Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritisA phase II four-week multicenter randomized double-blind placebo-controlled trial.код для вставкиСкачать
Arthritis & Rheumatism (Arthritis Care & Research) Vol. 51, No. 4, August 15, 2004, pp 549 –557 DOI 10.1002/art.20525 © 2004, American College of Rheumatology ORIGINAL ARTICLE Efﬁcacy and Safety of Four Doses of Lumiracoxib Versus Diclofenac in Patients With Knee or Hip Primary Osteoarthritis: A Phase II, Four-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial THOMAS J. SCHNITZER,1 JANNIE BEIER,2 PIET GEUSENS,3 PAUL HASLER,4 SANJAY K. PATEL,5 INGO SENFTLEBER,6 XAVIER GITTON,7 ALAN MOORE,7 VICTOR S. SLOAN,8 AND GYULA POÓR9 Objective. To compare the efﬁcacy and tolerability of the novel cyclooxygenase 2-selective inhibitor lumiracoxib with placebo and diclofenac in osteoarthritis (OA). Methods. Adults (n ⴝ 583) with knee or hip OA were randomized to receive for 4 weeks lumiracoxib 50, 100, or 200 mg twice daily or 400 mg once daily; placebo; or diclofenac 75 mg twice daily. Efﬁcacy assessments included overall joint pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated by adverse event and physician reporting. Results. All lumiracoxib doses were superior to placebo in relieving pain, improving stiffness, and improving physical function after 4 weeks. At study endpoint, pain relief was comparable among all lumiracoxib dosages and similar to diclofenac. Lumiracoxib tolerability was superior to diclofenac and comparable to placebo. Conclusion. Lumiracoxib provides predictable and sustained relief from pain, stiffness, and impaired physical function in OA. Lumiracoxib shows clinically comparable efﬁcacy and superior tolerability to diclofenac. KEY WORDS. Lumiracoxib; Diclofenac; Pain relief; Osteoarthritis. INTRODUCTION Osteoarthritis (OA) is not only the most common musculoskeletal disorder, affecting approximately 10% of the population worldwide and 16 –30 million people in the US (1– 4), but more importantly is a leading cause of pain, 1 Thomas J. Schnitzer, MD: Northwestern University Feinberg School of Medicine, Chicago, Illinois; 2Jannie Beier, MD: Private Rheumatology Practice, Odense, Denmark; 3 Piet Geusens, MD: Limburgs University, Diepenbeek, Belgium; 4Paul Hasler, MD: Felix Platter Spital, Basel, Switzerland; 5Sanjay K. Patel, MD: Adan House Surgery, Durham, United Kingdom; 6Ingo Senftleber, MD: Grabenbachstrasse 12, Messkirch, Germany; 7Xavier Gitton, MD, Alan Moore, MD: Novartis Pharma AG, Basel, Switzerland; 8Victor S. Sloan, MD: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; 9Gyula Poór, MD: National Institute of Rheumatology, Budapest, Hungary. Address correspondence to Thomas J. Schnitzer, MD, Northwestern Center for Clinical Research, 710 North Lake Shore Drive, Room 1020, Chicago, IL 60611. E-mail: email@example.com. Submitted for publication January 31, 2003; accepted in revised form September 14, 2003. loss of physical function, and reduction in health-related quality of life (5). Treatment of this condition begins with a foundation of patient education, exercise, optimization of weight, and social support to which pharmacologic management is added, as needed, to control pain and increase physical function (6 – 8). Despite having inferior efﬁcacy to nonsteroidal antiinﬂammatory drugs (NSAIDs) (9,10), acetaminophen has been proposed as the initial therapeutic agent in OA function (6 – 8). These recommendations are based largely on the superior safety and tolerability proﬁle of acetaminophen compared with traditional NSAIDs. The major serious side effect of traditional NSAIDs is gastrointestinal (GI) toxicity, manifest as peptic ulcers, perforations, or bleeding (11,12). Occurring at an annualized rate of 2– 4% in patients regularly taking full prescription doses, these events are a consequence of a reduction in prostaglandin synthesis due to inhibition of the cyclooxygenase (COX) pathway by NSAIDs (13). The discovery of a second COX isoenzyme (COX-2) and the subsequent