CLINICAL STUDIES
The efficacy and clinical utility of BEXTRA Tablets have been demonstrated in osteoarthritis (OA), rheumatoid arthritis (RA) and in the treatment of primary dysmenorrhea.
Osteoarthritis
BEXTRA was evaluated for treatment of the signs and symptoms of osteoarthritis of the knee or hip, in five double-blind, randomized, controlled trials in which 3918 patients were treated for 3 to 6 months. BEXTRA was shown to be superior to placebo in improvement in three domains of OA symptoms: (1) the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness and functional measures in OA, (2) the overall patient assessment of pain, and (3) the overall patient global assessment. The two 3-month pivotal trials in OA generally showed changes statistically significantly different from placebo, and comparable to the naproxen control, in measures of these domains for the 10 mg/day dose. No additional benefit was seen with a valdecoxib 20-mg daily dose.
Rheumatoid Arthritis
BEXTRA demonstrated significant reduction compared to placebo in the signs and symptoms of RA, as measured by the ACR (American College of Rheumatology) 20 improvement, a composite defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five: patient global, physician global, patient pain, patient function assessment, and C-reactive protein (CRP). BEXTRA was evaluated for treatment of the signs and symptoms of rheumatoid arthritis in four double-blind, randomized, controlled studies in which 3444 patients were treated for 3 to 6 months. The two 3-month pivotal trials compared valdecoxib to naproxen and placebo. The results for the ACR20 responses in these trials are shown below (Table 2). Trials of BEXTRA in rheumatoid arthritis allowed concomitant use of corticosteroids and/or disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate, gold salts, and hydroxychloroquine. No additional benefit was seen with a valdecoxib 20-mg daily dose.
Table 2 ACR20 Response Rate (%) in Rheumatoid Arthritis | Study 1 | Study 2 |
|---|
| BEXTRA 10 mg/day | 49%
(103/209) | 46% (103/226) |
| BEXTRA 20 mg/day | 48% (102/212) | 47%
(103/219) |
| Naproxen 500 mg BID | 44% (100/225) | 53% (115/219) |
| Placebo | 32% (70/222) | 32% (71/220) |
Primary Dysmenorrhea
BEXTRA was compared to naproxen sodium 550 mg in two placebo-controlled studies of women with moderate to severe primary dysmenorrhea. The onset of analgesia was within 60 minutes for BEXTRA 20 mg. The onset, magnitude, and duration of analgesic effect with BEXTRA 20 mg were comparable to naproxen sodium 550 mg.
Safety Studies
Studies in post-surgical patients (Investigational use)
Three placebo-controlled studies (two coronary artery bypass graft (CABG) surgery studies largely in patients with medial sternotomy placed on cardiopulmonary bypass and a single general surgery study) were conducted to evaluate the safety of the investigational agent, parecoxib sodium (the parenteral pro-drug of valdecoxib) and valdecoxib. Patients received parecoxib sodium for at least 3 days and then were transitioned to valdecoxib for a total treatment duration of 10–14 days. All patients received standard of care analgesia during treatment and all patients received low-dose aspirin prior to randomization and throughout the two CABG surgery studies.
In addition to routine adverse event reporting, pre-specified adverse events of interest were adjudicated according to pre-specified definitions by an independent committee who were blinded to treatment assignment. In the three studies, the overall routine adverse event profiles were similar between active treatments and placebo.
The first CABG surgery study evaluated patients treated with IV parecoxib sodium 40 mg bid for a minimum of 3 days, followed by treatment with valdecoxib 40 mg bid (parecoxib sodium/valdecoxib group) (n=311) or placebo/placebo (n=151) in a 14-day, double-blind placebo-controlled study. Nine pre-specified adverse event categories were evaluated (cardiovascular thromboembolic events, pericarditis, new onset or exacerbation of congestive heart failure, renal failure/dysfunction, upper GI ulcer complications, major non-GI bleeds, infections, non-infectious pulmonary complications, and death). There was a significantly (p<0.05) greater incidence of cardiovascular/thromboembolic events (myocardial infarction, ischemia, cerebrovascular accident, deep vein thrombosis and pulmonary embolism) detected in the parecoxib/valdecoxib treatment group compared to the placebo/placebo treatment group for the IV dosing period (2.2% and 0.0% respectively) and over the entire study period (4.8% and 1.3% respectively). Surgical wound complications (most involving the sternal wound) were observed at an increased rate with parecoxib/valdecoxib treatment.
