Efficacy and Safety Study of co.Don Chondrosphere to Treat Cartilage Defects

Prospective, Randomised, Open Label, Multicentre Phase-III Clinical Trial to Compare the Efficacy and Safety of the Treatment With the Autologous Chondrocyte Transplantation Product co.Don Chondrosphere (ACT3D-CS) With Microfracture in Subjects With Cartilage Defects of the Knee With a Defect Size Between 1 an 4 cm2

This is a prospective, phase III, multicenter, open label, randomised clinical trial of co.don chondrosphere®, a three-dimensional autologous chondrocyte transplantation product (ACT3D-CS)compared to the procedure of microfracture (MF)in the treatment of cartilage defects of knee joints.

After screening visit patients were booked for arthroscopy and at that time they were randomised to either ACT3D-CS with co.don chondrosphere® (Group A) or to MF(Group B), a marrow-stimulating method based on the penetration of the subchondral bone plate at the bottom of the cartilage defect. At the time of arthroscopy Patients of group B had their procedure of MF (treatment surgery) and patients of group A had their cells harvested from healthy cartilage. The cells are cultivated for 8-10 weeks in vitro to develope 3-dimensional spheroids , that are transplanted in an open knee procedure (treatment surgery)into the defect. Patients subsequently followed the same rehabilitation program and had post-surgery visits. After the 12-month-visit a interim analyses will be performed and the 24-month-visit is defined as final assessment. Then patients have follow-up assessments up to 60 months post-treatment-surgery.

Study Overview

• Status: Completed
• Conditions: Articular Cartilage Lesion of the Femoral Condyle
• Intervention / Treatment: Drug: co.don chondrosphere®; Procedure: Microfracture

Detailed Description

see above

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 12163
    • Gelenk-und Wirbelsäulenzentrum Steglitz
  • Berlin, Germany, 14050
    • DRK-Kliniken Westend
  • Dinslaken, Germany, 46535
    • St. Vinzenz-Hospital
  • Hannover, Germany, 30625
    • Orthopädische Klinik der Medizinischen Hochschule Hannover
  • Kiel, Germany, 24106
    • Lubinus Clinicum Kiel
  • Luckenwalde, Germany, 14943
    • DRK Krankenhaus Luckenwalde
  • Mannheim, Germany, 68167
    • Orthopädisch-Unfallchirurgisches Zentrum
  • Baden-Würrtemberg
    • Freiburg, Baden-Würrtemberg, Germany, 79106
      • Universitätsklinikum der Albert-Ludwig-Universität Freiburg, Department Othopädie und Traumatologie
  • Tühringen
    • Eisenberg, Tühringen, Germany, 07607
      • Waldkrankenhaus "Rudolf Elle" GmbH Klinik für Orthopädie und Unfallchirurgie
• Poland
  • Białystok, Poland, 15-276
    • Uniwersytecki Szpital Kliniczny w Białymstoku
  • Piekary Śląskie, Poland, 62
    • Wojewódzki Szpital Chirurgii Urazowej
  • Warszawa, Poland
    • Centrum Medycyny Sportowej

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 46 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients, age: between 18 and 50 years
2. Defect: isolated ICRS grade III or IV single defect chondral lesions on femoral condyles
3. Defect size: 1 to < 4 cm2 after debridement to healthy cartilage up to 6 mm in depth.Assessment with MRI at screening and per estimation during arthroscopy prior to randomization
4. Nearly intact chondral structure surrounding the defect as well as an intact corresponding joint area
5. Informed consent signed and dated by patient
6. Patient understands the strict rehabilitation protocol and follow-up programme and is willing to follow it
7. In case of pain, patient agrees to use only paracetamol mono- (max 4 g/day) or combination preparation and oral and/or topic NSAIDs during the trial and to discontinue the use of oral and/or topic NSAIDs and/or paracetamol combination preparation 1 week before each visit whereas the use of paracetamol monopreparation (max 4 g/day) is allowed. However, in the morning of the visit day, no pain medication is allowed. Other pain medications are allowed during surgical procedure and may be taken for a period not exceeding 4 weeks after surgery.

Exclusion Criteria:

1. Defects on both knees at the same time
2. Radiological signs of osteoarthritis
3. Osteochondritis dissecans (OCD)
4. Any signs of knee instability
5. Valgus or varus malalignment (more than 5° over the mechanical axis)
6. Clinically relevant second cartilage lesion on the same knee
7. More than 50 % resection of a meniscus in the affected knee or incomplete meniscal rim
8. Rheumatoid arthritis, parainfectious or infectious arthritis, and condition after these diseases
9. Pregnancy and planned pregnancy (no MRI possible)
10. Obesity (Body Mass Index >30)
11. Uncontrolled diabetes mellitus
12. Serious illness
13. Poor general health as judged by physician
14. Participation in concurrent clinical trials or previous trials within 3 months of screening
15. Previous treatment with ACT in the affected knee
16. Microfracture performed less than 1 year before screening in the affected knee
17. Alcohol or drug (medication) abuse
18. Meniscal transplant in the affected knee
19. Meniscal suture (in the affected knee) three months prior to baseline
20. Mosaicplasty (Osteoarticular Transplant System, OATS) in the affected knee
21. Having received hyaluronic acid intra-articular injections in the affected knee within the last 3 months before baseline
22. Taking specific osteoarthritis drugs such as chondroïtin sulfate, diacerein, nglucosamine,piascledine, capsaicin within 2 weeks before baseline
23. Corticosteroid treatment by systemic or intraarticular route within the last month of baseline or intramuscular or oral corticosteroïds within the last 2 weeks before baseline
24. Chronic use of anticoagulants
25. Any concomitant painful or disabling disease of the spine, hips or lower limbs that would interfere with evaluation of the afflicted knee
26. Any clinically significant or symptomatic vascular or neurological disorder of the lower extremities
27. Any evidence of the following diseases in the affected knee: septic arthritis, inflammatory joint disease, recurrent episodes of pseudogout, Paget's disease of bone, ochronosis, acromegaly, haemochromatosis, Wilson's disease, primary osteochondromatosis, heritable disorders, collagen gene mutation
28. Current diagnosis of osteomyelitis, human immunodeficiency virus (HIV-1,-2) and/or hepatitis C virus (HCV) infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: co.don chondrosphere®; co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose depends on the size of the defect, recommended dose is 10-70 spheroids/cm2 defect.	Drug: co.don chondrosphere®; co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose depends on the size of the defect, recommended dose is 10-70 spheroids/cm2 defect.; Other Names: ACT3D-CS
Active Comparator: Micofracture; A procedure in which the subchondral bone is perforated to allow a bloodcloth to form scar tissue.	Drug: co.don chondrosphere®; co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose depends on the size of the defect, recommended dose is 10-70 spheroids/cm2 defect.; Other Names: ACT3D-CS; Procedure: Microfracture; A procedure in which the subchondral bone is perforated to allow a bloodcloth to form new tissue.; Other Names: Subchondral drilling

