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RCT of ChondroCelect® (in an ACI Procedure) vs Microfracture in the Repair of Cartilage Defects of the Knee (TIGACT01)

Primary Purpose

Articular Cartilage Lesion of the Femoral Condyle

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

ChondroCelect implantation

Microfracture

About this trial

This is an interventional treatment trial for Articular Cartilage Lesion of the Femoral Condyle focused on measuring Cartilage, Articular, Femoral, Knee

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

AZ St. Jan Brugge, Department of Orthopedics
AZ St Lucas Brugge, Department of Orthopedics
Academisch Ziekenhuis, Vrije Universiteit Brussel, Department of Orthopedics
SPM Monica Antwerp
Ghent University Hospital, Department of Orthopedics
AZ St. Elisabeth, Department of Orthopedics
AZ Groeninge, Department of Orthopedics
University Hospitals Leuven, Department of Orthopedics
A.Z. Sint Jozef, Department of Orthopedics
Department of Orthopedic Surgery, School of Medicine, University of Zagreb
University Hospital Hannover, Department of Orthopedics
University Medical Center Utrecht, Department of Orthopedics

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

ChondroCelect

Microfracture

Arm Description

Outcomes

Primary Outcome Measures

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.

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)

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.

Secondary Outcome Measures

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.

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.

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).

Full Information

NCT ID

NCT00414700

First Posted

December 21, 2006

Last Updated

September 22, 2011

Sponsor

TiGenix n.v.

1. Study Identification

Unique Protocol Identification Number

NCT00414700

Brief Title

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

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2011

Overall Recruitment Status

Completed

Study Start Date

February 2002 (undefined)

Primary Completion Date

July 2006 (Actual)

Study Completion Date

January 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

TiGenix n.v.

4. Oversight

Data Monitoring Committee

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Articular Cartilage Lesion of the Femoral Condyle

Keywords

Cartilage, Articular, Femoral, Knee

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

118 (Actual)

8. Arms, Groups, and Interventions

Arm Title

ChondroCelect

Arm Type

Experimental

Arm Title

Microfracture

Arm Type

Active Comparator

Intervention Type

Drug

Intervention Name(s)

ChondroCelect implantation

Other Intervention Name(s)

CCI

Intervention Description

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.

Intervention Type

Procedure

Intervention Name(s)

Microfracture

Other Intervention Name(s)

subchondral drilling

Intervention Description

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

Primary Outcome Measure Information:

Title

Histomorphometry Safranin-O + Anti-Collagen II Antibody Staining

Description

Time Frame

12 months post-surgery

Title

Overall Histology Assessment on First Subscale of ICRS II Score

Description

Time Frame

12 months post-surgery

Title

Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 12-18 Months (Average)

Description

Time Frame

Average change from baseline in Overall KOOS at 12-18 months post-surgery

Secondary Outcome Measure Information:

Title

Change From Baseline in Overall Knee Injury and Osteoarthritis Outcome Score (KOOS) at 36 Months

Description

Time Frame

Change from baseline in Overall KOOS at 36 months post-surgery

Title

Number of Treatment Failures at 36 Months

Description

Time Frame

Continuous

Title

Safety: Adverse Events

Description

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).

Time Frame

continuous up to 60 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Daniël BF Saris, M.D., Ph.D.

Organizational Affiliation

University Medical Center Utrecht, Department of Orthopedics, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Johan Vanlauwe, M.D.

Organizational Affiliation

University Hospitals Leuven, Department of Orthopedics, Herestraat 49, 3000 Leuven, Weligerveld 1, 3212 Pellenberg, Belgium.

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Frank P Luyten, M.D., Ph.D.

Organizational Affiliation

Division of Rheumatology, Department of Muskuloskeletal Sciences, University Hospitals, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium

Official's Role

Study Director

Facility Information:

Facility Name

AZ St. Jan Brugge, Department of Orthopedics

City

Brugge

ZIP/Postal Code

8000

Country

Belgium

Facility Name

AZ St Lucas Brugge, Department of Orthopedics

City

Brugge

ZIP/Postal Code

8310

Country

Belgium

Facility Name

Academisch Ziekenhuis, Vrije Universiteit Brussel, Department of Orthopedics

City

Brussels

ZIP/Postal Code

1090

Country

Belgium

Facility Name

SPM Monica Antwerp

City

Deurne

ZIP/Postal Code

2100

Country

Belgium

Facility Name

Ghent University Hospital, Department of Orthopedics

City

Ghent

ZIP/Postal Code

9000

Country

Belgium

Facility Name

AZ St. Elisabeth, Department of Orthopedics

City

Herentals

ZIP/Postal Code

2200

Country

Belgium

Facility Name

AZ Groeninge, Department of Orthopedics

City

Kortrijk

ZIP/Postal Code

8500

Country

Belgium

Facility Name

University Hospitals Leuven, Department of Orthopedics

City

Leuven

ZIP/Postal Code

3000

Country

Belgium

Facility Name

A.Z. Sint Jozef, Department of Orthopedics

City

Malle

ZIP/Postal Code

2390

Country

Belgium

Facility Name

Department of Orthopedic Surgery, School of Medicine, University of Zagreb

City

Zagreb

ZIP/Postal Code

10000

Country

Croatia

Facility Name

University Hospital Hannover, Department of Orthopedics

City

Hannover

ZIP/Postal Code

30625

Country

Germany

Facility Name

University Medical Center Utrecht, Department of Orthopedics

City

Utrecht

ZIP/Postal Code

3584

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

12507589

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. Erratum In: J Orthop Res. 2003 May;21(3):572.

Results Reference

background

PubMed Identifier

12799178

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.

Results Reference

background

PubMed Identifier

11465712

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.

Results Reference

background

PubMed Identifier

8078550

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.

Results Reference

background

PubMed Identifier

14996869

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.

Results Reference

background

PubMed Identifier

16990391

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.

Results Reference

background

PubMed Identifier

18202295

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.

Results Reference

result

PubMed Identifier

19846694

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.

Results Reference

result

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

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