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Efficacy and Safety of Rofecoxib 12.5 Mg and Celecoxib 200 Mg in Two Similarly Designed Osteoarthritis Studies

Posted on: Thursday, 9 February 2006, 06:00 CST

By Birbara, C; Ruoff, G; Sheldon, E; Valenzuela, C; Et al

Key words: Celecoxib * Coxibs * Efficacy * Osteoarthritis * Pain * Rofecoxib

ABSTRACT

Objective: To compare the lower osteoarthritis (OA) dose of rofecoxib to the recommended dose of celecoxib in two identically designed studies.

Methods: Patients with knee OA were randomized (2:2:1 ratio: rofecoxib 12.5mg once daily (qd), celecoxib 200mg qd, or placebo, respectively). The primary endpoint was patient global assessment of response to therapy (PGART) averaged over 6 weeks on a five-point scale. Rofecoxib would be declared at least as effective as celecoxib if the lower bound of the 95% confidence interval (95% Cl) for difference in means was no lower than -0.5. Additional endpoints included Pain and Physical Function subscales of the Western Ontario and McMaster (WOMAC) OA Index. Adverse experiences (AEs) were recorded and combined from the two studies for analysis.

Results: Study 1 enrolled 395 patients (rofecoxib, n = 160; celecoxib, n = 157; placebo, n = 78). Study 2 enrolled 413 patients (rofecoxib, n = 159; celecoxib, n = 169; placebo, n = 85). Rofecoxib 12.5 mg was at least as effective as celecoxib 200 mg by PGART (Study 1 difference -0.09 [95% Cl: -0.32, 0.14] and Study 2 difference 0.02 [95% Cl: -0.20,0.24]), and both were significantly (p < 0.001) more effective than placebo. Comparable efficacy was also seen for WOWIAC Pain and Physical Function subscales with the active treatments. There was a significantly higher (p < 0.05) incidence of serious AEs with celecoxib than rofecoxib or placebo, none of which was drug-related. There were no significant differences in the pre-specified measurements of safety including drug-related AEs or discontinuations due to AEs, and the medications demonstrated similar safety as assessed by spontaneous reporting.

Conclusions: Rofecoxib 12.5mg and celecoxib 200 mg provided comparable efficacy over 6 weeks, and both were significantly more efficacious than placebo. The medications demonstrated similar safety compared to one another and placebo. The primary limitations of these studies were that they were only 6 weeks long and were powered for efficacy. Therefore, conclusions about long-term safety cannot be inferred.

Introduction

Osteoarthritis (OA) is the most common joint disorder in the world with a prevalence that increases with age1,2. An estimated 40 million Americans, or 68% over the age of 55, have symptoms of OA2,3. Patients with OA generally require medication for pain and other symptoms, and simple analgesics such as acetaminophen are still considered the drug of first choice, providing efficacy for many patients4,5. However, nonselective cyclooxygenase (COX)-1 and - 2 inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs) and COX- 2 selective inhibitors possess both analgesic and anti-inflammatory activity, and are generally considered more effective treatment options than simple analgesics such as acetaminophen4,5.

The COX-2 selective inhibitors were developed to provide an alternative to nonselective NSAIDs with improved gastrointestinal (GI) tolerability. At therapeutic doses, COX-2 selective inhibitors do not inhibit COX-1 generated prostanoids, which are critical for maintaining gastric mucosal protection and normal platelet function6,7. Subsequently, COX-2 selective inhibitors have demonstrated reductions in GI toxicity in large clinical studies as well as endoscopy studies compared to nonselective NSAIDs8-12.

In addition to their GI benefit, rofecoxib and celecoxib independently demonstrated comparable efficacy to nonselective NSAIDs for the management of OA. Prior to the voluntary withdrawal of rofecoxib, the lower of the approved rofecoxib daily doses for OA was 12.5mg, with a maximum recommended daily dose of 25mg. In OA clinical trials of 6 weeks to 1 year in duration, both rofecoxib doses significantly reduced joint pain and improved overall disease status to a similar level as comparator nonselective NSAIDs9,13-17. The approved OA regimens for celecoxib are lOOmg twice daily (bid) or 200 mg once daily (qd). In OA clinical trials of up to 12 weeks in duration, both celecoxib regimens demonstrated efficacy comparable to nonselective NSAID comparators18-21. In the above referenced studies, both COX-2 selective inhibitors had generally similar rates of non-GI adverse experiences (AEs) as the nonselective NSAIDs. Gastrointestinal AEs were less common with the COX-2 selective inhibitors than nonselective NSAIDs.