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of overall KOOS	Change of overall KOOS (Knee Injury and Osteoarthritis Outcome Score)from baseline (Day 0)to final assessment compared between ACT3D-CS (co.don chondrosphere) and MF (microfracture)	24 months after the end of the respective treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of overall KOOS	Change of overall KOOS(Knee Injury and Osteoarthritis Outcome Score) from baseline (Day 0) to 12 months, 36, 48, 60 months after the end of the respective treatment,compared between ACT3D-CS and MF	12, 36, 48, 60 months after the end of the respective treatment
Change of the 5 subscores of the KOOS	Change of the 5 subscores of the KOOS (Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec), knee related Quality of life (QoL)) for both treatment groups compared between ACT3D-CS and MF	12, 24, 36, 48, 60 months after the end of the respective treatment
MOCART (MRI Score)	MOCART (MRI Score) 12, 24, 36, 48 and 60 months after transplantation or microfracture compared between ACT3D-CS and MF	12, 24, 36, 48 and 60 months after transplantation or microfracture
Arthroscopy and biopsy	Arthroscopy and biopsy at 24 months after transplantation/ microfracture, assessment of cartilage repair after ACT3D and microfracture to be compared between ACT3D-CS and MF	24 months
ICRS Visual Histological Assessment Score	ICRS Visual Histological Assessment Score at final assessment (24 months) compared between ACT3D-CS and MF	24 months after respective treatment
Bern Score and additional histological assessment scores	Bern Score and additional histological assessment scores at final assessment (24 months) compared between ACT3D-CS and MF	24 months after the respective treatment
Change of ICRS/IKDC	Change of ICRS/IKDC from baseline (Day 0) to 12, 24, 36, 48 and 60 months after the end of the respective treatment, compared between ACT3D-CS and MF	12, 24, 36, 48 and 60 months after the end of the respective treatment
Change of modified Lysholm Score	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 ACT3D-CS and MF	12, 24, 36, 48 and 60 months after the end of the respective treatment
Days of absence from work (employment) and/or days of inability to follow usual activities	Days of absence from work (employment) and/or days of inability to follow usual activities during the last year or since the last visit, respectively, and time point when patient was back to work and/or to follow usual activities	annual
Safety Parameters	Frequence and type of adverse Events Vital signs Physical examination Concomitant pain medication Laboratory parameters	3,12,24 months after respective treatment

Collaborators and Investigators

• Sponsor: co.don AG
• Investigators: Principal Investigator: Stefan Fickert, Ph.D., Universitätsmedizin Mannheim

Publications and helpful links

General Publications

• Hoburg A, Niemeyer P, Laute V, Zinser W, Becher C, Kolombe T, Fay J, Pietsch S, Kuzma T, Widuchowski W, Fickert S. Matrix-Associated Autologous Chondrocyte Implantation with Spheroid Technology Is Superior to Arthroscopic Microfracture at 36 Months Regarding Activities of Daily Living and Sporting Activities after Treatment. Cartilage. 2021 Dec;13(1_suppl):437S-448S. doi: 10.1177/1947603519897290. Epub 2020 Jan 1.
• Niemeyer P, Laute V, Zinser W, Becher C, Kolombe T, Fay J, Pietsch S, Kuzma T, Widuchowski W, Fickert S. A Prospective, Randomized, Open-Label, Multicenter, Phase III Noninferiority Trial to Compare the Clinical Efficacy of Matrix-Associated Autologous Chondrocyte Implantation With Spheroid Technology Versus Arthroscopic Microfracture for Cartilage Defects of the Knee. Orthop J Sports Med. 2019 Jul 10;7(7):2325967119854442. doi: 10.1177/2325967119854442. eCollection 2019 Jul.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): September 1, 2017
• Study Completion (Actual): February 1, 2020

Study Registration Dates

• First Submitted: October 15, 2010
• First Submitted That Met QC Criteria: October 15, 2010
• First Posted (Estimate): October 18, 2010

Study Record Updates

• Last Update Posted (Actual): January 27, 2021
• Last Update Submitted That Met QC Criteria: January 26, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Cartilage defects; Knee joint; Femoral Condyle
• Other Study ID Numbers: cod16HS13; 2009-016466-82 (EudraCT Number)