Etoricoxib Versus Naproxen in Patients With Rheumatoid Arthritis: a Prospective, Randomized, Comparator-Controlled 121-Week Trial

By Matsumoto, Alan Melian, Agustin; Shah, Arvind; Curtis, Sean P

Key words: Etoricoxib – Naproxen – NSAIDs – Selective COX-2 inhibitors ABSTRACT

Background: Etoricoxib is a cyclooxygenase-2 (COX-2) selective inhibitor effective in the treatment of rheumatoid arthritis. An initial 12-week treatment study found that etoricoxib (90 mg once daily) was more effective than naproxen (500 mg twice daily) or placebo in treating rheumatoid arthritis. The present two-part extension of that study was performed to monitor tolerability and examine long-term efficacy of etoricoxib 90 mg or 120 mg compared with naproxen.

Methods: Patients completing the initial 12-week study and those discontinuing due to lack of efficacy, were eligible for the Extension Study Part I (12-52 weeks) and assigned (2:1:2 ratio) to receive etoricoxib (90 mg or 120 mg daily) or naproxen (500 mg twice daily); these patients remained on the same therapy for Extension Study Part II (52-121 weeks). Primary outcome measures included investigator and patient assessment of disease activity, and tender and swollen joint counts.

Results: Of 816 patients enrolled in the initial 12-week trial, 717 continued into the Extension Study Part I; 505 patients completed and 390 entered the Extension Study Part II, with 283 patients completing 121 weeks. Patients receiving etoricoxib (90 mg) or naproxen throughout the study experienced sustained efficacy in all outcomes, as did patients transitioning to etoricoxib (120 mg) following the initial 12-week trial. Patients transitioning from placebo to etoricoxib (90 mg) experienced rapid, sustained improvements in all outcome measures.

Conclusion: In conclusion, etoricoxib provided sustained efficacy throughout the 121-week study, with efficacy comparable to naproxen.

Introduction

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disorder that can result in serious disability and deformity. Patients experience pain, stiffness, and swelling in multiple joints. Pharmacologie treatment is aimed at controlling pain and inflammation, retaining physical functioning and quality of life, and preventing structural joint damage1. This treatment includes the use of nonsteroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase-2 (COX-2) selective inhibitors for symptomatic treatment and the use of disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate and tumor necrosis factor inhibitors, which can reduce progression of the disease. Additionally, although traditional non-steroidal anti-inflammatory drugs or COX-2 selective inhibitors offer symptomatic treatment of RA and do not affect disease progression, these agents are often used to reduce the pain and inflammation associated with the disease.

The use of traditional and COX-2 selective NSAIDs must be carefully evaluated by physicians based on each patient’s disease status and current medical risk factors, along with the pharmacologie profile of available treatments. While randomized clinical trials have demonstrated a lower relative risk of gastrointestinal (GI) toxicity with COX-2 selective inhibitors compared with traditional NSAIDs2’5, there are also other relevant tolerability and safety issues. Particularly, all NSAIDs have the potential to affect the renovascular system via inhibition of COX-2- mediated renal prostaglandin biosynthesis6. Emerging evidence from long-term placebo controlled trials, meta-analyses, and observational studies has also demonstrated an increased risk of thrombotic cardiovascular (CV) events versus placebo for NSAIDs with the exception of high-dose naproxen7’9. Therefore, when choosing a treatment regimen for patients who require analgesic and anti- inflammatory therapy, physicians must weigh the risks and benefits of selective COX-2 agents and traditional NSAIDs as well as the medical histories of individual patients who may be susceptible to GI, renovascular, or CV adverse events.

