Clinical Trial Results:
Prospective, Multicenter, Single-arm Phase III Clinical Trial to Evaluate the Efficacy and Safety of NOVOCART® Inject plus in the Treatment of Cartilage Defects of the Knee
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Summary
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EudraCT number |
2016-002817-22 |
Trial protocol |
HU CZ DE PL LT |
Global end of trial date |
22 Feb 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
18 Dec 2024
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First version publication date |
18 Dec 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AAG-G-H-1624
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03319797 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
TETEC AG
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Sponsor organisation address |
Aspenhaustrasse 18, Reutlingen, Germany, 72770
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Public contact |
Chief Medical Officer, Christoph Gaissmaier, +49 71211626103, christoph.gaissmaier@tetec-ag.de
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Scientific contact |
Head of Clinical Development, Alexandra Kirner, +49 71211626103, alexandra.kirner@tetec-ag.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Apr 2024
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Feb 2024
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate efficacy of NOVOCART® Inject plus for the treatment of cartilage defects of the knee based on the Knee injury and Osteoarthritis Outcome Score (KOOS) responder rate 24 month after transplantation.
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Protection of trial subjects |
Allowed concomitant medications: Outside the time windows specified in the trial protocol (washout, tissue harvest until 2 weeks post NOVOCART® Inject plus transplantation) normal standard of care had to be followed for pain management, deep vein thrombosis prophylaxis and for prophylactic antibiotics.
Regular follow-up visits were performed to monitor efficacy and safety after treatment.
Adverse events were to be documented.
Regular on-site monitoring as well as several quality-assurance audits by TETEC AG or its designees were performed.
Safety data were reviewed by TETEC AG/the medical monitor and an external Clinical Safety Board on a
regular basis.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
10 Oct 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Czechia: 35
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Country: Number of subjects enrolled |
Germany: 10
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Country: Number of subjects enrolled |
Hungary: 24
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Country: Number of subjects enrolled |
Lithuania: 32
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Country: Number of subjects enrolled |
Switzerland: 1
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Worldwide total number of subjects |
102
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EEA total number of subjects |
101
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
2
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Adults (18-64 years) |
100
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were enrolled and treated between October 2017 and February 2019 for focal symptomatic cartilage defects of the knee at 6 Czech, 5 Hungarian, 3 Lithuanian, 2 German, and 1 Swiss centers. | ||||||||||||||||
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Pre-assignment
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Screening details |
All patients with cartilage defects consulting the investigator during the recruitment phase of this clinical trial were informed of the trial. Patients who were interested in study participation, and had read the Patient Information and signed and dated the Patient Informed Consent form, were screened for eligibility (132 patients screened). | ||||||||||||||||
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Period 1
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Period 1 title |
Treatment and follow-up period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||
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Arms
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Arm title
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NOVOCART Inject plus | ||||||||||||||||
Arm description |
All patients were treated with NOVOCART Inject plus (hydrogel-based autologous chondrocyte implantation) | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
NOVOCART Inject plus
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intraarticular use, Local use
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Dosage and administration details |
Treatment with NOVOCART® Inject plus required 2 surgeries. During the first surgery, autologous chondrocytes for transplant production were harvested arthroscopically. About 3 to 4 weeks later, the finished product was implanted by arthroscopy or (mini)-arthrotomy. The final product was administered using a double chamber syringe which allows mixing of the 2 components and subsequent cross-linking of the cell-carrying hydrogel at the site of administration.
NOVOCART® Inject plus contained 2 - 8 million cells per mL cell suspension (about 8 - 32 million cells per 4 mL cell suspension). The total volume of NOVOCART® Inject plus was 5 mL (4 mL cell suspension and 1 mL cross-linker). The volume to be administered depended on the size of the prepared defect. At an application height of 2.0 mm, the dosage of NOVOCART® Inject plus was 0.3 to 1.3 million cells per cm2 defect area.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline data and treatment/follow-up period data are reported for the intent-to-treat population, i.e., all patients who were transplanted with Novocart Inject. The enrolled set corresponds to the safety population, i.e., all patients with cartilage tissue harvested for transplant production (102 patients). Two patients had cartilage harvested, but were finally not transplanted (1 withdrawal of consent, 1 unrelated AE requiring concomitant medication not compatible with surgery). |
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Baseline characteristics reporting groups
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Reporting group title |
Treatment and follow-up period
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Reporting group description |
All patients who had received NOVOCART Inject plus implantation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
NOVOCART Inject plus
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Reporting group description |
All patients were treated with NOVOCART Inject plus (hydrogel-based autologous chondrocyte implantation) | ||
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End point title |
Overall KOOS responder rate at 24 mo [1] | ||||||||||
End point description |
The KOOS 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. 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. In addition, the overall KOOS score, defined as the average of the 5 subscale scores (ensuring equal weighting of all subscales), can be calculated.
