Efficacy and safety of valdecoxib in treating the signs and symptoms of rheumatoid arthritis: a randomized, controlled comparison with placebo and naproxen

W. Bensen, A. Weaver1, L. Espinoza2, W. W. Zhao3, W. Riley3, B. Paperiello3 and D. P. Recker3,

St Joseph's Hospital and McMaster University, Hamilton, ON, Canada,
1 Arthritis Center of Nebraska, Lincoln, NE,
2 Louisiana State University Medical Center, New Orleans, LA and
3 Clinical Research & Development, Pharmacia Corporation, Skokie, IL, USA


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. To compare the efficacy of the COX-2 specific inhibitor valdecoxib with the conventional NSAID naproxen and placebo in treating rheumatoid arthritis (RA).

Methods. This multi-centre, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of valdecoxib 10 mg (n=209), 20 mg (n=212) or 40 mg once daily (q.d.) (n=221) with naproxen 500 mg b.i.d. (n=226) or placebo (n=222), in treating the signs and symptoms of RA. Efficacy was assessed by the number of patients responding to treatment according to the American College of Rheumatology-Responder Index (ACR-20).

Results. ACR-20 response was recorded for all randomized patients who received a single dose of study medication (above). Valdecoxib, at all administered doses, produced significant improvements in the ACR-20 Responder Index at weeks 2, 6 and 12 compared with placebo (P<=0.01). Valdecoxib and naproxen did not differ in terms of ACR-20 response rate and the three doses of valdecoxib were similar to one another. All three doses of valdecoxib were well tolerated.

Conclusions. Single daily doses of valdecoxib 10, 20 and 40 mg demonstrated efficacy that was superior to placebo and similar to naproxen in treating the signs and symptoms of RA. All three doses provided similar levels of efficacy.

KEY WORDS: COX-2 specific inhibition, Valdecoxib, Rheumatoid arthritis, NSAIDs, Prostaglandins.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Cyclooxygenase-(COX)-2 specific inhibitors and conventional non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used first line therapies for treating the signs and symptoms of rheumatoid arthritis (RA). These agents are often used in conjunction with disease-modifying anti-rheumatic drugs (DMARDs) such as hydroxychloroquine, sulphasalazine, methotrexate and leflunomide, which have a delayed onset of anti-inflammatory and disease-modifying effects [1]. Although DMARDs act as potent anti-inflammatory agents, there is a known risk of increased immune suppression associated with their use [2, 3]. Even with effective DMARDs, concomitant NSAID or COX-2 inhibitor use is frequently needed to reduce daily symptoms of pain and inflammation.

Conventional NSAIDs act through non-selective inhibition of both isoforms of cyclooxygenase (COX-1 and COX-2), the enzyme involved in prostaglandin synthesis [4]. In inflammatory diseases such as RA, high levels of COX-2 expression are rapidly induced by inflammatory cytokines, resulting in production of prostaglandins that further exacerbate inflammation [58]. The anti-inflammatory effects of conventional NSAIDs are mediated by inhibition of COX-2 [9, 10], whereas their inhibition of COX-1 causes serious gastrointestinal and bleeding effects.

Conventional NSAIDs are associated with low GI tolerability, including nausea, vomiting, dyspepsia, abdominal pain, diarrhoea and/or constipation [11], as well as the formation of gastroduodenal ulcers that can lead to potentially life threatening GI bleeding, perforations, and/or gastric outlet obstruction [12, 13]. Approximately 16 500 deaths occur per year in the US due to gastroduodenal injury caused by conventional NSAIDs [14, 15]. Conventional NSAIDs including naproxen and diclofenac lead to endoscopic gastroduodenal ulcer rates ranging from 15 to 40%, and gastrointestinal complications among patients using NSAIDs occur at an annualized incidence of about 1–2% [14]. Additionally, conventional NSAIDs impair platelet aggregation and increase the risk of bleeding, including GI bleeding [12, 16].

