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CLINICAL STUDIES Osteoarthritis (OA)
VIOXX has demonstrated significant reduction in joint pain compared to placebo. VIOXX was evaluated for the treatment of the signs and symptoms of OA of the knee and hip in placebo-and active-controlled clinical trials of 6 to 86 weeks duration that enrolled approximately 3900 patients. In patients with OA, treatment with VIOXX 12.5 mg and 25 mg once daily resulted in improvement in patient and physician global assessments and in the WOMAC (Western Ontario and McMaster Universities) osteoarthritis questionnaire, including pain, stiffness, and functional measures of OA. In six studies of pain accompanying OA flare, VIOXX provided a significant reduction in pain at the first determination (after one week in one study, after two weeks in the remaining five studies); this continued for the duration of the studies. In all OA clinical studies, once daily treatment in the morning with VIOXX 12.5 and 25 mg was associated with a significant reduction in joint stiffness upon first awakening in the morning. At doses of 12.5 and 25 mg, the effectiveness of VIOXX was shown to be comparable to ibuprofen 800 mg TID and diclofenac 50 mg TID for treatment of the signs and symptoms of OA. The ibuprofen studies were 6-week studies; the diclofenac studies were 12-month studies in which patients could receive additional arthritis medication during the last 6 months. Text Continues Below
Rheumatoid Arthritis (RA) VIOXX has demonstrated significant reduction of joint tenderness/ pain and joint swelling compared to placebo. VIOXX was evaluated for the treatment of the signs and symptoms of RA in two 12-week placebo-and active-controlled clinical trials that enrolled a total of approximately 2,000 patients. VIOXX was shown to be superior to placebo on all primary endpoints (number of tender joints, number of swollen joints, patient and physician global assessments of disease activity). In addition, VIOXX was shown to be superior to placebo using the American College of Rheumatology 20% (ACR20) Responder Index, a composite of clinical, laboratory, and functional measures of RA. VIOXX 25 mg once daily and naproxen 500 mg twice daily showed generally similar effects in the treatment of RA. A 50-mg dose once daily of VIOXX was also studied; however, no additional efficacy was seen compared to the 25-mg dose. Analgesia, including Dysmenorrhea In acute analgesic models of post-operative dental pain, post-orthopedic surgical pain, and primary dysmenorrhea, VIOXX relieved pain that was rated by patients as moderate to severe. The analgesic effect (including onset of action) of a single 50-mg dose of VIOXX was generally similar to 550 mg of naproxen sodium or 400 mg of ibuprofen. In single-dose post-operative dental pain studies, the onset of analgesia with a single 50-mg dose of VIOXX occurred within 45 minutes. In a multiple-dose study of post-orthopedic surgical pain in which patients received VIOXX or placebo for up to 5 days, 50 mg of VIOXX once daily was effective in reducing pain. In this study, patients on VIOXX consumed a significantly smaller amount of additional analgesic medication than patients treated with placebo (1. 5 versus 2.5 doses per day of additional analgesic medication for VIOXX and placebo, respectively). Special Studies The following special studies were conducted to evaluate the comparative safety of VIOXX. VIOXX GI Clinical Outcomes Research (VIGOR Study)
Study Design
The VIGOR study was designed to evaluate the comparative GI safety of VIOXX 50 mg once daily (twice the highest dose recommended for chronic use in OA and RA) versus naproxen 500 mg twice daily (common therapeutic dose). The general safety and tolerability of VIOXX 50 mg once daily versus naproxen 500 mg twice daily was also studied. VIGOR was a randomized, double-blind study (median duration of 9 months) in 8076 patients with rheumatoid arthritis (RA) requiring chronic NSAID therapy (mean age 58 years). Patients were not permitted to use concomitant aspirin or other antiplatelet drugs. Patients with a recent history of myocardial infarction or stroke and patients deemed to require low-dose aspirin for cardiovascular prophylaxis were to be excluded from the study. Fifty-six percent of patients used concomitant oral corticosteroids. The GI safety endpoints (confirmed by a blinded adjudication committee) included:
PUBs-symptomatic ulcers, upper GI perforation, obstruction, major or minor upper GI bleeding. Complicated PUBs (a subset of PUBs)-upper GI perforation, obstruction or major upper GI bleeding.
