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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Drug: PF-04136309
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-04136309<br> | Drug: PF-04136309<br>* 125 mg capsules. Dose will be 4 capsules BID for 2 weeks for a total of 500 mg for each dosing interval.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo will be matched to PF-04136309. Dose, frequency, and duration same as PF-04136309.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Domain Score at Week 2 | WOMAC: self-administered, disease-specific 24 item questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness, and physical function in participants with osteoarthritis (OA) of the hip and/or knee. It consists of 3 domains: pain, stiffness and physical function. WOMAC pain domain consists of 5 questions scored on 5 point Likert scale (0=minimum pain to 4=maximum pain) where higher score indicates higher pain. It assesses amount of pain experienced due to OA in the study joint in past 48 hours. Total possible pain domain score calculated by addition of scores of each 5 questions ranged from: 0 (minimum) - 20 (maximum), higher scores indicate higher pain. | Baseline, Week 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in WOMAC Pain Domain Score at Week 1 | WOMAC: self-administered, disease-specific 24 item questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness, and physical function in participants with OA of the hip and/or knee. It consists of 3 domains: pain, stiffness and physical function. WOMAC pain domain consists of 5 questions scored on 5 point Likert scale (0=minimum pain to 4=maximum pain) where higher score indicates higher pain. It assesses amount of pain experienced due to OA in the study joint in past 48 hours. Total possible pain domain score calculated by addition of scores of each 5 questions ranged from: 0 (minimum) - 20 (maximum), higher scores indicate higher pain. | Baseline, Week 1 | 
| Change From Baseline in WOMAC Stiffness Domain Score at Week 1 and Week 2 | WOMAC: self-administered, disease-specific 24 item questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness, and physical function in participants with OA of the hip and/or knee. It consists of 3 domains: pain, stiffness and physical function. WOMAC stiffness domain consist of 2 questions scored on 5 point Likert scale (0=minimum stiffness to 4= maximum stiffness), higher score indicates higher stiffness. It assesses stiffness (sensation of decreased ease) due to OA in study joint in past 48 hours. Total possible stiffness domain score calculated by addition of scores of each 2 questions ranged from: 0 (minimum) to 8 (maximum), higher scores indicate higher stiffness. | Baseline, Weeks 1, 2 | 
| Change From Baseline in WOMAC Physical Function Domain Score at Week 1 and Week 2 | WOMAC: self-administered, disease-specific 24 item questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness, and physical function in participants with OA of the hip and/or knee. It consists of 3 domains: pain, stiffness and physical function. WOMAC physical function consists of 17 questions scored on 5 point Likert scale (0=minimum physical impairment to 4=maximum physical impairment), higher score indicates worse function. It assesses worse function (ability to move/perform activity) due to OA in study joint in past 48 hours. Total possible score calculated by addition of scores of each 17 questions ranged from: 0 (minimum) to 68 (maximum), higher scores indicate worse function. | Baseline, Weeks 1, 2 | 
| Change From Baseline in WOMAC Total Score at Week 1 and Week 2 | WOMAC: self-administered, disease-specific instrument assessing clinically important, participant-relevant symptoms for pain, stiffness, physical function in participants with OA of the hip and/or knee. Index consists of 24 questions: 5 (pain), 2 (stiffness), 17 (physical function). Each question was assessed on a 5-point Likert scale (0= none to 4=extreme), higher score indicates worse function. Total WOMAC Score: summation of 24 component item scores, without any correction for relative importance of different subscales. Total score range 0 (minimum) to 96 (maximum), higher score indicate higher symptoms. | Baseline, Weeks 1, 2 | 
| Change From Baseline in WOMAC Importance Weighted Total Score at Week 1 and Week 2 | WOMAC: self-administered, disease-specific instrument assessing clinically important, participant-relevant symptoms for pain, stiffness, physical function in participants with OA of hip or knee. Index consists of 24 questions: 5 (pain), 2 (stiffness), 17 (physical function). Each question was assessed on a 5-point Likert scale; score range: 0 (none) to 4 (extreme) where higher score indicates worse function. Importance-weighted total WOMAC score weighs 3 subscales of pain, stiffness, physical function using factors of 0.42, 0.21, and 0.37 to account for relative importance. Total score calculated by applying factors and summing all domains ranged from 0 (minimum) to 35.24 (maximum), higher score indicate higher symptoms. | Baseline, Weeks 1, 2 | 
| Change From Baseline in 11 Point Numeric Pain Rating Scale (NRS) at Week 1 and Week 2 (Weekly Average) | NRS: participant rated their daily pain on 11-point Likert scale ranging from 0 (no pain) to 10 (worst possible pain) during past 24-hour period. Higher score indicates greater level of pain. | Baseline, Weeks 1, 2 | 
| Change From Baseline in 11 Point NRS at Each Day From Day 1 to Day 14 | NRS: participant rated their daily pain on 11-point Likert scale ranging from 0 (no pain) to 10 (worst possible pain) during past 24-hour period. Higher score indicates greater level of pain. | Baseline, Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 | 
| Number of Participants With at Least a 30 Percent (%) and 50% Reduction in Average Weekly Pain Score at Week 2: Last Observation Carried Forward (LOCF) | Participant rated their daily pain on 11-point Likert scale ranging from 0 (no pain) to 10 (worst possible pain) during past 24-hour period. Higher score indicates greater level of pain. In this outcome measure number of participants with at least 30% and 50% reduction in average weekly pain score at Week 2 from Baseline are reported. Average weekly score at Week 2 was average of daily pain scores from Day 8 to Day 14 and at Baseline it was average of daily pain scores from Day -6 to Day 0. | Baseline, Week 2 | 
| Change From Baseline in Patient's Global Assessment of Arthritic Condition at Week 1 and Week 2 | Participants answered the following question: Considering all the ways your arthritis affects you, how are you doing today? Participants rated their condition using the scale assessing the symptoms and limitations to carry out normal daily activities. Score ranged from 1 to 5; where 1= very good (No symptoms and limitations); 2= good (mild symptoms and no limitations); 3= fair (moderate symptoms and some limitations); 4= poor (severe symptoms and inability to carry out most activities); and 5= very Poor (very severe, intolerable symptoms and inability to carry out all activities). Higher scores indicated more limitations in carrying out normal activities. | Baseline, Weeks 1, 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PF-04136309 CCR2 osteoarthritic pain knee, phase 2 placebo multicenter double-blind placebo-controlled