The development of COX-2 specific inhibitors, which are COX-1-sparing at therapeutic doses, has allowed the effective treatment of pain and inflammation while eliminating many of the side effects typical of conventional NSAIDs [1723]. Currently available COX-2 specific inhibitors have demonstrated efficacy in the treatment of the signs and symptoms of RA [24, 25]. Valdecoxib, a novel COX-2 specific inhibitor that is approximately 28 000-fold more selective against COX-2 (hIC50=0.005 µM) than COX-1 (hIC50=140 µM) [26], has been developed for treatment of the signs and symptoms of RA and osteoarthritis (OA) and for the management of pain and has the advantage of once daily dosing.

The present study was designed to examine the efficacy and safety of valdecoxib in treating the signs and symptoms of RA by comparing single daily doses (q.d.) of valdecoxib 10, 20 and 40 mg with placebo and naproxen 500 mg b.i.d. Efficacy was assessed using the American College of Rheumatology-Responder Index (ACR-20). This index includes assessments of arthritis disease activity, pain, a laboratory measure of systemic inflammation and patients' functional disability [27].


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients
Patients who were of legal age of consent and had adult-onset RA, defined by ACR criteria, for at least 6 months were considered eligible [28]. Patients were required to have stable RA on conventional NSAID therapy for at least 1 month and a Functional Capacity Classification between I and II at the screening assessment [28]. Patients with RA in a flare state at the baseline assessment, within 2–7 days following discontinuation of conventional NSAID, full-dose aspirin or celecoxib, or 4–7 days following discontinuation of oxaprozin, piroxicam or rofecoxib, were included in the study. An RA flare state was defined as a Patient's and Physician's Global Assessment of Disease Activity of ‘fair’, ‘poor’ or ‘very poor’ at the baseline visit, with a minimum of six tender/painful joints and an increase of two joints (or 20%) over the screening visit, and three swollen joints with an increase of two joints (or 20%) over the screening visit. In addition, patients had to have either a minimum of 45 min of morning stiffness at baseline with a minimum increase of >=15 min compared with screening, or have Patient's Assessment of Arthritis Pain-VAS of >=40 mm (where 0=no pain and 100=most severe pain) with a minimum increase of 10 mm compared with screening.

Patients were excluded if they had any other form of inflammatory arthritis, or secondary or non-inflammatory arthritis that interfered with the evaluation of study medication in the treatment of RA. Patients with a history of malignancy, active GI disease, chronic or acute renal/hepatic disorders (including uncontrolled hypertension), or significant coagulation disorder were also excluded, as were patients who had received treatment for GI ulceration within 30 days of the first study dose. Patients who had received warfarin within 30 days, oral corticosteroids within 4 weeks or intra-articular/intra-muscular corticosteroids within 8 weeks, anti-neoplastics within 12 weeks, or anti-inflammatory analgesics within 48 h of study drug administration were not eligible. Patients taking low dose aspirin (<325 mg/day) for non-arthritic reasons were allowed to continue their aspirin regimen for the duration of the study. Patients were allowed to continue their DMARD therapy but those who changed their dosing or started taking any of the following during the outlined time periods prior to study drug administration were excluded: gold salts or anti-malarial drugs within 4 months; methotrexate >25 mg/week, sulphasalazaline >3 g/day, azathioprine, penicillamine, etanercept, leflunomide or antibiotics (e.g. monocycline or doxycycline) within 12 weeks; glucosamine chondroitin with 4 weeks.

Study design
This multi-centre, double-blind, placebo-controlled, randomized, 12-week trial compared the efficacy and safety of valdecoxib 10, 20 or 40 mg q.d. with naproxen 500 mg b.i.d. or placebo, in treating the signs and symptoms of RA. The study was conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki. The study period was preceded by a screening visit, a 2–7 day washout period and baseline visit. Efficacy and safety assessments were carried out at screening, baseline, and weeks 2, 6 and 12 after the start of study drug administration (or at early termination).

