| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients must display 1-2 symptomatic, focal cartilage lesion grade IIIIV
(according to the grading by the International Cartilage Repair
Society (ICRS)) from 2 to 8 cm2 on the femoral condyle and/or the
trochlea, have to be between 18-65 years old and must consent in oral
and written manner in order to be enrolled in the study. |
|
| E.1.1.1 | Medical condition in easily understood language |
Patients must display 1-2 severe, symptomatic,cartilage lesion from 2
to 8 cm2 in the knee, have to be between 18-65 years old and must
consent in order to be enrolled in the study. |
|
| E.1.1.2 | Therapeutic area | Not possible to specify |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
This proposed phase II trial seeks to primarily define whether a tissue
therapy for cartilage repair in the knee will improve the clinical efficacy
for the patient, leading to an increase of at least 10 points in the main
primary outcome (self-assessed score KOOS) after 24 months as
compared to the cell therapy group. Comparison between groups will
allow assessment of whether the tissue therapy is superior to the cell
therapy.
The KOOS score will be used to measure the primary outcome. The
primary endpoint is the difference in the KOOS at 24 months between
the two techniques (comparison of the efficacy of the technique). The
KOOS score, covering the fields of Symptoms, Pain, Activities of daily
life, Sport activities and Quality of life, is suitable for assessing the
improvement for the patient. This validated questionnaire is widely
used to assess efficacy of cartilage repair therapies. |
|
| E.2.2 | Secondary objectives of the trial |
The stability and integration as well as the morphological properties of
the graft will be assessed by the MOCART Score.
The remodeling of the tissue after implantation towards native
cartilage will be assessed by dGEMRIC evaluation (MRI) from the 24-
month assessment of the relative ΔR1.
The KOOS will be recorded for patients at baseline visit 1 or 2 and at
the 12- and 24-month follow-up assessments. Variations over time will
be recorded through completion of the questionnaires at enrolment and
at each follow-up visit (12 and 24 months after treatment).
Retrospectively data will be analyzed to identify the possibility of
treatment selection (tissue therapy vs. cell therapy) in relation to the
time after onset of symptoms (acute vs chronic cartilage lesions) in
order to determine if one treatment is more beneficial than the other
(e.g. higher stability, better integration etc.).
The study will evaluate the safety by the number of SADRs or SUSARs. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patient is ≥18 and ≤65 years old at time of screening.
• Patient has a localized articular cartilage defect of the femoral
condyle and/or the trochlea of the knee. 2 localized cartilage defects
are accepted if the total defect size is ≤ 8 cm2, both cartilage defects
are located at the femoral condyle and/or the trochlea and both
cartilage defects are to be treated with N-CAM or N-TEC.
• Patient has a defect of grade 3 or 4 according to the ICRS
classification.
• Patient has a defect size ≥2 and ≤8 cm2 as assessed by
MRI/arthroscopy.
• Patient has an opposite intact (≤ICRS Grade 1 ) articulating joint
surface (no "kissing lesions").
• Patient has an intact meniscus (maximum 1/3-resection).
• Patient has a stable knee joint or sufficiently reconstructed
ligaments. If not, ligament repair has to be done during the operation
or within 6 weeks of the planned cartilage treatment.
• Patient has a maximum baseline score of 75/100 in the KOOS
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 to
complete postoperative rehabilitation regimen. |
|
| E.4 | Principal exclusion criteria |
• Patient is unable to understand the patient information
• Patient is unable to undergo magnetic resonance imaging (MRI) or
is sensitive to gadolinium
• Patient has had prior surgical treatment of the target knee within 12
months using mosaicplasty and/or microfracture (Note: prior
diagnostic arthroscopy with debridement and lavage are acceptable
within 12 months). Anterior cruciate ligament repair is accepted, if the
target knee is stable or a primary ACL reconstruction is performed
within 6 weeks of the planned cartilage treatment.
• Patient has an onset of symptoms of > 5 years.
• Patient has a relevant meniscus tear. Partial meniscal removal
allowed, if not exceeding 1/3. Meniscus suture is not allowed in
parallel, but if successful, cartilage treatment might be added 12
months later.
