Assessment of Efficacy and Safety of 3 Different Doses of co.Don Chondrosphere to Treat Large Cartilage Defects

Prospective, Randomised, Open Label, Multicentre Phase II Clinical Trial to Investigate the Efficacy and Safety of the Treatment of Large Cartilage Knee Defects(4-10 cm²) With 3 Diff. Doses of the ACT Product co.Don Chondrosphere®

This is a prospective, randomised, open label, multicentre Phase II clinical trial to investigate the efficacy and safety of the treatment of large defects with 3 different doses of the autologous chondrocyte transplantation product co.don chondrosphere® (ACT3D-CS) in subjects with cartilage defects of the knee.

After screening visit patients were booked for arthroscopy and had their cells harvesting from healthy cartilage. After the arthroscopy the patients were randomised in one of the three dose-groups. 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 of all dose groups subsequently followed the same rehabilitation program and had post-surgery visits. The 12-month-visit is defined as final assessment. Then patients have follow-up assessments up to 60 months.

Study Overview

• Status: Completed
• Conditions: Large Articular Cartilage Lesions of the Femoral; Condyle, Trochlea, Tibia or Retropatellar
• Intervention / Treatment: Drug: co.don chondrosphere®

Detailed Description

see above

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 2

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
  • München, Germany, 85567
    • Orthopädiezentrum München Ost
  • Baden-Würrtemberg
    • Freiburg, Baden-Würrtemberg, Germany, 79106
      • Universitätsklinikum der Albert-Ludwig-Universität Freiburg, Department Othopädie und Traumatologie
    • Heidelberg, Baden-Würrtemberg, Germany, 69115
      • ATOS Klinikum Heidelberg, Zentrum für Knie- und Fußchirurgie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 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 on medial or lateral femoral condyle, trochlea, tibia and retropatellar defects, also OCD (in case of OCD: Bone grafting up to the level of the original bone lamella must be performed if bone loss exceeds 3 mm in depth)
3. Defect size: ≥ 4 to 10 cm2 after debridement to healthy cartilage; chondral lesions, including osteochondritis dissecans on femoral condyle, trochlea, tibia,retropatellar defects up to 6 mm in depth. Assessment with MRI at Screening and per estimation during arthroscopy prior to randomization
4. Nearly intact surrounding chondral structure around the defect as well as corresponding joint area
5. Informed consent signed by patient
6. Patient understands 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 mono-preparation (max 4 g/day) is allowed. However, in the morning of the visit day, no pain medication is allowed. However, in the morning of the visit day, no pain medication is allowed. Other pain medications are allowed during surgical operation 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. Any signs of knee instability
4. Valgus or varus malalignment (more than 5° over the mechanical axis)
5. Clinically relevant second cartilage lesion on the same knee
6. More than 50 % resection of a meniscus in the affected knee or incomplete meniscal rim
7. Rheumatoid arthritis, parainfectious or infectious arthritis, and condition after these diseases
8. Pregnancy and planned pregnancy (no MRI possible)
9. Obesity (Body Mass Index >30)
10. Uncontrolled diabetes mellitus
11. Serious illness
12. Poor general health as judged by physician
13. Participation in concurrent clinical trials or previous trials within 3 months of screening
14. Previous treatment with ACT in the affected knee
15. Microfracture performed less than 1 year before screening in the affected knee
16. Alcohol or drug (medication) abuse
17. Meniscal transplant in the affected knee
18. Meniscal suture (in the affected knee) three months prior to baseline
19. Mosaicplasty (Osteoarticular Transplant System, OATS) in the affected knee
20. Having received hyaluronic acid intra-articular injections in the affected knee within the last 3 months of baseline
21. Taking specific osteoarthritis drugs such as chondroitin sulfate, diacerein, n-glucosamine, piascledine, capsaicin within 2 weeks of baseline
22. Corticosteroid treatment by systemic or intra-articular route within the last month of baseline or intramuscular or oral corticosteroids within the last 2 weeks of baseline
23. Chronic use of anticoagulants
24. Any concomitant painful or disabling disease of the spine, hips or lower limbs that would interfere with evaluation of the afflicted knee
25. Any clinically significant or symptomatic vascular or neurological disorder of the lower extremities
26. 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
27. Current diagnosis of osteomyelitis, human immunodeficiency virus (HIV-1, 2) and/or hepatitis C (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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: co.don chondrosphere®, 3-7 spheroids/cm2; co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group A is 3-7 spheroids/cm2 defect	Drug: co.don chondrosphere®; co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group A is 3-7 spheroids/cm2 defect, in group B 10-30 spheroids/cm2 defect and in group C 40-70 spheroids/cm2 defect; Other Names: ACT3D-CS
Active Comparator: co.don chondrosphere®,10-30spheroids/cm2; co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group B is 10-30 spheroids/cm2 defect	Drug: co.don chondrosphere®; co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group A is 3-7 spheroids/cm2 defect, in group B 10-30 spheroids/cm2 defect and in group C 40-70 spheroids/cm2 defect; Other Names: ACT3D-CS
Active Comparator: co.don chondrosphere®,40-70spheroids/cm2; co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group C is 40-70 Spheroids/cm2 defect	Drug: co.don chondrosphere®; co.don chondrosphere® are spheroids in suspension, developed from autologous chondrocytes. The dose in group A is 3-7 spheroids/cm2 defect, in group B 10-30 spheroids/cm2 defect and in group C 40-70 spheroids/cm2 defect; Other Names: ACT3D-CS