In the second larger CABG surgery study, four pre-specified event categories were evaluated (cardiovascular/thromboembolic; renal dysfunction/renal failure; upper GI ulcer/bleeding; surgical wound complication). Patients were randomized within 24-hours post-CABG surgery to: parecoxib initial dose of 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO (20 mg Q12H) (n=544) for the remainder of a 10 day treatment period; placebo IV followed by valdecoxib PO (n=544); or placebo IV followed by placebo PO (n=548). A significantly (p=0.033) greater incidence of events in the cardiovascular/thromboembolic category was detected in the parecoxib /valdecoxib treatment group (2.0%) compared to the placebo/placebo treatment group (0.5%). Placebo/valdecoxib treatment was also associated with a higher incidence of CV thromboembolic events versus placebo treatment, but this difference did not reach statistical significance. Three of the cardiovascular thromboembolic events in the placebo/valdecoxib treatment group occurred during the placebo treatment period; these patients did not receive valdecoxib. Pre-specified events that occurred with the highest incidence in all three treatment groups involved the category of surgical wound complications, including deep surgical infections and sternal wound healing events (see table below).
Incidence of Prespecified Adverse Events in CABG Surgery Study 2 [n, (% of patients)] | Placebo/Placebo | Placebo/Valdecoxib | Parecoxib/Valdecoxib |
|---|
Total Number of Patients Treated
(Entire Study and IV Dosing Period) | 548 | 544 | 544 |
| (Oral Dosing Period) | 503 | 500 | 511 |
| Any Prespecified Adverse Event (Entire Study) | 22 (4.0) | 40 (7.4)
| 40 (7.4) |
| IV dosing period | 5 (0.9) | 10 (1.8) | 13 (2.4) |
| Oral dosing period | 17 (3.4) | 31 (6.2) | 27 (5.3) |
Cardiovascular Thromboembolic Events (Entire
Study) | 3 (0.5) | 6 (1.1) | 11 (2.0) |
| IV dosing period | 1 (0.2) | 3 (0.6) | 4 (0.7) |
| Oral dosing period | 2 (0.4) | 3 (0.6) | 7 (1.4) |
| Renal Failure/dysfunction Events (Entire Study) | 3 (0.5) | 4 (0.7) | 7 (1.3) |
| IV dosing period | 3 (0.5) | 4 (0.7) | 6 (1.1) |
| Oral dosing period | 0 (0.0) | 0 (0.0) | 1 (0.2) |
| Upper GI Ulcer Events (Entire Study) | 2 (0.4) | 4 (0.7) | 6 (1.1) |
| IV dosing period | 1 (0.2) | 1 (0.2) | 2 (0.4) |
| Oral dosing period | 1 (0.2) | 3 (0.6) | 4 (0.8) |
| Surgical Wound Events (Entire Study) | 16 (2.9) | 27 (5.0) | 20 (3.7) |
| IV dosing period | 2 (0.4) | 2 (0.4) | 2 (0.4) |
| Oral dosing period | 14 (2.8) | 25 (5.0) | 18 (3.5) |
General Surgery: In the third study, a large (N=1050) major orthopedic/general surgery trial, patients received an initial dose of parecoxib 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO (20 mg Q12H) (n=525) for the remainder of a 10 day treatment period, or placebo IV followed by placebo PO (n=525). There were no significant differences in the overall safety profile, including the four pre-specified event categories described above for the second CABG surgery study, for parecoxib sodium/valdecoxib compared to placebo treatment in these post-surgical patients (see table below).
