RCT of ChondroCelect® (in an ACI Procedure) vs Microfracture in the Repair of Cartilage Defects of the Knee

Articular Cartilage Lesion of the Femoral Condyle Clinical Trial

— TIGACT01  

Official title:

Prospective Multicenter Randomized Controlled Trial of ChondroCelect® (Via Autologous Chondrocyte Implantation) vs Microfracture (as Procedure) in the Repair of Symptomatic Cartilaginous Defects of the Femoral Condyles

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00414700
• Other study ID #: TIG/ACT/01/2000&Extension
• Secondary ID: BB IND 12491 000
• Status: Completed
• Phase: Phase 3
• First received: December 21, 2006
• Last updated: September 22, 2011
• Start date: February 2002
• Est. completion date: January 2010

Study information

• Verified date: September 2011
• Source: TiGenix n.v.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationBelgium: The Federal Public Service (FPS) Health, Food Chain Safety and EnvironmentFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Netherlands: Dutch Health Care InspectorateGermany: Paul-Ehrlich-InstitutCroatia: Ministry of Health and Social Care
• Study type: Interventional

Clinical Trial Summary

This is a phase III, multicenter, open-label, randomized controlled trial of ChondroCelect® in an Autologous Chondrocyte Implantation (ACI) procedure compared to the procedure of microfracture (MF) in the repair of symptomatic cartilage lesions of the knee. Eligible patients attended two screening visits and were booked for arthroscopy approximately 2 weeks later. At that time, patients were randomized to either ACI with ChondroCelect® or to MF, a procedure in which the subchondral bone is perforated to allow a bloodcloth to form scar tissue. Patients randomized to MF had the procedure performed at the time of their arthroscopy; those randomized to ACI with ChondroCelect® had their cells harvested during the arthroscopy and then returned to the clinic approximately 4 weeks later for an open knee procedure, during which the ACI procedure using ChondroCelect® was performed. Patients subsequently followed the same rehabilitation program and had follow-up assessments up to 12 months post-surgery. The 12-month visit was the end-of-study visit for the TIG/ACT/01/2000 protocol. Subject to satisfying the eligibility criteria, patients who had participated in the initial 12 month trial could enter the extension trial. The 12-month visit for the initial study was the baseline visit for the extension study. During the extension study, patients have follow-up assessments up to 60 months post-surgery.

Description:

see above

Recruitment information / eligibility

• Status: Completed
• Enrollment: 118
• Est. completion date: January 2010
• Est. primary completion date: July 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• Signed patient informed consent

• Symptomatic cartilage single lesion of the femoral condyle

• Lesion on femoral condyle between 1 and 5 cm²

• Agree to participate actively in a strict rehabilitation protocol and follow-up programme

• Agree to only use paracetamol mono-or combination preparation (max 4g/d) and Non-Steroidal Anti Inflammatory Drugs (NSAIDS) during the study and to discontinue this medication 2 weeks before the baseline visit and the follow-up visits. The use of paracetamol mono-preparation (max 4g/d) is allowed up to one week before the baseline visit and the follow-up visits.

• Females of childbearing age should use a proven method to prevent pregnancy

Exclusion Criteria:

• Participation in concurrent trials

• Participation in previous trials within 3 months

• Subjects with hepatitis, HIV or syphilis

• Malignancy

• Alcohol or drug (medication) abuse

• Poor general health as judged by Investigator

• Clinically relevant second cartilage lesion on the patella

• Patellofemoral cartilage lesion

• Osteochondritis Dissecans (OCD) : recent OCD (within 1 year before baseline), depth of lesion > 0.5cm, subchondral slerosis

• Advanced osteoarthritis (OA) : radiographic atlas of OA grade 2-3

• Known allergy to gentamicin or penicillins (or presence of multiple severe allergies)

• Complex ligamentous instability of the knee

• Meniscal transplant

• Meniscal suture with meniscal arrows (ipsilateral)

• Meniscus resection : if < 1 yr before baseline - lateral meniscus resection or medial meniscus resection of more than 50%. If > 1 yr before baseline - ipsilateral meniscus resection of more than 50%, controlateral meniscus resection of more than 50% if ipsilateral meniscus is not intact, combination of medial and lateral meniscus resection and one of both > 50%.

• Varus or valgus malalignment of more than 5°

• Mosaicplasty

• Microfracture performed less than 1 yr before baseline

• Having received hyaluronic acid intra-articular injections in the affected knee within the last 6 months of baseline

• Taking specific OA drugs such as chondroïtin sulfate, diacerein, n-glucosamine, piascledine, capsaicin within 2 weeks of the baseline visit

• Corticosteroïd treatment by systemic or intra-articular route within the last month of baseline or intramuscular or oral corticosteroïds within the last 2 weeks of baseline

• Chronic use of anticoagulants

• Uncontrolled diabetes

• Any concomitant painful or disabling disease of the spine,hips or lower limbs that would interfere with evaluation of the afflicted knee

• Any clinically significant or symptomatic vascular or neurologic disorder of the lower extremities

• Any evidence of the following diseases in the target joint : septic arthritis, inflammatory joint disease, gout, recurrent episodes of pseudogout, Paget's disease of bone, ochronosis, acromegaly, hemochromatosis, Wilson's disease, primary osteochondromatosis, heritable disorders, collagen gene mutation

• Current diagnosis of osteomyelitis

• Liver enzymes (SGOT, SGPT, Alkaline Phosphatase) of more then two times the upper limit of normal or any other result that is clinically important according to the Investigator

• CRP > 10 mg/l

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Articular Cartilage Lesion of the Femoral Condyle

Intervention

Drug:
• ChondroCelect implantation
10.000 cells/µl cell suspension for implantation (Autologous Chondrocyte Implantation). ChondroCelect consists of characterised autologous cartilage-forming cells expressing a specific marker profile. The dose depends on the size of the lesion. Recommended dose is 0.8 to 1.0 million cells/cm².