knowledge of its tissue distribution, regulation, expression, and function led to the COX-2 hypothesis: speciﬁc 549 550 inhibitors of COX-2 will provide equivalent efﬁcacy to traditional NSAIDs (which inhibit both COX-1 and COX-2 isoenzymes) but will result in greater GI safety (14). This hypothesis was formally tested by the development of COX-2–selective inhibitors and subsequent clinical investigations of these drugs. Results of trials with currently marketed COX-2–selective inhibitors have demonstrated an efﬁcacy proﬁle that is similar to traditional NSAIDs with superior GI safety, measured as fewer endoscopic GI ulcers and better GI tolerability (15–28). Large GI outcome studies with 2 COX-2–selective inhibitors, rofecoxib and celecoxib, have generally supported these ﬁndings but have generated additional questions regarding the longterm cardiovascular and GI safety of these agents (19,25, 29,30). Lumiracoxib is a novel COX-2–selective inhibitor chemically distinct from the other COX-2–selective inhibitors by virtue of the absence of a sulfur-containing moiety and the presence of a carboxylic acid group, making it a weakly acidic molecule (pKa 4.7) (31). Previous studies have demonstrated the efﬁcacy of lumiracoxib in acute dental pain (32,33), but this phase II dose-ranging study is the ﬁrst assessment of lumiracoxib in patients with OA. The primary goal of this study was to evaluate the efﬁcacy of different dosages and dosing regimens of lumiracoxib compared with both placebo and the maximum recommended therapeutic dosage (75 mg twice daily) of diclofenac. METHODS This was an international, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter study conducted over 4 weeks. The primary objective was to determine the efﬁcacy of lumiracoxib at 4 dosages, compared with placebo, in the treatment of OA as evaluated by the change in overall pain intensity in the most severely affected joint. Secondary objectives included the assessment of the safety and tolerability proﬁle of lumiracoxib compared with placebo, and the efﬁcacy, safety, and tolerability compared with the maximum therapeutic dosage of diclofenac (75 mg twice daily). The study was conducted at 50 centers in 7 countries (Belgium, Denmark, Germany, Hungary, Switzerland, UK, and US) between August and December 1999. The study was approved by the appropriate institutional review boards and was conducted according to Good Clinical Practice guidelines and in accordance with the Declaration of Helsinki (1964 and subsequent revisions). Patients provided written informed consent prior to any study procedure. Patients. Adult patients (aged 18 –75 years) were eligible to participate in the study if they had a clinical or radiographic diagnosis of primary OA of the knee or hip (diagnosed according to the American College of Rheumatology criteria) (34,35), had been symptomatic for at least 3 months prior to enrollment, and had received an NSAID or other analgesic therapy on a regular basis. Patients were required to have experienced a pain intensity of at least 40 Schnitzer et al mm on a 100-mm visual analog scale (VAS; 0 mm representing no pain and 100 mm representing very severe pain) in the most severely affected joint during the 24 hours prior to randomization. Patients were excluded from the trial if they had secondary OA or had a history of, or evidence of, speciﬁed confounding disorders (e.g., septic arthritis, inﬂammatory joint disease, gout, Paget’s disease, or articular fracture). Signiﬁcant medical problems that would, in the opinion of the investigator, inﬂuence outcomes were also grounds for exclusion, as were a history of GI bleeding; open knee or hip surgery within 1 year prior to study entry; anemia; or hepatic, renal, or blood coagulation disorders. Women who were pregnant, lactating, or who were not using adequate birth control (and were of childbearing age) were not eligible. Potentially confounding concomitant treatment, including physiotherapy, any NSAID, systemic corticosteroids, intraarticular