Incidence of Prespecified Adverse Events in CABG Surgery Study 2 [n, (% of patients)] | Placebo/Placebo | Parecoxib /Valdecoxib |
|---|
| Total Number of Patients Treated | 525 | 525 |
| Any Prespecified Adverse Event (Entire Study) | 17 (3.2) | 14 (2.7) |
| IV/IM dosing period | 6 (1.1) | 3 (0.6) |
| Oral dosing period | 11 (2.1) | 11 (2.1) |
| Cardiovascular Thromboembolic Events (Entire study) | 5 (1.0) | 5 (1.0) |
| IV/IM dosing period | 1 (0.2) | 2 (0.4) |
| Oral dosing period | 4 (0.8) | 3 (0.6) |
| Renal Failure/dysfunction Events (Entire study) | 0 (0.0) | 1 (0.2) |
| IV/IM dosing period | 0 (0.0) | 1 (0.2) |
| Oral dosing period | 0 (0.0) | 0 (0.0) |
| Upper GI Ulcer Events (Entire study) | 1 (0.2) | 1 (0.2) |
| IV/IM dosing period | 1 (0.2) | 0 (0.0) |
| Oral dosing period | 0 (0.0) | 1 (0.2) |
| Surgical Wound Events (Entire study) | 11 (2.1) | 9 (1.7) |
| IV/IM dosing period | 4 (0.8) | 0 (0.0) |
| Oral dosing period | 7 (1.3) | 9 (1.7) |
No significant differences were observed between the treatment groups
BEXTRA is contraindicated for the treatment of post-operative pain immediately following coronary artery bypass graft surgery and should not be used in this setting (See CONTRAINDICATIONS).
Cardiovascular Safety Analysis from Osteoarthritis and Rheumatoid Arthritis Studies
Randomized controlled clinical trials with BEXTRA longer than one year have not been conducted, nor have studies powered to detect differences in cardiovascular events in a chronic setting been conducted.
In an analysis of 10 randomized controlled clinical studies in osteoarthritis and rheumatoid arthritis, 4531 patients received BEXTRA in doses ranging from 10 mg to 80 mg for periods of 6 to 52 weeks. The majority of these patients received BEXTRA for 12 weeks or less. This analysis compared the incidence of serious cardiovascular events in BEXTRA-treated patients with the incidence of these events in patients receiving placebo (N=1142) or NSAID therapy (N=2261). In this analysis, no apparent differences were detected in the exposure-adjusted serious cardiovascular thromboembolic event rates between patients receiving BEXTRA, placebo and NSAIDs.
BEXTRA has not been studied in clinical trials beyond 12 months duration.
Gastrointestinal (GI) Endoscopy Studies with Therapeutic Doses
Scheduled upper GI endoscopic evaluations were performed with BEXTRA at doses of 10 and 20 mg daily in over 800 OA patients who were enrolled into two randomized 3-month studies using active comparators and placebo controls (Study 3 and Study 4). These studies enrolled patients free of endoscopic ulcers at baseline and compared rates of endoscopic ulcers, defined as any gastroduodenal ulcer seen endoscopically provided it was of "unequivocal depth" and at least 3 mm in diameter.
In both studies, BEXTRA 10 mg daily was associated with a statistically significant lower incidence of endoscopic gastroduodenal ulcers over the study period compared to the active comparators. Figure 1 summarizes the incidence of gastroduodenal ulcers in Studies 3 and 4 for the placebo, valdecoxib, and active control arms.
Safety Study with Supratherapeutic Doses
Scheduled upper GI endoscopic evaluations were performed in a randomized 6-month study of 1217 patients with OA and RA comparing valdecoxib 20 mg BID (40 mg daily) and 40 mg BID (80 mg daily) (4 to 8 times the recommended therapeutic dose) to naproxen 500 mg BID (Study 5). This study also formally assessed renal events as a primary outcome with supratherapeutic doses of BEXTRA. The renal endpoint was defined as any of the following: new/increase in edema, new/increase in congestive heart failure, increase in blood pressure (BP; >20 mm Hg systolic, >10 mm Hg diastolic), new/increase in BP treatment, new/increase in diuretic therapy, creatinine increase over 30% (or >1.2 mg/dL if baseline <0.9 mg/dL), BUN increase over 200% or >50 mg/dL, 24-hr urinary protein increase to >500 mg (if baseline 0–150 mg or >750 if baseline 151–300 or >1000 if baseline 301–500), serum potassium increase to >6 mEq/L, or serum sodium decrease to <130 mEq/L.