The primary efficacy endpoint of the study was the responder rate based on the overall KOOS after 24 months of treatment. The KOOS responder rate was defined as the proportion of patients with ≥10-point improvement in the overall KOOS from baseline. The responder rate is given here. The statistical analysis for timepoints up to 24 mo (95%-CI, p-values) is given in the attachment.
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End point type |
Primary
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End point timeframe |
24 months
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| 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: This was a single arm study, therefore no comparator group. Primary endpoint of the study was the overall KOOS responder rate at Month 24. A responder rate of 40% was the stipulated threshold for clinical relevance, and the statistical confirmation of a response rate >40% (i.e., lower 95% confidence interval boundary of >40% for the point estimate based on a binominal test) was required to conclude sufficient clinical efficacy of treatment in a confirmatory manner. Analysis given in attachment. |
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Attachments |
Primary analysis KOOS responder rate 24 mo |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Overall KOOS change from baseline | ||||||||
End point description |
The KOOS has been developed as an instrument to assess the patients' opinion about their knee and associated problems. The KOOS 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 the 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. In addition, the overall KOOS score, defined as the average of the 5 subscale scores (ensuring equal weighting of all subscales), can be calculated.
Data for 60 months follow-up is reported here. The summary of KOOS over time (absolute values and mean changes from baseline) and statistical analysis (LS mean changes, 95%-CI) is provided in the attachment.
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End point type |
Secondary
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End point timeframe |
60 months
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Attachments |
Analysis of overall KOOS changes from baseline ove Summary of overall KOOS |
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| No statistical analyses for this end point | |||||||||
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End point title |
KOOS subscore changes from baseline | ||||||||
End point description |
The KOOS has been developed as an instrument to assess the patients' opinion about their knee and associated problems. The KOOS 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 the 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.
Data for subscore "sports/rec" after 60 months follow-up is reported here. The summary of all KOOS subscores (absolute values and mean changes from baseline) and statistical analysis (LS mean changes, 95%-CI) of all subscores at 24 and 60 months is provided in the attachment.
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End point type |
Secondary
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End point timeframe |
60 months
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Attachments |
Summary of KOOS subscores at 24 and 60 mo Analysis of KOOS subscorechanges from baseline ove |
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| No statistical analyses for this end point | |||||||||
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End point title |
IKDC subjective score change from baseline | ||||||||
End point description |
The IKDC subjective score is an established, knee-specific, patient-reported outcome measure. The questionnaire covers 3 separate categories: "symptoms" (7 questions), "sports activity" (2 questions), and "current knee function" (1 question). The IKDC subjective total transformed score has a span from 0 to 100, with higher values indicating higher levels of function and lower levels of symptoms.
Data for changes from baseline at 60 months (mean and SD) is reported here. The summary of IKDC scores (absolute values and mean changes from baseline) and statistical analysis (LS mean changes, 95% CI) over time is provided in the attachment.
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End point type |
Secondary
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End point timeframe |
60 months
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Attachments |
Analysis of IKDC changes from baseline ove Summary of IKDC subjective score |
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| No statistical analyses for this end point | |||||||||
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End point title |
IKDC subjective responder rate | ||||||||||
End point description |
The IKDC subjective score is an established, knee-specific, patient-reported outcome measure. The questionnaire covers 3 separate categories: "symptoms" (7 questions), "sports activity" (2 questions), and "current knee function" (1 question). The IKDC subjective total transformed score has a span from 0 to 100, with higher values indicating higher levels of function and lower levels of symptoms.
IKDC responder rates are defined as follows.
Responder I: Response defined as an improvement of >20.5 points from baseline.
Responder II: Response defined as an improvement of ≥11.5 points from baseline.