injection into the study joint, chondroitin sulfate, glucosamine sulfate, diacerhein, minocycline, H2 blockers, proton-pump inhibitors, misoprostol, or antacids, were not permitted during the study period. After a washout period of 3–7 days, during which no NSAID therapy was permitted, eligible patients were randomized to receive lumiracoxib 50 mg twice daily, 100 mg twice daily, 200 mg twice daily, 400 mg once daily, diclofenac 75 mg twice daily, or placebo. Patients were permitted a maximum of 6 tablets (total dose 3 gm) of acetaminophen per day as rescue medication. Compliance with study treatment and the use of rescue medication were assessed through direct questioning and capsule/ tablet counting. Variables. The primary efﬁcacy comparison was between placebo and each active arm at week 4 of the overall joint pain intensity experienced in the most severely affected joint (hip or knee) over the previous 24 hours, using a 100-mm VAS. Overall joint pain intensity was assessed by asking subjects: “Please indicate with a vertical mark through the horizontal line the most pain you had from your OA joint over the last 24 hours.” The joint assessed to be the most severely affected at screening was evaluated for the entire study. Secondary efﬁcacy measures were overall joint (for the most severely affected joint) pain intensity according to the 100-mm VAS by visit (i.e., at weeks 1 and 2); patient’s and physician’s global assessment of disease activity using 100-mm VAS; assessment of pain, stiffness, and physical function using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC 3.1 Likert questionnaire) (36); and evaluation of functional impairment using the Health Assessment Questionnaire (HAQ) standard disability index. The global assessment of disease activity, the HAQ, and the WOMAC were applied at baseline and week 4. Safety variables included adverse events (AEs), serious AEs (SAEs), laboratory evaluations, vital signs, and physical examinations including a speciﬁc assessment of peripheral edema conducted each week. AEs were graded based on qualitative assessment of the extent or intensity of the AE by the investigator, or as reported by the subject. Lumiracoxib Versus Diclofenac in Osteoarthritis 551 Figure 1. Disposition of study participants. bid ⫽ twice daily; qd ⫽ once daily; AEs ⫽ adverse events. SAEs were deﬁned as any event that was fatal or considered life-threatening, which required prolonged hospitalization; caused permanent disability; or constituted cancer, congenital anomaly, or overdose. Statistical analyses. The sample size was calculated to detect an 11-mm difference between lumiracoxib and placebo for pain assessed on the VAS after 4 weeks of treatment, assuming a 20-mm SD and a dropout rate of 10%. A sample size of 85 patients per treatment group was required to ensure 80% power at a signiﬁcance level of 5% (two-sided) on the basis of these assumptions. Descriptive statistics were used for baseline demographics and background data. Homogeneity between treatment groups at baseline was assessed using a one-way analysis of variance F-test for continuous variables and a chi-square test for categorical variables. The efﬁcacy analyses were performed using a modiﬁed intent-to-treat (ITT) population, comprising all patients who were randomized to treatment, who had received 1 or more doses of trial medication, and for whom at least 1 postbaseline assessment was obtained. A postbaseline, last observation carried forward approach was used to account for any missing data points, thus, baseline data were not carried forward if postbaseline data were not available. All patients who were randomized and had received at least 1 dose of study medication were included in the safety evaluation. The conﬁrmatory analysis was performed on the ITT population to determine the minimum effective regimen that reached statistical signiﬁcance. The closed version of the multiple union intersection procedure of the Dunnett test according to Marcus and colleagues (37,38) was