cod16HS13

CO.DON AG

Warthestraße 21, Teltow, Germany, 14513

CO.DON AG, CO.DON AG, +49 341 99190 200, klifo@codon.de

CO.DON AG, CO.DON AG, +49 341 99190 200, klifo@codon.de

No

No

No

Final

28 Feb 2020

Yes

28 Feb 2020

Yes

09 Sep 2020

No

General Objectives: - Assessment of the long-term efficacy and safety of the three-dimensional autologous chondrocyte transplantation product ACT3D-CS in comparison to microfracture (MF) for the treatment of cartilage defects of knee joints. Primary Objectives: - Change of overall KOOS (Knee Injury and Osteoarthritis Outcome Score) from Day 0 (baseline for both treatment groups=day before arthroscopy) to final assessment at 24 months after the end of the respective treatment, compared between ACT3D-CS and MF. Secondary objectives: - Assessment of several efficacy variables for all follow-up time points until 60 months: Change of KOOS and Change of KOOS subscores, MOCART MRI score, Change of modified Lysholm Score, Histological scores for cartilage repair 24 months after the respective treatment (ICRS II Histological Score, Bern Score, International Cartilage Regeneration & Joint Preservation Society (ICRS) Visual Histological Assessment Score) - Safety variables

Compliance: As the application of the test product was performed once only, by the investigator, compliance issues were not anticipated. Compliance with the study treatment was good; only two patients received below-range doses of chondrosphere because of inadequate cell growth. Other protocol deviations were mostly the use of pain medication on days when this was not allowed, incomplete questionnaires or missing visits. All patients took part in, and were compliant with, the post-operative rehabilitation programme. Rescue medication: In case of pain, patients agreed only to use paracetamol in a mono- (maximum 4 g/day) or combination preparation and oral and/or topical NSAIDs during the trial, and to discontinue the use of these one week before each visit (whereby the use of paracetamol mono-preparation, maximum 4 g/day was allowed). However, in the morning of the visit day, no pain medication at all was allowed. Other pain medications were allowed during the surgical procedure and could be taken for a period not exceeding 4 weeks after surgery. Precautionary and prohibited medications and procedures: For Group A (ACT3D-CS) the following rule was instituted: If propofol was used for anaesthesia on the day of the first arthroscopy, the taking of patient's own blood for use in cultivation of the chondrocytes in the patient's serum was to take place at least 4 hours after the end of propofol application. This was done because serum containing propofol is not suitable for the cultivation of chondrocytes. Patient follow-up after treatment: Follow-up visits were performed at close intervals to monitor efficacy and safety after treatment. Monitoring/auditing: Regular on-site monitoring was performed (as described in detail in the Monitoring Plan of this study) as well as quality-assurance audits by CO.DON AG or its designees. The clinical monitor and auditor reviewed all eCRFs and written Informed Consent forms.

01 Oct 2010

No

No

Poland: 12

Germany: 90

102

102

0

0

0

0

0

0

102

0

0

Day 0 (before first arthroscopy)

Randomised - controlled

Yes

Spherox 10-70 spheroids/cm2 implantation suspension

M09AX02 (ACT code)

The product was originally named co.don chondrosphere® in the study protocol and the relevant study documents.

Solution and suspension for suspension for injection in pre-filled syringe

Intraarticular use

Harvesting of a cartilage biopsy under arthroscopy and arthroscopic administration of the product by implantation at a dose level of 10–70 spheroids/cm2.

No investigational medicinal product assigned in this arm

main study period (0-60 months)

Randomised - controlled

Yes

Spherox 10-70 spheroids/cm2 implantation suspension

M09AX02 (ACT code)

The product was originally named co.don chondrosphere® in the study protocol and the relevant study documents.

Solution and suspension for suspension for injection in pre-filled syringe

Intraarticular use

Harvesting of a cartilage biopsy under arthroscopy and arthroscopic administration of the product by implantation at a dose level of 10–70 spheroids/cm2.

No investigational medicinal product assigned in this arm

ACT3D-CS

Microfracture

Safety

All patients who signed an informed consent and were successfully randomised. ACT3D-CS: 52 patients Microfracture: 50 patients

ITT1

All patients who (i) were successfully randomised, (ii) received either ACT3D-CS on the day of implantation or microfracture on the day of arthroscopy, and (iii) completed the KOOS questionnaire at baseline and/or Day 0'. ACT3D-CS: 48 patients Microfracture: 49 patients

ITT2

All patients who (i) were successfully randomised, (ii) for whom an arthroscopy was performed and (iii) completed the KOOS questionnaire at baseline. (Thus, if a patient in the ACT3D-CS group left the study between arthroscopy and implantation, the patient was to be included in the ITT2 but not in the ITT1 population.) ACT3D-CS: 49 patients Microfracture: 50 patients