Etoricoxib is a COX-2 selective inhibitor that has proven to be an effective treatment for rheumatoid arthritis and has also exhibited improved gastrointestinal safety compared with nonselective NSAIDs3,5,10-12. A dose-ranging study found that etoricoxib (90 mg and 120 mg) was significantly more effective than placebo in an initial 8-week treatment period, with sustained efficacy during a 3-year extension13. A separate 12-week, double- blind, randomized, placebo- and comparator-controlled study reported that etoricoxib 90 mg once daily was significantly more effective than placebo and similar to naproxen 500 mg twice daily in the treatment of rheumatoid arthritis14. A similarly designed 12-week study reported statistically greater improvement with etoricoxib (90 mg) than with placebo or naproxen 500 mg twice daily10. Due to the chronic nature of RA, it is important to examine the long-term efficacy and tolerability of treatments (e.g., traditional and COX- 2 selective NSAIDs) that are commonly used. Therefore, we report the data from an extension of the latter, aforementioned 12-week study10, undertaken to evaluate the long-term maintenance of treatment effects. Specifically, two extension periods, 12-52 weeks (Extension Study Part I) and 52-121 weeks (Extension Study Part II), were designed to: (1) allow patients who received placebo in the initial treatment study to receive longterm active treatment with etoricoxib or naproxen, (2) allow successful completers to continue treatment for up to 121 weeks, (3) allow a dose escalation from etoricoxib 90 mg to 120mg, and (4) allow patients who tolerated treatment but discontinued due to lack of efficacy to receive further active treatment.

Patients and methods

This study was conducted at 88 sites in the United States. Extension Study Part I was conducted from January 2000 to July 2001 and Extension Study Part II was conducted from October 2000 to October 2002. The protocol and consent forms were approved by an Institutional Review Board or Ethics Review Committee for each study site. Each patient provided written informed consent for the 52- week trial (initial 12-week trial and Extension Study Part I, weeks 12-52) prior to enrolling in the initial 12-week trial. Written informed consent was also obtained prior to entry into the Extension Study Part II.

Patients

Patient eligibility was evaluated at entry into the initial 12- week study10. Eligible patients were > 18 years of age and fulfilled diagnostic criteria for rheumatoid arthritis as specified by the American Rheumatism Association 1987 revised criteria15. Patients were required to have a diagnosis of RA for at least 6 months prior to study entry, have used an NSAID for at least 25 of the 30 days preceding the screening visit, and exhibit a symptomatic flare after NSAID washout. Low-dose corticosteroid use (prednisone < 10mg/day) was permitted if the dose remained stable until week 16 of the Extension Study Part I, as were disease modifying anti-rheumatic drugs (DMARDs) if the dose remained stable until at least week 2. Inhibitors of tumor necrosis factor-alpha were excluded in the base study design since these agents were new and not commonly used during the time that the initial base study was designed. Concomitant low-dose aspirin (

Study design

The initial 12-week treatment study randomized patients to placebo, etoricoxib (90 mg once daily) or naproxen (500mg twice daily) (2:2:1)10. Treatment allocations for the initial study and Extension Part I were carried out using a computer-generated code determined prior to initial randomization. Randomization was stratified by use or non-use of low-dose corticosteroids. All patients who either completed the initial 12 weeks, or at least 2 weeks but discontinued due to lack of efficacy, were eligible for continuation. In Extension Study Part I, patients who received etoricoxib 90 mg once daily in the 12-week study were randomized to etoricoxib 90 mg once daily or etoricoxib 120 mg once daily in Extension Study Part II. Patients receiving placebo in the 12-week study were randomized to naproxen (500mg twice daily) or etoricoxib (90mg once daily). Patients on naproxen in the 12-week study continued on naproxen in the Extension Study Parti (Figure 1). Patients continuing into Extension Study Part II remained on the same treatment regimen received during Part I.

Study visits occurred at 14, 20, 28, 40, and 52 weeks from baseline for Extension Study Part I and at 69, 86, 104, and 121 for Extension Study Part II. Patients were to have taken their morning study therapy prior to clinic visits, and to schedule clinic visits at the same time in the morning throughout the study.

