Efficacy and Tolerability of Celecoxib versus Naproxen in Patients with Osteoarthritis of the Knee: a Randomized, Double-blind, Double-dummy Trial

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1 The Journal of International Medical Research 2012; 40: Efficacy and Tolerability of Celecoxib versus Naproxen in Patients with Osteoarthritis of the Knee: a Randomized, Double-blind, Double-dummy Trial MN ESSEX, P BHADRA AND GH SANDS Pfizer Inc., New York, New York, USA OBJECTIVE: To assess the efficacy and tolerability of celecoxib versus naproxen in patients with osteoarthritis (OA) of the knee. METHODS: This 6-month, randomized, double-blind, double-dummy trial was conducted at 47 centres in the USA. Patients with OA of the knee were randomized to receive 200 mg celecoxib orally once daily or 500 mg naproxen orally twice daily. The primary endpoint was defined as a 20% improvement from baseline to 6 months in Western Ontario and McMaster Universities (WOMAC) OA total score. RESULTS: A total of 586 out of 589 randomized patients received at least one dose of celecoxib (n = 294) or naproxen (n = 292). The primary endpoint (6-month response rate) was achieved by 52.7% and 49.7% of patients in the celecoxib and naproxen treatment groups, respectively. Significantly fewer discontinuations due to gastrointestinal adverse events occurred in patients receiving celecoxib than in those receiving naproxen (4.1% versus 15.1%, respectively). CONCLUSIONS: Over the 6- month study period, celecoxib provided similar improvements in OA symptoms to naproxen. In addition, celecoxib provided better upper gastrointestinal tolerability than naproxen. KEY WORDS: CELECOXIB; EFFICACY; KNEE; NAPROXEN; NONSTEROIDAL ANTI-INFLAMMATORY DRUGS; OSTEOARTHRITIS; TOLERABILITY: WOMAC SCORE Introduction Osteoarthritis (OA) of the knee is a major cause of pain and physical disability in the elderly, 1 with symptomatic disease affecting 10% of men and 13% of women aged 60 years in the USA. 2 While changes in the musculoskeletal system associated with aging increase the propensity for OA, factors such as joint injury, obesity and genetic predisposition are important in determining which joints are affected and the severity of disease. 1,3,4 The prevalence of OA of the knee is expected to increase as obesity rates rise and the population continues to age. 2,5 Many patients with OA take medication for long periods of time and have a number of comorbidities requiring the use of concomitant medication, increasing the likelihood of adverse events 6 10 including gastrointestinal (GI) injury. 11,12 There is an increasing demand for more effective and safer OA treatments. Clinical guidelines 1357

2 often recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for the relief of pain and inflammation associated with OA The cyclo-oxygenase 2 (COX- 2) selective NSAID celecoxib has proven efficacy in relieving pain and improving physical function in patients with OA Many studies of NSAIDs for the treatment of OA have been relatively short-term (6 12 weeks), 20,22,23,25,27,28 but patients with arthritis generally take medication for longer periods. In order for physicians to employ evidence-based medicine, data from longer treatment periods are needed. The present 6- month, randomized, double-blind, doubledummy trial was conducted in 47 centres in the USA in patients with symptomatic OA of the knee in order to evaluate the efficacy and tolerability of daily celecoxib compared with naproxen. Patients and methods PATIENTS This 6-month, multicentre, randomized, double-blind, double-dummy trial was conducted in 47 centres in the USA between March 2004 and January Men and women aged 40 years, with OA of the knee diagnosed according to American College of Rheumatology criteria 29 and who were determined by their physician to be eligible for chronic NSAID therapy, were considered for inclusion. Patients whose knee OA was in a flare state and who demonstrated functional capacity classification 29 grades I, II or III at the baseline visit were eligible for inclusion. Women of childbearing age were required to be using adequate contraception, not breastfeeding and to have a negative urine pregnancy test within 14 days before the baseline visit. Exclusion criteria were: (i) acute flare of inflammatory arthritis or gout/pseudogout within the past 2 years; (ii) acute trauma at the index joint within the