Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study In Subjects With Osteoarthritic Pain Of The Knee

A 2-WEEK, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED, PARALLEL-GROUP, PHASE 2, MULTICENTER STUDY OF PF-04136309 IN SUBJECTS WITH OSTEOARTHRITIC PAIN OF THE KNEE

To evaluate the efficacy, safety, tolerability, pharmacodynamics, and pharmacokinetics in patients with osteoarthritic pain of the knee. The most painful knee joint will be identified as the index joint at screening, and this joint will be used for all pain assessments throughout the study.

Inclusion Criteria:

• Male or female of any race, between the ages of 18 and 75 years inclusive
• Female subjects must be of non-childbearing potential and have a negative pregnancy test at Screening.
• Osteoarthritis of the knee of at least 6 months duration and meeting the American College of Rheumatology Criteria. For radiographic criteria the Xray must have been taken within the last 5 years. If none is available, one should be taken and the diagnostic criteria confirmed prior to randomization.
• Willing and able to discontinue all current analgesic therapy, including OTC pain medications and topical analgesics for OA pain, for period beginning with washout phase (lasting 2 days or 5 half-lives of patient's current analgesic medication prior to Day -6) and continuing for the entire duration of study. As an exception, acetaminophen may be used for non-joint related pain at doses ≤1 g/day at the discretion of a qualified member of the study team.
• If a subject has evidence or a history of clinically significant endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, renal, psychiatric, or neurological disease, the investigator must confirm that the disease is stable (at least 4 weeks) and under control.
• QTc interval ≤450 msec and a PR interval ≤210 msec on Screening ECG.

Exclusion Criteria:

• Pregnant or lactating females, and females of childbearing potential.

• Arthroscopy performed on index knee within 1 year of screening.

• Active depression as defined by or meeting The Hospital Anxiety and Depression Scale (HADS) of >10.

• Unwillingness to refrain from consumption of grapefruit or grapefruit juice from 7 days prior to the first dose of study medication until completion of the study.

• First degree or higher AV block, defined as PR interval >210 msecs, bundle branch block, fascicular block or intraventricular conduction delay or clinically relevant abnormality on screening ECG.

• Active malignancy of any type or history of a malignancy within 10 years (with the exception of subjects with a history of treated basal cell carcinoma).

• Symptomatic OA of the hip ipsilateral to index knee which the patient considers more painful than the knee.

• Use of prohibited medications as listed below, in the absence of appropriate washout period. The following analgesic agents must be discontinued within 48 hours or 5 half lives of the analgesic being washed out prior to the baseline period (Day -6 to Day 0);

  • NSAIDs and selective COX-2 inhibitors;
  • Acetaminophen ( as an exception acetaminophen may be used for non-joint related pain at doses ≤1g/day);
  • Opioids.
  • Oral or I/M corticosteroids within 4 weeks prior to screening. I/A steroids within 12 weeks prior to baseline in study joint or any other joints within 4 weeks prior to baseline, or I/A hyaluronic acid within 24 weeks prior to baseline;
  • Use of concomitant medications that are CYP3A inhibitors or CYP3A inducers, or that are P-glycoprotein substrates within 48 hours or 5 half lives prior to baseline.