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.

Study Overview

• Status: Completed
• Conditions: Osteoarthritis, Knee
• Intervention / Treatment: Drug: PF-04136309; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 159
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 120-752
    • Severance Hospital, Yonsei University College of Medicine
• United States
  • Florida
    • DeLand, Florida, United States, 32720
      • University Clinical Research-Deland, LLC
    • South Miami, Florida, United States, 33143
      • Miami Research Associates
    • South Miami, Florida, United States, 33143
      • Arthritis & Rheumatic Care Center
  • Kansas
    • Overland Park, Kansas, United States, 66212
      • Vince and Associates Clinical Research
    • Overland Park, Kansas, United States, 66212
      • Diagnostic Imaging Centers
  • Kentucky
    • Madisonville, Kentucky, United States, 42431
      • Commonwealth Biomedical Research, LLC
  • Missouri
    • Chesterfield, Missouri, United States, 63005
      • Covenant Health and Wellness Center
    • Creve Coeur, Missouri, United States, 63141
      • Metro Imaging West County
    • Saint Peters, Missouri, United States, 63376
      • Metro Imaging St. Peters
  • New York
    • New York, New York, United States, 10022-1009
      • Analgesic Development Limited
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • New Horizons Clinical Research
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • Omega Medical Research
    • Warwick, Rhode Island, United States, 02886
      • Statcare
  • Texas
    • San Antonio, Texas, United States, 78229
      • Diagnostics Research Group
    • San Antonio, Texas, United States, 78229
      • South Texas Radiology Group
  • Virginia
    • Arlington, Virginia, United States, 22205
      • IntegraTrials, LLC
    • Arlington, Virginia, United States, 22205
      • Commonwealth Orthopaedics and Rehabilitation PC
  • West Virginia
    • Clarksburg, West Virginia, United States, 26301
      • United Hospital Center Clinical Trials Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. SAE was defined as any untoward medical occurrence at any dose that: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AEs were events that occurred between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Treatment emergent AEs included both SAEs and all non-SAEs.	From Baseline up to 30 days after last dose of study drug (up to Day 44)
Number of Participants With Treatment Emergent Treatment Related AEs and SAEs	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. Treatment-emergent AEs were events that occurred between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A treatment-related AE was any untoward medical occurrence attributed to the study drug in a participant who received study drug. Treatment emergent AEs included both SAEs and all non-SAEs. A treatment-related SAE was a treatment-related AE and was defined as any untoward medical occurrence at any dose that: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Relatedness to study drug was assessed by the investigator.	From Baseline up to 30 days after last dose of study drug (up to Day 44)
Number of Participants Who Discontinued Due to Treatment Emergent AEs and Treatment Emergent Treatment Related AEs	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. Treatment-emergent AEs were events that occurred between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A treatment-related AE was any untoward medical occurrence attributed to the study drug in a participant who received study drug.	From Baseline up to 30 days after last dose of study drug (up to Day 44)
Number of Treatment-Emergent AEs by Severity	Treatment-emergent AEs were events that occurred between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. The severity grades (mild, moderate and severe) were defined as - Mild: did not interfere with participant's usual function, Moderate: Interfered to some extent with participant's usual function and Severe: Interfered significantly with participant's usual function.	From Baseline up to 30 days after last dose of study drug (up to Day 44)
Number of Treatment-Emergent Treatment-Related AEs by Severity	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. Treatment-emergent AEs were events that occurred between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A treatment-related AE was any untoward medical occurrence attributed to the study drug in a participant who received study drug. The severity grades (mild, moderate and severe) were defined as - Mild: did not interfere with participant's usual function, Moderate: Interfered to some extent with participant's usual function and Severe: Interfered significantly with participant's usual function.	From Baseline up to 30 days after last dose of study drug (up to Day 44)
Number of Participants Who Discontinued Due to Treatment-Emergent AEs According to Severity	Treatment-emergent AEs were events that occurred between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. The severity grades (mild, moderate and severe) were defined as - Mild: did not interfere with participant's usual function, Moderate: Interfered to some extent with participant's usual function and Severe: Interfered significantly with participant's usual function.	From Baseline up to 30 days after last dose of study drug (up to Day 44)
Number of Participants With Clinically Significant Change From Baseline in Blood Pressure and Pulse Rate	Criteria for clinical significance: sitting, standing or supine pulse rate <40 beats per minute (bpm) or >120 bpm; sitting, standing or supine diastolic blood pressure < 50 millimeter of mercury (mmHg); sitting, standing or supine systolic blood pressure < 90 mmHg. Clinical significance was judged by the investigator.	From Baseline up to Week 2
Number of Participants With Change (Increase) From Baseline in Electrocardiogram (ECG) Parameters	Change (increase) from baseline of greater than or equal to (>=) 25% in maximum PR Interval and maximum QRS complex in milliseconds (msec). Change (increase) from baseline of >= 30 msec and less than (<) 60 msec or change >= 60 msec in maximum QTc and maximum QT interval with Fridericia's Correction (QTcF).	Baseline up to Week 2
Plasma Concentration Versus Time of PF-04136309	In this outcome measure data for reporting arm PF-04136309 was collected and reported as planned.	Day 1 and Day 14: Pre-dose and 6,7 hours post-dose
Change From Baseline in Absolute Monocyte Count at Day 14		Baseline, Day 14
Change From Baseline in Percent Monocytes at Day 14	Monocytes (percent) were derived as monocyte absolute counts per white blood cell absolute counts*100.	Baseline, Day 14

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2008
• Primary Completion (Actual): November 27, 2008
• Study Completion (Actual): November 27, 2008

Study Registration Dates

• First Submitted: May 30, 2008
• First Submitted That Met QC Criteria: May 30, 2008
• First Posted (Estimate): June 3, 2008

Study Record Updates

• Last Update Posted (Actual): July 13, 2021
• Last Update Submitted That Met QC Criteria: June 21, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: PF-04136309 CCR2 osteoarthritic pain knee; phase 2 placebo multicenter double-blind placebo-controlled
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID Numbers: A9421006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.