Materials & Methods
Study Design
Patients were randomized at baseline (1:1) to receive celecoxib 200 mg q.d. or placebo for 6 weeks in two identically designed, concurrent, double-blind, parallel-group, multicenter studies (study 1 and 2). There were four study visits: screening (visit 1, 1–14 days prior to the first dose of study medication), baseline (visit 2, day 0, within 24 h of the first dose of study medication), week 2 (visit 3, day 14 ± 2 after the first dose of study medication) and week 6 (visit 4, day 42 ± 4 after the first dose of study medication). For patients who terminated early, the week 6 assessments were performed at termination.
Patients
Patients aged ≥40 years with diagnosed, active, symptomatic OA of the knee in a flare state, as determined by American College of Rheumatology criteria, were enrolled according to the following inclusion criteria: had failed prior treatment with both prescription strength naproxen (at least 750 mg/day for 2 weeks) and ibuprofen (at least 1200 mg/day for 2 weeks) within the past 5 years due to either lack of efficacy and/or tolerability; females of childbearing potential had a negative urine pregnancy test and had to be using an adequate method of contraception; if taking chronic NSAID therapy, patients were to complete a wash-out period for a minimum of 2 days; patients were to have a functional capacity class of I–III; a willingness to participate for 6 weeks and ability to provide informed consent. Exclusion criteria were: inflammatory arthritis or gout/pseudo-gout with an acute flare in the past 2 years; active symptomatic acute joint trauma in the index joint within past 3 months; previous or anticipated need for surgery on the index joint (knee arthroscopy for reasons other than arthritis was permitted as long as it was performed at least 90 days prior to screening); treatment with oral (4 weeks), intramuscular (2 months), intra-articular (3 months) or soft-tissue (2 months) injection of corticosteroids or intra-articular injection of hyaluronic acid in the index joint within 9 months of first dose of study medication; use of acetaminophen within 24 h of the baseline visit; treatment with anticoagulants, lithium, glucosamine and/or chondroitin sulfate; malignancy; treatment for esophageal, gastric, pyloric channel or duodenal ulceration; GI or cardiovascular disease; having >1.5 times the upper limit of normal for aspartate aminotransferase, alanine aminotransferase or other clinically significant laboratory abnormalities; known sensitivity to COX-2 inhibitors or related compounds; use of study drug in the past 30 days; participation in physical therapy for the index joint and use of a mobility-assisting device <6 weeks prior to the study.
Study End Points
The primary efficacy end point was change from baseline to week 6 in the Patient's Assessment of Arthritis Pain (VAS, measured on a 0 [no pain] to 100 [very severe pain] mm scale).
Secondary end points included the change in Western Ontario and McMaster Universities (WOMAC) OA Index from baseline to week 6, and the change in Patient's and Physician's Global Assessment of Pain from baseline to week 6.
Statistical Analysis
Identical statistical plans were followed for study 1 and 2, but distinct analyses were carried out on each data set. Analyses were performed on the modified intent-to-treat population defined as patients who had been randomized, received at least one dose of study medication, and had at least one post baseline pain assessment. The primary outcome was analyzed using a general linear model with effects for treatment, center and baseline VAS score in the model. Missing values were imputed using last observation carried forward. The differences in the least squares mean (LSM), standard error of the differences, two-sided 95% CI for the difference and p-values are presented.
WOMAC scores for the two treatment groups (celecoxib vs placebo) were compared and p-values, differences in the LSM, standard errors of the differences and 95% CIs for the differences are presented.
Classification of Patient's Global Assessment and Physician's Global Assessment were analyzed using the Cochran–Mantel–Haenszel test (row-mean-score-test), stratified by center.