past 3 months with active symptoms; (iii) surgery on the index joint within the past 6 months or surgery on the nonindex joint within the past 3 months; (iv) anticipated need for surgery or another invasive procedure on the index and/or nonindex joints during the study; (v) physical therapy on the index joint or use of a mobility assisting device (e.g. cane) for < 6 weeks prior to the screening visit; (vi) use of a walker-assisting device; (vii) use of oral (at 4 weeks before the first dose of study medication), intramuscular (at 2 months), intra-articular (at 3 months) or soft tissue (at 2 months) injections of corticosteroids; (viii) intra-articular injections of hyaluronic acid in the index joint 9 months before the first dose of study medication; (ix) use of paracetamol 24 h before the baseline visit; (x) use of anticoagulants or lithium; (xi) use of glucosamine and/or chondroitin sulphate, unless the dose had been stable for > 4 months or discontinued for 4 months; (xii) known sensitivity to nonselective or COX-2 selective NSAIDs, sulphonamides, aspirin or related compounds; (xiii) oesophageal, gastric, pyloric channel or duodenal ulceration 60 days prior to the first dose of study medication; (xiv) history of GI perforations, obstructions or bleeding; (xv) active GI disease; (xvi) renal or hepatic disease; (xvii) significant bleeding disorder; (xviii) diagnosis of unstable cardiovascular disease 6 months prior to study entry; or (xix) clinically significant laboratory abnormalities at screening. The use of nonstudy NSAIDs, antacids, histamine-2 receptor antagonists or protonpump inhibitors was prohibited, with the exception of aspirin at a stable dose of 325 mg/day for cardiovascular prophylaxis and calcium-containing antacids for osteoporosis prevention. The use of analgesics 1358

3 (paracetamol dose of 2 g/day for 3 consecutive days) for reasons other than arthritis was permitted if absolutely necessary, but not within 24 h of any visit. Topical pain relief to nonindex joints was allowed except within 48 h of any visit. STUDY DESIGN Patients were randomized at study entry in a 1 : 1 ratio to receive either 200 mg celecoxib orally once daily or 500 mg naproxen orally twice daily, using a computer-generated randomization scheme. All patients took study medication in the form of capsules (active drug or placebo) twice daily to maintain blinding. There were five study visits, defined as: screening (1 14 days prior to the first dose of study medication); baseline (within 24 h before the first dose of study medication; index joint designated at this visit); month 1 (days after the first dose of study medication); month 3 (days after the first dose of study medication); and month 6 (days after the first dose of study medication). Patients completed a 2-day washout period for analgesic medication before the baseline visit. Those who stopped taking study medication were encouraged to remain in the study and complete the scheduled visits, but could be discontinued from the study at any time by the investigator or at the patient s request. The institutional review board and/or an independent ethics committee at each centre approved the protocol. The study was conducted in accordance with the Declaration of Helsinki, 30 International Conference on Harmonisation good clinical practice guidelines, 31 the US Food and Drug Administration (FDA) regulations 32 and local regulatory requirements. All patients provided written informed consent prior to enrolment. STUDY ENDPOINTS The primary efficacy endpoint was the Western Ontario and McMaster Universities (WOMAC) 33 total score response rate at month 6, defined as a 20% improvement in total WOMAC OA score from baseline to 6 months. The WOMAC scale includes three subscales that are combined to generate a total score. The three subscales are: pain (five questions, each response ranging from 0 4); stiffness (two questions, each response ranging from 0 4); and physical function (17 questions, each response ranging from 0 4). A reduction in score indicates improvement. Those patients who did not complete 6 months of treatment were considered nonresponders for the purposes of this study. Secondary efficacy endpoints included changes from baseline to month 6 in: total and subscale WOMAC scores; the patient s and physician s global assessments of arthritis; and the patient s assessment of arthritis pain