used to compare the lumiracoxib regimens with placebo with respect to the primary efﬁcacy variable. The least-squares means were obtained using an analysis of variance model, which considered change from baseline in overall joint pain intensity as the response variable, with treatment and center as factors. The secondary analyses included an analysis of covariance to compare treatment groups with respect to primary and secondary efﬁcacy variables, with treatment and center as factors and the overall joint pain intensity at baseline as a covariate. All pairwise comparisons were performed at the level of 5% (two-sided) without adjusting for multiple comparisons. The assessment of safety was based upon the frequency of AEs, electrocardiogram results, vital signs, and on the consideration of notable laboratory values that fell outside predetermined ranges (e.g., doubling of creatinine levels or increase in creatinine ⬎2 mg/ml, increase in liver transaminase levels to ⬎3 times the upper limit of normal, anemia deﬁned as a ⱖ2 gm/dl reduction in hemoglobin from baseline). RESULTS Study population. A total of 583 patients were randomized (Figure 1) to receive either lumiracoxib 50 mg twice daily (n ⫽ 98), 100 mg twice daily (n ⫽ 96), 200 mg twice daily (n ⫽ 99), 400 mg once daily (n ⫽ 99), diclofenac 75 mg twice daily (n ⫽ 94), or placebo (n ⫽ 97). The treatment groups were well matched with no signiﬁcant differences in baseline demographics and disease characteristics (Table 1). In total, 65 (11%) patients discontinued treatment 552 Schnitzer et al Table 1. Patient characteristics* No. of patients Age, mean ⫾ SD years Sex, no. (%) Male Female BMI, mean ⫾ SD kg/m2 Disease duration, mean (range) years Lumiracoxib 50 mg bid Lumiracoxib 100 mg bid Lumiracoxib 200 mg bid Lumiracoxib 400 mg qd Diclofenac 75 mg bid Placebo Total 98 61.3 ⫾ 8.5 96 59.8 ⫾ 9.4 99 59.5 ⫾ 9.9 99 60.1 ⫾ 9.4 94 59.7 ⫾ 8.6 97 61.5 ⫾ 9.3 583 60.3 ⫾ 9.2 31 (32) 67 (68) 30.0 ⫾ 6.9 7.4 (0–45) 29 (30) 67 (70) 29.7 ⫾ 5.6 6.6 (0–30) 25 (25) 74 (75) 29.7 ⫾ 6.6 6.9 (0–51) 41 (41) 58 (59) 30.3 ⫾ 5.0 6.3 (0–29) 30 (32) 64 (68) 30.1 ⫾ 7.5 6.3 (0–36) 32 (33) 65 (67) 29.2 ⫾ 5.9 8.0 (0–55) 188 (32) 395 (68) 29.8 ⫾ 6.3 6.9 (0–55) * bid ⫽ twice daily; qd ⫽ once daily; BMI ⫽ body mass index. prior to the end of the study. The main reasons for withdrawal were the emergence of AEs (n ⫽ 32), lack of efﬁcacy (n ⫽ 10; with 6 in the placebo group), protocol violations (n ⫽ 9), and withdrawal of consent (n ⫽ 8). The mean exposure to study treatment in the 6 groups ranged from 26 to 28 days. The greatest percentage of patients taking rescue medication (68%) and the greatest use of rescue medication (mean of 1.1 tablets per day) were found in the placebo group. Between 48% and 60% of patients in the active treatment groups took rescue medication (mean of 0.4 to 0.6 tablets per day). No signiﬁcant differences were seen between any of the active treatment groups. Overall joint pain intensity. All doses of lumiracoxib were found to be effective in the conﬁrmatory analysis of the primary efﬁcacy variable: overall joint pain intensity. All were superior to placebo (P ⱕ 0.002) in terms of change from baseline from week 1 onward until study end (Figure 2). Mean overall joint pain intensity VAS scores at baseline of 64.7– 67.0 mm were reduced to 33.7–38.4 mm at week 4 with active treatment (all dosages of lumiracoxib and diclofenac) and from 67.9 mm to 50.2 mm with placebo. Thus, all doses of lumiracoxib showed signiﬁcantly lower joint pain intensity at 4 weeks compared with placebo, with a somewhat greater mean change for the lumiracoxib 400 mg once daily group. Throughout the study, there were no signiﬁcant differences in the degree of reduction of pain intensity between any of the 3 lumiracoxib doses administered twice daily compared with the 400 mg once daily dose, except for a modestly reduced effect for the 50 mg twice daily and 100 mg twice daily doses at week 1 Figure 2. Overall pain intensity measured using a 100-mm visual analog