Efficacy assessments
Efficacy was assessed by the number of patients responding to treatment according to the ACR-20 at each visit, as described previously [29]. Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity were measured on a 5-point scale, where 1=very good, 2=good, 3=fair, 4=poor and 5=very poor at each assessment. Patient's Assessment of Arthritis Pain-VAS [30, 31], and Tender/Painful Joint Score [29, 31] and Swollen Joint Score [32] on a scale of 0–3, were measured as previously described.

Patients completed an Assessment of Physical Function-mHAQ concerning eight areas of daily function. Patients graded their ability to perform these activities on a 4-point scale where 0=without difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to perform. Duration of morning stiffness and incidence of withdrawal due to lack of study drug efficacy were monitored throughout the study.

Safety assessments
General clinical safety was monitored by the incidence of treatment emergent signs and symptoms and adverse events at baseline and weeks 2, 6 and 12 of the study. Adverse events were graded as mild, moderate or severe by the investigator. Clinical laboratory tests and vital signs were monitored at screening, baseline and assessment visits.

Statistical analysis
The sample size was based on the expected percent of responders as defined by ACR-20 responder criteria. It was anticipated that 20% of placebo patients and 35% of patients assigned to receive active treatment would show a response. A sample size of 200 per treatment group was sufficient to detect this difference, with alpha=0.017 and 80% power.

The homogeneity of the treatment groups at baseline with respect to race/ethnic origin, gender, concurrent use of disease modifying drugs (DMARDs), history of upper GI bleeding and other medical conditions were examined using Pearson's chi-square test. Fisher's exact test was used if any subset of patients was less than five. The homogeneity of the treatment groups at baseline with respect to baseline arthritis assessments and all other baseline characteristics were examined using two-way analysis of variance (ANOVA) with treatment group and centre as factors.

Efficacy and safety analyses were performed on a modified intent-to-treat (ITT) cohort using the last observation carried forward (LOCF) method. The ITT cohort contained patients who were randomized to treatment and who received at least one dose of study medication. Pairwise comparisons of ACR-20 response were carried out at weeks 2, 6 and 12 using the Cochran–Mantel–Haenszel (CMH) test stratified by centre. Least squares (LS) mean change from baseline at each visit was analysed for all other efficacy measures. For continuous efficacy variables, overall comparisons across treatment groups, linear trend tests (excluding naproxen) and pairwise comparisons were carried out by analysis of covariance (ANCOVA) with treatment and centre as factors and baseline pain intensity as a covariant. The results of the primary pairwise comparisons for valdecoxib 20 and 40 mg q.d. vs placebo were interpreted using the Hochberg step-down procedure [33].

Overall comparison across treatment groups and pairwise comparisons for incidence of withdrawal due to lack of efficacy were performed by Fisher's exact test. The median time to withdrawal for each treatment group was calculated using the Kaplan–Meier product limit estimator with Miller's adjustment [34]. The incidence of adverse events and the incidence of adverse events causing withdrawal were included in a between-group analysis using Fisher's exact test.


    Results
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 Abstract
 Introduction
 Methods
 Results
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 References
 
Patient disposition
Patient disposition is summarized in Fig. 1Go. All patients who received at least one dose of study medication were included in the efficacy and safety analyses. A total of 313 patients were withdrawn prior to the completion of the study due to treatment failure, 66 were withdrawn due to adverse events, 42 were withdrawn due to protocol violation and seven were lost to follow-up. The numbers of patients in each treatment arm withdrawn due to these reasons are summarized in Fig. 1Go.



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FIG. 1. Patient disposition. One thousand and ninety patients were randomized to receive study medication and 624 patients completed the study. All patients were included in the efficacy and safety analyses.