Figure 1. Patient accounting and study design displaying 12-week base period, Extension Pan I, and Extension Part II. *p < 0.05 etoricoxib 120 mg versus naproxen. [dagger] Therapy was assigned at initial randomization. [double dagger] Patient lost to follow-up, moved, withdrew consent, protocol deviation, discontinued for other reasons, or study site was terminated Efficacy assessments

Efficacy assessments for Extension Study Part I included all components of the American College of Rheumatology (ACR) core set of outcome measures. The four prespecified primary endpoints were: tender joint count (total 68 joints); swollen joint count (total 66 joints); patient global assessment of disease activity (100-mm visual analog scale (VAS): O = ‘very well’, 100 = ‘very poor’); and investigator global assessment of disease activity (0-4 Likert scale: O = ‘very well’, 1 = ‘well’, 2 = ‘fair’, 3 = ‘poor’, 4 = ‘very poor’).

The response of a dose escalation from etoricoxib 90 mg to 120 mg, which occurred between the base study and Extension Study Part I, and the maintenance of efficacy were analyzed. The primary assessments for Extension Study Part II were patient global assessment of disease activity and investigator global assessment of disease activity.

Safety assessments

Safety assessments included physical examination, vital signs (including seated blood pressure measurements), laboratory assessments (serum chemistry, complete blood count, urinalysis), and reports of adverse experiences. Adverse experiences were categorized based on intensity, seriousness, and relation to study drug (possibly, probably, or definitely drug-related, probably not or definitely not drug-related). All potential serious thrombotic cardiovascular AEs and deaths, regardless of cause, and upper GI PUB (perforation, ulcer, or bleeds) events were adjudicated by separate expert case review committees that were blinded to treatment assignment according to previously described criteria2’5.

Statistical analysis

Efficacy analyses of treatment responses over time in Extension Study Part I were based on the modified intention-to-treat (ITT) approach (i.e., inclusion of all patients with a baseline measurement and at least one efficacy measurement). Baseline was defined at randomization during the initial 12-week study. Plots of Least Squares (LS) mean change from baseline by assigned treatment were used to assess efficacy with etoricoxib 90 mg or 120mg, or naproxen. LS mean change from baseline was computed using an analysis-of-covariance (ANCOVA) model with factors for treatment sequence, stratum (corticosteroid use), and baseline value as covariates. Assessment of treatment response over the entire 52 weeks was based on examination of plots of LS mean changes from baseline for patients who completed the 12-week study and continued on the same treatment (etoricoxib 90 mg or naproxen) in Extension Study Parts I and II. The slope of the response over the first 52 weeks was analyzed to examine the maintenance of treatment effects. An assessment of time-weighted average response over the entire 5 2- week study was performed for patients assigned the same therapy (etoricoxib 90 mg or naproxen) in both Parts I and II regardless of discontinuation in the initial study. Lastly, the effects of dose escalation in Extension Study Part II were assessed based on the LS mean change between the average of the last two assessments in the initial 12-week study and the average of the first two Extension Study Part I assessments, by specific treatment sequence, for the four primary endpoints. The LS mean change at each time point was computed using the last value carried forward method for plotting purposes; other summary statistics (i.e., average over time and slope analyses) were based only on observed data without any imputation.

Efficacy measures in Extension Study Part II were monitored by calculating mean changes +- standard error (SE] from baseline at each time point within each treatment group. No formal hypothesis testing was conducted. The study was exploratory for long-term effects of the maintenance of efficacy, thus multiplicity adjustments were not planned.

Safety data were tabulated by assigned treatment for clinical review. Ninety-five percent confidence intervals (CIs) for pairwise treatment differences (by proportion of patients) were calculated for all safety parameters. No formal statistical testing was performed for extension study safety data due to the lack of a placebo group, the lack of any pre-planned or powered specific hypotheses, and multiplicity issues.

