| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Osteoarthritis of the hip or knee |
|
| E.1.1.1 | Medical condition in easily understood language |
| Osteoarthritis of the hip or 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 | 21.1 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020108 |
| E.1.2 | Term | Hips 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 |
- Characterize the long-term risk of joint safety events in subjects with osteoarthritis of the knee or hip who receive tanezumab 2.5 mg or tanezumab 5 mg SC versus NSAID treatment (naproxen 500 mg BID, celecoxib 100 mg BID, or diclofenac ER 75 mg BID) over the course of 56-weeks of treatment using a composite endpoint (includes adjudication outcomes of rapidly progressive osteoarthritis type-1 or type-2, subchondral insufficiency fracture (SPONK), primary osteonecrosis, or pathological fracture).
-Demonstrate superior efficacy of tanezumab 2.5 mg and tanezumab 5 mg SC versus NSAID treatment (naproxen 500 mg BID, celecoxib 100 mg BID, or diclofenac ER 75 mg BID) at Week 16. |
|
| E.2.2 | Secondary objectives of the trial |
-Characterize the long-term joint safety risk using a composite endpoint (includes adjudication outcomes of rapidly progressive osteoarthritis (type-2 only), subchondral insufficiency fracture (or SPONK), primary osteonecrosis, or pathological fracture).
-Characterize the long-term risk of the following individual adjudication outcomes occurring: rapidly progressive osteoarthritis (type-1 only), rapidly progressive osteoarthritis (type-2 only), rapidly progressive osteoarthritis (type-1 or type-2 combined), subchondral insufficiency fracture (or SPONK), primary osteonecrosis,
and pathological fracture.
refer to protocol for further secondary objectives
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
- Male or female of any race,>=18 years of age.
- A diagnosis of osteoarthritis of the index hip or knee based on American College of Rheumatology criteria with X-ray confirmation (a Kellgren-Lawrence X-ray Grade of >=2 as diagnosed by the Central Reader).
-Subjects must meet the following criteria pertaining to their osteoarthritis treatment regimen:
•Documented history indicating that acetaminophen therapy has not provided sufficient pain relief;
•Currently receiving a stable dose regimen of oral NSAID therapy consisting of one of the NSAIDs presented in the following table, be tolerating this NSAID and be taking this medication regularly (defined as an average of at least 5 days per week) during the 30 day period prior to the Screening
visit.):
Table 7. Qualifying Pre-study NSAID Treatment Regimens
NSAID Qualifying Dose Range
Naproxen 440 mg/day* to 1000 mg/day
Celecoxib 200 mg/day (either 100 mg BID or 200 mg QD)
Diclofenac 100 mg/day to 150 mg/day
Aceclofenac 200 mg/day
Loxoprofen 120 mg/day to 180 mg/day
Ibuprofen 1200 mg/day to 3200 mg/day
Meloxicam 5 mg/day to 15 mg/day
Nabumetone 1000 mg/day to 2000 mg/day
Sulindac 200 mg/day to 400 mg/day
Ketoprofen 200 mg/day
•Maintain compliance with a stabilized dose regimen of either naproxen, diclofenac or celecoxib as specified in the protocol for at least the final 2 weeks of the Screening period.
AND at least 1 of the following criteria:
•Documented history indicating that tramadol treatment has not provided adequate pain relief or subject is unable to take tramadol due to contraindication or inability to tolerate;
•Documented history indicating that opioid treatment has not provided adequate pain relief or subject is unwilling to take opioids, or unable to take opioids due to contraindication or inability to tolerate.
- WOMAC Pain subscale NRS >=5 in the index knee or index hip at Screening.
- Female subjects of childbearing potential and at risk for pregnancy must agree to use 2 highly effective methods of contraception throughout the study and for 112 days (16 weeks) after the last dose of assigned subcutaneous investigational product. |
|
| E.4 | Principal exclusion criteria |
- History or radiographic evidence of other diseases that could confound efficacy assessments (e.g., rheumatoid arthritis).
- History or radiographic evidence of orthopedic conditions that may increase the risk of, or confound assessment of joint safety conditions during the study.
- Planned surgical procedure during the duration of the study.
- A past history of carpal tunnel syndrome (CTS) with signs or symptoms of CTS in the one year prior to Screening.
