A Study Of CP-195543 And Celecoxib Dual Therapy In Subjects With Rheumatoid Arthritis

Study Overview
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Brief Summary
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To evaluate the efficacy, safety and tolerability of CP-195543 and celecoxib dual therapy in subjects with rheumatoid arthritis

Detailed Description
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Trial enrollment was prematurely discontinued on December 3, 2007. The results of an interim efficacy and safety analysis demonstrated an overall poor tolerability profile and high discontinuation rate when dual therapy with CP-195543 and Celecoxib was administered. The decision to discontinue further enrollment in the trial was not based on any efficacy or serious safety concerns. Previously enrolled study participants continued in the study and the trial completed on February 27, 2008.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Of CP-195543 And Celecoxib Dual Therapy In The Treatment Of The Signs And Symptoms Of Rheumatoid Arthritis In Subjects Who Are Inadequately Controlled On Methotrexate

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: CP-195,543
* Drug: celecoxib
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of RA based upon the American college of Rheumatology 1987 revised criteria Active disease at Screening Stable dose of methotrexate between 10-25 mg/week oral or parenteral Exclusion Criteria: A diagnosis of any other inflammatory or secondary, noninflammatory arthritis that, in the opinion of the Investigator, would interfere with disease activity assessments A history of hypersensitivity or allergic type reactions to cyclooxygenase inhibitors, opiates, aspirin or sulfonamides

