| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Active knee Osteoarthritis (mild to moderate) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| 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 |
| The main objective is to evaluate the efficacy of ASC in mild to moderate knee OA based on increase in the rate of “strict” responders at 6 month, compared to placebo (vehicle: 0.5% glucose in saline with 4,5% human albumin). |
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| E.2.2 | Secondary objectives of the trial |
- The rate of “strict” responders and responders will be assessed at month 1, 3, 6, 12 and 24 in each group.
- Assessment of the potential structural benefit with evaluation of the Kellgren-Lawrence score on X-rays and progression of affected knee joints by quantitative MRI. Every patient will have these evaluations (X-rays and MRI) three times: first before the start of the treatment, to define the initial state, then at 12 and 24 months after the treatment to quantify the long term benefits/effects of the therapy.
- Assessment of the disability and the quality of life at 0, 1, 3, 6, 12 and 24 months with the following patient report outcomes: WOMAC questionnaire, KOOS questionnaire, SAS questionnaire, VAS pain and Short Form (SF)-36 questionnaire.
- Assessment of antalgic (paracetamol) medication during all the follow up (24 months). A reduction in dose or frequency of administration of paracetamol is an indirect marker of the benefits of ASC.
- Assessment of the safety.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Symptomatic mild to moderate osteoarthritis (OA) of the index knee as defined by the American college of Rheumatology (ACR):
- History of pain in the index knee ≥ 6 months, AND
- Kellgren-Lawrence (K-L) Grade 2 or 3 only, on plain radiographs of the index knee (including fixed flexion), AND
- Swelling of the index knee evaluated by the investigator
2. Must meet the following pain criteria at the time of screening/baseline visit since at least half of the days in the previous month:
- Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscores ≥ 40 mm on the 0-100 normalised scale
- Visual Analogic Scale (VAS) pain rating of at least 40 on a 100-mm scale
-Subject’s global assessment of the contralateral knee <20 mm by 100-mm using Visual Analogic Scale (VAS)
3. NSAID washout of at least 2 days before screening/baseline
4. BMI between 20-35 kg/m2 |
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| E.4 | Principal exclusion criteria |
1) Previous treatments acting on cartilage or bone metabolism (eg, oral or intravenous bisphosphonates <1 year previously, denosumab < 6 months, strontium ranelate or teriparatide or raloxifene <7 days prior to selection, and oral glucosamine ≥1500 mg/day or chondroitin sulphate ≥1000 mg/day <3 months previously)
2) Has had any trauma of the index knee in the previous 12 months prior to the screening visit
3) Has OA of the index knee that meets K-L classification criteria of grade 1 or 4
4) Osteoarthritis causing significant pain in any joint other than the identified knee as confirmed by a separate VAS at baseline for any other painful joint concerned (≥ 20 mm pain)
5) Significant trauma or surgery to the index knee within the last year or arthroscopy of the index knee within 12 months of screening (Not applicable in Germany and Netherland)
6) Prior to the screening visit, has received:
-Oral corticosteroid therapy within the previous 3 month, OR
-Intramuscular, intravenous or epidural corticosteroid therapy within the previous 6 months, OR
-Intra-articular injection of corticosteroids in the index within the previous 6 months, OR
-Intra-articular injection of hyaluronic acid in the index knee within the 6 months. OR
-Intra-articular injection of platelet rich plasma in the index knee within the 6 months.
7) Inflammatory or other rheumatic diseases defined by clinical examination and previous serum markers (such as rheumatoid arthritis, autoimmune disorder, seronegative spondyloarthritis, gout or pseudogout (defined as acute episodic attacks of swollen, painful joint in a patient with X-ray chondrocalcinosis or CPPD crystals)), History or evidence of infectious arthritis, Paget’s disease, Ochronosis, Wilson’s Disease, Primary osteochondromatosis
8) History of articular fracture of the target knee joint
9) History of heritable disorders (e.g. hypermobility) and collagen gene mutations
10) Immunodeficiency diseases
11) Alcoholics not in treatment and still drinking (14+ drinks/week)
12) Subjects with poorly controlled diabetes mellitus (HbA1C > 8%) or known concomitant vascular problems
13) Planned longer stay outside the region that prevents compliance with the scheduled visit
14) Severe misalignment of the knee (excessive varus or valgus ≥ 8°) at physical examination, as confirmed by standard radiograph
15) Severe osteoporosis with previous symptomatic vertebral or hip fractures
16) History of joint replacement of the knee or hip within the previous 12 months
17) Serious systemic diseases or infectious/inflammatory skin diseases in the area of the affected knee
18) Positive serology for HIV, hepatitis B, C and syphilis
19) History of cancer or blood dyscrasias, or previous chemotherapy, radiotherapy or immunotherapy
20) Contraindication to MRI, including MRI-incompatible internal devices (pacemaker, neurostimulator, cochlear implant, ocular foreign bodies, foreign bodies close to neurovascular structures)
21) Intolerance or allergy to local anaesthesia
22) Anticoagulant treatment
23) Overweight with body mass index (mass in Kg/size in m2) greater than 35 (obesity grade II).