Results

Patient accounting and characteristics

Of the 816 patients enrolled in the original clinical trial, 717 (87.9%) continued into the Extension Study Part I and 505 (61.9%) patients completed this 52-week extension (Figure 1). During the first extension, 55 patients (18.6%) discontinued naproxen therapy due to lack of efficacy, compared with 35 (12.6%) receiving etoricoxib (90mg) and 13 (9.0%) receiving etoricoxib 120mg (p < 0.05) (Figure 1). Across all groups, approximately 9 to 10% of patients discontinued any of the treatments due to adverse experiences. For patients entering the extension, baseline characteristics (Table 1) were similar among treatment groups, with a trend towards more patients in the etoricoxib group taking low- dose aspirin (

Of the 505 patients who completed the Extension Study Part 1,390 (77.2%) patients entered the Extension Study Part II and 283 (56%) completed the full 121 weeks (Figure 1). During the second extension, eight patients (5.3%) discontinued naproxen due to lack of efficacy compared with nine (5.8%) receiving etoricoxib (90mg), and seven (8.2%) receiving etoricoxib 120mg (Figure 1). A total of 16 patients (10.6%) discontinued naproxen due to adverse experiences compared with 13 (8.4%) receiving etoricoxib (90mg) and nine (10.6%) receiving etoricoxib 120 mg.

Efficacy over 52 weeks

As previously reported, during the base study period, etoricoxib 90 mg demonstrated significantly greater efficacy compared with naproxen10. Consistent with those results, in the current study, patients who transitioned from placebo to etoricoxib 90 mg experienced statistically greater improvements for swollen joint counts compared with those who transitioned from placebo to naproxen; the other efficacy endpoints demonstrated numeric differences that were not statistically significant favoring etoricoxib versus naproxen (Table 2). Patients who transitioned from etoricoxib 90 mg to etoricoxib 120 mg experienced no statistically significant increase in treatment effects; LS mean change of-2.30 (95% CI -3.55, -1.05) in tender joint counts, -1.70 (95% CI -2.69, – 0.71) in swollen joint counts; -0.69 (95% CI -3.91, 2.53) in patient global assessment, and -0.15 (95% CI -0.29, -0.01) in investigator global assessment.

Table 1. Baseline patient characteristics for patients participating in the Extension Study Pan I (weeks 12 to 52)

Table 2. LS mean (95% CI) difference in patients who transitioned from placebo to etoricoxib 90 mg or naproxen when entering the Extension Study Part I

Efficacy over 121 weeks

To examine the long-term maintenance effects of etoricoxib 90 mg and naproxen, outcomes were evaluated for patients assigned to the same therapy throughout the initial 12-week trial and Extension Studies Parts I and II (Figure 2). Comparable efficacy was observed in the etoricoxib 90 mg group and the naproxen group for all ACR core outcomes, including patient global assessment of disease activity, investigator global assessment of disease activity, tender joint count and swollen joint count. Figure 3 graphically demonstrates this with comparable treatment effect for etoricoxib 90 mg and naproxen over the course of the extension periods. The treatment effect observed with etoricoxib 90 mg is maintained throughout the two extension periods.

Figure 2. Patient and investigator global assessments of disease activity (100-mm visual analog scale), mean change from baseline (+- SE) for patients remaining on the same treatment from baseline to week 121

Safety and tolerability

The most frequent AEs regardless of cause are listed in Table 3. None of these AEs appeared to occur at a greater frequency in the etoricoxib versus the naproxen treatment groups. More drug-related AEs occurred in Extension Study Part I than in Part II (Table 3). Gastrointestinal nuisance symptoms were similar across all treatment groups and in both Extension Part I and Part II (Table 4).

Renovascular AEs during Extension Part I were generally similar for etoricoxib and naproxen with discontinuations due to hypertension-related AEs and congestive heart failure in two patients receiving etoricoxib 90 mg. In Extension Part II, hypertension-related AEs were more common with etoricoxib 120 mg compared with etoricoxib 90 mg or naproxen although no patients discontinued from the study due to a hypertension-related AE (Table 4). Four, one, and two patients in the etoricoxib 90 mg, etoricoxib 120 mg, and naproxen 1000 mg groups, respectively, had confirmed thrombotic CV serious AEs during Extension Part I. There were four, one, and five patients in the etoricoxib 90 mg, etoricoxib 120 mg, and naproxen 1000 mg groups, respectively, who had confirmed thrombotic CV serious AEs during Extension Part II (Table 4).

