Efficacy and safety of etodolac and naproxen in patients with osteoarthritis of the knee: a double-blind, placebo-controlled study

CLINICAL THERAPEUTICS%‘OL.

17, NO. 4, 1995

Efficacy and Safety of Etodolac and Naproxen in Patients with Osteoarthritis of the Knee: A Double-Blind, Placebo-Controlled Study Robin Dore, MD,’ Ian Ballard, MD,2 Ginger Constantine, MD,2 and Patricia McDonald, MBA2 ‘Private Practice, Anaheim, Philadelphia, Pennsylvania

California, and 2Wyeth-Ayerst Laboratories,

ABSTRACT A multicenter, parallel-group, doubleblind, randomized, outpatient study compared the efficacy and safety of etodolac versus naproxen in patients with osteoarthritis of the knee. After a washout period free of nonsteroidal anti-inflammatory drugs, 254 patients self-administered etodolac 400 mg (n = 86), naproxen 500 mg (n = 82) or placebo (n = 86) twice daily for 4 weeks. Compliance exceeded 90% in all three groups. Primary efficacy variables improved progressively from baseline in all three groups. The extent of improvement was greater in the etodolac and naproxen groups than in the placebo group (P IO.O03), except with respect to target joint tenderness (P = 0.028, etodolac vs placebo; P = 0.013, naproxen vs placebo). There were no statistical differences between active treatment groups (P > 0.1). At end point, twice as many pa-

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tients responded in the etodolac (59%) and naproxen groups (5 1%) than in the placebo group (26%; P I 0.01). There were no significant between-group differences in the numbers of patients who had an adverse experience, a serious adverse experience, or an adverse experience leading to study discontinuation; there were also no significant between-group differences in the distribution of adverse experiences. There were no unexpected clinical or laboratory experiences. Etodolac 400 mg twice daily was as effective and safe as naproxen 500 mg twice daily and both were superior to placebo in the management of osteoarthritis of the knee.

INTRODUCTION Osteoarthritis (OA) is the most common joint disease. I,* It is a leading cause of disability in the elderly and may affect 85% of adults who are between 75 and 79

0149-2918/95/$3.50

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years of age.’ The exact pathogenesis is unknown, and there are no specific laboratory findings. The diagnosis is based on clinical and radiologic findings.‘** OA is not curable. The goal of drug treatment is symptomatic relief. u Nonsteroidal antiinflammatory drugs (NSAIDs) are widely prescribed because of their efficacy and safety profiles in this treatment setting. In this study of etodolac, naproxen was chosen as the control drug because its efficacy and safety have been previously elucidated.3 Although naproxen and etodolac have been shown to be equally effective and well tolerated in small studiesM of patients with OA, pharmacologic differences exist between the two drugs. Etodolac is a pyranocarboxylic acid derivative, whereas naproxen is a propionic derivative. The elimination half-life of etodolac is shorter than that of naproxen.’ Finally, the results of preclinical and endoscopic studiesa-” in humans indicate that etodolac has less gastrointestinal toxicity than naproxen. Therefore, a large clinical study was designed and implemented to evaluate the relative efficacy and safety of the two NSAIDs compared with placebo in patients with OA of the knee. PATIENTS AND METHODS Patient Selection

Outpatient men and women 40 years of age or older were eligible if they had symptomatic, radiologically confirmed OA of the knee that required NSAID treatment. Patients were excluded if they had a connective tissue disorder; were scheduled for joint replacement within 1 year; had a history of gastrointestinal bleeding, renal or hepatic impairment, drug-induced skin

disorder, or any other illness likely to interfere with the evaluation or disposition of the study drug; had a contraindication to NSAIDs; or had recent corticosteroid, investigational, anticoagulant, or cytoprotective therapy. In addition, women who were pregnant, breast-feeding, or of childbearing potential and not using birth control were ineligible. The protocol and the informed consent form were reviewed and approved by institutional review boards. All patients were informed about the nature of the study before they signed the informed consent form. Study Protocol

This was a multicenter, parallel-group, double-blind, randomized, outpatient study. The protocol included a screening visit (visit l), a washout period, a baseline evaluation (visit 2), and follow-up evaluations at 2 and 4 weeks after starting the study drug (visits 3 and 4). Previous arthritis medications were discontinued at the screening visit. Long-acting NSAIDs were stopped for at least 7 days; others were stopped for at least five half-lives of the arthritis medication. Patients had to have active disease after the washout period as defined by the following primary efficacy variables: overall assessment of condition by both the patient and investigator had to be fair or poor; joint tenderness and walking pain had to be assessed as moderate to very severe. Secondary efficacy variables studied included inactivity stiffness, nighttime pain, and quality of sleep. If both knees were affected, the most severely affected was chosen as the target joint. Patients were randomized to receive identical-appearing capsules containing 657