Recent longer-term studies have demonstrated a significantly increased risk of cardiovascular (CV) events with COX-2 selective inhibitors22,23. However, following a joint advisory committee meeting concerning these risks, the Food and Drug Administration (FDA) stated in their conclusions that data from long-term controlled clinical trials do not clearly demonstrate that COX-2 selective agents confer a greater risk of serious adverse CV events than non-selective NSAIDs, and that pending new data, the risk should be considered a class effect. They further stated that the available data do not permit rank ordering of the COX-2 selective agents, and that all NSAIDs should be used at the lowest possible dose for the shortest period of time24.

Two similarly designed, previously completed studies in OA patients (VACT1 and VACT2) demonstrated that rofecoxib 25mg qd generally provided significantly better efficacy on most endpoints compared to celecoxib 200mg qd over a 6-week period25,26. In these studies, secondary analyses demonstrated that rofecoxib 12.5mg qd provided similar efficacy to celecoxib 200mg qd. No clinical study has been conducted with a pre-specified primary objective of demonstrating comparability of rofecoxib 12.5mg and celecoxib 200mg, both administered as once daily doses.

The studies included herein, which were designed as comparability studies, evaluated the efficacy of once daily doses of rofecoxib 12.5mg and celecoxib 200mg in the treatment of symptomatic OA. Because of their identical designs, the studies are being presented together to allow for side-by-side comparison of efficacy, while safety data are combined to provide greater precision in evaluating AEs. Although rofecoxib is no longer available for use, the study findings are relevant when considering the use of COX-2 selective inhibitors, especially at lower therapeutic doses.

Patients and methods

Patients

Two randomized, double-blind parallel-group, placebocontrolled studies were conducted at investigative sites in the United States from February to November 2003. The studies were initiated and completed prior to 30th September 2004, when Merck & Co. Inc., announced the voluntary worldwide market withdrawal of rofecoxib. They had identical protocols, approved by the Institutional Review Board at each study site, and were conducted in accordance with the International Conference of Harmonization Guidelines. Written informed consent was obtained from all patients at the screening visit prior to study enrollment.

Patients included in the studies were at least 40 years of age with a clinical diagnosis of knee OA for at least 6 months, and had an American Rheumatology Association (ARA) functional class rating of I, II, or III. Participants also had to require regular treatment with a nonselective NSAID, COX-2 selective inhibitor, or acetaminophen.

The eligibility criteria used for enrollment differed between patients who were prior nonselective NSAID and COX-2 selective inhibitor users compared to patients who were prior acetaminophen users. Prior users of nonselective NSAIDS and COX-2 selective inhibitors discontinued these medications at the screening visit and returned for evaluation after an appropriate washout period of 4 to 15 days, depending on the discontinued medication. They were eligible for randomization if they had a minimum of 40mm on 'patient assessed pain walking on a flat surface' (question 1 on the Western Ontario and McMaster Universities OA Index [WOMAC]), which had increased by at least 15 mm since discontinuing their original OA medication. They were also required to have a worsening in Investigator Global Assessment of Disease Status (IGADS) of at least 1 unit on a five-point categorical scale ('excellent', 'good', 'fair', 'poor', or 'very poor'). Patients previously taking acetaminophen for OA symptoms were permitted to continue with their medication until 12 hours before the second visit. Acetaminophen patients were required to have a measure of at least 40 mm for WOMAC pain walking on a flat surface and a rating of 'very poor', 'poor', or 'fair' on IGADS at both the screening visit and randomization visit while on acetaminophen; no flare of disease was required.

Patients who used low-dose aspirin (81 mg or less daily) for cardioprotective effects were permitted to continue low-dose aspirin use during the studies. Glucosamine and chondroitin sulfate, if taken for longer than 6 months, were also permitted if taken at the same stable dose for the duration of the studies. Use of the following agents was not permitted: intra-articular corticosteroids, sodium hyaluronate, or hylan G-F 20 (within the last 3 months); intravenous, intramuscular, or oral corticosteroids (within the last month); warfarin, ticlopidine, clopidogrel, prescription weight loss agents, or appetite suppressants; and topical, oral, or sys\temic analgesics other than study medications or acetaminophen.