Figure 2 summarizes the incidence rates of gastroduodenal ulcers and renal events that were seen in Study 5. BEXTRA 40 mg daily and 80 mg daily were associated with a statistically significant lower incidence of endoscopic gastroduodenal ulcers over the study period compared to naproxen. The incidence of renal events was significantly different between the BEXTRA 80 mg daily group and naproxen. The clinical relevance of renal events observed with supratherapeutic doses (4 to 8 times the recommended therapeutic dose) of BEXTRA is not known (see PRECAUTIONS — Renal Effects).
Figure 2 Incidence of Endoscopic Gastroduodenal Ulcers and Renal Events in the High-dose Safety Study
Renal Safety at the Therapeutic Chronic Dose
The renal effects of valdecoxib compared with placebo and conventional NSAIDs were also assessed by prospectively designed pooled analyses of renal events data (see definition above — Supratherapeutic Doses) from five placebo- and active-controlled 12-week arthritis trials that included 995 OA or RA patients given valdecoxib 10 mg daily. The incidence of renal events observed in this analysis with valdecoxib 10 mg daily (3%), ibuprofen 800 mg TID (7%), naproxen 500 mg BID (2%) and diclofenac 75 mg BID (4%) were significantly higher than placebo-treated patients (1%). In all treatment groups, the majority of renal events were either due to the occurrence of edema or worsening BP.
Gastrointestinal Ulcers in High-Risk Patients
Subset analyses were performed of patients with risk factors (age, concomitant low-dose aspirin use, history of prior ulcer disease) enrolled in four upper GI endoscopic studies. Table 3 summarizes the trends seen.
Table 3 Incidence of Endoscopic Gastroduodenal Ulcers in Patients With and Without Selected Risk Factors | Placebo-controlled Studies | Active-controlled Studies |
|---|
| Risk Factor | Placebo | Valdecoxib
(10–20 mg daily) | Valdecoxib
(10–80 mg daily) | Ibuprofen
800 mg TID | Naproxen
500 mg BID | Diclofenac
75 mg BID |
|---|
| No statistical conclusions can be drawn from these comparisons. |
| Age | | | | | | |
| <65 yrs | 3.7% (8/219) | 3.5% (17/484) | 3.7% (48/1306) | 8.2% (9/110) | 12.8% (51/397) | 13.2% (34/258) |
| ≥65 yrs | 5.8% (8/137) | 4.6% (12/262) | 7.6% (43/568) | 21.6% (16/74) | 22.0% (33/150) | 18.2% (25/137) |
| Concomitant Low Dose Aspirin Use | | | | | | |
| no | 4.4% (13/298) | 3.2% (21/650) | 3.8% (64/1671) | 9.8% (15/153) | 16.0% (75/468) | 12.8% (45/351) |
| yes | 5.2% (3/58) | 8.3% (8/96) | 13.3%(27/203) | 32.3% (10/31) | 11.4% (9/79) | 31.8% (14/44) |
| History of Ulcer Disease | | | | | | |
| no | 4.4% (14/317) | 3.4% (22/647) | 4.1% (68/1666) | 13.8% (22/160) | 13.3% (63/475) | 14.7% (52/354) |
| yes | 5.1% (2/39) | 7.1% (7/99) | 11.1% (23/208) | 12.5% (3/24) | 29.2% (21/72) | 17.1% (7/41) |
The correlation between findings of endoscopic studies, and the incidence of clinically significant serious upper GI events has not been established.
Platelets
In four clinical studies with young and elderly (≥65 years) subjects, single and multiple doses up to 7 days of BEXTRA 10 to 40 mg BID had no effect on platelet aggregation.
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