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Original Research ORIGINAL RESEARCH Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis ALAN KIVITZ, MD; GLENN EISEN, MD; WILLIAM W. ZHAO, PHD; TERRY BEVIRT, BS, MT (ASCP); AND DAVID P. R ECKER, MD Duncansville, Pennsylvania; Nashville, Tennessee; and Skokie, Illinois KEY POINTS FOR CLINICIANS groups, but not in the 20-mg valdecoxib group. All 3 valdecoxib doses were comparable to placebo in ■ The cyclooxygenase-2–specific inhibitor valde- coxib 10 or 20 mg once daily is as effective as ulcer incidence. naproxen 500 mg twice daily. ■ CONCLUSIONS Valdecoxib (10 and 20 mg once daily) is significantly superior to placebo and as ■ Valdecoxib at the recommended dose for treat- ment of osteoarthritis (10 mg once daily) had effective as naproxen (500 mg twice daily) in better upper gastrointestinal safety than improving moderate to severe osteoarthritis of the naproxen. knee. Upper gastrointestinal tract safety of valdecox- ib (5 and 10 mg) was comparable to that of placebo ■ OBJECTIVE We compared the efficacy and and significantly better than that of naproxen. upper gastrointestinal safety of the cyclooxygenase- ■ KEY WORDS Cyclooxygenase-2–specific 2–specific inhibitor valdecoxib with naproxen and inhibitors; osteoarthritis; nonsteroidal anti-inflamma- placebo in treating moderate to severe osteoarthritis tory drug; prostaglandin-endoperoxide synthase. (J of the knee. Fam Pract 2002; 51:530–537) ■ STUDY DESIGN This multicenter, random- ized, double-blind, placebo-controlled study com- urrent medical therapies for osteoarthritis pared the efficacy and upper gastrointestinal tract Cinclude conventional nonsteroidal anti-inflam- safety of valdecoxib at dosages of 5, 10, and 20 mg matory drugs (NSAIDs), acetaminophen, glu- once daily with placebo and naproxen at the dosage cosamine sulfate, and intra-artic- ■ of 500 mg twice daily. ular injections of corticosteroids see COMMENTARY ■ POPULATION We included patients who and hyaluronic acid. However, about this article by had been diagnosed with moderate to severe long-term use of corticosteroid Allen F. Shaughnessy, osteoarthritis of the knee according to the modified injections can exacerbate dam- PharmD criteria of the American College of Rheumatology. age to the affected joints.1,2 “Right ballpark, wrong base: ■ OUTCOMES MEASURED The Patient’s Conventional NSAIDs are asso- Assessing safety of NSAIDs” and Physician’s Global Assessment of Arthritis ciated with upper gastrointesti- ON PAGE 538 (PaGAA, PhGAA), Patient’s Assessment of Arthritis nal tract ulceration and inhibi- Pain–Visual Analog Scale (PAAP-VAS), and tion of platelet function.3 Western Ontario and McMaster’s Universities Cyclooxygenase-2 (COX- (WOMAC) Osteoarthritis indices were assessed at 2)–specific inhibitors have demonstrated equivalent baseline and at weeks 2, 6, and 12. Upper gas- efficacy to conventional NSAIDs in treating pain and trointestinal ulceration was assessed by pre- and inflammation associated with osteoarthritis and posttreatment endoscopies. rheumatoid arthritis. Further, COX-2–specific ■ RESULTS Valdecoxib 10 and 20 mg once daily From the Altoona Center for Clinical Research, Duncansville, PA (but not 5 mg once daily) demonstrated similar effi- (A.K.); the Department of Medicine, Vanderbilt University Medical cacy to naproxen at 500 mg twice daily, and all 3 Center, Nashville, TN (G.E.); and the Pharmacia Corporation, Skokie, dosages were superior to placebo for the PaGAA, IL (W.W.Z., T.B., D.R.). This work was sponsored by Pharmacia Corporation and Pfizer, Inc. Terry Bevirt, David P. Recker, and PhGAA, PAAP-VAS, and WOMAC Osteoarthritis Kenneth M. Verburg are employees of Pharmacia Corporation and indices at most assessments throughout the 12-week have stock interest within the company. Alan Kivitz has acted in study (P < .05). The incidence of endoscopically capacity of consultant for Pharmacia Corporation. Address reprint requests to David P. Recker, MD, Clinical Research and proven ulcers was significantly higher in the naprox- Development, Pharmacia Corporation, 5200 Old Orchard Road, en group than in the 5- and 10-mg valdecoxib Skokie, IL 60077. E-mail: [email protected]. 