using a mm visual analogue scale (VAS; 0 mm, no pain; 100 mm, very severe pain). For the patient s global assessment of arthritis, patients rated their condition on a scale of 1 5 (1, very good [asymptomatic and no limitation of normal activities]; 5, very poor [very severe, intolerable symptoms and inability to carry out normal activities] in answer to the question: Considering all the ways the OA in your knee affects you, how are you doing today? The physician s global assessment of arthritis was a similar five point scale, indicating the physician s opinion based on the patient s disease signs. The patient s and physician s global assessments of arthritis and the VAS data were assessed at baseline and months 1, 3 and 6. Other endpoints included the patient s assessment of arthritis pain response rate at month 6 (a 20% improvement in VAS score 1359

4 from baseline) and the change from week 1 to month 6 in GI distress score for patients remaining on study medication for 6 months compared with those who prematurely discontinued study treatment. GI distress score was measured on a VAS scale of mm (0 mm, no distress; 100 mm, complete distress). 34,35 Patients were required to record GI distress scores weekly in a diary and changes were calculated using the value at week 1 as baseline. SAFETY ASSESSMENTS Safety assessments included monitoring for adverse events (adverse drug reactions, illnesses with onset during the study and exacerbation of previous illnesses) and any clinically significant changes in vital signs at screening, baseline, and months 1, 3, and 6 or early termination. Adverse events were summarized using the Medical Dictionary for Regulatory Affairs preferred terms 36 and were subjectively classified by the investigator as mild, moderate or severe. STATISTICAL ANALYSES The sample size was calculated based on the primary efficacy endpoint (total WOMAC score response rate). Based on assumptions derived from studies carried out in the celecoxib development programme and postmarketing information it was anticipated that the response rates for celecoxib and naproxen would be approximately 37% and 25%, respectively. A sample of 250 patients per treatment group would, therefore, provide 80% power for a two-sided test at the 5% level of significance. Efficacy analyses were performed on the modified intent-to-treat (mitt) population (all randomized patients who received at least one dose of study medication and had at least one postbaseline follow-up efficacy measurement), and safety/tolerability analyses were performed on the safety population (all randomized patients who received at least one dose of study medication). The Cochran Mantel Haenszel test was used to analyse the primary efficacy endpoint, the changes in the patient s and physician s global assessments of arthritis and patient s assessment of arthritis pain (VAS) from baseline to month 6, and the patient s assessment of arthritis pain response rate at month 6. A general linear model was used to analyse the changes in total and subscale WOMAC scores from baseline to month 6, and the change in GI distress score from week 1 to month 6. Descriptive statistics were used to summarize treatment-emergent adverse events. All statistical tests were two-sided and were performed using the SAS statistical package version 8.0 or higher (SAS Institute Inc., Cary, NC, USA). A P-value < 0.05 was considered statistically significant. Results A total of 589 patients were randomized to the two treatments (celecoxib n = 296, naproxen n = 293); two patients in the celecoxib group and one in the naproxen group did not receive study medication but underwent at least one postbaseline efficacy measure. The safety and mitt populations, therefore, comprised 586 patients (celecoxib n = 294, naproxen n = 292). Demographic and baseline clinical characteristics of the two study groups are shown in Table 1. The majority of patients were Caucasian females. There were no statistically significant between-group differences in demographic or clinical characteristics at baseline. A similar percentage of patients remained on study medication for 6 months in both groups (celecoxib 202/294 [68.7%], naproxen 189/292 [64.7%]; Fig. 1). The 1360

