| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023476 |
| E.1.2 | Term | Knee osteoarthritis |
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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 |
This study has two primary objectives:
The first objective of this study is to compare the safety and efficacy of 1 x 4-mL and 2 x 4-mL IA injections of AVS-beta against 1 x 1-mL (40 mg/mL) IA injection of methylprednisolone acetate in treating patients with symptomatic knee OA.
Secondly, to demonstrate that the odds of positive response to treatment for symptomatic knee OA over 26 weeks (where positive response is defined with the OMERACT-OARSI [Pham et al., 2003, J Rheum] set of criteria) is higher in patients treated with a 1 x 4-mL and/or 2 x 4-mL IA injections of AVS-beta compared to patients treated with a course of methylprednisolone acetate |
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| E.2.2 | Secondary objectives of the trial |
Odds of positive response to treatment for symptomatic knee OA with a 1 and/or 2 x 4-mL IA injections AVS-beta compared to methylprednisolone acetate
The differences between -
WOMAC LK 3.1 A change from Baseline to Week 26 in AVS-beta and methylprednisolone acetate groups
WOMAC LK 3.1 A1 over 26 weeks and from Baseline to Week 26 in AVS beta and methylprednisolone acetate groups
WOMAC LK 3.1 A1 change from Baseline to Week 26 in AVS-beta and methylprednisolone acetate groups
WOMAC LK 3.1 C (physical function subscale) over 26 weeks and from Baseline to Week 26 in AVS-beta and the methylprednisolone acetate groups
Total WOMAC over 26 weeks and from Baseline to Week 26 in the AVS-beta and methylprednisolone acetate groups
PTGA over 26 weeks and from Baseline to Week 26 in AVS-beta and methylprednisolone acetate group
COGA over 26 weeks and from Baseline to Week 26 in AVS-beta and the methylprednisolone acetate groups
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A patient may be enrolled in this study if he/she meets all of the following criteria:
Screening:
1. Provides signed written informed consent.
2. Is able to read and understand the language and content of the study material, understand the requirements for follow-up visits, and is willing to provide information at the scheduled evaluations.
3. Is a male or female patient aged 40 years or older
4. Is ambulatory (assistive devices are allowed if used 3 months or more prior to Screening) with an active lifestyle and in good general health
5. Has documented diagnosis of OA of the target knee where the disease has existed for at least 3 months prior to Screening. Radiographic evidence of OA of the target knee at screening is considered adequate
6. Currently meets American College of Rheumatology (ACR) Criteria for OA as noted below:
o Knee pain for most days of prior month, and
o Osteophytes at joint margins (radiograph)
OR
o Knee pain for most days of prior month, and
o Synovial fluid typical of OA (laboratory), and
o Morning stiffness ≤ 30 minutes in duration, and
o Crepitus on active joint motion
OR
o Knee pain for most days of prior month, and
o Age ≥ 40 years, and
o Morning stiffness ≤ 30 minutes in duration, and
o Crepitus on active joint motion
7. Has continued target knee OA pain despite conservative treatment (e.g., weight reduction, physical therapy, analgesics)
8. Is willing to withhold intake of NSAIDs (including cyclooxygenase-2 [COX-2] inhibitors) and analgesics, for a washout period of up to 21 days (depending on medication).
9. Is willing to discontinue prohibited treatments and medications throughout the study duration
10. Is willing to withhold intake of pain medications for 48 hours prior to all study visits
Baseline:
11. If female, must have a negative serum pregnancy test (at Screening) and use a medically acceptable form of contraception for at least 1 month prior to Screening and continue use for the duration of the study. Otherwise, females must be surgically sterile, or postmenopausal (as documented in medical history) for at least 1 year.
12. Continues to meet all Screening inclusion/exclusion criteria
13. Has completed the pain and OA medication washout period
14. Has pain in the target knee as demonstrated by a score of 2 or 3 on the WOMAC LK 3.1 A1
15. Has a mean score of 1.5 to 3.5 on the WOMAC LK 3.1 A at Baseline (Day 0)
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| E.4 | Principal exclusion criteria |
A patient will be excluded from this study if he/she does not meet the specific inclusion criteria, or if he/she is/has:
1. Modified Kellgren-Lawrence Numerical Grading System of grade 0 or grade IV for the target knee confirmed by radiographs performed within 3 months prior to Screening (see definitions below): (0) None: No Features of OA (IV) Severe: Joint space greatly impaired, with sclerosis of subchondral bone
2. Clinically apparent tense effusion of the target knee
3. Significant valgus/varus deformities, ligamentous laxity, or meniscal instability as assessed by the Investigator
4. Acute disease or trauma leading to secondary OA of the target knee within 10 years prior to screening
5. Viscosupplementation in any joint including the target knee within 12 months prior to Screening
6. Had arthroplasty at the target knee at any time or any other previous surgery in the target knee within the 6 months prior to Screening, or planned surgery throughout the duration of the study
7. Receiving physical therapy (at an outpatient/clinic setting) for the target knee that was initiated within 1 month before Screening
8. History of septic arthritis in any joint
9. Concomitant inflammatory disease or other condition that affects the joints (e.g., rheumatoid arthritis, metabolic bone disease, psoriasis, gout, chondrocalcinosis and active infection, etc.)
