Primary ObjectiveTo demonstrate that the effectiveness of the NOVOCART® 3D plus autologouschondrocyte transplantation system is superior to microfracture for the treatment ofarticular cartilage defects of the knee by demonstrating superiority of the…
ID
Source
Brief title
Condition
- Tendon, ligament and cartilage disorders
- Bone and joint therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the patient*s functional outcome as measured by the
change
in the 2000 IKDC subjective knee form scores from baseline to the 36-month
followup
assessment.
Secondary outcome
* Change from baseline to 36-month visit in the Knee Injury and Osteoarthritis
Outcome Score (KOOS).
* In vivo performance measured by the 36-month assessment of the Magnetic
Resonance Observation of Cartilage Repair Tissue (MOCART) score. These
assessments will be performed on a subset of patients (64 in each
group) as described in the attached radiological study protocol
* Change from baseline to the 36-month visit in the IKDC objective physician
score.
* Change from baseline to the 36-month visit in the SF-36 to measure clinical
utility and summarize health-related quality-of-life and cost-effectiveness.
* Change from baseline to the 24-month visit in the above patient-reported
outcomes.
* Surgical time (cut-to-suture time).
* Length of incision.
Background summary
Articular cartilage injuries of the knee can lead to premature wear of the
joint and subsequent arthrosis. Conservative treatments merely treat the
symptoms of the disease and do not bring about any fundamental healing of the
lesions. If symptoms (e.g., pain) become more problematic, surgery is typically
recommended. There are several reparative surgical techniques used to treat
chondral cartilage defects of the knee. Reparative techniques include
microfracture, allograft reconstruction, autologous osteochondral
transplantation (*OATS** or *Mosaicplasty**) and autologous chondrocyte
transplantation or implantation (*ACT* or *ACI*). Bone marrow-stimulating
procedures such as microfracture mainly result in replacement tissue that is
inferior to natural hyaline cartilage in biomechanical properties and
viscoelastic characteristics. Osteochondral transfer procedures provide hyaline
cartilage to the grafted site, but there is a risk of donor site morbidity,
limiting these procedures to small defects. ACT is a treatment option that
differs from other reparative techniques in that it allows formation of
hyaline-like repair tissue. Five year results have recently become available
from a prospective, randomized study on conventional ACT using chondrocytes
versus microfracture in patients with clinical symptoms of not more than three
years. Clinically, ACT proved to be significantly better than microfracture,
and the difference was therapeutically relevant.
TETEC has developed NOVOCART® 3D plus Autologous Chondrocyte Transplantation
System, a cell-scaffold combination product composed of ex vivo expanded
autologous chondrocytes seeded on a bioresorbable biphasic collagen scaffold
transplanted using a minimally invasive approach. NOVOCART® 3D plus was
developed to facilitate healing with normal replacement cartilage with the
application of chondrocytes in a robust three-dimensional scaffold transplanted
using a minimally invasive procedure.
A retrospective survey of NOVOCART® 3D plus was conducted in Europe with a
total of 422 patients. The purpose of the survey was to gather information on
adverse outcomes, and changes from baseline in measures of pain, function, and
swelling. Review of the retrospective survey results shows an acceptable safety
profile combined with significant improvements in pain, function and swelling.
Based on the satisfactory results of the retrospective survey, TETEC AG is
conducting this clinical study.
Additional clinical evidence of the effectiveness of NOVOCART® 3D plus will be
obtained by conducting this large, long-term, randomized, controlled clinical
study. Patients will be randomized to one of the two study arms to protect
against potential selection bias. The control therapy, microfracture, is a
proven therapy considered to be the current standard of care. The clinical
study design calls for an interim analysis that allows the efficient use of
data to reach an early conclusion of the study without sacrificing scientific
rigor, thereby minimizing burden on the participating patients and
investigators.
Study objective
Primary Objective
To demonstrate that the effectiveness of the NOVOCART® 3D plus autologous
chondrocyte transplantation system is superior to microfracture for the
treatment of
articular cartilage defects of the knee by demonstrating superiority of the
subjective
IKDC score improvement from baseline to the score measured at the 36-month
assessment visit.
Secondary Objectives
* To assess the physician evaluation of the functional effectiveness of
NOVOCART® 3D plus.