During Extension Part I, there were three patients taking etoricoxib 90 mg, no patients taking etoricoxib 120mg, and six patients taking naproxen lOOOmg with confirmed upper GI events. In Extension Part II, there were two patients with confirmed upper GI clinical events, both of which were in the naproxen 1000 mg group. In total, these events consisted of upper GI hemorrhage, duodenal ulcer, and gastric ulcer.

Figure 3. Patient and investigator global assessments of disease activity (100-mm visual analog scale), mean change from baseline (+- SE) for patients on the same treatment from Extension Pan I to week 121 Discussion

This study confirmed the long-term efficacy of etoricoxib 90 mg and 120mg in treating the signs and symptoms of rheumatoid arthritis. Treatment effects were maintained throughout the 121- week study over a wide range of assessments including patient and physician global assessment of disease activity, and tender and swollen joint counts. The similar efficacy demonstrated between etoricoxib and naproxen in this extension study is somewhat in contrast to the statistically significant efficacy that was demonstrated with etoricoxib compared with naproxen during the base period10. This is likely explained by the fact that the extension includes a self-selected patient population that had a positive treatment response during the previous portion of the study. It is important to note, however, that a replicate study demonstrated no significant efficacy advantage for etoricoxib versus naproxen14; thus, it is possible that the statistical difference in the base period of the present study may be attributable to a type II error. However, similar to the base study, significantly more patients discontinued therapy due to lack of efficacy with naproxen versus etoricoxib during Extension Study Part I (12-52 weeks). Patients continuing naproxen and etoricoxib from the 12-week base study showed similar efficacy but, interestingly, patients transitioning from placebo to active therapy (etoricoxib 90 mg or naproxen 500 mg twice daily) showed a significantly greater improvement in efficacy with etoricoxib compared with naproxen. These data suggest that etoricoxib 90 mg provides rapid improvements in rheumatoid arthritis symptoms that are maintained over the long term. Additionally, the incidence of reported clinical AEs was generally similar between etoricoxib 90 mg and 120 mg and naproxen 500 mg twice daily during the extension.

Table 3. Summary of clinical AEs

Table 4. AEs of special interest for NSAIDs

The number of confirmed CV events in this study were too low to make definitive conclusions regarding the relative CV risk of etoricoxib compared with naproxen. In a pooled analysis of etoricoxib data from 12 clinical trials > 4 weeks in duration in patients with OA, RA, ankylosing spondylitis, and chronic low back pain, there was no discernible difference in the incidence of thrombotic CV events in patients treated with etoricoxib >/= 60 mg versus non-naproxen traditional NSAIDs (i.e. diclofenac and ibuprofen)16. However, a trend toward more events with etoricoxib versus naproxen 500 mg b.i.d. was observed in that analysis. Results from a recent meta-analysis of over 130 randomized controlled clinical trials9 suggests that the chronic use of all NSAIDs is associated with an elevated risk of CV events and that the risk with naproxen may be lower than other comparator NSAIDs. This may be due to naproxen’s potent and sustained anti-platelet effect across its dosing interval at 500 mg b.i.d.17. While this pooled analysis and other data suggest a lower CV risk for naproxen versus etoricoxib or any other selective or nonselective, traditional NSAID9, it should continue to be used with caution in patients at risk for thrombotic CV events, particularly in patients taking cardioprophylactic low- dose aspirin; unlike etoricoxib, naproxen has been shown to interfere with the antiplatelet effects of low-dose aspirin18-20.

Recent results from the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Program provide a more precise estimate of the CV risk of etoricoxib compared with the traditional NSAID diclofenac in over 34 000 patients with OA and RA, and over 50000 patient-years of exposure2122. The MEDAL program demonstrated comparable CV risk for etoricoxib and diclofenac. These results were consistent across all subgroups analyzed, including older versus younger patients, patients with OA versus RA, patients with or without diabetes, patients at lowest and highest CV risk, and patients taking low-dose aspirin versus not taking low-dose aspirin22. While the results from the MEDAL program cannot be extrapolated to other traditional and COX-2 selective NSAIDs, they provide useful information to assist physicians in determining the optimal treatment for patients with rheumatoid arthritis.