 
Treatment groups were comparable with respect to patient demographics and medical history (Table 1Go). The mean duration of RA reported by patients was 9.4–10.3 yr. There were no significant differences between treatment groups with respect to baseline arthritis assessments apart from mHAQ functional disability, which was higher in the valdecoxib 20 mg group and lower in the valdecoxib 10 mg group (P=0.03) (Table 1Go). Treatment groups were similar with respect to the percentage of patients taking methotrexate (55, 46, 47, 50 and 49% in the placebo, valdecoxib 10, 20 or 40 mg q.d., or naproxen 500 mg b.i.d. groups, respectively) and/or other DMARDs (25, 29, 29, 28 and 26% in the placebo, valdecoxib 10, 20 or 40 mg q.d., or naproxen 500 mg b.i.d. groups, respectively).


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TABLE 1. Patient baseline characteristics

 

Efficacy outcomes
All doses of valdecoxib produced a significant improvement in the signs and symptoms of RA for most efficacy measures compared with placebo, throughout the 12-week study period. Additionally, valdecoxib and the active comparator naproxen did not differ for most assessments of inflammation, pain and functional capacity.

The proportion of patients achieving an ACR-20 response was statistically significantly greater for all administered doses of valdecoxib, and naproxen, compared with placebo at weeks 2, 6 and 12 (P<=0.01) (Fig. 2Go). Primary pairwise comparisons of the valdecoxib groups demonstrated significant improvements for valdecoxib 20 mg (P<=0.01) and valdecoxib 40 mg (P<0.001) compared with placebo. All valdecoxib and naproxen treatment groups were similar with respect to the percentage of ACR-20 responders.



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FIG. 2. ACR-20 at the week 2, 6 and 12 assessments. Valdecoxib 10 mg q.d. was significantly different from placebo at weeks 2, 6 and 12 (**P<0.001). Valdecoxib 20 mg q.d. was significantly different from placebo at weeks 2 and 12 (**P<0.001) and week 6 (*P<=0.01). Valdecoxib 40 mg q.d. was significantly different from placebo at weeks 2, 6 and 12 (**P<0.001). Naproxen 500 mg b.i.d. was significantly different from placebo at week 2 (**P<0.001), and at weeks 6 and 12 (*P<=0.01).

 
For Patient's and Physician's Global Assessments of Disease Activity, LS mean change scores were significantly greater in response to all doses of valdecoxib compared with placebo and similar to naproxen 500 mg b.i.d. at weeks 2, 6 and 12 (P<=0.05) (Fig. 3Go).



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FIG. 3. Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity. All administered doses of valdecoxib and naproxen 500 mg b.i.d. produced statistically significant mean change from baseline compared with placebo (P<=0.05).

 
Inflammation was significantly improved among valdecoxib-treated patients over the 12-week study period. The number of tender/painful joints was significantly reduced in response to all doses of valdecoxib and naproxen compared with placebo (P<=0.01), as was the Tender/Painful Joint Score (P<=0.01) (Table 2Go). Similarly, significant reductions were seen in the number of swollen joints and the Swollen Joint Score in response to valdecoxib 10 and 40 mg compared with placebo (P<=0.05) (Table 2Go).


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TABLE 2. Effect of treatment on signs and symptoms of RA at week 12

 
In addition to improved assessments of disease activity and inflammation, valdecoxib provided significantly greater pain relief than placebo. LS mean change scores for Patient's Assessment of Arthritis Pain-VAS were significantly improved compared with placebo at Week 12, in response to all doses of valdecoxib (10, 20 and 40 mg q.d.) (P<0.001) (Table 2Go). All doses of valdecoxib and naproxen 500 mg b.i.d. were associated with similar changes from baseline for Patient's Assessment of Arthritis Pain-VAS.

Valdecoxib was associated with significant improvements in daily function compared with placebo, as measured by an RA-specific disability instrument (mHAQ) and Duration of Morning Stiffness. LS mean change from baseline in the mHAQ scores were significantly better for valdecoxib 10, 20 and 40 mg q.d. compared with placebo (P<0.001). Patients receiving valdecoxib and naproxen demonstrated similar LS mean change scores for mHAQ. Duration of morning stiffness, a well recognized clinical measure that correlates physical disability with the degree of inflammatory activity, was reduced in response to all doses of valdecoxib and naproxen compared with placebo (P<=0.01).