scale (VAS) in adult patients with primary osteoarthritis of the knee or hip who were randomized to receive lumiracoxib 50 mg twice daily (bid), 100 mg twice daily, 200 mg twice daily, 400 mg once daily (qd); or diclofenac 75 mg twice daily; or placebo for 4 weeks. P values were calculated on the least square means. **P ⫽ 0.002, lumiracoxib 50 mg twice daily versus placebo. ***P ⱕ 0.001, lumiracoxib 50 mg twice daily versus placebo. #P ⱕ 0.001, lumiracoxib 100 mg twice daily, 200 mg twice daily, and 400 mg once daily versus placebo. †P ⬍ 0.001, diclofenac 75 mg twice daily versus placebo. Lumiracoxib Versus Diclofenac in Osteoarthritis 553 Table 2. Patient’s and physician’s global assessments of disease activity at baseline and week 4* Patient’s global assessment of disease activity (VAS mm), mean ⴞ SD Physician’s global assessment of disease activity (VAS mm), mean ⴞ SD Treatment group No. Baseline Week 4 No. Baseline Week 4 Lumiracoxib 50 mg bid Lumiracoxib 100 mg bid Lumiracoxib 200 mg bid Lumiracoxib 400 mg qd Diclofenac 75 mg bid Placebo 95 94 92 98 92 96 63.1 ⫾ 17.5 62.0 ⫾ 18.5 64.0 ⫾ 17.3 63.7 ⫾ 16.5 62.2 ⫾ 16.2 62.5 ⫾ 18.1 38.8 ⫾ 21.5 37.8 ⫾ 22.2 37.5 ⫾ 24.0 35.6 ⫾ 24.1 34.4 ⫾ 23.0 50.0 ⫾ 23.0 94 94 91 96 92 95 59.1 ⫾ 15.7 56.6 ⫾ 17.1 61.3 ⫾ 14.7 59.6 ⫾ 15.1 57.2 ⫾ 15.6 60.4 ⫾ 15.7 37.3 ⫾ 20.2 33.4 ⫾ 20.4 34.3 ⫾ 20.0 33.1 ⫾ 21.3 33.4 ⫾ 18.5 47.3 ⫾ 22.1 * VAS ⫽ visual analog scale; bid ⫽ twice daily; qd ⫽ once daily. only (P ⬍ 0.05). At the study end, all dosages of lumiracoxib demonstrated comparable efﬁcacy to each other and to diclofenac 75 mg twice daily. Global assessment of disease activity. For the secondary endpoint, physician’s global assessment of disease activity, all of the active treatments (lumiracoxib and diclofenac) were signiﬁcantly superior to placebo at week 4 (all P ⱕ 0.001) (Table 2). Moreover, after 4 weeks of treatment, the results with each of the lumiracoxib dosages studied were similar to diclofenac 75 mg twice daily. Mean physician global assessment VAS scores at baseline of 56.6 – 61.3 mm were reduced to 33.1–37.3 mm at week 4 with active treatment (all dosages of lumiracoxib and diclofenac) and from 60.4 mm to 47.3 mm with placebo. Similarly, all active treatments (all dosages of lumiracoxib and diclofenac) were signiﬁcantly superior to placebo at week 4 for the patient’s global assessment (all P ⱕ 0.001) (Table 2); active treatments reduced mean VAS baseline scores of 62.0 – 64.0 mm to 34.4 –38.8 mm by week 4, whereas patients receiving placebo had a reduction from 62.5 mm at baseline to 50.0 mm at week 4. WOMAC assessments. The 3 WOMAC subscales were assessed as secondary efﬁcacy measures (Table 3). The WOMAC pain subscale score demonstrated that all lumiracoxib treatment regimens were as effective as diclofenac 75 mg twice daily. At week 4, all active treatment groups were statistically superior to placebo (mean score 8.1; P ⱕ 0.001 for lumiracoxib 50 mg twice daily [mean score 6.4], lumiracoxib 200 mg twice daily [mean score 6.4], lumira- coxib 400 mg once daily [mean score 5.7], and diclofenac 75 mg twice daily [mean score 6.2]; P ⫽ 0.006 for lumiracoxib 100 mg twice daily [mean score 6.8]). On the WOMAC physical function subscale, all active treatment groups, with the exception of lumiracoxib 100 mg twice daily, achieved statistically superior results at week 4 compared with placebo (mean score 27.3; P ⱕ 0.001, [mean scores 19.0 –21.5]; P ⫽ 0.056 for lumiracoxib 100 mg twice daily [mean score 23.2]). On the WOMAC stiffness subscale, the scores for all lumiracoxib dosages were similar to diclofenac. All active treatments achieved statistically superior scores compared with placebo (mean 3.5) at week 4 (P ⱕ 0.001 for lumiracoxib 50 mg twice daily, 200 mg twice daily, and 400 mg once daily; P ⫽ 0.035 for lumiracoxib 100 mg twice daily; P ⫽ 0.002 for diclofenac 75 mg twice daily). The mean score at week 4 was 2.7 for all active treatments except lumiracoxib 100 mg twice daily (mean score 3.0). Overall, the effects of the various