Etoricoxib in the treatment of osteoarthritis over 52-weeks: a double-blind, active-comparator controlled trial [NCT00242489]

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.

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].

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.

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.

Over the 46-week active comparator controlled period, etoricoxib 30, 60, and 90 mg had similar efficacy compared with diclofenac 150 mg (Figure 3). For both primary efficacy endpoints, the degree of clinical improvement relative to baseline was at or above the level of clinical importance, which was defined as 10 mm on the VAS WOMAC Pain Subscale or 0.5 Likert units on the Investigator Global Assessment of Disease Status [5]. Furthermore, this degree of improvement was maintained at a relatively constant level during the two extension periods for all active treatment groups (Figure 3).

To demonstrate the consistency of efficacy in patients on the same etoricoxib treatment over the 52-week treatment period, results for the subset of patients who received the same treatment for the entire 52-week period are also provided (Figure 4). The maximal treatment effect was reached during the base study at the end of Week 6 for the 30, 60, and 90 mg etoricoxib groups and maintained throughout the 52-week treatment period for the two primary endpoints, with small differences in efficacy favoring the 60 mg group [5].

During the 46-week active-comparator controlled period, etoricoxib 30, 60, and 90 mg and diclofenac 150 mg were generally well tolerated, consistent with previously reported results for Part 1 of the base study (Table 2). The incidence of clinical AEs was similar among the treatment groups. Clinical AEs determined by the investigator (blinded) to be possibly, probably, or definitely drug-related were slightly greater in the etoricoxib 90 mg and diclofenac 150 mg groups (23.0% and 24.5%, respectively) compared with etoricoxib 30 mg (17.2%) and etoricoxib 60 mg (17.6%). More patients in the diclofenac group discontinued due to an AE (11.8%) compared with the etoricoxib groups (3.0 to 6.8%).

A higher percentage of patients in the diclofenac group had GI nuisance symptoms (26.6%) than in the etoricoxib groups (16.5%, 16.7%, and 14.9% in the 30, 60, and 90 mg etoricoxib groups, respectively). Consistent with this, the percent of patients who discontinued due to these GI nuisance symptoms was higher in diclofenac (4.0%) than in the etoricoxib groups (0.0%, 1.0%, and 2.1% in the 30, 60, and 90 mg etoricoxib groups, respectively; Table 2). One patient (etoricoxib 90 mg) had a gastric ulcer during the 52 week period. This patient had a prior history of esophagitis and gastric erosion. There were no other reports of patients with GI perforations, ulcers, or bleeding events.

Lower extremity edema was reported for 4.5, 3.9, and 3.4% in the 30-, 60-, and 90-mg etoricoxib groups, respectively and 2.0% in the diclofenac group. There was evidence for a dose-related trend in the proportion of patients with hypertension: 2.0, 2.9, and 5.4% in the 30, 60, and 90 mg etoricoxib groups, respectively and 4.9% in the diclofenac group. One patient in the etoricoxib 30 mg group discontinued due to lower extremity edema and one patient in each of the following treatment groups discontinued due to hypertension: etoricoxib 30 and 90 mg and diclofenac. One patient (etoricoxib 60 mg) who had an AE that consisted of mild congestive heart failure and was felt by the investigator to not be drug related, continued on the study and recovered.

There was one confirmed CV thrombotic event during the active-comparator controlled period; a cerebrovascular accident occurred in a patient taking diclofenac 150 mg. The event was deemed to not be drug-related and the patient was discontinued from the study after being put on low-dose aspirin therapy (an excluded medication).

Laboratory AEs were reported for 5.6, 5.0, 9.6, and 18.6% in the 30, 60, and 90 mg etoricoxib and 150 mg diclofenac groups, respectively during the active-comparator controlled period (Table 3). Drug-related laboratory AEs were reported for 2.0, 0.0, 4.1, and 11.8 % in the 30, 60, and 90 mg etoricoxib and 150 mg diclofenac groups, respectively. The most frequently reported laboratory AEs were increased levels of ALT and AST, which accounted for much of the higher incidence of laboratory AEs in the diclofenac group. Elevated levels of these enzymes were reported in a greater percent of patients in the diclofenac group (10.8%) versus the etoricoxib groups (1.0 to 2.1%) (Table 3). Three patients on diclofenac discontinued due to ALT/AST increases compared with no patients in the etoricoxib group. The largest change from baseline in ALT was observed at Week 20 in the diclofenac group (42.4%). Mean ALT decreased in subsequent weeks in the diclofenac group (6.6% above baseline at Week 52). Mean AST was also higher in the diclofenac group vs. the etoricoxib groups, but decreased over time. Two patients on etoricoxib (1 in the 30 mg group and 1 in the 90 mg group) and one patient on diclofenac 150 mg discontinued due to an increase in serum creatinine. Serum creatinine returned to baseline following discontinuation of study medication in these three patients.

In addition to the analysis of patients during the active-comparator controlled period, safety data is presented showing rates of most common AEs and AEs of special interest (GI and renovascular AEs) per 100 patient-years for all patients treated with etoricoxib 30, 60, or 90 mg or diclofenac in either the placebo-controlled or active comparator-controlled periods (this includes patients that received a different treatment during the placebo-controlled period) (Table 4). The AEs occurring at the highest rate were upper respiratory infection, headache, and diarrhea. Lower extremity edema occurred at a higher rate in the etoricoxib groups compared with diclofenac. Hypertension occurred at a higher rate in the etoricoxib 90 mg and diclofenac groups compared with the etoricoxib 30 mg and 60 mg groups.