osteoarthritis

When patients with osteoarthritis were treated with etoricoxib, their pain, inflammation and activity were significantly improved. Two 52-week double-blind randomized clinical trials were conducted in about 1000 patients with knee or hip osteoarthritis, and hand osteoarthritis was evaluated in 2 1% patients. In these two trials, after 12 weeks of treatment, the curative effect of etocoxib (60 mg, once a day 1 time) group was better than that of placebo group, and the curative effect was similar to that of naproxen (500 mg, twice a day) group during the whole 52-week treatment period. The degree of pain, joint stiffness and joint tenderness of the patients were significantly reduced, and the activity was significantly improved. The clinical efficacy was shown within 2 days after the start of the trial and continued throughout the trial. In patients with hand osteoarthritis, the relief of pain and stiffness and the improvement of physical function are better than those in placebo group, and the curative effect is similar to that in naproxen group.

In the third trial of about 600 patients, the efficacy of etoricoxib (60 mg once a day) group was better than that of placebo group within 6 weeks of treatment (the evaluation method was similar to the previous two trials). During the 92-week treatment period, the results of patients' self-evaluation and researchers' evaluation were similar between the etoricoxib group and the diclofenac group (50 mg, three times a day).

In the other four trials, 9 13 patients were selected. During the treatment period of 12 weeks (using the same evaluation method as the above test), the once-a-day 30mg group was better than the placebo group. Two of the trials showed that during the treatment period of 12 weeks, the efficacy of 30mg ibuprofen once a day was similar to that of 800 mg ibuprofen three times a day. Two other trials showed that the efficacy of the 30mg once daily group was similar to that of the 200mg once daily group during the treatment period of 12 and 26 weeks.

Acute gouty arthritis

When treating patients with moderate or severe pain (acute gouty arthritis, about 150), after 8 days of treatment with etocoxib (120 mg, once a day 1 time), the degree of relieving joint pain and inflammation (tenderness, swelling and erythema) is similar to that of indomethacin (50 mg, three times a day). Pain relief (first measurement) was observed 4 hours after treatment.

Special research

MEDAL is an international long-term (MEDAL) research project, which is a forward-looking research project, relying on the treatment of arthritis with coxib and diclofenac. The comprehensive data of three independent, randomized, double-blind, active drug (diclofenac) controlled trials (MEDAL trial, EDGE II and EDGE) were used to evaluate the cardiovascular safety results. The MEDAL project also assessed the safety of the upper and lower digestive tracts. In this project, 347,065,438+0 patients with osteoarthritis (OA) and rheumatoid arthritis (RA) were selected, and etoricoxib 60 mg daily 1 time (osteoarthritis) or etoricoxib 90 mg daily 1 time (osteoarthritis and rheumatoid arthritis, the dose was 65,438+recommended dose of osteoarthritis. About 12800 patients used drugs for more than 24 months, and some patients received treatment for more than 42 months.

Patients selected for this program have a wide range of cardiovascular and digestive tract baseline risk factors. About 47% patients have a history of hypertension, about 12% patients have a history of symptomatic atherosclerotic coronary heart disease (ASCVD), and about 38% patients have increased cardiovascular risk factors at baseline [defined as having a history of symptomatic ASCVD or having at least two cardiovascular risk factors (hypertension, diabetes, dyslipidemia, family history of cardiovascular disease and smoking). Patients with myocardial infarction, coronary artery bypass grafting or percutaneous coronary intervention within 6 months before screening were excluded. Gastric mucosal protective agents and low-dose aspirin are allowed in the experiment. About 50% patients use gastric mucosal protective agent, and about 35% patients use low-dose aspirin. In the experiment, etoricoxib 60 mg and 90 mg showed similar efficacy to diclofenac.

The cardiovascular and gastrointestinal safety data are summarized as follows. Other important safety data (including renal vascular data) can be found in Side Effects.

Cardiovascular data: MEDAL project showed that the incidence of thrombotic cardiovascular serious adverse events (including cardiovascular and cerebrovascular events and peripheral vascular events) in etoricoxib group was similar to that in diclofenac group (see table 1). For the primary end point (confirmed thrombotic cardiovascular events), the relative risk between the etoricoxib and diclofenac groups was 0.95(95% confidence interval: 0.8 1, 0. 1 1) in the preset primary analysis. The incidence of different types of embolism events (such as myocardial infarction and stroke) is similar between etoricoxib and diclofenac. The incidence of thrombotic cardiovascular events was similar between etoricoxib group and diclofenac group during the whole trial period, including some patients who had been treated for more than 24 months. In all subgroup analyses, including all patients with baseline cardiovascular risk, there was no significant difference in the incidence of embolic events between etoricoxib group and diclofenac group. The cardiovascular mortality and total mortality of etoricoxib group and diclofenac group were similar.