530 ■ The Journal of Family Practice • JUNE 2002 • VOL. 51, NO. 6 VALDECOXIB VS NAPROXEN FOR OSTEOARTHRITIS FIGURE 1 Patient’s global assessment of arthritis 4.2 3.8 Placebo (n = 205) Valdecoxib 5 mg QD (n = 201) 3.4 Valdecoxib 10 mg QD (n = 205) Mean Score 3.0 Valdecoxib 20 mg QD (n = 201) Naproxen 500 mg BID (n = 204) 2.6 0 02 6 12 Weeks *Placebo significantly different from all treatments except valdecoxib 5 mg; P < .05. Scale score = 1 (very good) to 5 (very poor). inhibitors significantly reduce the incidence of gas- ular cartilage on the Index Knee also were excluded. trointestinal ulceration and bleeding side effects Patients were not eligible if they had active gastroin- caused by conventional NSAIDs.4,5 Valdecoxib testinal disease, gastrointestinal tract ulceration 30 (Bextra; Pharmacia Corporation and Pfizer days before the trial, a significant bleeding disorder, Corporation) is a novel COX-2–specific inhibitor that or a history of gastric or duodenal surgery. Patients is approximately 28,000-fold more selective against with an esophageal, gastric, pyloric channel, or duo- COX-2 than against COX-1. As a potent COX-2–spe- denal ulcer or a score of at least 10 for esophageal, cific inhibitor, valdecoxib is expected to provide effi- gastric, or duodenal erosions at the pretreatment cacy equivalent to conventional NSAIDs for treat- endoscopy examination also were excluded. ment of arthritis and spare the COX-1–related side effects. This randomized, placebo-controlled, dou- Study design ble-blind, 12-week study was designed to test this This multicenter, randomized, double-blind, place- hypothesis by comparing the efficacy and upper gas- bo-controlled study compared the efficacy and trointestinal tract safety of valdecoxib with that of upper gastrointestinal tract safety of valdecoxib at naproxen, a leading conventional NSAID comparator. dosages of 5, 10, and 20 mg once daily with place- bo and naproxen at a dosage of 500 mg twice daily METHODS in relieving moderate to severe osteoarthritis of the Study population knee. The trial was conducted in 85 centers in the Ambulatory adults who had been diagnosed with United States and Canada, in accordance with the moderate to severe osteoarthritis of the knee accord- principles of good clinical practice and the ing to the modified criteria of the American College Declaration of Helsinki. Eligible patients were ran- of Rheumatology6,7 were eligible to participate in the domized to treatment groups and self-administered trial. Patients were recruited from primary care and oral study medication. Patients were randomized to rheumatology specialty settings. Patients who had study treatment in the order in which they were baseline scores of at least 40 mm on the Patient’s enrolled into the study by using a treatment Assessment of Arthritis Pain–Visual Analog Scale sequence that was determined by a Searle-prepared (PAAP-VAS) and baseline categorical scores of poor computer-generated randomization schedule. to very poor on the Patient’s (PaGAA) and Patients received their allocated study medications in Physician’s (PhGAA) Global Assessments of Arthritis bottles labeled A and B according to the randomiza- were included.8,9 Any patient suffering from inflam- tion schedule. Personnel at the study centers carried matory arthritis, gout, pseudogout, Paget disease, or out the assessments and remained blinded through- any chronic pain syndrome that might interfere with out the study. Eligible patients were enrolled and assessment of the Index Knee was excluded from discontinued regular pain medication. Patients dis- the trial. Patients diagnosed with osteoarthritis of the continued their normal medications at the following hip ipsilateral to the Index Knee, severe anserine specified times before the baseline endoscopy: bursitis, acute joint trauma, or complete loss of artic- NSAIDs (including full-dose aspirin at a dosage of The Journal of Family Practice • JUNE 2002 • VOL. 51, NO. 6 ■ 531 VALDECOXIB VS NAPROXEN FOR OSTEOARTHRITIS ≥325 mg/day) at 48 hours, corticosteroid injections at enced symptoms suggestive of an ulcer. The endo- 4 weeks, and intra-articular injections of corticos- scopists performing baseline and 12-week (early teroid or hyaluronic acid preparations at 3 and 6 termination) assessments remained blinded months, respectively. The use of antiulcer drugs, throughout the study. including H2 blockers, proton pump inhibitors, misoprostol, and sucralfate, was discontinued at least General safety assessments 24 hours before the baseline endoscopy. Clinical laboratory tests were performed at screening, baseline, weeks 2, 6, and 12, or at early termination, Efficacy assessments and a complete physical examination was performed The following arthritis assessments were made at at screening and final visits. The incidence of adverse baseline and at 2, 6, and 12 weeks or at early ter- events occurring in each treatment arm was moni- mination after study drug administration. PaGAA or tored throughout the study. Adverse events occurring PhGAA was measured on a 5-point categorical within 7 days and serious adverse events occurring scale, where 1 = very good, 2 = good, 3 = fair, within 30 days of the last study dosage of medication 4 = poor, and 5 = very poor. The PAAP-VAS was were included in the safety analyses. measured
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