5 TABLE 1: Demographic and clinical characteristics at baseline of patients with osteoarthritis (OA) of the knee who were randomized to receive either 200 mg celecoxib orally once daily or 500 mg naproxen orally twice daily for 6 months Celecoxib Naproxen Characteristic n = 296 n = 293 Age, years a 60.0 ± 10.7 (39 92) 60.7 ± 11.1 (39 89) Gender b Males 104 (35.1) 95 (32.4) Females 192 (64.9) 198 (67.6) Race/ethnic origin b Caucasian 210 (70.9) 213 (72.7) Black 36 (12.2) 34 (11.6) Asian 28 (9.5) 24 (8.2) Other 22 (7.4) 22 (7.5) Time from diagnosis of OA in index 7.2 ± 8.1 ( ) 8.5 ± 9.0 ( ) knee to screening visit, years American College of Rheumatology criteria 29 functional capacity classification b I 5 (1.7) 6 (2.0) II 224 (75.7) 217 (74.1) III 67 (22.6) 70 (23.9) IV 0 (0.0) 0 (0.0) WOMAC 33 OA total score a 53.9 ± 14.8 (11 90) 54.3 ± 15.1 (15 93) Data presented as mean ± SD (range), or n (%) of patients. WOMAC, Western Ontario and McMaster Universities. No statistically significant between-group differences (P 0.05): a general linear model with treatment and centre as factors; b Cochran Mantel Haenszel test stratified by centre. median duration of treatment was days (range days) in the celecoxib group and days (range days) in the naproxen group. Fewer patients in the celecoxib group than in the naproxen group discontinued treatment because of an adverse event considered by the investigator to be related to study medication (18/294 [6.1%] and 38/292 [13.0%], respectively). Information regarding concomitant medication use was provided by 284 patients in the celecoxib group and 283 patients in the naproxen group. Concomitant medication was used by 246 patients in each group (86.6% and 86.9% in the celecoxib and naproxen groups, respectively). The most commonly used medications in the celecoxib and naproxen groups were aspirin (55 and 61 patients, respectively), multivitamins (39 and 38 patients, respectively) and tocopherol (25 and 30 patients, respectively). There was no significant between-group difference in response rate, with similar numbers of patients in the celecoxib and naproxen groups having a 20% improvement in total WOMAC score from baseline to month 6 (Table 2). There were also no significant between-group differences in response rate in the pain, stiffness, or physical function WOMAC subscales. Improvements in both the patient s and physician s global assessments of arthritis from baseline to month 6 were similar in both groups (Table 3). In addition, there was no significant between-group difference in 1361

6 Not randomized (n = 158) Screened (n = 747) Randomized (n = 589) Celecoxib 200 mg once daily (n = 296) Naproxen 500 mg twice daily (n = 293) 294 a patients received treatment and were evaluable for adverse events 292 a patients received treatment and were evaluable for adverse events 202 patients remained on study drug for 6 months 189 patients remained on study drug for 6 months 44 patients discontinued due to adverse events 64 patients discontinued due to adverse events a Two patients in the celecoxib group and one in the naproxen group did not receive study medication but underwent at least one postbaseline efficacy measure, so the safety and modified intent-to-treat populations comprised 586 patients (celecoxib n = 294, naproxen n = 292) FIGURE 1: Flow chart showing the process of screening, treatment randomization and treatment withdrawals for the patients with osteoarthritis of the knee who were randomized to receive either 200 mg celecoxib orally once daily or 500 mg naproxen orally twice daily for 6 months the least square mean change in patient s assessment of arthritis pain (VAS score) from baseline to month 6 ( 39.3 and 41.2 for celecoxib and naproxen, respectively). The VAS pain score response rates (20% improvement from baseline to month 6) were also not significantly different between the two groups (63.2% and 58.6%, respectively). There were also no significant between-group differences in the change in GI distress score throughout the study period (Fig. 2). Serious adverse events were experienced by 3.1% (9/294) of patients in the celecoxib group and by 2.7% (8/292) in the naproxen group (Table 4). The majority of serious adverse events were considered unrelated to the study drugs. Serious treatment-related adverse events occurred in 0.7% (2/294) of patients in the celecoxib group (one case each of atrial fibrillation and anaphylaxis) and 0.3% (1/292) in the naproxen group (thrombocytopenia). There was one reported serious GI adverse event (haemorrhage), 1362

