Long Term Safety and Efficacy Study of Tanezumab in Subjects With Osteoarthritis of the Hip or Knee

• Incidence of a predefined composite endpoint [ Time Frame: 80 weeks ]
  Composite endpoint consists of adjudicated outcomes specified in protocol
• Change from Baseline in WOMAC Pain Subscale Score [ Time Frame: Week 16 ]
  Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale
• Change from Baseline in WOMAC Physical Function Subscale Score [ Time Frame: Week 16 ]
  Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function subscale
• Change from Baseline in Patient's Global Assessment of Osteoarthritis [ Time Frame: Week 16 ]

• Incidence of individual adjudication outcomes [ Time Frame: 80 Weeks ]
  Adjudication outcomes specified in protocol
• Incidence of all cause total joint replacements [ Time Frame: 80 weeks ]
  All cause total joint replacement is as defined in the protocol
• Change from Baseline in Minimum Joint Space Width of the index knee [ Time Frame: Weeks 56 and 80 ]
  For subjects with Kellgren Lawrence Grade 2 or 3 osteoarthritis of the index knee
• Change from Baseline in Minimum Joint Space Width of the index hip [ Time Frame: Weeks 56 and 80 ]
  For subjects with Kellgren Lawrence Grade 2 or 3 osteoarthritis of the index hip
• Incidence of subjects with progression of osteoarthritis in the index knee according to Bland and Altman method [ Time Frame: Weeks 56 and 80 (separately) ]
  For subjects with Kellgren Lawrence Grade 2 or 3 osteoarthritis of the index knee
• Incidence of subjects with progression of osteoarthritis in the index hip according to Bland and Altman method [ Time Frame: Weeks 56 and 80 (separately) ]
  For subjects with Kellgren Lawrence Grade 2 or 3 osteoarthritis of the index hip
• WOMAC Pain subscale change from Baseline [ Time Frame: Weeks 2, 4, 8, 24, 32, 40, 48, 56 and 64 ]
• WOMAC Physical Function subscale change from Baseline [ Time Frame: Weeks 2, 4, 8, 24, 32, 40, 48, 56 and 64 ]
• Patient's Global Assessment of Osteoarthritis change from Baseline [ Time Frame: Weeks 2, 4, 8, 16 (Japan only), 24, 32, 40, 48, 56 and 64 ]
• OMERACT OARSI responder index [ Time Frame: Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 ]
• Treatment Response: Reduction in the WOMAC Pain subscale of 30%, 50%, 70% and 90% [ Time Frame: Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 ]
• Cumulative distribution of percent change from Baseline in the WOMAC Pain subscale score [ Time Frame: Weeks 16, 24, and 56 ]
  Endpoint for summary only
• Treatment Response: Reduction in the WOMAC Physical Function subscale of 30%, 50%, 70% and 90%. [ Time Frame: Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 ]
• Cumulative distribution of percent change from Baseline in the WOMAC Physical Function subscale score [ Time Frame: Weeks 16, 24, and 56 ]
  Endpoint for summary only
• Treatment Response: Improvement of 2 points in Patient's Global Assessment of Osteoarthritis [ Time Frame: Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 ]
• Average pain score in the index joint change from Baseline [ Time Frame: Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 40, 48, 56 and 64 ]
• WOMAC Stiffness subscale change from Baseline [ Time Frame: Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 ]
• WOMAC Average change from Baseline [ Time Frame: Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 ]
• WOMAC Pain Subscale Item: Pain When Walking on a Flat Surface, change from Baseline [ Time Frame: Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 ]
• WOMAC Pain Subscale Item: Pain When Going Up or Down Stairs, change from Baseline [ Time Frame: Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 ]
• Work Productivity and Activity Impairment Questionnaire for Osteoarthritis (WPAI:OA) impairment scores change from Baseline [ Time Frame: Weeks 16, 24, 56 and 64 ]
• EuroQol 5 Dimension (EQ 5D 5L) dimensions and overall health utility score [ Time Frame: Baseline and Weeks 8, 16, 24, 40, 56 and 64 ]
• Treatment Satisfaction Questionnaire Medicine v.II (TSQM v.II) satisfaction with effectiveness, side effects and convenience, and overall satisfaction [ Time Frame: Weeks 16 and 56 ]
• Patient Reported Treatment Impact Assessment Modified (mPRTI) [ Time Frame: Weeks 16 and 56 ]
• Incidence and Time to discontinuation due to Lack of Efficacy [ Time Frame: 56 Weeks ]
• Incidence of Rescue Medication Use [ Time Frame: Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 ]
• Amount of Rescue Medication Taken [ Time Frame: Weeks 2, 4, 8 and 16 ]
• Health Care Resource Utilization [ Time Frame: Baseline and Weeks 64, and 80 ]
• Lower Extremity Activity Scale: change from Baseline [ Time Frame: Weeks 4, 8, 16, 24, 56 and 80 ]
  All subjects
• Change from Baseline in average daily minutes of physical activity [ Time Frame: Weeks 16 and 56 ]
  A subset of subjects
• Change from Baseline in average daily physical activity counts [ Time Frame: Weeks 16 and 56 ]
  A subset of subjects
• Change from Baseline in average daily minutes of moderate to vigorous physical activity [ Time Frame: Weeks 16 and 56 ]
  A subset of subjects
• Change from Baseline in average daily minutes of bouted (sustained) moderate to vigorous physical activity [ Time Frame: Weeks 16 and 56 ]
  A subset of subjects
• Change from Baseline in average daily step count [ Time Frame: Weeks 16 and 56 ]
  A subset of subjects
• Incidence of Subjects with Adverse Events [ Time Frame: 80 Weeks ]
• Orthostatic (supine/standing) blood pressure [ Time Frame: Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80 ]
• Survey of Autonomic Symptom scores [ Time Frame: Screening and Weeks 24, 56 and 80 ]
• Neurologic examinations [ Time Frame: Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80 ]
  Neuropathy Impairment Score [NIS]
• Anti tanezumab antibody levels [ Time Frame: Baseline, Weeks 8, 16, 32, 48, 56 and 80 ]
• Incidence of Physical Examination Findings [ Time Frame: Screening and Week 56 ]
• Incidence of Subjects with Clinical Laboratory Test Abnormalities [ Time Frame: Baseline, Weeks 16 and 64 ]
  Hematology and blood chemistry values
• Change from Baseline Sitting Blood Pressure [ Time Frame: Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80 ]
• Change from Baseline Sitting Heart Rate [ Time Frame: Baseline, Weeks 2, 4, 8, 16, 34, 32, 40, 48, 56, 64 and 80 ]
• Change from Baseline 12-lead Electrocardiogram [ Time Frame: Screening, Weeks 56 and 80 ]
• Number of Days of Rescue Medication Use [ Time Frame: Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64 ]