Patients with a concurrent medical (or arthritic) disease that potentially could confound the evaluation of efficacy, including inflammatory arthritis and metabolic disorders associated with arthritis, were excluded from the studies. Also excluded were patients with isolated patello-femoral disease manifested by primary anterior knee pain; plans for imminent joint replacement; a history of acute injury of the study joint within the previous 2 years; clinical or laboratory evidence of systemic disease that would contradict the use of nonselective NSAIDs or acetaminophen; serum creatinine greater than 2.0mg/dL or serum transaminases exceeding 1.5 the upper limit of normal; uncontrolled angina or congestive heart failure; myocardial infarction, cardiopulmonary bypass surgery, or angioplasty within 1 year; uncontrolled hypertension; a history of stroke or transient ischemic attack within 1 year; a history of alcohol or substance abuse within 5 years, and a history of allergic reaction to COX-2 selective inhibitors, nonselective NSAIDs, acetaminophen, or sulfa drugs.

Study design

Patients who met baseline eligibility criteria were randomly assigned, using a computer-generated allocation schedule, in a 2:2:1 ratio to rofecoxib 12.5mg qd, celecoxib 200mg qd, or placebo, respectively, for 6 weeks. Allocations to treatment groups were stratified based on the type of previous OA medication use (NSAID/ COX-2 selective inhibitor versus acetaminophen). A double-dummy design was used to maintain patient and investigator blinding: one tablet of rofecoxib 12.5 mg and one capsule of celecoxib-matching placebo; one capsule of celecoxib 200 mg and one tablet of rofecoxib- matching placebo; or one tablet of rofecoxibmatching and one capsule of celecoxib-matching placebo. Compliance was assessed by pill count and verified by patient recorded use. Patients who missed more than 20% of scheduled doses were considered non-compliant but were not discontinued from the studies.

Clinical efficacy and safety data, including laboratory monitoring, were collected at weeks 2, 4, and 6 after the randomization (baseline) visit. Patients were allowed to take acetaminophen (maximum dose 2600mg/day) as rescue therapy for OA pain if the study medication did not provide adequate pain control, and were instructed to discontinue use 12 hours before study visits. Acetaminophen use was documented at weeks 2, 4, and 6.

For all patients unable to complete 6 weeks of treatment, a discontinuation visit was required within 48 hours of study withdrawal. The primary reason for discontinuation (e.g., lack of efficacy, AE, inability to comply with study protocol, or other) was recorded. All clinical and laboratory evaluations scheduled for the final study visit were performed at the discontinuation visit.

Efficacy assessment

Efficacy was assessed at each visit using the Patient Global Assessment of Response to Therapy (PGART) questionnaire (a five- point categorical scale where 0 = none, 1 = poor, 2 = fair, 3 = good, and 4 = excellent) as the primary endpoint. The primary analysis of PGART utilized the average of the scored responses over 6 weeks of treatment (weeks 2, 4, and 6). The WOMAC was included as a secondary endpoint (with questions measured on a 0 to 100mm visual analogue scale [VAS])27,28. Patients completed the entire 24- question WOMAC. The secondary study endpoints included the WOMAC 'Pain subscale' and 'Physical Function subscale'. The Pain subscale included the first five WOMAC questions individually rated from 0 = no pain to 100 = extreme pain. The Physical Function subscale included WOMAC questions 8-24 individually rated from 0 = no difficulty to 100 = extreme difficulty. Analysis of these variables was based upon the average change (over weeks 2, 4, and 6) from baseline.

