| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Osteoarthritis of the knee |
|
| E.1.1.1 | Medical condition in easily understood language |
| Osteoarthritis of the knee |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023476 |
| E.1.2 | Term | Knee osteoarthritis |
| E.1.2 | System Organ Class | 100000004859 |
|
| 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 primary objective of this study is to assess the magnitude and duration of pain relief of a single intra-articular (IA) injection of FX006, an extended release formulation of triamcinolone acetonide (TCA), relative to normal saline (placebo control). |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the effect of FX006 on the magnitude and duration of pain relief relative to triamcinolone acetonide injectable suspension, immediate release (commercially available) (TCA IR).
- To assess the effect of FX006 on function, responder status, global impressions of change, stiffness, and consumption of analgesic medications relative to both controls.
- To assess the safety and general tolerability of a single IA injection of FX006 relative to both controls. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written consent to participate in the study
2. Willingness and ability to comply with the study procedures and visit schedules and ability to follow verbal and written instructions
3. Male or female ≥40 years of age
4. Symptoms associated with OA of the knee for ≥ 6 months prior to Screening (patient reported is acceptable)
5. Currently meets American College of Rheumatology (ACR) Criteria (clinical and radiological) for OA (Altman et al, 1986) as follows:
• Knee pain
• at least 1 of the following:
o Age > 50 years
o Stiffness < 30 minutes
o Crepitus
• Osteophytes
6. Kellgren-Lawrence (K-L) Grade 2 or 3 in the index knee based on X-ray performed during Screening (locally read)
• Grade 2: definite osteophytes and possible narrowing of joint space
• Grade 3: moderate multiple osteophytes, definite narrowing of joint space and some sclerosis and possible deformity of bone ends
7. Index knee pain for >15 days over the last month (as reported by the patient)
8. Mean score of ≥ 5 and ≤ 9 on the 24-hr average pain score (0-10 numeric ratings scale (NRS)) using the average daily ratings for at least 5 of the 7 days prior to Day 1
9. No more than one 24-hr average pain score (0-10 NRS) reported as “10” during the 7 days prior to Day 1
10. If bilateral OA exists, pain in the contralateral knee must be less than pain in the index knee as reported by the patient
11. Body mass index (BMI) ≤ 40 kg/m2
12. Ambulatory and in good general health
13. Willingness to abstain from use of protocol-specified restricted medications and non-pharmacological therapies during the study |
|
| E.4 | Principal exclusion criteria |
Patients fulfilling at least one of the following criteria may not be included in the study:
Disease-related criteria
1. Any condition that could possibly confound the patient’s assessment of index knee pain in judgment of the investigator (i.e., ipsilateral hip OA, gout, radicular low back pain and hip pain that is referred to the knee that could cause misclassification, pain in any other area of the lower extremities or back that is equal to or greater than the index knee pain)
2. Fibromyalgia, Reiter’s syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or arthritis associated with inflammatory bowel disease
3. History of infection in the index knee
4. Clinical signs and symptoms of active knee infection or crystal disease of the index knee within 1 month of Screening
5. Unstable joint (such as a torn anterior cruciate ligament) within 12 months of Screening Previous or concomitant OA treatment-related criteria
6. IA corticosteroid (investigational or marketed) in any joint within 3 months of Screening
7. IA hyaluronic acid (investigational or marketed) in the index knee within 6 months of Screening
8. Intramuscular (IM) or oral corticosteroids (investigational or marketed) within 1 month of Screening
9. Any other IA investigational drug/biologic use within 6 months of Screening
10. Prior use of FX006
11. Prior arthroscopic or open surgery of the index knee within 12 months of Screening
12. Planned/anticipated surgery of the index knee or any other surgery that would require use of a restricted
medication during the study period Patient-related criteria
13. Known hypersensitivity to any form of triamcinolone
14. History of sarcoidosis or amyloidosis
15. Active or history of malignancy within the last 5 years, with the exception of resected basal cell carcinoma, squamous cell carcinoma of the skin, or effectively managed cervical carcinoma
16. Known active or quiescent systemic fungal, bacterial (including tuberculosis), viral or parasitic infections, or ocular herpes simplex