PP

All patients of the ITT1 population without major protocol violations (according to the statistical analysis plan: Visit missing (for non-inclusion in the PP set, this was only treated as a major protocol violation for the analysis at the missed visit in question; for subsequent visits attended by the patient it was treated as a minor violation), early discontinuation (before visit after 6 weeks), Inclusion/Exclusion criteria violation at screening or baseline, randomised patients for ACT3D-CS not treated by ACT3D-CS, treatment failure, manufacture of ACT3D-CS not possible, any major violation of GCP by participants of the trial (except patients), withdrawal of informed consent by the patient was treated as a major protocol violation for the purposes of statistical analysis, although the withdrawal as such was explicitly permitted by the study protocol in line with GCP. ACT3D-CS: 23 patients Microfracture: 27 patients

ACT3D-CS

Microfracture

ACT3D-CS

Microfracture

Safety

All patients who signed an informed consent and were successfully randomised. ACT3D-CS: 52 patients Microfracture: 50 patients

ITT1

All patients who (i) were successfully randomised, (ii) received either ACT3D-CS on the day of implantation or microfracture on the day of arthroscopy, and (iii) completed the KOOS questionnaire at baseline and/or Day 0'. ACT3D-CS: 48 patients Microfracture: 49 patients

ITT2

All patients who (i) were successfully randomised, (ii) for whom an arthroscopy was performed and (iii) completed the KOOS questionnaire at baseline. (Thus, if a patient in the ACT3D-CS group left the study between arthroscopy and implantation, the patient was to be included in the ITT2 but not in the ITT1 population.) ACT3D-CS: 49 patients Microfracture: 50 patients

PP

All patients of the ITT1 population without major protocol violations (according to the statistical analysis plan: Visit missing (for non-inclusion in the PP set, this was only treated as a major protocol violation for the analysis at the missed visit in question; for subsequent visits attended by the patient it was treated as a minor violation), early discontinuation (before visit after 6 weeks), Inclusion/Exclusion criteria violation at screening or baseline, randomised patients for ACT3D-CS not treated by ACT3D-CS, treatment failure, manufacture of ACT3D-CS not possible, any major violation of GCP by participants of the trial (except patients), withdrawal of informed consent by the patient was treated as a major protocol violation for the purposes of statistical analysis, although the withdrawal as such was explicitly permitted by the study protocol in line with GCP. ACT3D-CS: 23 patients Microfracture: 27 patients

Knee Injury and Osteoarthritis Outcome Score (42-item, self-administered, self-explanatory questionnaire)

Primary

Change of overall KOOS from Day 0 (baseline for both treatment groups = pre-arthroscopy assessment) to final assessment 24 months after the end of the respective treatment, compared between the two study treatment groups (ACT3D-CS and microfracture).

Repeated-measures ANCOVA testing for non-inferiority of the change in overall KOOS (Day0 - 24 months) of ACT3D-CS vis-à-vis microfracture at 24 months (least-square mean difference from baseline for ACT3D-CS minus mean difference from baseline for microfracture).

ACT3D-CS v Microfracture

97

Pre-specified

5.5

2-sided

Knee Injury and Osteoarthritis Outcome Score (42-item, self-administered, self-explanatory questionnaire). Data for 60 months follow-up is reported here. Data for other follow-up time points is provided in attachment (V1 - 6 weeks, V2 - 3 months, V3 - 6 months, V4 - 12 month, V5 - 18 months, V6 - 24 months, V7 - 36 months, V8 - 48 month, V9 - 60 month).

Secondary

Change of overall KOOS from baseline (Day 0) to 12 months (interim analysis), 24 months (final analysis) and 36, 48 and 60 months follow-up analyses were compared between ACT3D-CS and microfracture.

Knee Injury and Osteoarthritis Outcome Score (42-item, self-administered, self-explanatory questionnaire). Data for 60 months follow-up is reported here. Data for other follow-up time points is provided in attachment (V1 - 6 weeks, V2 - 3 months, V3 - 6 months, V4 - 12 month, V5 - 18 months, V6 - 24 months, V7 - 36 months, V8 - 48 month, V9 - 60 month).

Secondary

Change of overall KOOS from Day 0 for microfracture (day before arthroscopy) or from Day 0' (day before implantation) for ACT3D-CS to 12, 24, 36, 48 and 60 months after the end of respective treatment.

Knee Injury and Osteoarthritis Outcome Score (42-item, self-administered, self-explanatory questionnaire). Data for subscore "pain" 60 months follow-up is reported here. Data for all Subscores and follow-up time points is provided in the attachment (V1 - 6 weeks, V2 - 3 months, V3 - 6 months, V4 - 12 month, V5 - 18 months, V6 - 24 months, V7 - 36 months, V8 - 48 month, V9 - 60 month).

Secondary

Change of the 5 subscores of the KOOS (pain, other symptoms, function in daily living (activities of daily living), function in sport and recreation, knee-related quality of life) from baseline (Day 0) to 12, 24, 36, 48 and 60 months.