Valdecoxib and naproxen treatments were associated with a significantly lower incidence of withdrawal due to treatment failure than placebo (P<0.001). Time to event analyses demonstrated that patients in the placebo group withdrew faster than in the four active treatment groups (Fig. 4Go).



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FIG. 4. Time to withdrawal due to treatment failure. Single daily doses of valdecoxib 10, 20 and 40 mg, and naproxen 500 mg b.i.d., provided a significantly longer time to withdrawal due to treatment failure compared with placebo (P<0.001). There were no significant differences between any of the valdecoxib doses or naproxen.

 

Safety outcomes
The overall incidence of adverse events in the naproxen 500 mg b.i.d., valdecoxib 20 and 40 mg q.d. groups were significantly higher than placebo (P<=0.05) but were similar to one another (Table 3Go). The incidence of adverse events in the valdecoxib 10 mg q.d. group was not significantly different from placebo. Overall, there were a higher number of GI-related adverse events, including dyspepsia, abdominal pain and nausea, in the naproxen group compared with the valdecoxib 10 and 20 mg q.d. groups (P<=0.05).


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TABLE 3. Most common adverse events

 
Thromboembolic events (angina pectoris, coronary artery disorder, and/or myocardial infarction) were reported by a single patient in each of the valdecoxib and naproxen treatment groups. No significant difference in hypertension was reported for valdecoxib 10 or 20 mg compared with placebo. Hypertension occurred in 1% of valdecoxib 10 mg, 1.4% of valdecoxib 20 mg, 2.7% of valdecoxib 40 mg, and 2.7% of naproxen 500 mg patients compared with 0% in the placebo group. There was no significant increase in aggravated hypertension at any dose of valdecoxib compared with placebo. Increases in BUN and serum creatinine were similar between placebo and the active treatment groups with increases occurring in <1.5% of patients in any treatment group.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Although there have been advances in DMARD therapy, COX-2 specific inhibitors and NSAIDs remain important therapies to control the pain and inflammation of RA even in many patients on effective DMARD regimes. This study demonstrates that the anti-inflammatory and analgesic activity of valdecoxib is similar to the conventional NSAID naproxen, and significantly better than placebo, in treating the signs and symptoms of RA. Single daily doses of valdecoxib 10, 20 and 40 mg and naproxen 500 mg b.i.d. demonstrated significantly improved efficacy in most assessments of inflammation, pain and physical function compared with placebo in patients with RA, as demonstrated by sustained improvements in the ACR-20 over 12 weeks. Valdecoxib (10 and 20 mg) was also better tolerated than naproxen from a GI perspective.

The data presented here confirm previous studies that have demonstrated the effectiveness of COX-2 specific inhibitors compared with conventional NSAIDs, such as naproxen and diclofenac, in improving the inflammation and pain associated with RA, and in improving the functional ability of treated patients [24, 25, 35]. Single daily doses of valdecoxib 10, 20 and 40 mg provided improvements in pain and physical function, as measured by the ACR-20, that are similar to previously published data for celecoxib and rofecoxib [25, 35]. The high placebo response observed in this study is possibly due to the fact that patients had to discontinue regular analgesia prior to the baseline assessment and have RA in a flare state to be eligible for the study. Furthermore, this high placebo response was similar to other studies comparing the efficacy of COX-2 specific inhibitors in RA patients, where a flare design has been employed [25, 35]. Valdecoxib and naproxen also demonstrated a considerably slower rate of withdrawal due to treatment failure compared with the placebo group, suggesting durable efficacy in treating the chronic pain and inflammation of RA. Valdecoxib provides a new option for physicians in prescribing medication for the treatment of pain and inflammation associated with RA, and an alternative other than conventional NSAIDs for patients who did not previously respond to other COX-2 specific inhibitors.