• Chronic Pain
• Osteoarthritis, Hip
• Osteoarthritis, Knee

• Drug: NSAID
  Orally administered NSAID (naproxen 500 mg, celecoxib 100 mg or diclofenac 75 mg) twice daily for 56 weeks
• Biological: Tanezumab 2.5 mg
  Subcutaneous injection of tanezumab 2.5 mg every 8 weeks for 56 weeks
• Biological: Tanezumab 5 mg
  Subcutaneous injection of tanezumab 5 mg every 8 weeks for 56 weeks

• Active Comparator: NSAID
  Subcutaneous injection of placebo for tanezumab every 8 weeks plus oral NSAID (naproxen 500 mg, celecoxib 100 mg or diclofenac 75 mg) twice daily for 56 weeks
  Intervention: Drug: NSAID
• Experimental: Tanezumab 2.5 mg
  Subcutaneous injection of tanezumab 2.5 mg every 8 weeks plus oral placebo for NSAID (naproxen, celecoxib or diclofenac ER) twice daily for 56 weeks
  Intervention: Biological: Tanezumab 2.5 mg
• Experimental: Tanezumab 5 mg
  Subcutaneous injection of tanezumab 5 mg every 8 weeks plus oral placebo for NSAID (naproxen, celecoxib or diclofenac) twice daily for 56 weeks
  Intervention: Biological: Tanezumab 5 mg