Procedure:
• Microfracture
A procedure in which the subchondral bone is perforated to allow a bloodcloth to form scar tissue.

Locations

Country	Name	City	State
Belgium	AZ St Lucas Brugge, Department of Orthopedics	Brugge
Belgium	AZ St. Jan Brugge, Department of Orthopedics	Brugge
Belgium	Academisch Ziekenhuis, Vrije Universiteit Brussel, Department of Orthopedics	Brussels
Belgium	SPM Monica Antwerp	Deurne
Belgium	Ghent University Hospital, Department of Orthopedics	Ghent
Belgium	AZ St. Elisabeth, Department of Orthopedics	Herentals
Belgium	AZ Groeninge, Department of Orthopedics	Kortrijk
Belgium	University Hospitals Leuven, Department of Orthopedics	Leuven
Belgium	A.Z. Sint Jozef, Department of Orthopedics	Malle
Croatia	Department of Orthopedic Surgery, School of Medicine, University of Zagreb	Zagreb
Germany	University Hospital Hannover, Department of Orthopedics	Hannover
Netherlands	University Medical Center Utrecht, Department of Orthopedics	Utrecht

Sponsors (1)

Lead Sponsor	Collaborator
TiGenix n.v.

Countries where clinical trial is conducted

Belgium,  Croatia,  Germany,  Netherlands, 

References & Publications (8)

Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994 Oct 6;331(14):889-95. — View Citation

Dell'Accio F, De Bari C, Luyten FP. Microenvironment and phenotypic stability specify tissue formation by human articular cartilage-derived cells in vivo. Exp Cell Res. 2003 Jul 1;287(1):16-27. — View Citation

Dell'Accio F, De Bari C, Luyten FP. Molecular markers predictive of the capacity of expanded human articular chondrocytes to form stable cartilage in vivo. Arthritis Rheum. 2001 Jul;44(7):1608-19. — View Citation

Dell'Accio F, Vanlauwe J, Bellemans J, Neys J, De Bari C, Luyten FP. Expanded phenotypically stable chondrocytes persist in the repair tissue and contribute to cartilage matrix formation and structural integration in a goat model of autologous chondrocyte implantation. J Orthop Res. 2003 Jan;21(1):123-31. Erratum in: J Orthop Res. 2003 May;21(3):572. — View Citation

Knutsen G, Engebretsen L, Ludvigsen TC, Drogset JO, Grøntvedt T, Solheim E, Strand T, Roberts S, Isaksen V, Johansen O. Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. J Bone Joint Surg Am. 2004 Mar;86-A(3):455-64. — View Citation

Rosenzweig A. Cardiac cell therapy--mixed results from mixed cells. N Engl J Med. 2006 Sep 21;355(12):1274-7. — View Citation

Saris DB, Vanlauwe J, Victor J, Almqvist KF, Verdonk R, Bellemans J, Luyten FP; TIG/ACT/01/2000&EXT Study Group. Treatment of symptomatic cartilage defects of the knee: characterized chondrocyte implantation results in better clinical outcome at 36 months — View Citation

Saris DB, Vanlauwe J, Victor J, Haspl M, Bohnsack M, Fortems Y, Vandekerckhove B, Almqvist KF, Claes T, Handelberg F, Lagae K, van der Bauwhede J, Vandenneucker H, Yang KG, Jelic M, Verdonk R, Veulemans N, Bellemans J, Luyten FP. Characterized chondrocyte — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Histomorphometry Safranin-O + Anti-Collagen II Antibody Staining	Histomorphometry on end point biopsies at 12 months post-surgery. Safranin-O (ratio 0-1)+ anti-Collagen II antibody (ratio 0-1) stain signal expressed as a ratio of the total cartilage surface area (Saf O + anti Coll II divided by total surface = ratio 0-2). Safranin-O stains proteoglycans and anti-Collagen II antibody reflects the presence of Collagen II.	12 months post-surgery	No
Primary	Overall Histology Assessment on First Subscale of ICRS II Score	Overall histology assessment of cartilage repair, first subscale of International Cartilage Repair Society II (ICRS II) score by two blinded independant histopathologists on a visual analogue scale (VAS 0-100mm) from worst (0) to best (100)	12 months post-surgery	No
Primary	Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average)	Overall Knee injury and Osteoarthritis Outcome score (average of 4 KOOS subdomains, Sports not included) at the average of 12-18 months (calculated by averaging change from baseline measurements at 12 and 18 months). Best score = 100; worst score = 0. The analysis was the average of the change from baseline at the 12 and 18 months timepoints.	Average change from baseline in Overall KOOS at 12-18 months post-surgery	No
Secondary	Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months	Overall Knee injury and Osteoarthritis Outcome score (average of 4 KOOS subdomains: Activities of Daily Living, Quality of Life, Symptoms and Stiffness Pain; Sports not included) at 36 months (change from baseline). Best = 100; worst = 0.	Change from baseline in Overall KOOS at 36 months post-surgery	No
Secondary	Number of Treatment Failures at 36 Months	Participants with failed treatment - defined as the number of patients who underwent a reintervention of the index lesion - at 36 months.; The index lesion is the lesion that was initially treated in the study.	Continuous	Yes
Secondary	Safety: Adverse Events	Side effects are recorded as the number of patients with adverse events. These events are coded according to the Medical Dictionary for Regulatory Affairs (MedDRA terms).	continuous up to 60 months	Yes