10. Symptomatic peripheral vascular disease of the study leg (prior or current)
11. Clinically significant venous or lymphatic stasis present in the study leg
12. Using protocol-prohibited medication/treatments for chronic pain that patient cannot be withdrawn from prior to study treatment at Baseline and throughout the duration of the study
13. Any musculoskeletal condition that would impede measurement of efficacy at the target knee
14. Symptomatic OA of the contralateral knee or of the ipsilateral hip, or symptomatic patello-femoral OA of the target knee, that is not responsive to acetaminophen / paracetamol (APAP) and requires other therapy
15. Systemic, or IA injection of corticosteroids in any joint within 3 months prior to Screening
16. Active infection, or history of an infection within the past 12 months, in the area to be injected
17. Any significant chronic skin disorder that could interfere with evaluation of the injection site
18. Heparin or crystalline warfarin (i.e., Coumadin®) anticoagulant therapy
19. Any known contraindication to acetaminophen/paracetamol (APAP
20. Any known contraindication to IA corticosteroids
21. Started the use of glucosamine, chondroitin sulfate, diacerhein, or avocado/soya extracts within 2 months prior to Screening
22. Uncontrolled diabetes mellitus, diabetic neuropathy, or infectious complications; end-stage hepatic or renal disease; or patients on immunosuppressive therapy
23. Current malignancy or treatment for malignancy within the past 5 years, except non-melanoma skin cancer
24. Active asthma that may require periodic treatment with systemic steroids during the study period (note: inhaled steroids for this condition are allowed)
25. Any significant medical condition (e.g., significant psychiatric or neurological disorders, active alcohol/drug abuse, etc.) or other factor (e.g., planned relocation) that the Investigator feels would interfere with study evaluations and study participation
26. Used an investigational drug, device, or biologic within 3 months before Screening
27. Females who are pregnant, lactating or unwilling to use medically acceptable contraception, or women unwilling to perform a pregnancy test before administration of study treatment
28. Ongoing litigation for workers compensation for musculoskeletal injuries or disorders
29. Hypersensitivity to hyaluronan or its derivatives
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Performances :
Primary Efficacy Objective;
This study has two primary objectives:
The first objective of this study is to compare the safety and efficacy of 1 x 4-mL and 2 x 4-mL IA injections of AVS-beta against 1 x 1-mL (40 mg/mL) IA injection of methylprednisolone acetate in treating patients with symptomatic knee OA.
Secondly, to demonstrate that the odds of positive response to treatment for symptomatic knee OA over 26 weeks (where positive response is defined with the OMERACT-OARSI [Pham et al., 2003, J Rheum] set of criteria) is higher in patients treated with a 1 x 4-mL and/or 2 x 4-mL IA injections of AVS-beta compared to patients treated with a course of methylprednisolone acetate
Secondary Efficacy Variables;
Odds of positive response to treatment for symptomatic knee OA with a 1 and/or 2 x 4-mL IA injections AVS-beta compared to methylprednisolone acetate
The differences between -
WOMAC LK 3.1 A change from Baseline to Week 26 in AVS-beta and methylprednisolone acetate groups
WOMAC LK 3.1 A1 over 26 weeks and from Baseline to Week 26 in AVS beta and methylprednisolone acetate groups
WOMAC LK 3.1 A1 change from Baseline to Week 26 in AVS-beta and methylprednisolone acetate groups
WOMAC LK 3.1 C (physical function subscale) over 26 weeks and from Baseline to Week 26 in AVS-beta and the methylprednisolone acetate groups
Total WOMAC over 26 weeks and from Baseline to Week 26 in the AVS-beta and methylprednisolone acetate groups
PTGA over 26 weeks and from Baseline to Week 26 in AVS-beta and methylprednisolone acetate group
COGA over 26 weeks and from Baseline to Week 26 in AVS-beta and the methylprednisolone acetate groups
The longitudinal response profiles of the AVS-beta treatment groups and the methylprednisolone acetate group with plots of summary statistics (e.g., mean, median, interquartile range) and, when applicable, confidence intervals for the total WOMAC LK 3.1 score, and for the WOMAC LK 3.1 A, WOMAC LK 3.1 A1, and WOMAC LK 3.1 C subscores
The proportions of patients who had a 1-category improvement from Baseline in WOMAC LK 3.1 A at Week 26 between the AVS-beta treatment groups and the methylprednisolone acetate group
The change from Baseline in the SF-36 total and subscales at Week 26 between the AVS-beta treatment groups and the methylprednisolone acetate group
The use of rescue medication (APAP) at each scheduled visit for the AVS-beta treatment groups and the methylprednisolone acetate group
Efficacy parameters in the Initial Cohort Repeat Treatment Phase for each AVS-beta treatment group
2. Safety:
Safety will be determined using the incidence of treatment-emergent AEs, clinical laboratory evaluations, vital signs, and physical examination findings. AEs will be categorized using a standardized coding dictionary (e.g., Medical Dictionary for Regulatory Activities [MedDRA]).
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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 | No |
| 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 | Information not present in EudraCT |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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 |
| Depo-medrone is the comparator to a medical device under investigation |
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| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | Information not present in EudraCT |
| 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 |
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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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| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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