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etodolac 200 mg, naproxen 250 mg, or placebo (each provided by Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania). Patients were instructed to take two capsules twice daily at 8 AM and 8 PM with 6 ounces of water. If a patient experienced an adverse gastrointestinal event or had difficulty maintaining this schedule, the study drug could be taken with morning and evening meals. Concomitant NSAIDs (except for maintenance of low-dose aspirin or an occasional non-anti-inflammatory analgesic for nonarthritic pain), corticosteroids, salicylate-containing topical preparations, and new or altered physiotherapy were prohibited. Maintenance of low-dose aspirin (maximum of 325 mg/d) as antithrombosis prophylaxis and occasional use of non-antiinflammatory analgesics for nonarthritic pain were permitted. Patients returned for efficacy, safety, and compliance evaluations after 2 and 4 weeks of treatment. Compliance was determined by use of a capsule count. Safety was determined by recording study events and vital signs. A study event was defined as any negative event that a patient experienced during the study, including adverse events, treatment-emergent signs and symptoms, and new intercurrent illnesses.

Statistical Analysis All statistical tests were two tailed with an overall alpha level of 0.05. Pairwise comparisons were Bonferroni adjusted for multiple comparisons with a significance level of 0.017. Baseline patient comparability by treatment group was tested by use of a one-way analysis of variance (ANOVA) for parametric variables and Pearson’s chi-square statistic for nonparametric variables.

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For all analyses, baseline was defined as the last assessment before starting the study drug; end point was defined as the assessment at week 4 or, for patients who discontinued the study prematurely, the last assessment. Five-point scales were used to assess overall condition (1 = poor; 2 = fair; 3 = good; 4 = very good; 5 = excellent) and other efficacy variables (0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe). Efficacy analyses were performed on mean values at baseline and on mean changes from baseline at weeks 2 and 4. For each efficacy variable, the oneway ANOVA model was used to evaluate between-group differences, including terms for center and treatment groups. The model was also tested for the effect of covariates by use of an analysis of covariante. Interaction terms that were not significant were removed from the model. ANOVA assumptions were tested using the Kolmogorov D statistic as a test of normality and Levene’s test for homogeneity of variance. None of these assumptions were met, so an analysis of rank-transformed data was used. Analyses were performed for the percentages of patients in each response category at each evaluation period. To analyze response at end point, a responder was defined as a patient who had a good or better physician’s and patient’s overall assessment, who had mild or no joint tenderness and walking pain, and who did not discontinue medication prematurely because of a drug-related adverse event. The Cochran-Mantel-Haenszel test was used to determine between-group differences and pairwise comparisons. For the safety analysis, Fisher’s exact test was used to test between-group differences in the incidences of adverse events. For the laboratory analyses, de-

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Table I. Baseline patient demographics

Variable Mean age (y) Mean body weight (lb) Sex (%) Male Female Race (%) White Black Hispanic Other Premature discontinuation (%) Adverse experience Insufficient therapeutic effect Patient noncompliance Admission criteria violation Other

and reasons for premature Etodolac (n = 86)

Naproxen (n = 82)

Placebo (n = 86)

63.8 191

63.7 194

63.6 193

34 (40) 52 (60)

30 (37) 52 (63)

30 (35) 56 (65)

76 (88) 6 (7) 3 (3) l(1) 20 (23) 11 (13) 4 (5) 3 (3) l(1) 1 (I)

72 (88)

77 (90)

7 (9) 2 (2) l(1) 15 (18)

6 3 0 35

scriptive statistics were calculated at each visit for change from baseline. Laboratory abnormalities were defined according to predetermined limits of clinically significant changes. The Pearson’s chisquare test was used to test between-group differences in laboratory abnormalities; when groups were not similar, Fisher’s exact test was used to perform pairwise comparisons.