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Celecoxib<br>Celecoxib with placebo therapy. | Drug: celecoxib<br>* Celecoxib is a nonsteroidal anit-inflammatory drug (NSAID) marketed worldwide (in the United States [US] as Celeberex) and approved for the relief of signs and symptoms of osteoarthritis.<br>|
| Other: Methotrexate<br>Background Methotrexate taken in both CP-195,543/Celecoxib and Celecoxib only arms. | Drug: Methotrexate<br>* Methotrexate is a folate analogue that, based on it efficacy and safety in RA, is commonly used as frontline DMARD treatment in patients with moderate to severe disease who do not respond to NSAIDs alone.<br>|
| Experimental: CP-195,543<br>CP-195,543 and Celecoxib dual therapy. | Drug: CP-195,543<br>* CP-195543 is a potent and specific antagonist of the leukotriene B4 (LTB4) receptor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | ACR20 response: greater than or equal to (>=) 20 percent (%) improvement in tender joint count; >=20% improvement in swollen joint count; and >=20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP). | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 1, 2, 4 and 8 | ACR20 response: >=20% improvement in tender joint count; >=20% improvement in swollen joint count; and >=20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP). | Week 1, 2, 4, 8 | 
| Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response | ACR50 response: >=50% improvement in tender joint count; >=50% improvement in swollen joint count; and >=50% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP). | Week 1, 2, 4, 8, 12 | 
| Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response | ACR70 response: >=70% improvement in tender joint count; >=70% improvement in swollen joint count; and >=70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP). | Week 1, 2, 4, 8, 12 | 
| Change From Baseline in Tender/Painful Joint Count (TJC) at Week 1, 2, 4, 8 and 12 | Participants were assessed for tender/painful joints using a 28-joint count comprised of left and right shoulders, elbows, wrists, proximal interphalangeal joints, metacarpophalangeal joints and knees. Artificial joints were not assessed. | Baseline, Week 1, 2, 4, 8, 12 | 
| Change From Baseline in Swollen Joint Count (SJC) at Week 1, 2, 4, 8 and 12 | Participants were assessed for swollen joints using a 28-joint count comprised of left and right shoulders, elbows, wrists, proximal interphalangeal joints, metacarpophalangeal joints and knees. Artificial joints were not assessed. | Baseline, Week 1, 2, 4, 8, 12 | 
| Change From Baseline in Patient's Assessment of Arthritis Pain at Week 1, 2, 4, 8 and 12 | Patient's assessment of arthritis pain was assessed using a 100 millimeter (mm) visual analogue scale (VAS) with range: 0 = no pain to 100 = worst possible pain. | Baseline, Week 1, 2, 4, 8, 12 | 
| Change From Baseline in Patient's Global Assessment of Arthritis at Week 1, 2, 4, 8 and 12 | Patient's global assessment of arthritic condition assessed all the ways participants' illness and health conditions affect them at the time of assessment. The response was scored on a 5-point scale: 1 = Very Good (Asymptomatic and no limitation of normal activities), 2 = Good (Mild symptoms and no limitation of normal activities), 3 = Fair (Moderate symptoms and limitation of some normal activities), 4 = Poor (Severe symptoms and inability to carry out most normal activities) and 5 = Very Poor (Very severe symptoms which are intolerable and inability to carry out all normal activities). | Baseline, Week 1, 2, 4, 8, 12 | 
| Change From Baseline in Physician's Global Assessment of Arthritis at Week 1, 2, 4, 8 and 12 | Investigator assessed overall appearance of arthritis at the time of the visit. The response was scored on a 5-point scale: 1 = Very Good (Asymptomatic and no limitation of normal activities), 2 = Good (Mild symptoms and no limitation of normal activities), 3 = Fair (Moderate symptoms and limitation of some normal activities), 4 = Poor (Severe symptoms and inability to carry out most normal activities) and 5 = Very Poor (Very severe symptoms which are intolerable and inability to carry out all normal activities). | Baseline, Week 1, 2, 4, 8, 12 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 1, 2, 4, 8 and 12 | Health Assessment Questionnaire-Disability Index (HAQ-DI): participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3, where 0 = least difficulty and 3 = extreme difficulty. | Baseline, Week 1, 2, 4, 8, 12 | 
| Change From Baseline in C-Reactive Protein (CRP) at Week 1, 2, 4, 8 and 12 | The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. | Baseline, Week 1, 2, 4, 8, 12 | 
| Change From Baseline in Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (3 Variables) (DAS28-3 [CRP]) at Week 1, 2, 4, 8 and 12 | DAS28-3 (CRP) was calculated from the SJC and TJC using the 28 joints count and CRP. It was calculated as DAS28-3 (CRP) = 1.15 + 1.10 * ([0.56 * square root of TJC] + [0.28 * square root of SJC] + [0.36 * natural logarithm of {CRP+1}]). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-3 (CRP) <= 3.2 implied low disease activity and >3.2 to 5.1 implied moderate to high disease activity, and DAS28-3 (CRP) <2.6 = remission. | Baseline, Week 1, 2, 4, 8, 12 | 
| Change From Baseline in Duration of Morning Stiffness at Week 1, 2, 4, 8 and 12 | Duration of morning stiffness was defined as the time elapsed between the time participant woke up and was able to resume normal activities without stiffness in hours (duration was recorded in hours to the nearest quarter. For those participants with unrelenting stiffness, duration was recorded as 24 hours). | Baseline, Week 1, 2, 4, 8, 12 | 
| Number of Participants Who Withdrew From Study Due to Lack of Efficacy |  | Baseline up to Week 12 | 
| Time to Withdrawal Due to Lack of Efficacy |  | Baseline up to Week 12 | 
| Number of Participants With Clinical Laboratory Abnormalities | Following parameters were analyzed for laboratory examination: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); liver function (aspartate aminotransferase, alanine aminotransferase, total bilirubin, lactate dehydrogenase, alkaline phosphatase, albumin, total protein); renal function (blood urea nitrogen, creatinine, uric acid); electrolytes (sodium, potassium, chloride, calcium, phosphate, bicarbonate); clinical chemistry (glucose, creatine kinase); immunology (CRP); urinalysis (dipstick [urine specific gravity, decimal logarithm of reciprocal of hydrogen ion activity {pH} of urine, glucose, protein, blood, ketones, bilirubin], microscopy [urine RBC, WBC, urate crystals, calcium, oxalate, miscellaneous [urine mucus and leucocytes]). | Baseline up to Week 13 |