* To evaluate health-related quality-of-life improvement.
* To evaluate cartilage (tissue-structure) regenerative effects of NOVOCART® 3D
plus.
* To assess surgical parameters.
Safety Objective
The safety objective of the study is to demonstrate the safety of the NOVOCART®
3D
plus autologous chondrocyte transplantation system when used as intended. The
safety results of NOVOCART® 3D plus will not be compared to microfracture
because of the distinctive risk profile and safety expectation for NOVOCART® 3D
plus.
Study design
This is a prospective, randomized, multi-center, unmasked clinical study
designed to
demonstrate the superiority of NOVOCART® 3D plus compared to microfracture for
the treatment of articular cartilage defects of the knee. The study requires a
36-month follow-up period for the pivotal phase to achieve its primary and
secondary
objectives. Study participants will be followed in a 5 year (post surgery)
long-term
follow up phase to collect long-term data. The arthroscopic microfracture
technique of
Steadman will be used in conjunction with a defined rehabilitation program. The
study uses a sequential design to compare NOVOCART® 3D plus to microfracture
procedure on patients. The design of the study allows one pre-planned interim
analysis using the data from the first 67% patients who complete their 36-month
follow-up to assess the primary endpoint. If the evidence is found to be
significant,
against the O*Brien-Fleming boundary and in favor of NOVOCART® 3D plus, an early
claim of study success will be made. The study will be continued until the
enrollment
ceiling has been reached and all participating patients have completed the
study. A
final report including all enrolled patients will be submitted to update the
European
Public Assessment Report (EPAR) and product labeling.
Intervention
* TETEC AG NOVOCART® 3D plus Autologous Chondrocyte Transplantation System.
OR
* Microfracture technique according to Steadman._
Study burden and risks
Benefits.
Based on current knowledge about the mechanism of action of the ATIMPs
and the promising results from animal studies and from human therapeutic
experience with the product NOVOCART® 3D plus and similar therapeutic
principles,
it is expected that the patients who participate in this clinical study will
benefit from
the treatment with the ATIMP. Signs and symptoms of the underlying disease are
anticipated to improve such that oral pain therapy can be reduced or even
tapered
off.
Scientific Benefit.
Laboratory studies and earlier surveys in humans using similar
approaches for traumatic diseases of the knee have already suggested that the
ATIMP can significantly improve the outcome of such patients. Hence, this
clinical
study will serve to scientifically evaluate the response of patients suffering
from
trauma associated changes in the knee. If the results are positive, further
investigations will be conducted in order to expand the indication for all
patients with
trauma-associated cartilage defects.
It is necessary to develop and evaluate new, promising and easy-to-handle
therapeutic alternatives for trauma-associated cartilage defects, considering
increasing numbers of patients and the lack of alternatives to prevent secondary
degeneration in patients suffering from this disorder.
Risk-Benefit Assessment.
The currently known risks of adverse reactions to the
ATIMP, or those associated with the medical procedures that are used during the
study in order to handle the ATIMP, are very small when considering the expected
improvement to the individual participant or to the entire group of patients
suffering
from this disease.
Aspenhaustrasse 18
Reutlingen 72770
DE
Aspenhaustrasse 18
Reutlingen 72770
DE
Listed location countries
Age
Inclusion criteria
*Patient is * 18 and * 65 year old at time of screening
*Patient has a localized articular cartilage defect of the femoral condyle or the trochlea of the knee. 2 localized cartilage defects are accepted if the total defect size is * 6 cm2 post-debridement, both cartilage defects are located at the femoral condyle and/or the trochlea and both cartilage defects are to be treated with NOVOCART® 3D plus or microfracture..
* Patient has a defect size * 2 and * 6 cm2post-debridement.
* Patient has an intact (< Grade 2 ICRS classification) articulating joint surface (no *kissing lesions*).
* Patient has an intact meniscus (maximum 1/2-resection).
*Patient has a stable knee joint or sufficiently reconstructed ligaments. If not, ligament repair has to be done within 6 weeks to the planned cartilage treatment (ACT/microfracture).
*Patient has free range of motion of the affected knee joint or *10 degrees of extension and flexion loss.
*Patient has a defect of grade III or IV according to the ICRS classification.
*Patient has a maximum baseline score of 60/100 on the 2000 IKDC subjective knee evaluation.