Study Results
Gastrointestinal Safety in VIGOR
The VIGOR study showed a significant reduction in the risk of development of PUBs, including complicated PUBs in patients taking VIOXX compared to naproxen (see Table 1). Table 1
VIGOR-Summary of Patients with Gastrointestinal Safety Events 1
COMPARISON TO NAPROXEN GI Safety Endpoints
VIOXX 50 mg
daily
(N= 4047) 2 n 3 (Cumulative
Rate 4 ) Naproxen
1000 mg daily
(N= 4029) 2
n 3 (Cumulative
Rate 4 ) Relative Risk of
VIOXX compared
to naproxen 5
95% CI 5 PUBs 56 (1.80) 121 (3.87) 0.46* (0.33, 0.64)
Complicated PUBs 16 (0.52) 37 (1.22) 0.43* (0.24, 0.78)
1 As confirmed by an independent committee blinded to treatment, 2 N= Patients randomized, 3 n= Patients with events, 4 Kaplan-Meier cumulative rate at end of study when at least 500 patients remained (approx. 10 1/ 2 months), 5 Based on Cox proportional hazard model
*p-value 0.005 for relative risk compared to naproxen The risk reduction for PUBs and complicated PUBs for VIOXX compared to naproxen (approximately 50%) was maintained in patients with or without the following risk factors for developing a PUB (Kaplan-Meier cumulative rate of PUBs at approximately 10 1/ 2 months, VIOXX versus naproxen, respectively): with a prior PUB (5. 12, 11.47); without a prior PUB (1. 54, 3.27); age 65 or older (2. 83, 6.49); or younger than 65 years of age (1. 48, 3.01). A similar risk reduction for PUBs and complicated PUBs (approximately 50%) was also maintained in patients with or without Helicobacter pylori infection or concomitant corticosteroid use. Other Safety Findings Cardiovascular Safety The VIGOR study showed a higher incidence of adjudicated serious cardiovascular thrombotic events in patients treated with VIOXX 50 mg once daily as compared to patients treated with naproxen 500 mg twice daily (see Table 2). This finding was largely due to a difference in the incidence of myocardial infarction between the groups. (See Table 3.) (See PRECAUTIONS, Cardiovascular Effects.) Adjudicated serious cardiovascular events (confirmed by a blinded adjudication committee) included: sudden death, myocardial infarction, unstable angina, ischemic stroke, transient ischemic attack and peripheral venous and arterial thromboses. VIOXX (rofecoxib tablets and oral suspension) 9556413 Table 2
VIGOR-Summary of Patients with Serious Cardiovascular
Thrombotic Adverse Events 1 Over Time
COMPARISON TO NAPROXEN Treatment Group Patients Randomized 4 Months 2 8 Months 3 10 ½ months 4 VIOXX 50 mg 4047 Total number of events 17 29 45
Cumulative Rate * 0.46% 0.82% 1.81%* Naproxen 1000 mg 4029 Total number of events 9 1519
Cumulative Rate * 0.23% 0.43% 0.60%
1 Confirmed by blinded adjudication committee, 2 Number of patients remaining after 4 months were 3405 and 3395 for VIOXX and naproxen respectively, 3 Number of patients remaining after 8 months were 2806 and 2798 for VIOXX and naproxen respectively, 4 Number of patients remaining were 531 and 514 for VIOXX and naproxen respectively.
*Kaplan-Meier cumulative rate.
* p-value <0.002 for the overall relative risk compared to naproxen by Cox proportional hazard model Table 3
VIGOR-Serious Cardiovascular
Thrombotic Adverse Events 1 VIOXX 50 mg
N 2 =4047
n 3 Naproxen 1000 mg
N 2 =4029
n 3 Any CV thrombotic event 45 * 19
Cardiac events 28** 10
Fatal MI/ Sudden death 5 4
Non-fatal MI 18** 4
Unstable angina 5 2
Cerebrovascular 11 8
Ischemic stroke 9 8
TIA 2 0
Peripheral 6 1 1
Confirmed by blinded adjudication committee, 2 N= Patients randomized, 3 n= Patients with events
* p-value <0.002 and ** p-value 0.006 for relative risk compared to naproxen by Cox proportional hazard model For cardiovascular data from 2 long-term placebo-controlled studies, see PRECAUTIONS, Cardiovascular Effects. Upper Endoscopy in Patients with Osteoarthritis and Rheumatoid Arthritis The VIGOR study described above compared clinically relevant outcomes. Several studies summarized below have utilized scheduled endoscopic evaluations to assess the occurrence of asymptomatic ulcers in individual patients taking VIOXX or a comparative agent. The results of outcomes studies, such as VIGOR, are more clinically relevant than the results of endoscopy studies (see CLINICAL STUDIES, Special Studies, VIGOR). Two identical (U. S. and Multinational) endoscopy studies in a total of 1516 patients were conducted to compare the percentage of patients who developed endoscopically detectable gastroduodenal ulcers with VIOXX 25 mg daily or 50 mg daily, ibuprofen 2400 mg daily, or placebo. Entry criteria for these studies permitted enrollment of patients with active Helicobacter pylori infection, baseline gastroduodenal erosions, prior history of an upper gastrointestinal perforation, ulcer, or bleed (PUB), and/ or age 65 years. However, patients receiving aspirin (including low-dose aspirin for cardiovascular prophylaxis) were not enrolled in these studies. Patients who were 50 years of age and older with osteoarthritis and who had no ulcers at baseline were evaluated by endoscopy after weeks 6, 12, and 24 of treatment. The placebo-treatment group was discontinued at week 16 by design. Treatment with VIOXX 25 mg daily or 50 mg daily was associated with a significantly lower percentage of patients with endoscopic gastroduodenal ulcers than treatment with ibuprofen 2400 mg daily. See Figures 1 and 2 for the results of these studies.