Safety assessment

Safety was assessed by complete physical examination during the screening visit and at 6 weeks. At baseline and at each scheduled clinic visit, vital signs (blood pressure, heart rate, and respiratory rate) were obtained with the patient in a sitting position after a 10-minute rest. Complete blood count, serum chemistry panel, and urinalysis were obtained at screening and the final study visit. Spontaneously reported AE data were collected at each clinic visit and assessed by the investigator with regard to intensity, seriousness, duration, relationship to study drug, and any necessary action. All serious AEs, whether or not related to the investigational protocol, were evaluated. Independent, blinded adjudication committees evaluated cardiovascular and gastrointestinal AEs. The CV committee was composed of 3 separate subspecialty committees, one each for cardiac, cerebrovascular, and peripheral events, and made up of cardiologists, neurologists, and vascular specialists, respectively, who are expert in the treatment of ischemic syndromes as well as the medical aspects of clinical trials. Each subspecialty contained three members. The GI committee was composed of three voting members, all clinicians, at least two of whom were gastroenterologists. If a consensus was not reached in the preliminary adjudication, final adjudication was by majority vote.

Statistical methods

All patients randomized who took at least one dose of study medication, and had at least one on-treatment assessment, were included in a modified Intentionto-Treat (mITT) analysis. The last on-treatment observation was carried forward in the event of missing data for all efficacy analyses. With 150 patients per active study medication arm and 75 placebo patients, there was 97% power to show comparable efficacy between rofecoxib 12.5mg and celecoxib 200 mg on the five-point categorical PGART scale, assuming no difference between rofecoxib and celecoxib groups, a margin of clinical comparability of 0.5, a within-group standard deviation of 1.1, and a two-sided test, with an α-level of 0.05.

The predefined primary efficacy endpoint was the mean PGART averaged over the 6 weeks of therapy. Rofecoxib 12.5mg was to be considered at least as effective as celecoxib 200 mg if the lower bound of the 95% confidence interval for the difference in means was no less than -0.5 points (in favor of celecoxib)29. An ANOVA model, with factors for treatment group, previous OA treatment strata (NSAID/COX-2 selective inhibitor or acetaminophen), and baseline IGADS, was used to compare treatment groups in terms of the mean PGART over 6 weeks. It was prespecified that if the primary endpoint was established, rofecoxib and celecoxib would be evaluated for superiority compared to placebo.

Secondary efficacy endpoints included the WOMAC Pain and Physical Function subscales. For the mean WOMAC Pain and Physical Function subscales, change from baseline averaged over weeks 2, 4, and 6 was evaluated for comparison of rofecoxib and celecoxib using an ANOVA model with factors for treatment group, previous OA treatment strata, and baseline WOMAC score at randomization. For these WOMAC subscales, rofecoxib was considered at least as effective as celecoxib if the lower bound of the 95% confidence interval for the difference in means was no greater than 10mm (in favor of celecoxib). If the secondary endpoints were established for the active treatments, it was prespecified that rofecoxib and celecoxib would be evaluated for superiority compared to placebo.

Because of the identical study designs, AE data for the two studies were combined to provide greater precision in evaluating AEs. Prespecified endpoints for analysis of safety included the incidence of serious AEs, drug-related AEs, AEs which cause discontinuation, edema-related AEs causing discontinuations, hypertensionrelated events causing discontinuations, congestive heart failure, and gastrointestinal AEs. Fisher's exact test was used to compare treatment groups in terms of the incidence of prespecified safety assessments.

Results

Patient disposition and demographics

Study 1 enrolled 395 patients (rofecoxib 12.5mg, n = 160; celecoxib 200mg, n = 157; and placebo, n = 78), while Study 2 enrolled 413 patients (rofecoxib 12.5mg, n = 159; celecoxib 200mg, n = 169; and placebo, n = 85) (Table 1). Discontinuation rates were similar with rofecoxib and celecoxib in each study. Discontinuations were more common in the placebo treatment groups than the active treatment groups in both studies. The majority of patients who discontinued in all treatment groups did so because of a lack of efficacy, which occurred less often with the active treatments (approximately 5%) than with placebo (approximately 18%). There were no significant differences between treatment groups within the two studies in discontinuation rates due to AEs.

The baseline characteristics of the patients within the rofecoxib, celecoxib, and placebo treatment groups in each study were similar (Table 2). The majority of patients were female and Caucasian, with a mean age of approximately 60 years. The majority of patients had IGADS scores assessed as 'poor'. Most patients were receiving NSAIDs or COX-2 selective inhibitors, as opposed to acetaminophen, at randomization. Low-dose aspirin use was 17% to 21% in Study 1, and 23% to 28% in Study 2.