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 (FA)determined for each dosage group and between the dosage groups.	12 months after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Change of overall KOOS	Change of overall KOOS from baseline (Day 0) to 24,36, 48 and 60 months follow-up, FU) after transplantation determined for each dosage group and compared between the dosage groups	24, 36, 48, 60 months after transplantation
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)) determined for each dosage group and between the dosage groups	12, 24, 36 ,48, 60 months after transplantation
Assessment of MRIs by the MOCART-Score (MRI Score)	Assessment of MRIs by the MOCART-Score (MRI Score) at 12, 24, 36, 48 and 60 months after transplantation compared between the dosage groups	12, 24, 36, 48 and 60 months after transplantation
Assessment of cartilage repair using an Arthroscopy and take a biopsy	Arthroscopy and biopsy at 12 months after transplantation, assessment of cartilage repair after ACT3D to be compared for each dosage group and between the dosage groups	12 months after transplantation
Assessment of the histology from the biopsy by ICRS Visual Histological Assessment Score	Assessment of the ICRS Visual Histological Assessment Score at final assessment (FA, 12 months) determined for each dosage group and compared between the dosage groups	12 months after transplantation
Assessment of the histology from the biopsy by the Bern Score and additional histological scores	Assessment of the histology from the biopsy by the Bern Score and additional histological assessment scores at final assessment (12 months) determined for each dosage group and compared between the dosage groups	12 months after transplantation
Change of ICRS/IKDC	Change of ICRS/IKDC from baseline (Day 0) to 12, 24, 36, 48 and 60 months after transplantation determined for each dosage group and compared between the dosage groups	12, 24, 36, 48 and 60 months after transplantation
Assessment of change of modified Lysholm Score	Change of modified Lysholm Score from baseline (Day 0) to 12, 24, 36, 48 and 60 months after transplantation determined for each dosage group and compared between the dosage the groups	12, 24, 36, 48 and 60 months after transplantation
Frequency and type of adverse events	Frequency and type of adverse events	3,12, 24, 36, 48, 60 months after transplantation
Measurement of blood pressure, pulse and laboratory parameters	Measurement of the vital signs and physical examination, laboratory parameters at 3 and 12 months after transplantation.	3, 6, 12, 24, 36, 48, 60 months after transplantation

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, John T, Becher C, Izadpanah K, Diehl P, Kolombe T, Fay J, Siebold R, Fickert S. Safety and Efficacy of Matrix-Associated Autologous Chondrocyte Implantation With Spheroids for Patellofemoral or Tibiofemoral Defects: A 5-Year Follow-up of a Phase 2, Dose-Confirmation Trial. Orthop J Sports Med. 2022 Jan 18;10(1):23259671211053380. doi: 10.1177/23259671211053380. eCollection 2022 Jan.
• Becher C, Laute V, Fickert S, Zinser W, Niemeyer P, John T, Diehl P, Kolombe T, Siebold R, Fay J. Safety of three different product doses in autologous chondrocyte implantation: results of a prospective, randomised, controlled trial. J Orthop Surg Res. 2017 May 12;12(1):71. doi: 10.1186/s13018-017-0570-7.
• Niemeyer P, Laute V, John T, Becher C, Diehl P, Kolombe T, Fay J, Siebold R, Niks M, Fickert S, Zinser W. The Effect of Cell Dose on the Early Magnetic Resonance Morphological Outcomes of Autologous Cell Implantation for Articular Cartilage Defects in the Knee: A Randomized Clinical Trial. Am J Sports Med. 2016 Aug;44(8):2005-14. doi: 10.1177/0363546516646092. Epub 2016 May 20.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2010
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: October 18, 2010
• First Submitted That Met QC Criteria: October 20, 2010
• First Posted (Estimate): October 21, 2010

Study Record Updates

• Last Update Posted (Actual): March 19, 2018
• Last Update Submitted That Met QC Criteria: March 15, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: knee joint; large cartilage defects; femoral condyle, tibia, trochlear, retropatellar
• Other Study ID Numbers: cod 16HS14; 2009-016816-20 (EudraCT Number)