*Patient is willing and able to give written informed consent to participate in the study and to comply with all study requirements, including attending all follow-up visits and assessments and postoperative rehabilitation regimen.
Exclusion criteria
Only selected (preoperative) exclusion criteria have been listed below. For the complete list see protocol.
Preoperative exclusion criteria:
* Patient is the investigator or any subinvestigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol.
* Patient is unable to undergo magnetic resonance imaging (MRI).
* Patient has prior surgical treatment of the target knee using mosaicplasty and/or microfracture (Note: prior diagnostic arthroscopy with debridement and lavage are acceptable). Anterior cruciate ligament repair are accepted, if the target knee is stable or a primary ACL reconstruction is performed within 6 weeks to the planned cartilage treatment (ACT/microfracture).
* Patient has radiologically apparent degenerative joint disease in the target knee as determined by Kellgren and Lawrence grade > 2.
* Patient has chronic inflammatory arthritis, and/or infectious arthritis.
* Patient has joint space narrowing >1/3 in the target knee when compared to the other knee or <3 mm joint space measured on X-ray.
* Patient has an instable knee joint or unsufficiently reconstructed ligaments. If ligament repair is necessary, the repair has to be performed within 6 weeks to the planned cartilage treatment (ACT/microfracture).
* Patient has malalignment (no valgus- or varus-deformity) in the target knee. In suspected cases, the mechanical axis must be established radiographically through complete leg imaging during standing and in a.p. or rather p.a. projection.
The Mikulicz line is not allowed to deviate more than 5 mm of the Eminentia intercondylaris.
If alignment is necessary, surgery has to be performed within 6 weeks to the planned cartilage treatment (ACT/microfracture).
* Patient has prior surgical treatment of clinical relevance of the target knee.
* Patient has an osteochondral defect.
* Patient has bilateral lower limb pain or low back pain.
* Patient has a known systemic connective tissue disease.
* Patient has a known history of diabetes.
* Patient has a known autoimmune disease.
* Patient has a known immunological suppressive disorder or is taking immunosuppressants.
Patient is currently systemically or intra-articularly taking steroids and/or has used steroids within the last 30 days prior to the planned arthroscopy (tissue harvest/microfracture).
* The patient has a known history of HIV/AIDS.
* The patient has a known history of Treponema pallidum (syphilis).
* The patient has an active hepatitis B or C infection with verified antigens. Patients with a cured hepatitis B or C infection and/or verified antibodies are not excluded.
* The patient has at the site of surgery an active systemic or local microbial infection, eczematization or inflammable skin alterations (including Protozoonosis: Babesiosis, Trypanosomiasis (e.g. Chagas-Disease), Leishmaniasis, persistent bacterial infections, like Brucellosis, spotted and typhus fever, other Rickettsiosis, Leprosy, Recurrent Fever, Melioidosis or Tularaemia).
* Patient has a known history of cancer.
* Patient has a known allergy against any of the ingredients of the IMP (NOVOCART® 3D plus).e.g. bovine proteins
* Patient is taking indomethacin or other NSAIDs as acute anti-pain and/or antiinflammatory
medication.
* Patient has a known history of osteoporosis;
also patients with primary hyperparathyroidism, hyperthyroidism, chronic renal
failure or patients with prior pathological fractures independent of the genesis.
* Patient has any degenerative muscular or neurological condition that would interfere with evaluation of outcome measures including but not limited to Parkinson*s disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).
* Patient has a body mass index (BMI) >35 kg/m2.
* Patient is a woman who is pregnant, lactating or anticipates becoming pregnant within 24 months after surgery.
* Patient is currently participating, or has participated in any other clinical study within 3 months prior to the screening visit.
* Patient has known current or recent history of illicit drug or alcohol abuse or dependence defined as the continued use of alcohol or drugs despite the development of social, legal or health problems.
* Patient has psychiatric or cognitive impairment that, in the opinion of the investigator, would interfere with the patient*s ability to comply with the study requirements, e.g., Alzheimer*s disease.
* Patient has any other condition, which, in the opinion of the investigator, would make the patient unsuitable for the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-005798-22-NL |
| ClinicalTrials.gov | NCT01656902 |
| CCMO | NL49836.000.14 |