Study of the Analgesic Efficacy and Safety of Subcutaneous Tanezumab in Subjects With Osteoarthritis of the Hip or Knee.

A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY OF THE ANALGESIC EFFICACY AND SAFETY OF THE SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB IN SUBJECTS WITH OSTEOARTHRITIS OF THE HIP OR KNEE

Tanezumab is a monoclonal antibody that binds to and inhibits the actions of nerve growth factor (NGF). The Nerve Growth Factor Inhibitor (NGFI) class may offer an important breakthrough in the treatment of chronic pain and is under clinical investigation for the treatment of pain associated with osteoarthritis or other chronic pain conditions.

The primary objective of this study is to demonstrate superior efficacy of tanezumab 5 mg and 2.5 mg administered subcutaneously (SC) every 8 weeks versus placebo at Week 24 in subjects with osteoarthritis of the knee or hip. The 2.5 mg dose was shown to provide efficacy benefits with a favorable safety profile when administered intravenously in previous Phase 3 clinical trials. The 5 mg dose is expected to provide added efficacy benefit over the 2.5 mg dose based on data from previous studies.

This is a randomized, double blind, placebo controlled, parallel group multicenter Phase 3 study of the efficacy and safety of tanezumab when administered by SC injection for 24 weeks compared to placebo in subjects with osteoarthritis of the knee or hip. A total of approximately 810 subjects will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio (ie, 270/group). The randomization will be stratified by index joint (hip or knee), and most severe Kellgren-Lawrence grade (of any knee or hip joint) at study entry (grade 2, 3 or 4). Subjects will receive up to three SC doses of one of the following treatments at an 8-week interval between each injection:

1. tanezumab 2.5 mg;
2. tanezumab 5 mg;
3. Placebo to match tanezumab. The study is designed with a total (post-randomization) duration of 48 weeks and will consist of three periods: Screening (up to 37 days), Double-blind Treatment (24 weeks) and Safety Follow-up (24 weeks). The Screening Period (beginning up to 37 days prior to Randomization) includes a Washout Period (lasting a minimum of 2 days for all prohibited pain medications), if required, and an Initial Pain Assessment Period (the 7 days prior to Randomization/Baseline).

Week 24 is the landmark analysis in this study. Subjects who do not complete the Double-blind Treatment period will enter and complete the 24-week Early-termination follow-up period.

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 at least 2 as diagnosed by the Central Reader
• A history of insufficient pain relief from acetaminophen along with a history of insufficient pain relief from, inability to tolerate or contraindication to taking NSAIDs, and tramadol or opioid treatments.
• WOMAC Pain subscale score of at least 5 in the index hip or knee 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 (e.g. 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 (e.g. fibromyalgia, 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.
• 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.