Inclusion Criteria:

• A diagnosis of osteoarthritis of the index hip or knee based on American College of Rheumatology criteria with Kellgren Lawrence X ray Grade of 2 as diagnosed by the Central Reader
• Currently receiving a stable dose regimen of oral NSAID (naproxen, celecoxib, diclofenac, aceclofenac, loxoprofen, ibuprofen, meloxicam, nabumetone, sulindac or ketoprofen) as described in the protocol along with a history of insufficient pain relief from, inability to tolerate or contraindication to taking acetaminophen and, tramadol or opioid treatments. Subjects must also maintain a stabilized, protocol specified NSAID dose regimen for at least the final 2 or 3 weeks of the Screening period
• WOMAC Pain subscale score of at least 5 in the index knee or hip at Screening
• Be willing to discontinue all non study pain medications for osteoarthritis and not use prohibited pain medications throughout the duration of the study
• Female subjects of childbearing potential must agree to comply with protocol specified contraceptive requirements

Exclusion Criteria:

• Subjects exceeding protocol defined BMI or body weight limits
• History of other diseases specified in the protocol (eg, inflammatory joint diseases, crystalline diseases such as gout or pseudogout) that may involve the index joint and that could interfere with efficacy assessments
• Radiographic evidence of protocol specified bone or joint conditions in any screening radiograph as determined by the central radiology reviewer
• A history of osteonecrosis or osteoporotic fracture
• History of significant trauma or surgery to a knee, hip or shoulder within the previous year
• Planned surgical procedure during the duration of the study
• Presence of conditions (eg, fibromyaliga, radiculopathy) associated with moderate to severe pain that may confound assessments or self evaluation of osteoarthritis pain
• Signs or symptoms of carpal tunnel syndrome in the year prior to Screening
• Considered unfit for surgery based upon American Society of Anesthesiologists physical classification system for surgery grading, or subjects who would not be willing to undergo joint replacement surgery if required
• Contraindications to magnetic resonance imaging
• History of intolerance or hypersensitivity to the 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
• History of intolerance or hypersensitivity to acetaminophen or any of its excipients or existence of a medical condition or use of concomitant medication for which the use of acetaminophen is contraindicated
• Use of prohibited medications without the appropriate washout period prior to Screening or Initial Pain Assessment Period
• History of cancer within 5 years of Screening, except for cutaneous basal cell or squamous cell cancer resolved by excision
• Subjects with signs and symptoms of clinically significant cardiac disease as described in the protocol
• Diagnosis of a transient ischemic attack in the 6 months prior to Screening, diagnosis of stroke with residual deficits that would preclude completion of required study activities
• History, diagnosis, or signs and symptoms of clinically significant neurological disease such as but not limited to peripheral or autonomic neuropathy
• History, diagnosis, signs or symptoms of any clinically significant psychiatric disorder
• History of known alcohol, analgesic or drug abuse within 2 years of Screening
• Previous exposure to exogenous NGF or to an anti-NGF antibody
• History of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal antibody or IgG fusion protein
• Poorly controlled hypertension as defined in the protocol or taking an antihypertensive that has not been stable for at least 1 month prior to Screening
• Evidence of protocol defined orthostatic hypotension at Screening
• Disqualifying score on the Survey of Autonomic Symptoms questionnaire at Screening
• Screening AST, ALT, serum creatinine or HbA1c values that exceed protocol defined limits
• Presence of drugs of abuse in screening urine toxicology panel
• Positive hepatitis B, hepatitis C or HIV test results indicative of current infection
• Participation in other investigational drug studies within protocol defined time limits
• Pregnant, breastfeeding or female subjects of childbearing potential who are unwilling or unable to follow protocol required contraceptive requirements
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the judgment of the investigator, would make the subject inappropriate for entry into this study