This study (Protocol 007) was conducted in 55 centers in the United States. The study protocol and procedures were approved by local Institutional Review Boards of each study center. All patients gave written informed consent prior to participation in the original study and before continuation in each study extension.
Entry criteria
Eligible patients for the base study were a minimum of 40 years old and had both clinical and radiographic evidence of OA of the knee with symptoms for at least 6 months prior to study entry, and met American Rheumatism Association (ARA) functional class I, II or III. All patients required NSAID therapy for 25 of the 30 days prior to the screening and were required to meet predefined clinical flare criteria in order to be eligible for allocation [5]. Patients were eligible for the extension studies if they successfully completed the original base study, and they had to have completed the first extension without protocol violation to be eligible for the second extension.
Exclusion criteria for the base study included: significant renal impairment (calculated creatinine clearance <30 mL/min); clinically significant abnormalities on screening physical or laboratory examinations; class III/IV angina or uncontrolled congestive heart failure; uncontrolled hypertension; stroke or a transient ischemic attack within 2 years; active hepatic disease; a history of recent neoplastic disease, acute meniscal injury to the study joint within 2 years of study entry; arthroscopy in the study joint within 6 months of study entry; weight in excess of 280 pounds (120 kg) or allergy to acetaminophen or conventional NSAIDs. Patients were also excluded if they required systemic corticosteroids, warfarin, low-dose aspirin or ticlopidine, or if they had required intra-articular steroids for joints other than the study joint within the month prior to study entry or to the study joint in the 2 months prior to study entry. For the extension periods reported here, patients who experienced an AE that led to discontinuation from study therapy during a previous treatment period or were considered protocol violators were excluded from participation.
Study design
The base study was a 2-part, 14-week, parallel-group study which was followed by 2 consecutive, double-blind, active-comparator-controlled extensions (12 and 26 weeks, respectively). Part I of the base study was placebo-controlled; part II and the 2 extensions were active-comparator controlled. The base study was conducted to define the clinically active dose range of etoricoxib in patients with OA; the extension studies were conducted to evaluate the safety, tolerability and observe the efficacy of etoricoxib over an additional 38 weeks. With the base and extension studies, patients could have participated for a total of up to 52 weeks.
Following discontinuation of previous therapy and a subsequent flare of clinical OA symptoms, eligible patients with OA of the knee were randomized to receive placebo, etoricoxib 5, 10, 30, 60, or 90 mg daily for 6 weeks (part I) according to a computer generated allocation schedule. Patients continued in Part II for an additional 8 weeks in which patients who were on placebo, etoricoxib 5, or 10 mg were given diclofenac 150 mg or etoricoxib 30 mg. Additionally, 50% of patients who were on etoricoxib 30 mg in part I continued on the same treatment while the other 50% were given etoricoxib 60 mg. Similarly, 50% of patients on etoricoxib 60 mg in part I continued on the same treatment while the other 50% were given etoricoxib 90 mg. Patients taking etoricoxib 90 mg in Part I continued on the same treatment (Figure 1). Upon completion of the 14 week base study, patients continued to receive the same treatment throughout the extension studies as in Part II (Figure 1). The treatment groups for Part I and II and all subsequent extensions were pre-assigned at randomization; blinding of patients and study staff was maintained throughout [5].
Efficacy and safety assessments
The efficacy data reported here are for the 46-week active comparator controlled period (Weeks 6 to 52), during which efficacy assessments were made at Treatment Weeks 6, 8, 14, 20, 26, 34, 42, and 52. However, the efficacy over the entire 52-week period (base study and extension period) is also shown to assess the maintenance of effect over the entire treatment period for the subset of patients who received the same treatment for the entire 52-week period. Efficacy was evaluated using the following two primary endpoints for the active comparator controlled period: the Western Ontario and McMaster Universities OA index (WOMAC) VA 3.0 Pain Subscale (100 mm Visual Analog Scale [VAS] ;0 = no pain and 100 = extreme pain) and Investigator Global Assessment of Disease Status (0 – 4 point scale; where 0 = very well and 4 = very poor).
Safety and tolerability data reported here are also from the active-comparator controlled period for patients received the same study medication for up to 46 weeks, Week 6 to 52. As with efficacy, safety evaluations were made at study visits on Treatment Weeks 6, 8, 14, 20, 26, 34, 42, and 52. Vital signs were monitored at each of these visit. Laboratory studies including a complete blood count (CBC), serum chemistry panel, and urinalysis were performed at each visit. Clinical and laboratory AEs were recorded throughout the study; the investigator assessed the relation of AEs to study medication, the outcome of the AE, and any action taken. Identification and evaluation of AEs by the investigator, including those deemed to be "serious" according to regulatory definitions, were done while still blinded to study treatment.
Statistical analysis
Treatment response was assessed mainly through interpretation of graphical presentations. For each efficacy endpoint, these graphs represented the least-squares mean (LS Mean) changes from baseline and the corresponding standard errors at each time point. LS mean changes were estimated from an analysis of covariance (ANCOVA) model with treatment sequence as the main factor and baseline value (at the Flare/Randomization Visit) as a covariate. The efficacy analyses were based on a modified intention-to-treat principle where all patients who entered the first extension, had a baseline value and at least one post-baseline measurement in the analysis period were included. For efficacy, missing values were imputed by the last value measured prior to that visit (last-value-carried-forward method). However, the efficacy values measured in part II of the base study were not carried forward to the first extension. The two extensions were assessed as one continuous treatment period, and all patients who entered the first extension were included in the efficacy and safety analyses.
The maintenance of efficacy over 52 weeks was evaluated based upon the subgroup of patients who received the same treatment and dose throughout the entire study (i.e. from the start of the base study to the end of the extension studies, which include only patients taking etoricoxib 30, 60, and 90 mg over 52 weeks). The LS mean changes from baseline (observed value at the Flare/Randomization visit of the base study) were plotted and tabulated for these 3 subgroups of patients from the Screening Visit to Week 52.
The following AEs were prespecified for evaluation: patients with one or more clinical AEs; drug-related clinical AEs; serious clinical AEs (i.e. any AE that results in death, is life threatening, results in persistent or significant disability, prolongs an existing inpatient hospitalization, or any event that jeopardizes the patient based on appropriate medical judgment); clinical AEs resulting in discontinuation of therapy; digestive system AEs (including abdominal pain) resulting in discontinuation of therapy; lower extremity edema AEs; discontinuations due to lower extremity edema AEs; hypertension AEs resulting in discontinuation of therapy; and AEs related to congestive heart failure, pulmonary edema, or cardiac failure. GI nuisance symptoms (i.e. abdominal pain, acid reflux, dyspepsia, epigastric discomfort, heartburn, nausea, and vomiting), adverse experiences that are common among patients who use nonselective NSAIDs, were examined. Also, laboratory parameters that were prespecified for evaluation included hemoglobin, hematocrit, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum creatinine.