Results for responder rate definition I after 60 months is given here. Results for both responder definitions at all measured timepoints is presented in the attachment.
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End point type |
Secondary
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End point timeframe |
60 months
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Attachments |
IKDC responder rates over time through Mon |
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| No statistical analyses for this end point | |||||||||||
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End point title |
IKDC objective physician score | ||||||||||||||
End point description |
The IKDC objective score is performed by the investigator to evaluate a variety of knee conditions including ligament, meniscal, articular cartilage, arthritis, and patellofemoral injuries. The assessment consists of a functional assessment of the knee (range of motion, rotation, crepitation), as well as instrumental and/or imaging-based evaluation of the different compartments. The form contains items that fall into one of 7 measurement domains. The 7 domains assessed by the
knee examination form are:
1. Effusion
2. Passive Motion Deficit
3. Ligament Examination
4. Compartment Findings
5. Harvest Site Pathology
6. X-ray Findings
7. Functional Test
In a final evaluation only the first 3 groups are evaluated and classified into "normal", "nearly normal", "abnormal", and "severely abnormal". The worst group grade determines the final evaluation.
Here the results after 60 months follow-up are shown. Other timepoints are given in the attachment.
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End point type |
Secondary
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End point timeframe |
60 months
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Attachments |
IKDC objective score |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
EQ-5D-5L index change from baseline | ||||||||
End point description |
The EQ-5D is a standardized measure of health status. This measure consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).
The EQ-5D-5L health states can be converted to a single index value. The hypothetical range of the index value is from -0.661 (death) to 1 (perfect health) based on the validated national value set for Germany published in 2018.
In addition to the assessment of the 5 dimensions, the EQ also includes a 20 cm vertical visual analogue scale (EQ-VAS), where the endpoints are labelled “best imaginable health state” (value 100) and “worst imaginable health state” (value 0).
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End point type |
Secondary
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End point timeframe |
60 months
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Attachments |
EQ-5D-5L change in index Summary of EQ-5D-5L values |
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| No statistical analyses for this end point | |||||||||
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End point title |
EQ-5D-5L VAS change from baseline | ||||||||
End point description |
The EQ-5D is a standardized measure of health status. This measure consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).
The EQ-5D-5L health states can be converted to a single index value. The hypothetical range of the index value is from -0.661 (death) to 1 (perfect health) based on the validated national value set for Germany published in 2018.
In addition to the assessment of the 5 dimensions, the EQ also includes a 20 cm vertical visual analogue scale (EQ-VAS), where the endpoints are labelled “best imaginable health state” (value 100) and “worst imaginable health state” (value 0).
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End point type |
Secondary
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End point timeframe |
60 months
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Attachments |
Analysis EQ-5D-5L change in VAS Summary of EQ-5D-5L VAS |
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| No statistical analyses for this end point | |||||||||
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End point title |
MOCART 2.0 sum score | ||||||||
End point description |
The Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score version 2.0 was used to assess in vivo performance of cartilage repair. The MOCART 2.0 total score consists of 7 items and ranges from 0 points (no repair) to 100 score points (normal cartilage). The results of the MOCART sum score after 60 months are presented here. MOCART sum scores for other timepoints (separated by smaller and larger defects) are given in the attachment. Results refer to the number of lesions (not the number of patients).
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End point type |
Secondary
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End point timeframe |
60 months
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Attachments |
MOCART 2.0 per lesion size |
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| No statistical analyses for this end point | |||||||||
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End point title |
T2 mapping | ||||||||||||
End point description |
T2 relaxation time measurement is an established marker for cartilage water and collagen content as well as collagen organization that reflects the integrity and vitality of cartilage and cartilage regenerated tissue. The T2 relaxation time measured in the repair tissue can be set in relation to the T2 relaxation time measured in the surrounding healthy cartilage, thereby resulting in a "global" T2 ratio (if only the full-thickness tissue areas are measured) and in a "zonal" T2 ratio (if, in addition, the differences in T2 relaxation times in the superficial and deep zones of the cartilage areas are considered). Ideal global and zonal T2 ratios are "1" (indicating no difference between regenerate and normal tissue), and the ratio range of 0.8 to 1.2 is regarded as "normal" (and was therefore employed for the analyses of the T2 ratios). Here zonal T2 ratios at 60 months are given (based on the number of lesions). Zonal and global T2 ratios at all timepoints are given in the attachment.