- History of intolerance or hypersensitivity to the relevant oral NSAID (naproxen, celecoxib or diclofenac) the subject could be randomized to receive or any of its excipients or existence of a medical condition or use of concomitant medication for which the use of this NSAID is contraindicated (refer to product labeling).
- Signs and symptoms of clinically significant cardiac disease within 6 months of the study (e.g., unstable angina, myocardial infarction, resting bradycardia, poorly controlled or untreated hypertension) as defined in the protocol or subjects with any other cardiovascular illness that in the opinion of the Investigator would render a subject unsuitable to participate in the study or Subjects with a history of heart block requiring ongoing treatment or that is associated with symptoms.
- History, diagnosis, or signs and symptoms of clinically significant neurological disease (e.g., transient ischemic attack, stroke, peripheral or autonomic neuropathy) as specified in the protocol
- Subjects with evidence or symptoms consistent with autonomic dysfunction (e.g., orthostatic hypotension and/or autonomic symptoms) as defined in the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Incidence of a predefined composite endpoint consisting of adjudication outcomes of rapidly progressive osteoarthritis (type-1 or type-2), subchondral insufficiency fracture (or SPONK), primary osteonecrosis, or pathological fracture (primary composite endpoint).
The co-primary efficacy endpoints are:
-Change from Baseline to Week 16 in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale.
-Change from Baseline to Week 16 in the WOMAC Physical Function subscale.
-Change from Baseline to Week 16 in the Patient’s Global Assessment of Osteoarthritis. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to the protocol |
|
| E.5.2 | Secondary end point(s) |
Bone and Joint Safety:
-Incidence of a predefined composite endpoint consisting of adjudication outcomes of rapidly progressive osteoarthritis (type-2 only), subchondral insufficiency fracture (or SPONK), primary osteonecrosis, or pathological fracture.
Refer to protocol for other Bone and Joint Safety endpoints
Radiographic:
-Change from Baseline to Week 56 and Week 80 in Medial or Lateral Minimum Joint
Space Width of the index knee (for subjects with Kellgren-Lawrence Grade 2 or 3 medial or lateral osteoarthritis of the index knee).
- Change from Baseline to Week 56 and Week 80 in Minimum Joint Space Width of the index hip (for subjects with Kellgren-Lawrence Grade 2 or 3 osteoarthritis of the index hip).
Refer to protocol for other Radiographic endpoints
Efficacy
-WOMAC Pain subscale change from Baseline to Weeks 2, 4, 8, 24, 32, 40, 48, 56 and Week 64.
-WOMAC Physical Function subscale change from Baseline to Weeks 2, 4, 8, 24, 32, 40, 48, 56 and Week 64.
- Patient’s Global Assessment of Osteoarthritis change from Baseline to Weeks 2, 4, 8, 16 (Japan only), 24, 32, 40, 48, 56 and Week 64.
-OMERACT-OARSI responder index at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
-Treatment Response: Reduction in the WOMAC Pain subscale of >=30%, >=50%, >=70% and >=90% at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and Week 64.
Refer to protocol for other Efficacy endpoints
Activity Level Monitoring
- Lower Extremity Activity Scale: change from Baseline to Weeks 4, 8, 16, 24, 56 and Week 80 (all subjects).
- Change from Baseline to Weeks 16 and 56 in average daily minutes of physical activity (a subset of subjects).
- Change from Baseline to Weeks 16 and 56 in average daily physical activity counts (a subset of subjects).
- Change from Baseline to Weeks 16 and 56 in average daily minutes of moderate to vigorous physical activity (a subset of subjects).
Refer to protocol for other Activity Level Monitoring endpoints
General Safety
-Adverse Events.
- Standard safety assessments (safety laboratory testing [chemistry, hematology], sitting vital signs, electrocardiogram (ECG; 12-lead).
Refer to protocol for other Safety endpoints |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to the protocol |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarker data analysis will be conducted according to the tanezumab biomarker analysis plan. |
|
| 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 | No |
| 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 | 10 |
| 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 |
| Brazil |
| Bulgaria |
| Colombia |
| Croatia |
| Japan |
| Korea, Republic of |
| Lithuania |
| Mexico |
| New Zealand |
| Peru |
| Philippines |
| Russian Federation |
| Serbia |
| Slovakia |
| Taiwan |
| Ukraine |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| 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 | 11 |
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