MOCART - Magnetic Resonance Observation of Cartilage Repair Tissue (including 9 subscores). Number of subjects analyzed varies between follow-up time points (see subject numbers in the attachment). Data for 60 months follow-up is reported here. Data for other follow-up time points is provided in the attachment (V1 - 6 weeks, V2 - 3 months, V3 - 6 months, V4 - 12 month, V5 - 18 months, V6 - 24 months, V7 - 36 months, V8 - 48 month, V9 - 60 month).

Secondary

MOCART (MRI Score) 12, 24, 36, 48 and 60 months after implantation or microfracture compared between the treatment groups.

Assessment of cartilage repair according to ICRS compared between the treatment groups. This was only assessed for those patients who had consented to the additional arthroscopy as a “second-look” arthroscopy to be performed during Visit 6 (24 months follow-up). Here we only state data for number of patients with "normal" ICRS grade I cartilage as assessed during “second-look” arthroscopy. The full data for all ICRS grades is presented in the attachment in % of the number of patients assessed in the respective treatment arm.

Secondary

Arthroscopy and biopsy 24 months after implantation/microfracture.

This scoring system allows one to assess the quality of the regenerated tissue and the extent to which its characteristics resemble those of native hyaline cartilage. The highest score of 3 reflects an ideal repair result of the hyaline cartilage, whereas the lowest score of 0 reflects the poorest repair result. Analyzed was the number of patients reaching a certain result in a certain criterion. Here we present only the number of patients for the criterion "surface" with the result "Smooth/continuous". All other data can be found in the attachment.

Secondary

at final assessment (24 months) compared between the treatment groups

The Bern scoring system was applied to assess the formation of repair tissue in the R-biopsies (taken at "second-look"arthroscopy). The scoring includes the uniformity and intensity of the extracellular matrix (ECM) staining by Safranin O, which stains the proteoglycans in cartilage ECM (maximum score of 3). In addition, it assesses the amount of matrix present between the cells, as mature hyaline cartilage displays a low cell density with large amounts of matrix (maximum score of 3). The last category evaluates cellular morphology (maximum score of 3). A maximum score of 9 can be obtained, which would reflect mature hyaline cartilage. Markers stained: collagen type II, aggrecan, collagen type I, CEP-68 (CRTAC1), EBF3, COMP, osteocalcin, LPL, S100B, NRN1, DLK1/Pref-1 and CD13 collagen type I, II, aggrecan, CEP-68 (CRTAC1), COMP and S100B.

Secondary

at final assessment (24 months) compared between the treatment groups.

ICRS II was developed comprising 14 criteria to assess parameters related to chondrocyte phenotype and tissue structure based on immunohistochemical staining. A visual analogue scale (0-100 mm) is used for scoring.

Secondary

at final assessment (24 months) compared between the treatment groups

The Lysholm Score (Lysholm Knee Scale) is an 8-item questionnaire that was originally designed as an outcome measure for ligament reconstruction but is commonly used as a measure for knee chondral damage. By removing the swelling item and using unweighted scores, a modified version of the Lysholm Knee Scale according to Smith et al. (2008) was used as an outcome measure for knee chondral damage. Data for 60 months follow-up is reported here. Data for other follow-up time points is provided in attachment (V1 - 6 weeks, V2 - 3 months, V3 - 6 months, V4 - 12 month, V5 - 18 months, V6 - 24 months, V7 - 36 months, V8 - 48 month, V9 - 60 month).

Secondary

Change of modified Lysholm Score from baseline (Day 0) to 12, 24, 36, 48 and 60 months after the end of the respective treatment, compared between the treatment groups

With the IKDC Subjective Knee Evaluation Form of the ICRS Cartilage Injury Evaluation Package (2000), the patient assesses his/her subjective symptoms and functioning of the knee during the past 4 weeks. The IKDC Subjective Knee Evaluation Form is scored by summing the scores for the individual items and then transforming the score to a scale that ranges from 0 to 100. The overall IKDC score was assessed in terms of the grades A–D, where ‘A’ represents a good rating and ‘D’ a poor one. Here we only state the number of patients with grade A at 60 months follow-up in the respective treatment arms. Data for all follow-up time points and grades is provided in the attachment in % of the number of patients (V1 - 6 weeks, V2 - 3 months, V3 - 6 months, V4 - 12 month, V5 - 18 months, V6 - 24 months, V7 - 36 months, V8 - 48 month, V9 - 60 month).

Secondary

from baseline (Day 0) to 12, 24, 36, 48 and 60 months after the end of the respective treatment, compared between the treatment groups

From baseline to 60-month follow-up. The start day of adverse-event reporting was the date on which the Informed Consent form was signed by the patient.

Please note: The frequency threshold for reporting non-serious adverse events was ≥3 patients over all reporting groups.

15.1

ACT3D-CS

Microfracture