Figure 1
COMPARISON TO IBUPROFEN
Life-Table Cumulative Incidence Rate of Gastroduodenal
Ulcers 3mm** (Intention-to-Treat) Placebo Rofecoxib 25mg
Rofecoxib 50mg
Ibuprofen 2400 mg (N= 158) (N= 186)
(N= 178)
(N= 167) Cumulative
Incidence
Rate
(%) Time by Treatment
3.4
9.9* 2.9 4.1*
9.6*
4.7
7.3* 14.7*
18. 8 27. 7 45.8 0
10
20
30
40
50 6-Week 12-Week*** 24-Week U. S. Study * p < 0.001 versus ibuprofen 2400 mg
** Results of analyses using a 5mm gastroduodenal ulcer endpoint were consistent.
*** The primary endpoint was the cumulative incidence of gastroduodenal ulcer at 12 weeks. Figure 2
COMPARISON TO IBUPROFEN
Life-Table Cumulative Incidence Rate of Gastroduodenal
Ulcers 3mm** (Intention-to-Treat) VIOXX (rofecoxib tablets and oral suspension) 9556413 0.00
5.1* 3.4 5.3*
9.9* 6.9 8.8* 12. 4* 20. 2
29.2 46. 8 Time by Treatment
6-Week 12-Week*** 24-Week Multinational Study
0
10
20
30
40
50 Placebo Rofecoxib 25mg
Rofecoxib 50mg
Ibuprofen 2400 mg (N= 182) (N= 187)
(N= 182)
(N= 187) Cumulative
Incidence
Rate
(%) * p < 0.001 versus ibuprofen 2400 mg
** Results of analyses using a 5mm gastroduodenal ulcer endpoint were consistent.
*** The primary endpoint was the cumulative incidence of gastroduodenal ulcer at 12 weeks. In a similarly designed 12-week endoscopy study in RA patients treated with VIOXX 50 mg once daily (twice the highest dose recommended for chronic use in OA and RA) or naproxen 1000 mg daily (common therapeutic dose), treatment with VIOXX was associated with a significantly lower percentage of patients with endoscopic gastroduodenal ulcers than treatment with naproxen. A similarly designed 12-week endoscopy study was conducted in OA patients treated with low-dose enteric coated aspirin 81 mg daily, low-dose enteric coated aspirin 81 mg plus VIOXX 25 mg daily, ibuprofen 2400 mg daily, or placebo. There was no difference in the cumulative incidence of endoscopic gastroduodenal ulcers in patients taking low-dose aspirin plus VIOXX 25 mg as compared to those taking ibuprofen 2400 mg daily alone. Patients taking low-dose aspirin plus ibuprofen were not studied. (See PRECAUTIONS, Drug Interactions, Aspirin.) Serious clinically significant upper GI bleeding has been observed in patients receiving VIOXX in controlled trials, albeit infrequently (see WARNINGS, Gastrointestinal (GI) Effects -Risk of GI Ulceration, Bleeding, and Perforation). Assessment of Fecal Occult Blood Loss in Healthy Subjects
Occult fecal blood loss associated with VIOXX 25 mg daily, VIOXX 50 mg daily, ibuprofen 2400 mg per day, and placebo was evaluated in a study utilizing 51 Cr-tagged red blood cells in 67 healthy males. After 4 weeks of treatment with VIOXX 25 mg daily or VIOXX 50 mg daily, the increase in the amount of fecal blood loss was not statistically significant compared with placebo-treated subjects. In contrast, ibuprofen 2400 mg per day produced a statistically significant increase in fecal blood loss as compared with placebo-treated subjects and VIOXX-treated subjects. The clinical relevance of this finding is unknown. Platelets Multiple doses of VIOXX 12.5, 25, and up to 375 mg administered daily up to 12 days had no effect on bleeding time relative to placebo. There was no inhibition of ex vivo arachidonic acid-or collagen-induced platelet aggregation with 12.5, 25, and 50 mg of VIOXX. Because of its lack of platelet effects, VIOXX is not a substitute for aspirin for cardiovascular prophylaxis. (See PRECAUTIONS, Cardiovascular Effects.) Page: << Prev | 1 | 2 | 3 | 4 | 5
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