dosages of lumiracoxib on all WOMAC scores at week 4 were similar. Health Assessment Questionnaire. Signiﬁcant differences in the HAQ score were observed for the lumiracoxib 50 mg twice daily (mean score 0.8; P ⫽ 0.007), lumiracoxib 200 mg twice daily (mean score 0.8; P ⫽ 0.008), lumiracoxib 400 mg once daily (mean score 0.7; P ⫽ 0.009), and diclofenac 75 mg twice daily (mean score 0.7; P ⫽ 0.001) groups compared with placebo (mean score 1.0) after 4 weeks of treatment. Although the HAQ score for the 100 mg twice daily group improved over the course of the study, at week 4 the comparison with placebo was not Table 3. WOMAC subscale scores at baseline and week 4* WOMAC pain, mean ⴞ SD WOMAC physical function, mean ⴞ SD WOMAC stiffness, mean ⴞ SD Treatment group No. Baseline No. Week 4 No. Baseline No. Week 4 No. Baseline No. Week 4 Lumiracoxib 50 mg bid Lumiracoxib 100 mg bid Lumiracoxib 200 mg bid Lumiracoxib 400 mg qd Diclofenac 75 mg bid Placebo 96 95 96 97 94 95 9.8 ⫾ 3.6 9.6 ⫾ 3.0 9.6 ⫾ 3.7 9.5 ⫾ 3.3 9.5 ⫾ 3.4 9.6 ⫾ 3.5 95 94 92 97 92 93 6.4 ⫾ 4.1 6.8 ⫾ 3.9 6.4 ⫾ 4.0 5.7 ⫾ 3.9 6.2 ⫾ 4.0 8.1 ⫾ 3.6 96 94 95 98 93 95 31.8 ⫾ 12.1 31.1 ⫾ 11.3 31.5 ⫾ 11.8 32.0 ⫾ 11.2 31.1 ⫾ 12.6 32.7 ⫾ 10.4 96 93 91 97 90 94 21.5 ⫾ 13.7 23.2 ⫾ 13.0 20.8 ⫾ 14.1 19.0 ⫾ 12.8 20.0 ⫾ 13.2 27.3 ⫾ 12.7 96 94 92 98 91 92 4.4 ⫾ 1.6 4.3 ⫾ 1.6 4.2 ⫾ 1.6 4.3 ⫾ 1.7 4.0 ⫾ 1.5 4.2 ⫾ 1.5 96 94 92 98 91 93 2.7 ⫾ 1.7 3.0 ⫾ 1.8 2.7 ⫾ 1.8 2.7 ⫾ 1.9 2.7 ⫾ 1.8 3.5 ⫾ 1.8 * WOMAC ⫽ Western Ontario and McMaster Universities Osteoarthritis Index; bid ⫽ twice daily; qd ⫽ once daily. 554 Schnitzer et al Table 4. Most frequent adverse events (>5% for any group)* Adverse event Gastrointestinal disorders Abdominal pain† Diarrhea Nausea Constipation Dyspepsia Abdominal distension Cardiac disorders Edema‡ Nervous system disorders Headache Dizziness (excluding vertigo) Fatigue Infections and infestations Nasopharyngitis Lumiracoxib 50 mg bid n ⴝ 98 no. (%) Lumiracoxib 100 mg bid n ⴝ 96 no. (%) Lumiracoxib 200 mg bid n ⴝ 99 no. (%) Lumiracoxib 400 mg qd n ⴝ 99 no. (%) Diclofenac 75 mg bid n ⴝ 94 no. (%) Placebo n ⴝ 97 no. (%) 4 (4.1) 8 (8.2) 4 (4.1) 5 (5.1) 6 (6.1) 3 (3.1) 6 (6.3) 2 (2.1) 8 (8.3) 3 (3.1) 4 (4.2) 3 (3.1) 7 (7.1) 6 (6.1) 4 (4.0) 1 (1.0) 3 (3.0) 2 (2.0) 6 (6.1) 10 (10.1) 1 (1.0) 5 (5.1) 2 (2.0) 0 (0.0) 14 (14.9) 10 (10.6) 10 (10.6) 6 (6.4) 6 (6.4) 5 (5.3) 6 (6.2) 4 (4.1) 1 (1.0) 2 (2.1) 2 (2.1) 2 (2.1) 5 (5.1) 11 (11.5) 8 (8.1) 8 (8.1) 5 (5.3) 4 (4.1) 4 (4.1) 2 (2.0) 7 (7.3) 4 (4.2) 5 (5.1) 5 (5.1) 2 (2.0) 2 (2.0) 5 (5.3) 1 (1.1) 9 (9.3) 1 (1.0) 0 (0.0) 5 (5.2) 2 (2.0) 1 (1.0) 2 (2.1) 1 (1.0) 1 (1.0) 3 (3.1) 3 (3.0) 3 (3.0) 5 (5.3) 2 (2.1) * bid ⫽ twice daily; qd ⫽ once daily; excl. ⫽ excluding. † With one exception, which occurred in the placebo group, this includes upper abdominal pain only. ‡ Although not always speciﬁed, it can be assumed that all patients had peripheral/lower limb edema. signiﬁcant (mean score 0.9; P ⫽ 0.177). No statistically signiﬁcant differences were seen either between the different lumiracoxib treatment groups or between any lumiracoxib dosage and diclofenac. Safety and tolerability. The majority of AEs reported were mild to moderate in intensity in all treatment groups. The incidence of any AE (i.e., including mild to severe, treatment related, and nontreatment related) was similar across the 4 lumiracoxib dosage groups and the placebo group (Table 4). No dosage-related trend was observed in the incidence of AEs overall, or in moderate to severe AEs. The most frequently reported treatment-related AEs across all treatment groups (including placebo and diclofenac) were diarrhea, nausea, dyspepsia, and edema. The proportion of patients experiencing at least 1 GI-related AE was markedly higher among patients treated with diclofenac 75 mg twice daily (41.5%) compared with placebo (17.5%) and each lumiracoxib group (23.2–26.5%). Moreover, the incidence of moderate to severe GI AEs was greater in patients treated with diclofenac 75 mg twice daily than with all lumiracoxib groups combined (for diclofenac, lumiracoxib all doses, and placebo, respectively: abdominal pain, 9%, 2%, and 3%; nausea, 5%, 1%, and 1%; dyspepsia, 3%, 2%, and 1%). Edema was generally mild in degree and reported with an incidence ranging from 4.1% in the placebo group to 11.5% in the group receiving lumiracoxib 100 mg twice daily. Moderate to severe edema was reported in 4% of patients receiving diclofenac 75 mg twice daily, in 1% of those receiving lumiracoxib (all dosages), and in none of the patients who received placebo. There was no evidence of dosage-dependent edema in the lumiracoxib groups and no moderate to severe edema was seen at the highest doses. No SAEs were reported in any of the active treatment groups. One SAE was reported for a patient randomized to placebo. In general, notable abnormal laboratory test results did not follow any clinically relevant pattern in any treatment group. Discontinuations due to AEs were similar among each of the lumiracoxib treatment groups and placebo. However, there were more discontinuations due to AEs in the diclofenac 75 mg twice daily group (14%) than in the placebo (4%) and lumiracoxib (3–5%) groups. DISCUSSION The results presented here demonstrate the efﬁcacy of the novel COX-2–selective inhibitor lumiracoxib in relieving the signs and symptoms of OA. Four dosages of lumiracoxib (50 mg twice daily, 100 mg twice daily, 200 mg twice daily, and 400 mg once daily) were tested to establish the minimum effective dosage regimen for the treatment of OA. In terms of overall joint pain intensity, all dosages of lumiracoxib afforded signiﬁcantly greater pain relief than placebo over 4 weeks of treatment. Throughout the study, all dosages of lumiracoxib were equally effective in lowering pain intensity, although at week 1 there was a modestly greater improvement in pain relief with the 400 mg once daily lumiracoxib dose when compared with the 50 and 100 mg twice daily doses. All secondary efﬁcacy endpoints supported these observations. Each of the WOMAC subscales demonstrated signiﬁcant differences at week 4 between each of the active agents and placebo. Similarly, changes in patient and physician global assessment of disease activity, as well as the HAQ score, showed consistent signiﬁcant differences between all active arms and placebo. No consistent signiﬁcant differences in these endpoints were observed between the different lumiracoxib dosages. Lumiracoxib Versus Diclofenac in Osteoarthritis A comparison of a once-daily versus a twice-daily dosing regimen of lumiracoxib was speciﬁcally undertaken in this study. No signiﬁcant differences in efﬁcacy measures were seen between the lumiracoxib 400 mg once-daily and 200 mg twice-daily dosing regimens, and both were comparable in terms of efﬁcacy to the maximum therapeutic dosage of diclofenac used in this study. These data support the once-daily dosing option with lumiracoxib, which has important implications for convenience and compliance with therapy. This is particularly important among elderly patients who often ﬁnd multiple daily dosing regimens difﬁcult to adhere to or complex (39,40). The sustained efﬁcacy of lumiracoxib in relieving pain over 24 hours stands in distinction to the pharmacokinetic proﬁle of this drug, as lumiracoxib has a relatively short plasma half-life (plasma t ⁄ of 3– 6 hours) (41). The basis for the prolonged pharmacodynamic action of lumiracoxib is unknown but may relate to the fact that it is an acidic compound, unlike the other currently available COX-2 inhibitors. Acidic NSAIDs are known to be retained over time at higher concentrations in synovial ﬂuid compared with plasma (42). Diclofenac, an acidic dual-inhibitor NSAID, has been shown by several investigators to have a longer half-life in synovial ﬂuid than in plasma in patients with synovial effusions (43– 47) and the efﬁcacy of diclofenac administered twice daily has been shown to be more consistent with its pharmacokinetic proﬁle in synovial ﬂuid rather than in plasma (48). Similarly, data demonstrate