7 TABLE 2: Change from baseline to month 6 (or early termination) in total and subscale Western Ontario and McMaster Universities (WOMAC) osteoarthritis scores 33 in patients with osteoarthritis of the knee who were randomized to receive either 200 mg celecoxib orally once daily or 500 mg naproxen orally twice daily for 6 months (modified intent-to-treat population, n = 586) Celecoxib Naproxen WOMAC total or subscale n = 294 n = 292 Total a Responders b, n (%) 155 (52.7) 145 (49.7) LSM change (SE) 22.2 (1.1) 22.6 (1.1) Pain subscale Responders b, n (%) 163 (55.4) 147 (50.3) LSM change (SE) 4.9 (0.2) 5.0 (0.2) Stiffness subscale Responders b, n (%) 153 (52.0) 150 (51.4) LSM change (SE) 1.8 (0.1) 1.9 (0.1) Physical function subscale Responders b, n (%) 155 (52.7) 146 (50.0) LSM change (SE) 15.4 (0.8) 15.7 (0.8) a Sum of pain, stiffness and physical function subscale scores. b Patients with 20% decrease (improvement) in WOMAC score from baseline to month 6. LSM, least squares mean. No statistically significant between-group differences (P 0.05); general linear model with change from baseline as dependent variable and factors for treatment, centre and baseline WOMAC score (total or subscale, as appropriate) as covariates. which occurred in a patient receiving naproxen, but this was not considered treatment-related. Serious cardiovascular adverse events were reported in five patients; three in the celecoxib group (exacerbation of coronary artery disease; severe bradycardia and arrhythmia; atrial fibrillation) and two in the naproxen group (small vessel ischaemic disease; chest pain). The episode of atrial fibrillation in the celecoxib group was the only serious cardiovascular adverse event considered to be treatment related by the investigator. There were no myocardial infarctions, strokes or deaths during the study period. The numbers of all-cause and treatmentrelated adverse events were similar in both groups (Table 4), with GI adverse events being the most commonly reported (Table 5). When GI disorders were stratified by severity, fewer moderate or severe GI adverse events occurred in the celecoxib group than the naproxen group (37 moderate/seven severe and 54 moderate/13 severe, respectively). In addition, fewer patients in the celecoxib group than in the naproxen group experienced moderate or severe nausea (six and nine patients, respectively), abdominal pain (one and six patients, respectively), or dyspepsia (19 and 21 patients, respectively). The numbers of patients discontinuing due to all-cause and treatment-related adverse events were lower in the celecoxib group than in the naproxen group (Table 4). The most common adverse events that led to discontinuation were GI disorders (Table 5). Although GI adverse events were reported at similar frequencies in the two treatment groups they were less often cited as the reason for discontinuation by patients 1363

8 TABLE 3: Patient s and physician s global assessments of arthritis at baseline, month 6 (or early termination) and change from baseline in patients with osteoarthritis of the knee who were randomized to receive either 200 mg celecoxib orally once daily or 500 mg naproxen orally twice daily for 6 months Celecoxib Naproxen Global assessment measure Patient Physician Patient Physician Baseline, n Very good 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Good 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Fair 65 (22.0) 72 (24.3) 74 (25.3) 70 (23.9) Poor 200 (67.6) 201 (67.9) 180 (61.4) 194 (66.2) Very poor 31 (10.5) 23 (7.8) 39 (13.3) 29 (9.9) Month 6, n a Very good 47 (16.5) 41 (14.4) 59 (20.7) 48 (16.8) Good 126 (44.2) 136 (47.7) 122 (42.8) 138 (48.4) Fair 95 (33.3) 87 (30.5) 85 (29.8) 82 (28.8) Poor 14 (4.9) 18 (6.3) 14 (4.9) 16 (5.6) Very poor 3 (1.1) 3 (1.1) 5 (1.8) 1 (0.4) Change from baseline, n a Improved b 152 (53.3) 155 (54.4) 155 (54.4) 156 (54.7) No change 130 (45.6) 127 (44.6) 125 (43.9) 128 (44.9) Worsened c 3 (1.1) 3 (1.1) 5 (1.8) 1 (0.4) Data presented as n (%) of patients. a Percentages based on the number of patients from the modified intent-to-treat population of 586 patients for whom there were data at the month 6/early termination visit. b Reduction of at least two grades or a change to very good. c Increase of at least two grades or a change to very poor. No statistically significant between-group differences (P 0.05); Cochran Mantel Haenszel test stratified by