Digestive tract data: For the confirmed clinical events of upper digestive tract (perforation, ulcer, bleeding; PUB), the incidence of etoricoxib group per 100 patient-year was 0.67 (95% confidence interval: 0.57, 0.77), and the relative risk of diclofenac group was 0.97 (95% confidence interval: 0.85, 1. 10). The incidence of complicated upper digestive tract clinical events per 100 patient year in etoricoxib group and diclofenac group was similar (0.30 and 0.32). Because the risk of upper gastrointestinal events increases with age, the incidence of these events in elderly patients was evaluated. The highest risk reduction was observed in patients ≥ 75 years old; The incidence of etoricoxib was lower than that of diclofenac (10.35 [95% ci 0.94,10.87] and 2.78[95% CI 2. 14) per year of patients with upper gastrointestinal clinical events. The incidence of confirmed upper gastrointestinal events was also evaluated in patients taking low-dose aspirin and/or gastric mucosal protective agent at the same time, and the results are shown in Table 2. Between etoricoxib group and diclofenac group, the ratio of clinical events in lower digestive tract diagnosed per 100 patient year was 0.32[95% confidence interval 0.25,0.39] and 0.38[5% confidence interval 0.3 1 0.46], and the relative risk was 0.84 (95% confidence interval)

Gastrointestinal tolerance is defined as the patient's suspension of the trial due to any clinical (such as dyspepsia, abdominal pain, ulcer) or laboratory examination (such as elevated ALT and AST) gastrointestinal related adverse events (including liver events). Each trial in MEDAL also evaluated the tolerance of digestive tract. The EDGE and EDGE II tests evaluated the tolerance of digestive tract as the main end point. These two trials compared etocoxib (90 mg once a day) and diclofenac (150 mg once a day) in patients with osteoarthritis (EDGE) and rheumatoid arthritis (EDGE II). The secondary purpose of MEDAL trial is to compare the difference of digestive tract tolerance between etoricoxib 60mg (osteoarthritis) or 90 mg (osteoarthritis and rheumatoid arthritis) and diclofenac (150 mg once a day). In all three trials, etoricoxib showed better digestive tract tolerance than diclofenac (P

In each trial of MEDAL project, the suspension of trials due to liver-related adverse events was also evaluated. In all three trials, for patients with osteoarthritis and rheumatoid arthritis, the incidence of trial termination in etocoxib 60 and 90 mg treatment groups was significantly lower than that in diclofenac 150 mg treatment group.

Other thrombotic cardiovascular safety data

In the comprehensive analysis of all IIB ~ V clinical trials lasting for 4 weeks or more (excluding MEDAL project), there was no significant difference in the incidence of thrombotic cardiovascular serious adverse events among patients receiving the following treatments: etocoxib ≥ 30 mg (n=2 147 patients, with an average exposure period of about 309 days), Non-naproxen NSAIDs (ibuprofen 2400 mg/ day or diclofenac 150 mg/ day, n= 1470 patients, and patients taking naproxen 500 mg twice a day (n= 1497 patients, the average exposure time was about 42/kloc-0. Some selective cyclooxygenase? 1 inhibitors and selective cyclooxygenase? The difference of antiplatelet activity between inhibitors may have clinical significance for patients at risk of thrombosis. Selective cyclooxygenase? Inhibitors can reduce the production of prostacyclin in the whole body (probably endothelium) without affecting platelet thromboxane.

Comprehensive analysis of cardiovascular events

In the initial clinical development study, about 3 100 patients took ≥ 60mg of this product every day for 12 weeks.

There was no significant difference in the incidence of thrombotic cardiovascular serious adverse events between patients taking etoricoxib ≥ 60mg or non-naproxen NSAIDs. The incidence of these events in patients taking etoricoxib was higher than that in patients taking naproxen 500mg twice a day. For patients with risk factors of thromboembolism, the difference in antiplatelet activity between some NSAID that inhibit COX- 1 and selective COX-2 inhibitors may have clinical significance. Selective COX-2 inhibitors reduce the formation of cyclic prostaglandin in the whole body (possibly endothelium), but do not affect platelet thromboxane.

Other digestive tract safety data

In order to evaluate whether the digestive tract toxicity of COX-2 inhibitor etoricoxib is lower than that of non-selective NSAID, the following special studies were carried out.