17. Any infection requiring intravenous antibiotics within 4 weeks of Screening or oral antibiotics within 2 weeks of Screening
18. History of osteomyelitis
19. Known or clinically suspected infection with human immunodeficiency virus (HIV), hepatitis B or C viruses
20. Any clinically significant electrocardiogram (ECG) abnormality as judged by the Investigator
21. Patients requiring or likely to require chronic treatment with corticosteroids during the study period based on patient medical history
22. Uncontrolled diabetes as indicated by a hemoglobin A1c (HbA1c) of > 7.5% (> 59 mmol/mol)
23. Active psychiatric disorder including psychosis (e.g., schizophrenia), bipolar disorder, uncontrolled anxiety disorder and major depressive disorder
24. History of or active Cushing’s syndrome
25. Positive drug screen (amphetamines, barbiturates, benzodiazepines (indicated as a muscle relaxant), cocaine, opiates, tetrahydrocannabinol (THC))
26. Active substance abuse (drugs or alcohol), history of chronic substance abuse within the past year, or prior chronic substance abuse judged by the investigator as likely to recur during the study
27. Skin breakdown at the knee where the injection would take place
28. Women who are pregnant or nursing
29. Women of child-bearing potential (not surgically sterile or post-menopausal for at least 1 year as documented in medical history) not using a highly effective method of contraception (abstinence; oral, injected or implanted hormonal methods of contraception; intrauterine device (IUD) or intrauterine system (IUS); condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; or male sterilization (vasectomy))
30. Use of immunomodulators, immunosuppressives, or chemotherapeutic agents within 5 years of Screening
31. Has received a live or live attenuated vaccine within 3 months of Screening
32. Use of any other investigational drug or device within 30 days of Screening or an investigational biologic within 60 days of Screening
33. Any other clinically significant acute or chronic medical conditions (e.g., bleeding disorder) that, in the judgment of the Investigator, would preclude the use of an IA corticosteroid or that could compromise patient safety, limit the patient’s ability to complete the study, and/or compromise the objectives of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy
Average daily (24-h) pain intensity score on a 0 to 10 NRS scale with 0 indicating ‘no pain’ and 10 indicating ‘pain as bad as you can imagine’ (Dworkin et al¸ 2005; Cleeland and Ryan, 1994) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The study will involve a Screening period (up to 21 days) and 7 out-patient visits (Days 1 [Baseline], Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24). Each patient will be evaluated for a total of 24 weeks after treatment. Patients will be evaluated for efficacy and safety. |
|
| E.5.2 | Secondary end point(s) |
Efficacy
Worst daily pain intensity score on a 0 to 10 NRS scale with 0 indicating ‘no pain’ and 10 indicating ‘pain as bad as you can imagine’ (Dworkin et al¸ 2005)
• WOMAC Osteoarthritis Index (LK 3.1, 5-point scale): pain, stiffness and function domains independently and collectively (Bellamy et al, 1988).
• PGIC: 7-point scale (Farrar et al, 2001; Guy, 1976; Dworkin et al, 2005) (Appendix 3).
• CGIC: 7-point scale (Guy, 1976) (Appendix 3).
• KOOS Quality of Life (QOL) Subscale (http://www.koos.nu/)
• SF-12 (1 week recall version) (http://www.sf-36.org/tools/sf12.shtml)
• Responder status as defined by:
o Proportion of patients experiencing either >50%, >30% or >20% decrease (improvement) in pain from baseline in weekly mean of the average daily (24-hr) pain intensity scores (substantial, at least moderate and minimum clinically important difference, respectively, as defined by Dworkin et al, 2008)
o Outcome Measures in Rheumatology (OMERACT) - Osteoarthritis Research Society International (OARSI) criteria (Pham, 2004)
• Time of onset of pain relief (based on average daily pain intensity scores)
• Consumption of rescue medication
Safety
• AEs
• Physical examinations
• Index knee examinations
• Index knee X-rays
• Vital signs
• ECGs
• Clinical laboratory evaluations |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The study will involve a Screening period (up to 21 days) and 7 out-patient visits (Days 1 [Baseline], Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24). Each patient will be evaluated for a total of 24 weeks after treatment. Patients will be evaluated for efficacy and safety. |
|
| 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 | 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) | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Australia |
| Canada |
| Denmark |
| Estonia |
| Hong Kong |
| Lithuania |
| New Zealand |
| Romania |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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