centre. receiving celecoxib than by those receiving naproxen (P < ; Table 5). Upper abdominal pain, abdominal distension, constipation, dyspepsia, gastro-oesophageal reflux disease and nausea were among those symptoms associated with the largest between-group differences in rate of discontinuation for GI adverse events. When these GI adverse events were combined, celecoxib was significantly better tolerated by patients than naproxen (P = ). Discussion In this 6-month trial, 200 mg celecoxib once daily demonstrated similar efficacy to 500 mg naproxen twice daily in the treatment of symptoms associated with OA. This finding was consistent across various measures, including a 20% improvement in WOMAC scores, patient assessment of arthritis pain (VAS score), and both the patient s and physician s global assessments of arthritis from baseline to month 6. These 6-month study results support findings from 12-week trials in OA patients in which 200 mg celecoxib once daily demonstrated similar efficacy in terms of pain relief and improvement in physical function to 500 mg naproxen twice daily. 20,22,25 Celecoxib was generally well tolerated, with a similar incidence of general adverse events to that seen with naproxen. The 1364

9 A Patients who completed the study Change in GI distress (VAS) Treatment group Celecoxib 200 mg once daily (n = 202) Naproxen 500 mg twice daily (n = 189) Time in study (weeks) B Patients who prematurely discontinued treatment followed to the time of discontinuation Change in GI distress (VAS) Treatment group Celecoxib 200 mg once daily (n = 92) Naproxen 500 mg twice daily (n = 103) Time in study (weeks) FIGURE 2: Week by week change from baseline (week 1) in gastrointestinal (GI) symptoms, as measured by the GI distress score (visual analogue scale [VAS]), for the patients with osteoarthritis of the knee who were randomized to receive either 200 mg celecoxib orally once daily or 500 mg naproxen orally twice daily for 6 months (compiled from the modified intent-to-treat population of 586 patients for whom there were data; n values shown in the Fig.) change in GI distress (VAS score) was similar in the two treatment groups, but there were fewer discontinuations due to GI adverse events in patients receiving celecoxib than in those receiving naproxen, suggesting celecoxib may have a more favourable GI tolerance profile than naproxen. The results of the present study are consistent with other trials that have demonstrated improved GI tolerance of celecoxib over nonselective NSAIDs, 20,21,25,37 and evidence suggests that celecoxib is associated with fewer tolerancerelated GI adverse events than nonselective NSAIDs The current study was not designed to evaluate differences between the two drugs in the incidence of serious GI events, such as bleeding or ulcer, but the single serious GI adverse event reported (GI haemorrhage) in a patient receiving naproxen was not deemed to be treatment- 1365

10 TABLE 4: Overview of treatment-emergent adverse events in patients with osteoarthritis of the knee who were randomized to receive either 200 mg celecoxib orally once daily or 500 mg naproxen orally twice daily for 6 months (safety population, n = 586) All-cause Treatment-related Celecoxib Naproxen Celecoxib Naproxen Adverse event measure n = 294 n = 292 n = 294 n = 292 Total a (65.6) 197 (67.5) 124 (42.2) 142 (48.6) Serious b 9 (3.1) 8 (2.7) 2 (0.7) 1 (0.3) Severe c 25 (8.5) 24 (8.2) 10 (3.4) 10 (3.4) Discontinuation of treatment 44 (15.0) 64 (21.9) 30 (10.2) 49 (16.8) Dose reduction or temporary 9 (3.1) 11 (3.8) 6 (2.0) 6 (2.1) discontinuation Data presented as number of adverse events or n (%) of patients. Includes data up to 30 days after the last dose of study medication. A total of two patients (one in each treatment group) discontinued due to adverse events that were not treatment-emergent and are not included in this table. a An adverse event occurring more than once in the same patient was counted once. A patient with two or more adverse events contributed once to the count for each different adverse event. b Any adverse event that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or resulted in congenital anomaly/birth defect. c Determined subjectively by the investigator (mild, moderate, or severe). related. Practitioners must balance these current findings with the increased risk of serious GI adverse events known to be associated with NSAIDs. 