PGART

The PGART scores averaged over 6 weeks were similar between rofecoxib and celecoxib in Study 1 (rofecoxib, 2.20 vs. celecoxib, 2.29) and in Study 2 (rofecoxib, 2.29 vs. celecoxib, 2.28) (Figures 1A and 1B). The difference in PGART response met the prespecified comparability criteria in Study 1 (difference -0.09 [95% CI: -0.32, 0.14, p = 0.441]) and Study 2 (difference 0.02 [95% CI: -0.20, 0.24, p = 0.871]). PGART scores with rofecoxib and celecoxib were also similar at 2, 4, and 6 weeks in both studies.

Compared to placebo patients, rofecoxib patients had significantly greater improvements in PGART scores in Study 1 (2.20 vs. 1.59, p < 0.001) and Study 2 (2.29 vs. 1.61, p \< 0.001), as did celecoxib patients compared to placebo patients in Study 1 (2.29 vs. 1.59, p < 0.001) and Study 2 (2.28 vs. 1.61, p < 0.001) (Figures IA and IB). PGART scores were significantly greater (p < 0.01) with both rofecoxib and celecoxib compared to placebo at 2, 4, and 6 weeks in both studies.

WOMAC

WOMAC pain subscale

Measurement of response to treatment with the WOMAC Pain and Physical Function subscales demonstrated that once daily rofecoxib 12.5mg and celecoxib 200 mg were comparable. The mean improvement in the WOMAC pain subscale scores over 6 weeks in Study 1 was -26.30mm with rofecoxib, -27.30mm with celecoxib, and -19.24mm with placebo (Figure 2A). The mean improvement in Study 2 was -30.21mm with rofecoxib, -28.51mm with celecoxib, and -20.95mm with placebo (Figure 2B). The difference in WOMAC Pain subscale response was within the prespecified comparability bounds (10mm) in Study 1 (difference 1.00 [95% CI: -3.89, 5.90, p = 0.687]) and Study 2 (difference -1.70 [95% CI: -6.69, 3.29, p = 0.502]). WOMAC Pain subscale scores with rofecoxib and celecoxib were also within the comparability bounds at 2, 4, and 6 weeks in both studies. Rofecoxib and celecoxib demonstrated significantly greater response than placebo in Study 1 and Study 2 (Figures 2A and 2B).

Table 1. Patients' disposition

WOMAC physical function subscale

The mean improvement in the WOMAC Physical Function subscale scores over 6 weeks in Study 1 was -23.57mm with rofecoxib, - 26.52mm with celecoxib, and -16.90mm with placebo (Figure 3A). The mean improvement in Study 2 was -25.60mm with rofecoxib, -23.71 mm with celecoxib, and -17.45mm with placebo (Figure 3B). Similar to results seen with the Pain subscale, the difference in the WOMAC Physical Function subscale response between rofecoxib and celecoxib was within the prespecified comparability bounds (10mm) in Study 1 (difference 2.94 [95% CI: -1.75, 7.64, p = 0.219]) and Study 2 (difference -1.89 [95% CI: -6.71, 2.93, p = 0.441]). WOMAC Physical Function subscale scores with rofecoxib and celecoxib were also within the comparability bounds at 2, 4, and 6 weeks in both studies. Rofecoxib and celecoxib demonstrated significantly greater response than placebo in Study 1 and Study 2 (Figures 3A and 3B).

Table 2. Demographics

Figure 1. Patient global assessment of response to therapy (PGART) (least squares means) measured on a five-point Liken scale: weeks 2, 4, and 6 and average over weeks 2, 4, and 6. PGART is measured on a five-point Liken scale: 0 = none, 1 = poor, 2 = fair, 3 = good, 4 = excellent. Note: p-values correspond to significance level for ANOVA model with factors for baseline investigator global assessment of disease status (IGADS), prior OA treatment medication strata and treatment group. Error bars indicate standard error

Figure 2. WOMAC pain subscale change from flare visit (least squares means) measured on a 0-100 mm visual analog scale: weeks 2, 4, and 6 and average over weeks 2, 4, and 6. WOMAC pain subscale: 0 (no pain) to 100mm (extreme pain). Negative change from baseline indicates improvement. Note: p-values correspond to significance level for ANOVA model with factors for baseline VKOMAC pain subscale, prior OA treatment medication strata and treatment group. Error bars indicate standard error