24) Participation in another clinical trial or treatment with another investigational product within 30 days prior to inclusion in the study.
25) Abnormal blood tests:
-Hepatic (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] > 2 × upper limit of normal [ULN]),
-Renal (clearance < 30 ml/min/1,73 m2),
pancreatic or biliary disease, except asymtomatic bile stones
-Blood coagulation disorders, Anaemia (≤ 10 g/dL) or platelet count of ≤ 100 × 109/L
26) Significant medical problems, such as uncontrolled hypertension, symptomatic heart failure, or any other clinically relevant condition or current medication that in the opinion of the investigator contra-indicates the use of any of the study or rescue medications
27) Pregnant or lactating women, or premenopausal women not using an acceptable form of birth control. For example : Intrauterine device, Hormonal based contraception, Double barrier contraception (condom and occlusive cap), Abstinence (no sexual activity).
28) Known allergies to protein products (horse or bovine serum, or porcine trypsin) used in the ex vivo cell production process
29) Known hypersensitivity to study drug or additives: albumin, sodium caprylate, sodium chlorid, potassium chlorid, ciprofloxacin, cefazoline, heparin (if used in the participating country)
30) Known hypersensitivity to antibiotics :
• beta-lactam antibiotics (cefazoline) and lincosamides (clindamycin) (if used in the participating country)
• penicillin antibiotics and aminoglycosides for Germany only
31) Known hypersensitivity to chlorhexidine or other components or contraindications of Hibiscrub and iodine or other components or contraindications of Betadine Scrub (if used in the participating country)
32) Cancer or immunodeficiency disease |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| - The primary endpoint is the rate of “strict” responders defined by the OMERACT OARSI (Pham et al, 2003) as improvements from baseline in WOMAC pain or physical function subscores ≥ 50% and absolute changes ≥ 20 mm at 6 month, compared to placebo (vehicle: 0.5% glucose in saline with 4,5% human albumin). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- Kellgren-Lawrence scores will be assessed on the basis of X-rays (conventional standing antero-posterior radiograph with fixed location JSW). Joint space width will be measured at baseline, one-year and 2-years post-injection as previously described (Kothari M, Guermazi A, von Ingersleben G, et al. Fixed-flexion radiography of the knee provides reproducible joint space width measurements in osteoarthritis. Eur Radiol 2004;14:1568–73). Joint space narrowing less than 0.5 mm will be considered as significant.
- Progression of affected knee joints by quantitative MRI will include volumetric measurement (cartilage volume, thickness, surface area, 3D shape) from a 3D T1 spoiled gradient echo MRI sequence with fat saturation and 1.5 mm slice thickness performed at baseline, months 12 and 24 MOAKS semi-quantitative knee scoring will use PDFS sequences in axial, coronal and sagittal planes and a T1-weighted coronal acquisition, all with 3.0 mm slice thickness. Every patient will be scanned three times: first before the start of the treatment, to define the initial state of joint, then at 12 and 24 months after the treatment to quantify the long term benefits/effects of the therapy, in particular absence of progression at 24 months post-treatment. Additional MRI scans can be performed.
- Disability and life quality (WOMAC, KOOS questionnaire, SAS questionnaire and Short Form (SF)-36 scores) measures will be assessed at 0, 1, 3, 6, 12 and 24 months. The secondary clinical outcomes will include: SAS score, WOMAC total score, and WOMAC stiffness subscores; patient and physician global assessments of disease activity; quality of life assessment (KOOS questionnaire and SF-36 scores).
- OARSI response will be assessed at month 1, 3, 6, 12 and 24. Patients will be classified as responders defined by improvements from baseline in at least 2 of the 3 next values (WOMAC pain, WOMAC function and VAS pain), as follows of at least 20%, together with an absolute change of 10 mm on a 0-100 scale
- Paracetamol (Acetaminophen) medication: the drug consumption will be assessed throughout the study at each visit. A reduction in dose or frequency of administration of paracetamol is an indirect marker of the benefits of ASC therapy.
- SAS score
- VAS pain in the affected knee
- SF-36 score
- patient and physician global assessments of disease activity (VAS)
- Adverse events will be evaluated at each visit.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Months 1, 3, 6, 12 and 24 |
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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 | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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