11,12 The occurrence of serious cardiovascular adverse events was infrequent and similar in the two treatment groups, although the current study was neither designed nor powered to investigate cardiovascular adverse events. There is evidence to suggest that all NSAIDs may increase cardiovascular risk to a similar level, 8 10 and all prescription NSAIDs, including celecoxib and naproxen, have received the same cardiovascular warning from the FDA. 40 The PRECISION trial, in which celecoxib is being compared with naproxen and ibuprofen, is expected to answer the question of overall benefit risk of NSAIDs in the treatment of arthritis pain. Given the importance of GI and cardiovascular safety with NSAID use, American College of Rheumatology 19 and National Institute for Health and Clinical Excellence 16,41 guidelines stress the importance of the assessment of relevant risk factors in individual patients prior to treatment selection. The current study assessed a wide range of patient-reported outcomes covering efficacy and safety over a 6-month treatment period. Although this trial was completed several years ago, data regarding long-term efficacy and tolerability of treatments for conditions such as OA remain relevant for current patient care. Patients must be able to tolerate medication in order to receive the efficacy benefits, and information on relative tolerability is useful when clinicians make treatment decisions for their patients. A strength of the present study was the use of naproxen, one of the most commonly used NSAIDs in the USA, as the active comparator. 1366

11 TABLE 5: Incidence of all-cause treatment-emergent adverse events reported in 2% of patients with osteoarthritis of the knee who were randomized to receive either 200 mg celecoxib orally once daily or 500 mg naproxen orally twice daily for 6 months (safety population, n = 586) Patients reporting adverse Discontinuation due to event adverse event Celecoxib Naproxen Celecoxib Naproxen Adverse event n = 294 n = 292 n = 294 n = 292 Gastrointestinal disorders 128 (43.5) 138 (47.3) 12 (4.1) 44 (15.1) a Dyspepsia 41 (13.9) 46 (15.8) 2 (0.7) 5 (1.7) Abdominal distension 21 (7.1) 16 (5.5) 2 (0.7) 4 (1.4) Diarrhoea 20 (6.8) 11 (3.8) 1 (0.3) 1 (0.3) Nausea 19 (6.5) 24 (8.2) 2 (0.7) 6 (2.1) Abdominal discomfort 13 (4.4) 12 (4.1) 1 (0.3) 2 (0.7) Flatulence 11 (3.7) 12 (4.1) 0 (0.0) 1 (0.3) Abdominal pain, upper 11 (3.7) 18 (6.2) 1 (0.3) 5 (1.7) Gastro-oesophageal reflux disease 9 (3.1) 6 (2.1) 0 (0.0) 3 (1.0) Constipation 7 (2.4) 10 (3.4) 1 (0.3) 4 (1.4) Abdominal pain 5 (1.7) 8 (2.7) 1 (0.3) 3 (1.0) Stomach discomfort 5 (1.7) 6 (2.1) 0 (0.0) 1 (0.3) General disorders 34 (11.6) 36 (12.3) 18 (6.1) 19 (6.5) Drug ineffective 13 (4.4) 11 (3.8) 12 (4.1) 11 (3.8) Peripheral oedema 5 (1.7) 11 (3.8) 1 (0.3) 2 (0.7) Infections and infestations 29 (9.9) 37 (12.7) 1 (0.3) 2 (0.7) Nasopharyngitis 5 (1.7) 8 (2.7) 0 (0.0) 0 (0.0) Upper respiratory tract infection 4 (1.4) 7 (2.4) 0 (0.0) 0 (0.0) Musculoskeletal disorders 45 (15.3) 29 (9.9) 9 (3.1) 7 (2.4) Arthralgia 18 (6.1) 10 (3.4) 2 (0.7) 2 (0.7) Back pain 9 (3.1) 4 (1.4) 1 (0.3) 1 (0.3) Nervous system disorders 24 (8.2) 26 (8.9) 3 (1.0) 2 (0.7) Headache 8 (2.7) 6 (2.1) 2 (0.7) 1 (0.3) Skin and subcutaneous disorders 11 (3.7) 13 (4.5) 1 (0.3) 1 (0.3) Rash 6 (2.0) 4 (1.4) 1 (0.3) 0 (0.0) Data presented as n (%) of patients. Includes data up to 30 days after the last dose of study medication. If a patient had more than one occurrence in the same category, only the most severe occurrence was included. a P < versus celecoxib group; Fisher s exact test. In addition, the celecoxib dose used was that approved and recommended by the FDA for treatment of OA. The current study, therefore, provides valuable information to help physicians make treatment decisions for their patients with OA. The findings of the current study are limited by the short-term nature of the treatment period relative to the years of drug therapy usually received by patients with OA. The efficacy and tolerability of celecoxib for OA treatment over a 1 2-year period has, however, been previously demonstrated. 37,42,43 While these current data are limited to 6 months, the numerous efficacy and tolerability measures may provide useful information for practitioners when choosing therapy for their patients with OA. 1367

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