Long Term Safety and Efficacy Study of Tanezumab in Japanese Adult Subjects With Chronic Low Back Pain

A PHASE 3 RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED, MULTICENTER STUDY OF THE LONG-TERM SAFETY AND EFFICACY OF SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB IN JAPANESE ADULT SUBJECTS WITH CHRONIC LOW BACK PAIN

This study will investigate the long-term safety and efficacy of a fixed dose of tanezumab 5 mg and 10 mg administered subcutaneously (SC) seven times at 8 week intervals. The primary objective of this study is to evaluate the long term safety of tanezumab 5 mg and 10 mg administrated SC every 8 weeks (7 administrations). In addition, the study will evaluate the long term analgesic efficacy of tanezumab 5 mg and 10 mg SC administered every 8 weeks (7 administrations).

This is a randomized, double-blind, active-controlled, multicenter, parallel-group Phase 3 study of the safety and efficacy of tanezumab when administered by SC injection for up to 56 weeks in subjects with chronic low back pain. Subjects will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio. Treatment groups will include: 1) Placebo SC matching tanezumab administered at an 8-week interval (total of 7 times) plus celecoxib 100 mg twice a day (BID) to be administered orally for 56 weeks; 2) Tanezumab 5 mg SC administered at an 8-week interval (total of 7 times) plus placebo matching celecoxib to be administered orally BID for 56 weeks; 3) Tanezumab 10 mg SC administered at an 8-week interval (total of 7 times) plus placebo matching celecoxib to be administered orally BID for 56 weeks. The study is designed with a total duration (post-randomization) of up to 80 weeks and will consist of three periods: Screening (up to 37 days; includes a Washout Period and an Initial Pain Assessment Period [IPAP]), a Double-blind Treatment Period (56 weeks) and a Follow-up Period (24 weeks). The Screening Period (beginning up to 37 days prior to Randomization) includes a Washout Period (lasting 2 to 32 days), if required, and an IPAP (the 5 days prior to Randomization/Baseline). Prior to entering the study, subjects must be experiencing some benefit (eg, analgesic effect) from their current stable dose regimen of oral NSAID (celecoxib, loxoprofen or meloxicam) treatment, be tolerating their NSAID regimen, 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.

Inclusion Criteria:

• Duration of chronic low back pain for ≥3 months, and treatment with agents for low back pain for ≥3 months.
• Primary location of low back pain must be between the 12th thoracic vertebra and the lower gluteal folds, with or without radiation into the posterior thigh, classified as Category 1 or 2 according to the classification of the Quebec Task Force in Spinal Disorders.
• Subjects must be experiencing some benefits from their current stable dose regimen of oral NSAID (celecoxib, loxoprofen or meloxicam) treatment as described in the protocol, be tolerating their NSAID regimen, be taking this medication regularly during the 30 day period prior to the Screening visit and must have had some improvement in low back pain, but still require additional pain relief at Screening.
• Subjects must maintain a stabilized, protocol specified NSAID dose regimen for at least the final 2 or 3 weeks of the Screening period.
• Low Back Pain Intensity (LBPI) score of ≥5 at Screening.
• Subjects must be willing to discontinue all pain medications for chronic low back pain except rescue medication and investigational product and not use prohibited pain medications throughout the duration of the study.
• Female subjects of childbearing potential and at risk for pregnancy must agree to comply with protocol specified contraceptive requirements.

Exclusion Criteria:

• Subjects exceeding protocol defined BMI limits.

• Diagnosis of osteoarthritis of the knee or hip as defined by the ACR combined clinical and radiographic criteria.

  • Subjects who have Kellgren Lawrence Grade > or =2 radiographic evidence of hip or Grade > or =3 radiographic evidence of knee osteoarthritis will be excluded.
  • Subjects who have Kellgren Lawrence Grade < or =2 radiographic evidence of knee osteoarthritis but who do not meet ACR criteria and do not have pain associated with their knee osteoarthritis will be allowed.

• Subjects with symptoms and radiologic findings consistent with osteoarthritis in the shoulder.

• History of lumbosacral radiculopathy within the past 2 years, history of spinal stenosis associated with neurological impairment, or history of neurogenic claudication.

• Back pain due to recent major trauma within 6 months prior to Screening.

• Surgical intervention during the past 6 months for the treatment of low back pain.

• Planned surgical procedure during the duration of the study.

• History or radiographic evidence of other diseases that could confound efficacy or safety assessments (eg, 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.

• History of osteonecrosis or osteoporotic fracture.

• History of significant trauma or surgery to a knee, hip, or shoulder within the previous year.

• Signs or symptoms of carpal tunnel syndrome in the one 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 celecoxib/acetaminophen or any of its excipients or existence of a medical condition or use of concomitant medication for which the use of celecoxib/acetaminophen is contraindicated.

• Use of prohibited medications or prohibited non-pharmacological treatments without the appropriate washout period (if applicable) prior to Screening or IPAP.

• History of known alcohol, analgesic or narcotic abuse within 2 years of Screening.

• Presence of drugs of abuse or illegal drugs in the urine toxicology screen obtained at Screening.

• History of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal antibody or IgG-fusion protein.

• Signs and symptoms of clinically significant cardiac disease.

• 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.

• 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 of cancer within 5 years prior to Screening, except for cutaneous basal cell or squamous cell cancer resolved by excision.

• Expected to undergo a therapeutic procedure or to use any analgesic other than those specified in the protocol throughout the pre-treatment and treatment periods that is likely to confound assessment of analgesic efficacy or safety.

• Previous exposure to exogenous NGF or to an anti-NGF antibody.

• Screening AST, ALT, serum creatinine or HbA1c values that exceed protocol defined limits.

• Positive Hepatitis B, Hepatitis C, or HIV tests at screening indicative of current infection.

• History, diagnosis, or signs and symptoms of clinically significant neurological disease or clinically significant psychiatric disorder.

• Pregnant, breastfeeding or female subjects of childbearing potential who are unwilling or unable to follow protocol required contraceptive requirements.

• Participation in other investigational drug studies within protocol defined time limits.

• 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.