Clinical trial NCT00414700: RCT of ChondroCelect® (in an ACI Procedure) vs Microfracture in the Repair of Cartilage Defects of the Knee
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Articular Cartilage Lesion of the Femoral Condyle
Keywords: Cartilage
Articular
Femoral
Knee
Lead sponsor: TiGenix n.v.
Sponsor class: INDUSTRY
First posted: 2006-12-22
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Histomorphometry Safranin-O + Anti-Collagen II Antibody Staining
timeFrame: 12 months post-surgery
measure: Overall Histology Assessment on First Subscale of ICRS II Score
timeFrame: 12 months post-surgery
measure: Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average)
timeFrame: Average change from baseline in Overall KOOS at 12-18 months post-surgery
Secondary outcomes:
measure: Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months
timeFrame: Change from baseline in Overall KOOS at 36 months post-surgery
measure: Number of Treatment Failures at 36 Months
timeFrame: Continuous
measure: Safety: Adverse Events
timeFrame: continuous up to 60 months
Other outcomes:
Locations:
city: Brugge
country: Belgium
facility: AZ St. Jan Brugge, Department of Orthopedics
city: Brugge
country: Belgium
facility: AZ St Lucas Brugge, Department of Orthopedics
city: Brussels
country: Belgium
facility: Academisch Ziekenhuis, Vrije Universiteit Brussel, Department of Orthopedics
city: Deurne
country: Belgium
facility: SPM Monica Antwerp
city: Ghent
country: Belgium
facility: Ghent University Hospital, Department of Orthopedics
city: Herentals
country: Belgium
facility: AZ St. Elisabeth, Department of Orthopedics
city: Kortrijk
country: Belgium
facility: AZ Groeninge, Department of Orthopedics
city: Leuven
country: Belgium
facility: University Hospitals Leuven, Department of Orthopedics
city: Malle
country: Belgium
facility: A.Z. Sint Jozef, Department of Orthopedics
city: Zagreb
country: Croatia
facility: Department of Orthopedic Surgery, School of Medicine, University of Zagreb
city: Hannover
country: Germany
facility: University Hospital Hannover, Department of Orthopedics
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht, Department of Orthopedics
Study officials:
affiliation: University Medical Center Utrecht, Department of Orthopedics, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
name: Daniël BF Saris, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospitals Leuven, Department of Orthopedics, Herestraat 49, 3000 Leuven, Weligerveld 1, 3212 Pellenberg, Belgium.
name: Johan Vanlauwe, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Division of Rheumatology, Department of Muskuloskeletal Sciences, University Hospitals, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium
name: Frank P Luyten, M.D., Ph.D.
role: STUDY_DIRECTOR
References:
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. doi: 10.1016/S0736-0266(02)00090-6.
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. doi: 10.1016/s0014-4827(03)00036-3.
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. doi: 10.1002/1529-0131(200107)44:73.0.CO;2-T.
citation: 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. doi: 10.1056/NEJM199410063311401.
citation: Knutsen G, Engebretsen L, Ludvigsen TC, Drogset JO, Grontvedt 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(3):455-64. doi: 10.2106/00004623-200403000-00001.
citation: Rosenzweig A. Cardiac cell therapy--mixed results from mixed cells. N Engl J Med. 2006 Sep 21;355(12):1274-7. doi: 10.1056/NEJMe068172. No abstract available.
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 implantation results in better structural repair when treating symptomatic cartilage defects of the knee in a randomized controlled trial versus microfracture. Am J Sports Med. 2008 Feb;36(2):235-46. doi: 10.1177/0363546507311095.
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 in a randomized trial compared to microfracture. Am J Sports Med. 2009 Nov;37 Suppl 1:10S-19S. doi: 10.1177/0363546509350694. Epub 2009 Oct 21.