• Patient has radiologically apparent degenerative joint disease in the
target knee as determined by Kellgren and Lawrence grade >2.
• Patient has evidence of joint disease e.g. chronic inflammatory
arthritis, and/or infectious arthritis.
• Patient has an unstable knee joint or insufficiently reconstructed
ligaments. If ligament repair is necessary, the repair has to be
performed during the operation or within 6 weeks of the planned
cartilage treatment.
• Patient has malalignment (no valgus- or varus-deformity) in the
target knee ≥ 5°. 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. If alignment surgery is
necessary, surgery has to be performed within 6 weeks of the planned
cartilage treatment.
• Patient has an osteochondral defect (defined as bony substancedefect of >3mm depth). Bone marrow edema is allowed.
• Any concomitant painful or disabling disease of the spine, hips, or
lower limbs that would interfere with evaluation of the afflicted knee.
• Patient has a known systemic connective tissue disease.
• Patient has a known autoimmune disease.
• Patient has a known immunological suppressive disorder or is taking
immunosuppressives.
• Patient is currently systemically or intra-articularly taking steroids
and/or has used steroids within the 30 days prior to the planned
treatment.
• The patient has a known history of HIV/AIDS. (Protection of staff)
• The patient has a known history of Treponema pallidum (syphilis).
(Protection of staff)
• 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. (Protection of staff)
• 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, such as
Brucellosis, spotted and typhus fever, other Rickettsiosis, Leprosy,
Recurrent Fever, Melioidosis or Tularaemia).
• Patient has a known history of cancer.
• Patient has a known history of primary hyperparathyroidism,
hyperthyroidism, reduced kidney function (GFR > 80 ml/min), or prior
pathological fractures, independent of the genesis.
• Patient has any degenerative muscular, vascular or neurological
condition that would interfere with evaluation of outcome measuresincluding but not limited to Parkinson's disease, amyotrophic lateral
sclerosis (ALS), or multiple sclerosis (MS).
• Patient has a body mass index (BMI) >30 kg/m2.
• Patient 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.
• Patient is unable to tolerate local anesthesia
• Any known allergies, especially for porcine collagen, penicillin or
streptomycin
• Patient is unwilling and/or unable 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 to
complete postoperative rehabilitation regimen.
Intraoperative Exclusion Criteria:
• Patient has a total defect size <2 or defect size extends graft size
and could therefore not be treated in total.
• Patient has >2 independent cartilage lesions
• Patient has symptomatic full-thickness (ICRS Grade 3 or 4) of
patella or tibial plateau.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
KOOS score: The primary endpoint is the KOOS subjective score at the
24-month visit. The difference in the KOOS-score will be compared
between the two groups (Comparison of Efficacy of Treatment) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
MOCART Score (MRI): The MRI will be performed at 3, 12, 24 months
follow-up visits and MOCART scores calculated. (Assessment of
stability and integration)
• dGEMRIC evaluation (MRI): The relative delta R1 will be evaluated
by dGEMRIC and recorded at 3, 12, 24 months follow-up visits and
referenced to the native cartilage of the treated knee. (Assessment of
quality of the repair tissue)
• A further questionnaire (EQ-5d) at 12 and 24 month and an
additional time point (12 month) for KOOS will allow the more detailed
analysis of the clinical development of the patient's recovery and
elucidate changes in the perceived quality of life before and after
treatment.
Other outcomes:
• Retrospective analysis of primary and secondary endpoint data with
regard to the onset of symptoms to identify a possible selection of
treatment of acute (onset < 1 years) or chronic (onset >1 years)
lesions
Safety:
• Any AE and SAEs will be recorded regarding event descriptions,
onset, resolution dates and relationship to the IMP. All SADR or SUSAR
will be reported to Basel as leading center and the respective
authorities. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
MRI and dGEMRIC will be performed at 3, 12, 24 months follow-up.
questionnaires will be performed after 12 and 24 months follow-up.
Retrospective Analysis will be performed at the end of the study.
AEs will be recorded throughout the study. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| two treatment arms (N-TEC and N-CAM) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Croatia |
| Germany |
| Italy |
| Switzerland |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| last visit of last Patient in the trial |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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