monitored and supposed to remain low after typical post-surgical procedure responses.
    End point values
    		 IMPACT - Safety analysis day 1 IMPACT - Safety analysis week 1 IMPACT - Safety analysis week 2 IMPACT - Safety analysis week 4 IMPACT - Safety analysis week 6
    Number of subjects analysed
    35
    35
    35
    35
    35
    Units: millimole(s)/hour
    arithmetic mean (full range (min-max))
        Erythrocyte sedimentation rate count
    7 (2 to 28)
    8.4 (1 to 34)
    6.2 (2 to 18)
    5.0 (1 to 19)
    5.1 (1 to 18)
    No statistical analyses for this end point

    Primary: Change in numeric rating scale for pain between day 1 to week 6

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    End point title
    		 Change in numeric rating scale for pain between day 1 to week 6
    End point description
    End point type
    Primary
    End point timeframe
    Preop, day 1, week 1, week 2, week 4, week 6
    End point values
    		 IMPACT - Baseline IMPACT - Safety analysis day 1 IMPACT - Safety analysis week 1 IMPACT - Safety analysis week 2 IMPACT - Safety analysis week 4 IMPACT - Safety analysis week 6
    Number of subjects analysed
    35
    35
    35
    35
    35
    35
    Units: points
    46
    33
    18
    14
    10
    8
    Statistical analysis title
    		 NRS test
    Comparison groups
    IMPACT - Baseline v IMPACT - Safety analysis week 6 v IMPACT - Safety analysis week 4 v IMPACT - Safety analysis week 2 v IMPACT - Safety analysis day 1 v IMPACT - Safety analysis week 1
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Change in leukocyte count between day 1 to week 6

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    End point title
    		 Change in leukocyte count between day 1 to week 6 [3]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1, week 1, week 2, week 4, week 6
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A clinical immune/rheumatologist independent of the design and surgical treatment team performed the clinical monitoring. No signs of a foreign body response were identified by the independent rheumatologist. Levels were monitored and supposed to remain low after typical post-surgical procedure responses.
    End point values
    		 IMPACT - Safety analysis day 1 IMPACT - Safety analysis week 1 IMPACT - Safety analysis week 2 IMPACT - Safety analysis week 4 IMPACT - Safety analysis week 6
    Number of subjects analysed
    35
    35
    35
    35
    35
    Units: 1000/µL
    8
    8
    8
    7
    7
    No statistical analyses for this end point

    Secondary: Change in VAS pain score from baseline to 18 months postop

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    End point title
    		 Change in VAS pain score from baseline to 18 months postop
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 3 months, 6 months, 12 months and 18 months
    End point values
    		 IMPACT - Baseline IMPACT - 3 months IMPACT - 6 months IMPACT - 12 months IMPACT - 18 months
    Number of subjects analysed
    35
    35
    35
    35
    35
    Units: point scale
        arithmetic mean (standard deviation)
    45.3 ± 24.2
    12.9 ± 9
    15.3 ± 8.9
    13.3 ± 10.2
    9.7 ± 15.4
    No statistical analyses for this end point

    Secondary: Change in KOOS from baseline to 18 months postop

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    End point title
    		 Change in KOOS from baseline to 18 months postop
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 3 months, 6 months, 12 months and 18 months
    End point values
    		 IMPACT - Baseline IMPACT - 3 months IMPACT - 6 months IMPACT - 12 months IMPACT - 18 months
    Number of subjects analysed
    35
    35
    35
    35
    35
    Units: Point scale
        arithmetic mean (standard deviation)
    57.9 ± 16.1
    76.6 ± 11.1
    79.9 ± 12.9
    83.5 ± 10.6
    85.4 ± 13.3
    No statistical analyses for this end point

    Secondary: Grade score at second look arthroscopy

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    End point title
    		 Grade score at second look arthroscopy
    End point description
    End point type
    Secondary
    End point timeframe
    At 12 months
    End point values
    		 IMPACT - second look
    Number of subjects analysed
    33
    Units: macroscopic ICRS score
        Grade 1
    22
        Grade 2
    11
    No statistical analyses for this end point

