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

Phase 3

Completed

• Conditions: Articular Cartilage Lesion of the Femoral Condyle
• Interventions: Drug: ChondroCelect implantation; Procedure: Microfracture

• Registration Number: NCT00414700
• Lead Sponsor: TiGenix n.v.

Brief 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.

Detailed Description

see above

Study Timeline

• Study Start: 2002-02
• Primary Completion: 2006-07
• Study First Submitted: 2006-12-21
• Study First Submitted QC: 2006-12-21
• Study First Posted: 2006-12-22
• Results First Submitted: 2009-05-06
• Results First Submitted QC: 2009-12-14
• Study Completion: 2010-01
• Results First Posted: 2010-01-18
• Status Verified: 2011-09
• Last Update Submitted: 2011-09-22
• Last Update Posted: 2011-09-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 118

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

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ChondroCelect	ChondroCelect implantation	-
Microfracture	Microfracture	-

Primary Outcome Measures

Name	Time	Method
Histomorphometry Safranin-O + Anti-Collagen II Antibody Staining	12 months post-surgery	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.
Overall Histology Assessment on First Subscale of ICRS II Score	12 months post-surgery	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)
Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average)	Average change from baseline in Overall KOOS at 12-18 months post-surgery	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months	Change from baseline in Overall KOOS at 36 months post-surgery	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.
Number of Treatment Failures at 36 Months	Continuous	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.
Safety: Adverse Events	continuous up to 60 months	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).

Trial Locations

Locations (12)

AZ St. Jan Brugge, Department of Orthopedics; 🇧🇪 Brugge, Belgium

SPM Monica Antwerp; 🇧🇪 Deurne, Belgium

Ghent University Hospital, Department of Orthopedics; 🇧🇪 Ghent, Belgium

AZ Groeninge, Department of Orthopedics; 🇧🇪 Kortrijk, Belgium

AZ St Lucas Brugge, Department of Orthopedics; 🇧🇪 Brugge, Belgium

Department of Orthopedic Surgery, School of Medicine, University of Zagreb; 🇭🇷 Zagreb, Croatia

University Medical Center Utrecht, Department of Orthopedics; 🇳🇱 Utrecht, Netherlands

Academisch Ziekenhuis, Vrije Universiteit Brussel, Department of Orthopedics; 🇧🇪 Brussels, Belgium

AZ St. Elisabeth, Department of Orthopedics; 🇧🇪 Herentals, Belgium

University Hospitals Leuven, Department of Orthopedics; 🇧🇪 Leuven, Belgium

University Hospital Hannover, Department of Orthopedics; 🇩🇪 Hannover, Germany

A.Z. Sint Jozef, Department of Orthopedics; 🇧🇪 Malle, Belgium