E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Repair of localized, full-thickness cartilage defects of the femoral condyle (medial, lateral or trochlea) of 2-6cm². |
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E.1.1.1 | Medical condition in easily understood language |
Repair of cartilage defects of the knee. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Cell Physiological Phenomena [G04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052913 |
E.1.2 | Term | Cartilage operation |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007705 |
E.1.2 | Term | Cartilage damage |
E.1.2 | System Organ Class | 100000004863 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057104 |
E.1.2 | Term | Cartilage repair |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064112 |
E.1.2 | Term | Cartilage graft |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 |
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 24-month assessment visit. |
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E.2.2 | Secondary objectives of the trial |
• 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 and microfracture.
• To assess surgical parameters.
• To assess the proportion of treatment failures |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
MR Examination Protocols and Data Handling, KS_N3D_DOK12_5.0, 25.05.2018 |
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E.3 | Principal inclusion criteria |
Pre-operative inclusion criteria:
At visit 1 patients must meet the following inclusion criteria for enrollment; all criteria must be answered with “yes” before the patient is scheduled for arthroscopy:
1. Patient is ≥ 18 and ≤ 65 years old at screening or (in selected countries only) is a pediatric patient (14 to 17 years old) with closed epiphyseal growth plate (confirmation of closure of the epiphyseal growth plate of the index knee by X-ray or MRI required).
2. 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 and the size of each individual lesion is ≥ 2 cm2, 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.
3. Patient has a defect size ≥ 2 and ≤ 6 cm2. Note: defect size can be estimated by MRI at visit 1 if no data is available from medical history.
4. Patient has an intact articulating joint surface (≤ Grade 2 International Cartilage Repair Society [ICRS] classification, no “kissing lesions”). Note: ICRS classification can be estimated by MRI at visit 1 if no data is available from medical history.
5. Patient has an intact meniscus; a maximum of 50% resection is allowed. Note: status of meniscus can be estimated at visit 1 if no data is available from medical history.
6. Patient has a stable knee joint or sufficiently reconstructed ligaments. If not, ligament repair must be done before, during or within 6 weeks after cartilage treatment (ACT/microfracture).
7. Patient has free range of motion of the affected knee joint or ≤ 10° of Extension and flexion loss.
8. Patient has a defect-grade of III or IV according to the ICRS classification. Note: ICRS classification can be estimated by MRI at visit 1 if not data is available from medical history.
9. Patient has a baseline score of ≤ 60/100 on the 2000 International Knee Documentation Committee (IKDC) subjective knee evaluation.
10. 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.
11. Mandatory for France only: Patient benefits of a health insurance regimen.
Intra-operative inclusion criteria:
Patients who are eligible for the study according to the inclusion/exclusion criteria assessed at visit 1 will be scheduled for arthroscopy (visit 2). At visit 2, the following inclusion criteria from visit 1 need to be confirmed; all criteria must be answered with “yes” before the patient is randomized into the study:
1. Patient is not pregnant as confirmed by urine pregnancy test before arthroscopy.
2. 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 and the size of each individual lesion is ≥ 2 cm2, 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.
3. Patient has a defect size ≥ 2 and ≤ 6 cm2 post-debridement.
4. Patient has an intact articulating joint surface (≤ Grade 2 International Cartilage Repair Society [ICRS] classification;) no “kissing lesions”).
5. Patient has an intact meniscus; a maximum of 50% resection is allowed (no indication for concurrent meniscus transplant).
6. Patient has a stable knee joint or sufficiently reconstructed ligaments. If not, ligament repair must be done during or within 6 weeks after cartilage Treatment (ACT/microfracture).