Effects on blood pressure and fluid retention are important considerations for physicians when prescribing traditional and COX- 2 selective NSAIDs for their patients, since all NSAIDs have the potential to affect renal function due to inhibition of renal prostaglandin biosynthesis6. In this study, the incidence of hypertension-related adverse events with etoricoxib use was similar to that seen in the naproxen group during Extension Study Part I, but the incidence was higher for etoricoxib versus naproxen during Extension Part II in a dose-related manner, although none of the hypertension AEs resulted in discontinuations. While all NSAIDs have the potential to affect renal function, these agents have demonstrated differential effects with regard to renovascular AEs. A pooled analysis of 4770 patients from eight well-controlled trials suggested an incidence of edema, hypertension, and serum creatinine elevations with etoricoxib, similar to that found with other traditional NSAIDs23. In the MEDAL program, the incidence of clinically important renovascular adverse events such as congestive heart failure with etoricoxib 90 mg and discontinuations due to hypertension with etoricoxib 60 and 90 mg were higher compared with diclofenac 150 mg. Consistent with observations from Extension Part II of the present trial, the observed increased incidence of hypertension with etoricoxib in the MEDAL Program was also dose- related. These data reinforce the importance of closely monitoring patients on traditional or COX-2 selective NSAID therapy for hypertension, renal dysfunction, and edema.

This trial was not designed to evaluate GI safety and there were too few GI clinical events observed in this extension trial to make any definitive conclusions regarding the relative risk of GI clinical events with etoricoxib 90 mg versus naproxen 500 mg b.i.d. In a previous 12-week, randomized, double-blind, placebo controlled upper GI endoscopy study in rheumatoid arthritis ([asymptotically =]75%) and osteoarthritis patients, it was demonstrated that etoricoxib 120 mg treatment resulted in a significantly lower proportion of patients experiencing gastric or duodenal ulcers and erosions compared with naproxen 500 mg b.i.d.24. A pooled analysis of the etoricoxib development program demonstrated improved upper GI safety for etoricoxib versus traditional NSAIDs (e.g., ibuprofen and naproxen)”. In the MEDAL Program, etoricoxib demonstrated a significantly reduced risk of uncomplicated upper GI events than the traditional NSAID diclofenac25. These results were maintained in arthritis patients taking low-dose aspirin or proton pump inhibitors.

Conclusions

Etoricoxib 90 mg and 120mg daily and naproxen 500 mg twice daily were generally well tolerated and provided substantial improvements in the symptoms of rheumatoid arthritis that were maintained throughout the 121-week study period. A dose-related increase in renovascular events (i.e., hypertension-related AEs) for etoricoxib that was greater than that observed with naproxen was observed. Although the incidences of CV and upper GI events were generally similar for each treatment group, these results should be observed in context with larger databases that have shown a lower risk of upper GI events for etoricoxib compared with naproxen and a lower risk of CV events with naproxen compared with other COX-2 selective NSAIDS including etoricoxib9’11.

Acknowledgments

This study was funded by a grant from Merck & Co, Inc. The authors thank Anish Mehta of Merck Research Laboratories and Wendy Horn for their assistance in the writing of this manuscript. They also thank Dr Paul Cavanaugh of Merck Research Laboratories for his critical review of the manuscript.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3803_5, Accepted for publication: 02 July 2007

Published Online: 10 August 2007

doi: 10.1185/030079907X219625

Alan Matsumoto(a), Agustin Melian(b), Arvind Shah(b) and Sean P. Curtis(b)

a Arthritis and Rheumatism Associates, Wheaton, MD, USA

b Merck Research Laboratories, Rahway, NJ, USA

Address for correspondence: Dr Sean P. Curtis, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. Tel.: + 1 732 594 8416; Fax: + 1 732 594 8140; sean_curtis@merck.com

Copyright Librapharm Sep 2007

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