All doses of valdecoxib were associated with significant anti-inflammatory and analgesic efficacy. These improvements were associated with changes in global scores as well as functional improvement based on changes that occurred in the mHAQ functional disability index. Differences favouring higher doses of valdecoxib were not statistically significant vs the lower dose, and both the 10 and 20 mg doses were well tolerated. Valdecoxib was efficacious in all subgroups analysed, including patients with varying disease duration and those concurrently using corticosteroids, methotrexate or other DMARDs. In general, the efficacy of valdecoxib and naproxen was comparable. The improvement in naproxen-treated patients observed in our study is similar to previously reported results from RA efficacy trials with this agent and other NSAIDs [6]. Taken together, our results suggest that inhibition of COX-2 alone is both sufficient and necessary to achieve full anti-inflammatory and analgesic efficacy in RA patients, as no differences in efficacy were observed when compared to non-selective COX inhibition.

Severe GI complications such as ulceration, perforation and GI bleeding are significant risk factors of conventional NSAID treatment [12, 13]. Furthermore, the risk of serious NSAID-induced GI complications increases with time and patients who require long-term treatment for chronic pain and inflammation, as is the case for patients with RA and OA, are particularly at risk [36]. Valdecoxib treatment has been associated with an incidence of GI ulceration that is comparable to placebo and significantly lower than the conventional NSAIDs ibuprofen, diclofenac and naproxen [37, 38], and it does not affect platelet aggregation responses or bleeding times in healthy adults [39]. These data suggest that the rates of GI and haematological complications associated with non-selective inhibition of COX-1 by conventional NSAIDs will be reduced with valdecoxib treatment, although further studies are required to substantiate this safety advantage.

In addition to the risk of serious GI complications, persistent NSAID use is also associated with low GI tolerability, with a variety of unpleasant symptoms including dyspepsia, nausea, vomiting, diarrhoea/or constipation and abdominal pain [11, 40]. Such complications cause discomfort and pain and frequently lead to poor patient compliance and/or discontinuation of the medication [41]. The improved GI tolerability of COX-2 specific inhibitors compared with conventional NSAIDs is consistent with data from the present study demonstrating fewer GI-related adverse events for patients treated with valdecoxib 10 and 20 mg q.d. compared with naproxen. Specifically, the rates of dyspepsia, abdominal pain and nausea were lower in valdecoxib 10 and 20 mg q.d.-treated patients compared with those who received naproxen. In terms of general safety, all three doses of valdecoxib were well tolerated. In particular, thromboembolic and renal adverse events occurred in less than 3% of the study population in any treatment group and no significant differences were observed between placebo and valdecoxib 10 and 20 mg. At a supratherapeutic dose of 40 mg, valdecoxib was also similar to placebo for most measured cardiovascular and renal events. Both valdecoxib at the supratherapeutic dose of 40 mg and naproxen at its usual daily dose of 1000 mg were associated with significant increases in levels of hypertension (2.7%) compared with placebo (0%).

The efficacy profile, rapid onset and long duration of action, combined with the improved tolerability/safety profile that is characteristic of COX-2 specific inhibitors, indicate that valdecoxib is a good therapeutic alternative for patients with RA who require long-term treatment for significant pain and inflammation.


    Acknowledgments
 
This work was sponsored by Pharmacia Corporation and Pfizer Inc. D. P. Recker, W. W. Zhao, W. Riley and B. Paperiello are all employees of the Pharmacia Corporation. Drs W. Bensen, A. Weaver and L. Espinoza acted in the capacity of consultants for Pharmacia.


    Notes
 
Correspondence to: D. P. Recker, Clinical Research and Development, Pharmacia Corporation, 5200 Old Orchard Road, Skokie, IL 60077, USA. Back


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 Methods
 Results
 Discussion
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Submitted 21 August 2001; Accepted 13 March 2002