7. Patient has a defect grade of III or IV according to the ICRS classification. |
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E.4 | Principal exclusion criteria |
Pre-operative exclusion criteria:
At visit 1 none of the following exclusion criteria must apply to any enrolled patient; all criteria must be answered with “no” before the patient is scheduled for arthroscopy:
1. Patient is the investigator or any subinvestigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the study.
2. Patient is unable to undergo magnetic resonance imaging (MRI).
3. Patient has prior surgical treatment of the target knee using mosaicplasty, autologous chondrocyte transplantation and/or microfracture. Note: prior diagnostic arthroscopies with debridement and lavage are acceptable. Ligament repair is accepted, if performed before, during or within 6 weeks after cartilage treatment (ACT/microfracture).
4. Patient has radiologically apparent degenerative joint disease in the target knee as determined by Kellgren and Lawrence grade ≥ 2 (see Appendix A).
5. Patient has chronic inflammatory arthritis and/or infectious arthritis.
6. 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.
7. Patient has malalignment (valgus- or varus-deformity) in the target knee. Note: In suspected cases, the mechanical axis must be established radiographically by complete leg imaging in standing position 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 before, during or within 6 weeks after cartilage treatment (ACT/microfracture).
8. Patient has prior surgical treatment of clinical relevance of the target knee.
9. Patient has an osteochondral defect.
10. Patient has bilateral lower limb pain or low back pain.
11. Patient has a known systemic connective tissue disease.
12. Patient has a current uncontrolled diabetes.
13. Patient has a known history of autoimmune disease.
14. Patient has a known history of immunological suppressive disorder or is taking immunosuppressants.
15. Patient is currently systemically or intra-articularly taking steroids and/or has used steroids within the last 30 days prior to screening visit 1.
16. The patient has a history of HIV/AIDS.
17. The patient has a history of syphilis (Treponema pallidum).
18. The patient has an active hepatitis B or C infection with verified antigens. Note: Patients with a cured hepatitis B or C infection and/or verified antibodies are not excluded.
19. 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).
20. Patient has a known history of cancer within the past 5 years.
21. Patient has a known history of osteoporosis; also patients with primary hyperparathyroidism or hyperthyroidism without satisfactory treatment, chronic renal failure or patients with prior pathological fractures independent of the genesis are excluded.
22. 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).
23. Patient has a body mass index (BMI) >35 kg/m2.
24. Patient is a woman who is pregnant or lactating. Note: contraception is indicated for female patients of childbearing potential until the day of cartilage treatment. Female patients who are unwilling to practice a medically acceptable method of birth control until the day of cartilage treatment cannot be included.
25. Patient is currently participating, or has participated in any other clinical study within 3 months prior to the screening visit.
26. Patient has known current or recent history of illicit drug or alcohol abuse or dependence
27. 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.
28. Patient has any other condition, which, in the opinion of the investigator, would make the patient unsuitable for the study.
29. Patient has a history of HTLV. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the patient’s functional outcome as measured by the change in the 2000 IKDC subjective knee score from baseline to the 24-month follow-up assessment.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to the 24-month follow-up assessment. |
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E.5.2 | Secondary end point(s) |
• Change from baseline to the 24-month visit in the IKDC objective physician score.
• Change from baseline to the 24-month visit in the Knee Injury and Osteoarthritis Outcome Score (KOOS); individual KOOS subscores and KOOS5 (composite score including all 5 subscores) will be assessed. Proportion of treatment failures at month 24
• Change from baseline to the 24-month visit in the SF-36 to measure clinical utility and summarize health-related quality-of-life and cost-effectiveness.
• In vivo performance measured by the 24-month assessment of the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score and T2 mapping. These assessments will be performed on a subset of patients (64 in the NOVOCART® 3D plus group and 32 in the microfracture group) as described in section 7.3.3 and in the attached radiological study protocol
• Surgical time (cut-to-suture time).
•Length of incision ( NOVOCART® 3D plus group only)
•Proportion of treatment failures at month 24 (see section 7.2.7) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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 | Yes |
E.8.2.3.1 | Comparator description |
Surgical procedure: microfracture |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 34 |
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 |
Austria |
France |
Germany |
Hungary |
Latvia |
Lithuania |
Poland |
Switzerland |
United Kingdom |
Czechia |
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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
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Last patient, last visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
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 |