    Secondary: Mean change in KOOS from baseline to 3 and 18 months

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    End point title
    		 Mean change in KOOS from baseline to 3 and 18 months
    End point description
    End point type
    Secondary
    End point timeframe
    Questionnaire at 3 and 18 months.
    End point values
    		 IMPACT - Baseline IMPACT - 3 months IMPACT - 18 months
    Number of subjects analysed
    35
    35
    35
    Units: point scale
        arithmetic mean (standard deviation)
    57.9 ± 16.1
    85.4 ± 13.3
    79.9 ± 12.9
    Statistical analysis title
    		 Repeated-measures analysis of variance
    Statistical analysis description
    Predefined statistical analyses were performed with SPSS version 21.0 (IBM, Chicago, IL). A repeated-measures analysis of variance was used to test for differences in clinical outcome between baseline and 3, 6 and 18 months after surgery.
    Comparison groups
    IMPACT - Baseline v IMPACT - 3 months v IMPACT - 18 months
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Confidence interval
    Notes
    [4] - To test for differences in clinical outcome.

    Secondary: Mean change in VAS pain from baseline to 18 months

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    End point title
    		 Mean change in VAS pain from baseline to 18 months
    End point description
    End point type
    Secondary
    End point timeframe
    Questionnaire 18 months after surgery
    End point values
    		 IMPACT - Baseline IMPACT - 18 months
    Number of subjects analysed
    35
    35
    Units: Point scale
        number (not applicable)
    45.4
    15.3
    Statistical analysis title
    		 Repeated-measures analysis of variance
    Comparison groups
    IMPACT - Baseline v IMPACT - 18 months
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 1E-7
    Method
    		 ANOVA
    Confidence interval

    Secondary: STR analysis

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    End point title
    		 STR analysis
    End point description
    Detection of DNA of the allogeneic MSCs within the detection limit of the assay (1 in 100,000 cells).
    End point type
    Secondary
    End point timeframe
    At 12 months with the second look arthroscopy
    End point values
    		 IMPACT - biopsy
    Number of subjects analysed
    33
    Units: cells
        number (not applicable)
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    General adverse events were monitored througout the study.
    Adverse event reporting additional description
    A data safety monitoring board (DSMB) was assembled.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Serious adverse events
    		 Overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 35 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Overall trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 35 (62.86%)
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Nervous system disorders
    Vasovagal episode
    Additional description: Vasovagal episode in the morning (light headed, sweaty, nausea, temporary black cloud like spots in eye sight)
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Headache
    Additional description: After surgery
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Nausea
    Additional description: Nausea after surgery
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    4
    Pain
    Additional description: Pain of the knee
         subjects affected / exposed
    12 / 35 (34.29%)
         occurrences all number
    15
    Immune system disorders
    Elevated erythrocyte sedimentation rate
    Additional description: After surgery
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    C-reactive protein increased
    Additional description: Elevated C-reactive protein level
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    4
    Leukocytosis
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Pruritus
    Additional description: Facial pruritus after surgery
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Renal and urinary disorders
    Urinary retention
    Additional description: After surgery
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Increase in pain and instability
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Crepitations
    Additional description: Crepitations of the knee
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Swelling
    Additional description: Swelling of the knee
         subjects affected / exposed
    5 / 35 (14.29%)
         occurrences all number
    7
    Swelling and pain
    Additional description: Swelling and pain of toes
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Lesion in trochlea
    Additional description: Lesion in trochlea detected during arthroscopy at 12 months
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Meniscus tear
    Additional description: Meniscus tear detected during arthroscopy at 12 months
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2013
    Removal of KOOS <55 points from inclusion criteria and change in the MRI protocol.
    22 Nov 2013
    Change in the IMPD concerning the correction in dosage of cells.
    06 May 2014
    Lowering the frequency of follow-up moments at the first period after surgery.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28600828
    http://www.ncbi.nlm.nih.gov/pubmed/27507787
    http://www.ncbi.nlm.nih.gov/pubmed/27401932
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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