that the synovial ﬂuid half-life of lumiracoxib is prolonged compared with its plasma half-life (49,50). Thus, regardless of its relatively short plasma half-life, lumiracoxib administered once daily has been shown in this study to provide excellent sustained pain relief, comparable to one of the current standard therapies for OA. The short plasma half-life coupled with once-daily dosing may also prove beneﬁcial in reducing some exposurerelated side effects, but this requires evaluation in further studies speciﬁcally focused on this issue. In this study, the overall number of AEs was small in all treatment groups, but discontinuations were primarily related to AEs associated with the GI system. There was no evidence of a relationship between lumiracoxib dosage and the frequency of AEs. Gastrointestinal AEs occurred more frequently in the diclofenac 75 mg twice daily group than in any lumiracoxib group or the placebo group. Speciﬁcally, the incidence of GI AEs was markedly lower in patients treated with lumiracoxib than in those who received diclofenac 75 mg twice daily, indicating that lumiracoxib is signiﬁcantly better tolerated in the GI system. These results are consistent with previous reports of the low rate of GI adverse effects with other COX-2–selective inhibitors (15,19,20,25,26,28,51). Differences in the rates of other AEs between patients treated with lumiracoxib and either placebo or diclofenac were not marked. The study was too small and not designed to detect clinically meaningful differences in most safety endpoints. In summary, over the 4-week period of this study, lumiracoxib provided effective relief from the symptoms of OA (pain and stiffness), improved overall physical function, and was well tolerated. All dosage regimens of lumiracoxib were signiﬁcantly more effective than placebo and 12 555 comparable to diclofenac in relieving the signs and symptoms of OA. Lumiracoxib had a tolerability proﬁle comparable to that of placebo and superior GI tolerability, even at the highest dosage studied, compared with the nonselective NSAID diclofenac (75 mg twice daily), while providing similar efﬁcacy. 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Ann Rheum Dis 2002;61 Suppl 1:128 Abstract THU0233. 50. Scott G, Rordorf C, Reynolds C, Kalbag J, Looby M, Milosav- Lumiracoxib Versus Diclofenac in Osteoarthritis ljev S, et al. Pharmacokinetics of lumiracoxib in plasma and synovial ﬂuid. Pharmacokinet 2004;43:467–78. 51. McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol 2001;30: 11– 8. APPENDIX A: INVESTIGATORS In Belgium: Dr. P. Geusens (Diepenbeek); Dr. M. Malaise (Liege); Dr. F. Raeman (Merksem); and Dr. W. Verdickt (Turnhout). In Denmark: Dr. T. Aaboe (Copenhagen NV); Dr. J. Beier (Odense C); Dr. H. Bliddak (Frederiksberg); Dr. E. Gustavsen (Aarhus C); and Dr. H. H. Ibfelt (Hilleroed). In Hungary: Dr. G. Genti (Kistarcsa); Dr. G. Poór (Budapest); Dr. F. Szanyo (Gyor); and Dr. L. Tamasi (Miskolc). In Germany: Dr. H. Grobecker (Regensburg); Dr. A. Rump (Freiburg); Dr. E. Schell (Nuernberg); Dr. H. Schneider 557 (Messkirch); and Dr. H. U. Wilhelm (Stuttgart). In Switzerland: Dr. A. Aeschlimann (Zurzach); Dr. F. Hasler (Chur); Dr. P. Hasler (Basel); Dr. T. Lehmann (Bern); and Dr. R. Theiler (Aarau). In the UK: Dr. G. Charlwood (Kent); Dr. J. Fraser (Wigan); Dr. J. Miller (Cheshire); Dr. S. Patel (County Durham); Dr. J. Robinson (Liverpool); Dr. M. Salman (Oxfordshire); and Dr. B. Silvert (Bolton). In the US: Dr. G. Botstein (Suwanee, GA); Dr. J. Cush (Dallas, TX); Dr. J. Ervin (Kansas City, MO); Dr. K. Fye (San Francisco, CA); Dr. M. Greenwald (Rancho Mirage, CA); Dr. E. Hurd (Dallas, TX); Dr. S. Krumholz (West Palm Beach, FL); Dr. K. Lucas (Atlanta, GA); Dr. W. Palmer (Omaha, NE); Dr. J. Perkins (Boulder, CO); Dr. J. Rosen (Coral Gables, FL); Dr. C. Saadeh (Amarillo, TX); Dr. M. Sack (Austin, TX); Dr. T. Schnitzer (Chicago, IL); Dr. L. Taber (Phoenix, AZ); Dr. A. Weaver (Lincoln, NE); Dr. R. Williams (Augusta, GA); and Dr. D. Yocum (Tucson, AZ).