Upper Gastrointestinal Endoscopy in Patients with Rheumatoid Arthritis or Osteoarthritis In two double-blind endoscopic studies lasting for 12 weeks, the cumulative incidence of gastric and duodenal ulcers in patients receiving etoricoxib (120mg once a day) was lower than that in patients receiving non-selective NSAID (naproxen 500mg twice a day or ibuprofen 800mg three times a day). In this study, 700 patients with osteoarthritis or rheumatoid arthritis were treated, and in study 2, 2655 patients with osteoarthritis were treated. Compared with placebo, the cumulative incidence of digestive tract ulcer in patients treated with etoricoxib is higher. (See Figure 2 for test results) Figure 2 Cumulative incidence of gastric and duodenal ulcers ≥ 3 mm* (intentional treatment) in two endoscopic studies lasting 12 weeks.

* It is consistent with the analysis result that the end point is gastric and duodenal ulcer ≥ 5 mm.

* * p & lt0.00 1 relative to naproxen 500 mg, twice a day.

1p=0.007 800 mg ibuprofen, three times a day.

Two endoscopic studies included the following patients with high risk of digestive tract ulcer: patients with active helicobacter pylori infection; Gastroduodenal erosion at baseline; Past history of perforation, ulcer or bleeding (pub); And/or concomitant use of corticosteroids. 400 patients (28%) were over 65 years old. In these high-risk subgroups, the gastrointestinal safety of etoricoxib is still superior to naproxen or ibuprofen.

Summary and analysis of gastrointestinal safety

In the summary analysis of all phase IIb to V clinical studies (except MEDAL project trials) including 4 weeks or more, non-selective NSAID (naproxen 1000 mg/ day, diclofenac 150 mg/ day and ibuprofen 2400 mg/ day; Total number = 2967 patients, with an average treatment time of about 182 days) and multiple doses of etocoxib (with a dose range of 30 mg/ day to 120mg/ day, N = 4 107 patients, with an average treatment time of about 220 days). In the first year of treatment, the incidence of PUB events in the etoricoxib treatment group was about half that in the non-selective NSAID treatment group (etoricoxib was 1. 13 event/100 patient year, and NSAID was 2.64 event/100 patient year; The relative risk is 0.47 [95% confidence interval: 0.28, 0.76]). During the whole follow-up period, the results were consistent.

Summary and analysis of clinical tolerance of digestive tract

Eight clinical trials were conducted in about 4000 patients with osteoarthritis, rheumatoid arthritis or chronic low back pain. In the scheduled summary analysis of these eight trials, the incidence of the following end points was evaluated: 1) The trial was suspended due to upper gastrointestinal symptoms; 2) Stop the trial due to any gastrointestinal adverse events; 3) Using new gastric mucosal protective agents (including H2 receptor antagonists, misoprostol and proton pump inhibitors); 4) Use any new digestive tract drugs. Compared with patients treated with non-selective NSAID (naproxen 500 mg twice daily or diclofenac 50mg three times daily), patients treated with etoricoxib (60, 90 or 120 mg/d) had a reduced risk of these endpoints by about 50%. There was no significant difference between etoricoxib and placebo.

Evaluation of fecal occult blood loss in healthy subjects

In a study of 62 healthy men, the whole gastrointestinal mucosal integrity and fecal occult blood loss of subjects who received etocoxib 120mg once a day, ibuprofen 2400mg once a day and placebo were evaluated by using red blood cells labeled with 5 1Cr. Compared with the subjects treated with placebo, there was no significant increase in occult blood loss after 4 weeks of treatment with etoricoxib 120mg.

In contrast, ibuprofen (2400mg once a day) significantly increased the loss of fecal occult blood compared with subjects receiving placebo and etoricoxib.

Study on renal function in the elderly

In a randomized, double-blind, placebo-controlled parallel study, the effects of etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily) and placebo on urinary sodium excretion, blood pressure and other renal function parameters were evaluated within 65,438+05 days. Subjects took 200 mg daily.

During the two-week treatment, the effects of etoricoxib, celecoxib and naproxen on urinary sodium excretion were similar. Compared with placebo, all active control drugs can increase systolic blood pressure; However, compared with celecoxib and naproxen, the results of blood pressure increase on day 14 (mean systolic blood pressure change from baseline: 7.7 mmHg in the etocoxib group, 2.4 mmHg in the celecoxib group and 3.6 mmHg in the naproxen group) were statistically significant.