Figure 3. WOMAC physical function subscale change from flare visit (least squares means) measured on a 0-100mm visual analog scale: weeks 2, 4, and 6 and average over weeks 2, 4, and 6. WOMAC physical function subscale: 0 (no pain) to 100mm (extreme pain). Negative change from baseline indicates improvement. Note: p-values correspond to significance level for ANOVA model with factors for baseline WOMAC physical function subscale, prior OA treatment medication strata and treatment group. Error bars indicate standard error

Safety

For the evaluation of safety, the data from the individual studies were combined for analysis. The overall safety of once daily rofecoxib 12.5 mg, celecoxib 200mg, and placebo was generally similar based upon their AE profiles (Table 3). There were no significant differences in the pre-specified measurements of safety including drug-related AEs or discontinuations due to AEs. Celecoxib had significantly more serious AEs than rofecoxib (1.8% vs. 0.0%; p < 0.05), and numerically more than placebo (0.6%). Serious AEs included six patients who received celecoxib, none of which was considered to be drug-related (chest pain; renal insufficiency and urosepsis; non-cardiac chest pain and anxiety; squamous cell carcinoma; metrorrhagia, breast cancer, and postmenopausal bleeding; and impaired healing). One patient who received placebo had a serious AE (transient ischemic attack and hypertensive crisis), which was considered drug-related, and was the only confirmed thrombotic cardiovascular event identified by the cardiovascular adjudication committee. The incidence of gastrointestinal AEs was similar in the active treatment groups and compared to placebo. There were three edemarelated AEs causing discontinuation, two (0.6%) in the rofecoxib group and one (0.6%) in the placebo group; none occurred in the celecoxib group. The rates of hypertensionrelated AEs causing discontinuation, and congestive heart failure AEs, and the incidence rate of these AEs were not significantly different in the three treatment groups. The incidence of vital sign and laboratory abnormalities in the active treatment groups were low and similar to placebo.

Discussion

These 6-week, double-blind, placebo-controlled studies were designed to test the comparability in efficacy and safety of the lower recommended OA dose of rofecoxib (12.5mg qd) and the recommended OA dose of celecoxib (200 mg qd) at the time of the study. This study demonstrated that rofecoxib 12.5mg was, in all ways measured over 6-week time points, comparable in efficacy and safety to celecoxib 200 mg. Both COX-2 selective inhibitors demonstrated significantly greater efficacy and similar safety to placebo.

Table 3. Clinical adverse events (studies 1 and 2 combined)

The current study utilized efficacy endpoints from three domains considered relevant to treatment of symptomatic OA: patient global assessment, pain, and physical function. PGART was chosen as the primary endpoint because it is considered to have high validity in providing an overall assessment of treatment response27. It provides a comprehensive assessment of efficacy from the patients' perspective and is applicable in both clinical trial and clinical practice settings. In contrast, WOMAC uses focused questions to quantitate improvement in specific symptoms of OA, including pain and physical function28.

The results of the present study are consistent with those reported in an earlier study of patients with OA of the knee (VACTl) by Geba et al.25. The investigators conducted a 6-week, double- blind study, of 382 patients randomized to rofecoxib 25 mg qd (n = 95), rofecoxib 12.5mg qd (n = 96), celecoxib 200mg qd (n = 97), or acetaminophen 4000mg qd (n = 94). There was no placebo arm and, because the maximal dose of acetaminophen was tested, no rescue analgesia with acetaminophen was allowed. Rofecoxib 12.5mg qd and celecoxib 200 mg qd provided similar improvement on all PGART and WOMAC endpoints in VACT1. The incidences of AEs were similar among all four treatment groups. Similar trends were seen in the larger (1578 patients) VACT2 study, which also compared treatment with rofecoxib 25mg qd, rofecoxib 12.5mg qd, celecoxib 200 mg qd, and acetaminophen 4000 mg qd, in which celecoxib 200 mg and rofecoxib 12.5 mg qd demonstrated similar efficacy. Importantly, at all doses the COX-2 selective inhibitors demonstrated superior efficacy to acetaminophen 4000 mg qd and similar safety26. Two additional studies by McKenna et al.30 and Gibofsky et al.31 compared rofecoxib 25 mg and celecoxib 200 mg, but did not include rofecoxib 12.5mg.