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End point type |
Secondary
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End point timeframe |
60 months
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Attachments |
Summary of T2 global and zonal ratios |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Overall KOOS responder rate up to 60 mo | ||||||||||
End point description |
The KOOS 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. 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. In addition, the overall KOOS score, defined as the average of the 5 subscale scores (ensuring equal weighting of all subscales), can be calculated.
The overall KOOS responder rate was defined as the proportion of patients with ≥10-point improvement in the overall KOOS from baseline. Here, the results at 60 months are given. Results of earlier timepoints are provided in the attachment.
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End point type |
Other pre-specified
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End point timeframe |
60 months
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Attachments |
Overall KOOS responder rates over time through Mon |
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| No statistical analyses for this end point | |||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
60 months
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Adverse event reporting additional description |
Adverse events were collected at each scheduled and unscheduled visit.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
NOVOCART Inject plus
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Reporting group description |
The safety population consists of all patients who have undergone tissue harvest for transplant production. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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22 Mar 2017 |
- A single knee x-ray was added to the baseline examinations, since the Kellgren and Lawrence grade (needed for eligibility assessment) can only be assessed by
plain radiography;
- Correction of patella malalignment was additionally allowed to be performed during Visit 3/implantation visit (previously: only before Visit 3);
- It was clarified that any concomitant surgeries performed at Visit 3 should be completed before the NOVOCART® Inject plus injection into the defect |
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06 Jun 2017 |
- It was added to pre-operative inclusion criterion No. 1 that the closure of the epiphyses in pediatric patients has to be confirmed by MRI or x-ray;
- It was added to pre-operative exclusion No. 5 that patients, who had failed prior biologic reconstructive procedure, could only be included, if these procedures had been performed ≥24 months prior to Visit 1 (previously: 12 months);
- A further sensitivity analysis taking into account the concomitant analgesic medication was added;
- Time since start of target knee symptoms was added as a covariable to the covariate analyses. In addition, subgroups (dichotomized at the sample median) were formed based on the variables "time since diagnosis" and "time since start of target knee symptoms" |
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14 Mar 2018 |
- The treatment failure definition was changed (according to the old definition, any re-intervention on the transplant area was to be classified as treatment failure). The rationale for the change was the fact that corrective surgery without otherwise destroying the integrity of the transplant area (e.g., a removal of hypertrophic tissue) is not necessarily associated with treatment failure. This point was addressed with the revised treatment failure definition: "all surgical reinterventions affecting the closed surface of the transplant area (the surface is not closed when the defect area is grade 3 or 4 ICRS) and/or require additional cartilage repair modalities on the target defect"
- Defect etiology in eligibility criteria was no longer limited to defects caused by trauma or osteochondritis dissecans but patients with focal cartilage defects
irrespective of defect etiology could be included.
-According to the preceding protocol version, target defects were not allowed to be located on articulating joint areas (e.g., trochlea and patella). With amendment No. 3, defects were accepted to be located on articulating joint areas, as long as the articulating joint surface opposite to the defect was intact;
- It was added to the inclusion criteria that the defect(s) to be treated need to have a well-contained chondral structure surrounding the defect
- According to the preceding protocol version, any diffuse chondromalacia was an exclusion criterion. With amendment No. 3, patients with Grade 1 chondromalacia according to the Outerbridge classification were allowed to be included;
- The definition of the intent-to-treat (ITT) population was changed from "all patients having tissue harvested" to "all patients who have received NOVOCART® Inject plus implantation"; |
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07 Apr 2020 |
An interim analysis of efficacy and safety data was originally planned once 66% of the planned number of patients had completed the 24-month period and could be evaluated for the primary endpoint. However, due to the exponential patient recruitment curve it turned out that the main analysis (=all patients have
completed the 24-months period) would have been due only 3 months after the planned interim analysis. As the sole purpose of this interim look was to serve as
a potential trigger for the start of marketing authorization application activities, an interim analysis 3 months prior to the main analysis was not considered
reasonable. Therefore, it was decided to omit the interim analysis and to move directly to the main analysis. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/35354310 http://www.ncbi.nlm.nih.gov/pubmed/37655236 http://www.ncbi.nlm.nih.gov/pubmed/38501741 |
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