An Extension Protocol for Participants of Genzyme-Sponsored;Prospective, Randomized, Open-Label, Parallel-Group, Multicenter Study of Matrix-Induced Autologous Chondrocyte Implantation (MACI® implant) for the Treatment of Symptomatic Articular Cartilage Defects of the Femoral Condyle Including the Trochlea

An articular cartilage defect is damage to articular cartilage which may occur
from an acute traumatic injury or through progressive mechanical degeneration.
They occur along a spectrum of disease and severity. At one end of this
spectrum are small, acute lesions that are often diagnosed incidentally at the
time of knee arthroscopy, and are not necessarily initially symptomatic. At the
other end are larger, more chronic lesions that are often symptomatic and
usually do not heal appropriate on their own.
Current treatment algorithms for chondral lesions consider a number of factors
including patient demographics, lesion characteristics (eg, size, location, and
prior treatment) and overall joint factors (eg, alignment and concurrent
pathology) to achieve optimal patient outcomes. Interventions include
autologous chondrocyte implantation (ACI), marrow stimulation techniques (MSTs)
such as abrasion arthroplasty, drilling and microfracture, and mosaicplasty
(also known as osteochondral transplantation). Other treatment options include
knee washout (lavage) with or without debridement.
Matrix-induced autologous chondrocyte implantation (MACI® implant) is an
autologous cartilage repair treatment for repair of articular cartilage defects
in symptomatic patients, and has been predominantly administered in the knee
joint. For this procedure a cartilage biopsy is taken during a surgical
procedure, which will be seeded onto a porcine membrane to grow into the MACI
Implant product. During e second surgical procedure the product is placed back
into the defect.
Genzyme study MACI00206 is a prospective, randomized, open-label,
parallel-group, multicenter clinical trial of MACI implant versus arthroscopic
microfracture for the treatment of symptomatic articular cartilage defects of
the femoral condyle, including the trochlea. The MACI00206 study was designed
to build on the clinical experience with MACI implant in the treatment of
full-thickness articular cartilage defects compared with microfracture.
Additionally, the study assesses the structural cartilage repair generated by
MACI implant and microfracture by histological evaluation and magnetic
resonance imaging and includes efficacy and safety evaluation up to 2 years
post-treatment.
The Committee for Advanced Therapies (CAT) of the European Medicines Agency
(EMEA) has recently published a reflection paper on in vitro cultured
chondrocyte containing products for cartilage repair of the knee. In this
document it is recommended that a 3-year follow-up assessment of clinical
efficacy be completed.
This extension study has been designed to examine the 5-year efficacy and
safety of MACI implant, compared with arthroscopic microfracture, in patients
who received study treatment in the MACI00206 study.

The objective of this study is to examine the 5-year efficacy and safety of
Matrix-Induced Autologous Chondrocyte Implantation (MACI® Implant), compared
with arthroscopic microfracture, in patients who received study treatment in
Genzyme-sponsored study MACI00206 for treatment of symptomatic articular
cartilage defects of the femoral condyle, including the trochlea.

This is an open-label, multicenter, 3-year extension study for patients who
received study treatment (MACI implant or microfracture) in the MACI00206 study.
Patients will have until the end of the visit window for the last visit of this
extension study (Week 260 + 6 weeks) to consent to enter this extension study;
written informed consent is required prior to enrollment in the study.
Efficacy and safety assessments will be performed at scheduled visits 3, 4 and
5 years following treatment in MACI00206 (i.e., at Weeks 156, 208 and 260
post-arthrotomy for patients treated with MACI implant or at Weeks 156, 208 and
260 post-arthroscopy for patients treated with microfracture). Patients*
MACI00206 data will be utilized for statistical analysis (e.g., for treatment
failure analysis) in this extension study.
Patients withdrawn from the MACI00206 study prior to their scheduled Week 104
visit and enrolled into the MACI00809 study will have their remaining scheduled
assessment (from the MACI00206 study) within the MACI00809 study in addition to
the assessments mentioned for Weeks 156, 208 and 260. Note that data for any
visits for which the visit window has passed will not be collected and will be
considered
missing.
Any patient requiring surgical re-treatment of the treated defect(s) and
meeting other specific criteria relating to changes in the condition of the
treated knee joint will be considered a treatment failure and may be asked to
attend an unscheduled visit for treatment failure evaluation. Patients who are
considered treatment failures may receive appropriate alternative treatment, at
the discretion of the Investigator, which may include MACI implant.
Additionally, patients who do not meet the specific treatment failure criteria
as defined in this protocol but require re-treatment in the opinion of both the
Investigator and the Treatment Failure Evaluation Committee, may also receive
re-treatment which may include MACI implant. All patients requiring
re-treatment with MACI implant will receive
MACI as investigational product provided for rescue treatment. Patients
determined to be treatment failures will not be withdrawn from this extension
study.

Patients are asked to completed questionnaries during the follow up visits 3, 4
and 5 years following treatment in MACI00206 (ie, at Weeks 156, 208 and 260
post-arthrotomy for patients treated with MACI implant or at Weeks 156, 208 and
260 post-arthroscopy for patients treated with microfracture).
In addition Magnetic resonance imaging (MRI) assessments of structural repair
parameters at Weeks 156 and 260 following treatment in MACI00206 will be made.

Patients withdrawn from the MACI00206 study prior to their scheduled Week 104
visit and enrolled into the MACI00809 study will have their remaining scheduled
assessment from the MACI00206 study within the MACI00809 study in addition to
the assessments mentioned for Weeks 156, 208 and 260. Patients who are
considered treatment failures may be asked to attend an unscheduled visit for
treatment failure evaluation.

Although the patient will not receive any further treatment as part of this
study they may be retreated if needed. The investigator will assess improvement
using appropriate evaluations and will discuss the retreatment possibilities
with the patient. These may include, but are not limited to, MACI implant or
microfracture. There may be other side effects or discomforts from your
retreatment in this study (if applicable) that are not yet known.
Risks involved with retreatment by MACI implant: If the patient is retreated
with MACI implant, the cartilage defect will be treated with a surgical implant
consisting of their own live cartilage cells (obtained during the MACI00206
study) on a collagen membrane. As with any surgical implant, there are risks
of infection, failure of implant fixation, and/or failure to relieve your
symptoms. In earlier clinical trials with MACI implant, very few reactions have
been identified as causally related to MACI implant. These reactions included
overgrowth of the implanted cartilage tissue, or separation of the membrane
from the defect site (either complete or partially, possibly leading to loose
bodies in the joint).

Possible risks involved with MRI: Interference with internal devices. Patients
will be asked if they have any internal device or implant such as a heart
pacemaker, metal pins or a medication pump.

Reproductive risks:
A female patient or a female partner of the patient who becomes pregnant, is
strongly recommended by Genzyme to immediately inform the study doctor. When
the patient or the female partner agrees, follow up information concerning the
pregnancy and the outcome can be obtained and shared with Genzyme.

Benefit:
there may not be direct medical benefits for the patients. However, we hope the
information learned from this study will benefit other patients with cartilage
defects in the future.