The low incidence of AEs in the present studies confirms findings in other clinical trials which indicate that rofecoxib 12.5mg and celecoxib 200mg are well tolerated over 6 weeks13-17,19,21. AE rates, including GI AEs, were generally similar among rofecoxib, celecoxib, and placebo. Serious AEs were significantly greater with celecoxib, none of which was considered drug-related. This is consistent with the findings in the 6-week VACT studies that rofecoxib 12.5 mg and celecoxib 200 mg have similar tolerability and safety profiles to acetaminophen 4000 mg, which is generally considered to be one of the safest analgesics25,26. In both the McKenna and Gibofsky studies, no meaningful differences in overall AEs or specific AEs were detected between rofecoxib 25 mg and celecoxib 200 mg30,31.

Because COX-2 mediated prostaglandins help maintain sodium and water balance, it is not unusual to find a small number of patients treated with these agents with peripheral edema, hypertension, and changes in blood pressure32. Both COX-2 specific inhibitors in our studies were well tolerated, as evidenced by the low incidence of renal AEs during the study. No significant differences were shown for edema-related AEs causing discontinuation, hypertension-related AEs causing discontinuation, or for incidence of congestive heart failure in this study. Previous evidence suggests that at doses providing a similar degree of COX-2 inhibition, both nonselective NSAIDs and COX-2 selective inhibitors have similar effects on renal mechanisms responsible for vascular tone and salt and water balance33,34. However, other factors, such as the individual drugs' pharmacokinetics and pharmacodynamics, the effects of which were not evaluated in this study, also differentiate NSAIDs and COX-2 selective inhibitors.

Recent events have increased the attention on the long-term cardiovascular safety of the nonselective NSAIDs and COX-2 selective inhibitors22,23,35. In the present studies, cardiovascular AEs were pre-specified for review by \an independent adjudication committee. No serious thrombotic cardiovascular AEs occurred with 6 weeks of treatment with rofecoxib 12.5mg qd or celecoxib 200 mg qcl. However, our studies were considerably shorter than those trials (which lasted up to 3 years), evaluated lower doses, and were not designed or powered to evaluate safety thoroughly. As such, longterm safety cannot be concluded from our results. In consideration of the recent data indicating increased CV risk with long-term use of higher doses of NSAIDs and COX-2 selective inhibitors, and considering the demonstrated efficacy with rofecoxib at the lowest FDA-approved dose of 12.5mg, a long-term, low-dose study would be of interest.

Conclusions

In conclusion, these studies demonstrated that the lower recommended daily dose of rofecoxib 12.5mg (at the time of the study) was at least as effective as the recommended daily dose of celecoxib 200 mg for the treatment of OA over a 6-week period. Both COX-2 selective inhibitors were generally similar to each other and to placebo on safety endpoints. While rofecoxib has been voluntarily withdrawn from the market, these results provide useful information on the importance of comparing doses with similar efficacy and using validated endpoints assessed at clinically meaningful time points when conducting clinical studies of NSAIDs in the treatment of OA.

Acknowledgments

Declaration of interest: This study was funded by Merck & Co. Inc.

We would like to thank the clinical investigators and their study site personnel who contributed to the enrollment of study patients and supervised study conduct. We would also like to thank Steven Smugar, MD for his assistance with the preparation of the manuscript, and Lori Brozena and Susan Woll for their contributions to study conduct.

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

Paper CMRO-3156_4, Accepted for publication: 28 October 2005

Published Online: 09 December 2005

doi: 10.1185/030079906X80242

C. Birbara(a), G. Ruoff(b), E. Sheldon(c), C. Valenzuela(d), A. Rodgers(d), R. A. Petruschke(d), D. J. Chang(d) and A. M. Tershakovec(d)

a Clinical Pharmacology Study Group, Worcester, MA, USA

b Westside Family Medical Center, Kalamazoo, MI, USA

c Miami Research Associates, Miami, FL, USA

d Merck & Co. Inc., West Point, PA, USA

Address for correspondence: Dr. Charles Birbara, Clinical Pharmacology Study Group, 26 Queen Street, Worcester, MA 01610, USA. Tel.: +1-508-799-2674; Fax: +1-508-799-2586; email: cabirbara@aol.com

Copyright Librapharm Jan 2006

Source: Current Medical Research and Opinion

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