RESULTS Patients A total of 254 11 centers (Table icant differences among the three

discontinuation.

patients were enrolled at I). There were no signifin demographic features treatment groups. The

7 (9) 4 (5) 0 (0) 3 (4) l(1)

(7) (3) (0) (41)

8 (9) 22 (26) l(1) 4 (4) 0 (0)

mean age was 63.7 years; most patients were women (63%) and white (89%). Four fifths of patients took at least one nonNSAID concomitant medication during the study for nonarthritic problems. Acetaminophen was used by 12% of patients in the etodolac group, 16% in the naproxen group, and 22% in the placebo group. Corresponding percentages of low-dose aspirin for antithrombosis prophylaxis were 5%, lo%, and 13%, respectively. More than 90% of patients in each group were compliant at weeks 2 and 4; there were no significant between-group differences in compliance. Approximately twice as many patients prematurely discontinued placebo compared with etodolac and naproxen (Table I). The most common reason for discontinuing etodolac or naproxen

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Table II. Treatment

effects on primary efficacy variables. P

Mean Change from Baseline (%) Etodolac

Etodolac

VS

vs

vs

Naproxen

Placebo

Placebo

0.4 (26) 0.5 (35)

0.608 0.835

0.002 0.000

0.000 0.000

1.o (70) 1.3 (94)

0.3 (25) 0.5 (32)

0.872 0.878

0.001 0.000

0.001 0.000

Joint tenderness+ Week 2 -0.9 (-39) Week 4 -1.1 (-49)

-1 .o (-43) -1.3 (-51)

-0.6 (-24) -0.8 (-35)

0.347 0.763

0.020 0.028

0.002 0.013

Walking pain+ Week 2 Week 4

-1 .o (-39) -1.4 (-53)

-0.5 (-19) -0.6 (-22)

0.585 0.420

0.003 0.001

0.001 0.000

Etodolac (n = 86)

Naproxen (n = 82)

Placebo (n = 86)

Physicians’ overall assessment* Week 2 0.9 (55) Week 4 1.2 (70)

1.0 (62) 1.3 (86)

Patients’ overall assessment* Week 2 0.9 (61) Week 4 1.2 (75)

-0.9 (-35) -1.1 (-47)

Naproxen

*An increase indicates improvement (1 = poor; 2 = fair; 3 = good; 4 = very good; 5 = excellent). +A decrease indicates improvement (0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe).

was adverse events, whereas the most common reason for stopping placebo was insufficient therapeutic effect.

At baseline, the three treatment groups had similar physicians’ overall assessment scores, which improved progressively (Table II). Pairwise comparisons revealed that the extent of improvement was greater in the etodolac and naproxen groups than in the placebo group (P IO.O02), and there were no significant differences between the two active treatment groups (P 2 0.608).

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Patients’ assessment scores were consistent with physicians’ scores. The extent of improvement in patients’ assessment scores was greater in the etodolac and naproxen groups than in the placebo group (P I 0.001) and similar in the two active treatment groups (P 2 0.872). Likewise, improvement in the other two primary efficacy variables, joint tenderness and walking pain, was similar in the two active treatment groups (P 2 0.347). When physicians’ overall assessment scores were categorized, all patients had poor or fair conditions at baseline. After 2 weeks of treatment, 25% of patients in the etodolac group and 26% in the naproxen

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80

Etodolac

Naproxen

Placebo

Treatment Group Figure.

Response rates at end point in patients with osteoarthritis randomized to receive a 4-week course of etodolac, naproxen, or placebo. No differences existed between active treatment groups. *Pc 0.001, etodolac versus placebo; +P< 0.01, naproxen versus placebo.

group had very good or excellent conditions, compared with only 3% of patients in the placebo group (Pc 0.000, etodolac vs placebo; P = 0.001, naproxen vs placebo; P > 0.1, etodolac vs naproxen). Corresponding rates after 4 weeks were 37% for the etodolac group, 40% for the naproxen group, and 10% for the placebo group (P= 0.001, etodolac vs placebo and naproxen vs placebo; P > 0.1, etodolac vs naproxen). Similar findings were observed for the other three primary efficacy variables, except that the between-group differences in severity of joint tenderness that were observed at week 2 (P = 0.01, etodolac vs placebo; P c 0.05, naproxen vs placebo); were no longer significant at week 4 (P= 0.127 and P = 0.191, respectively).

Responders were defined as patients who had good-to-excellent overall assessments by physicians and patients and moderate to no joint tenderness and walking pain. Response rates at end point were twice as high in the etodolac and naproxen groups compared with the placebo group (P< 0.001, etodolac vs placebo; P < 0.01, naproxen vs placebo), and there were no significant differences between the two active treatment groups (figure). There were no between-group differences in secondary efficacy variables at baseline. Pairwise comparisons of inactivity stiffness scores revealed that etodolac, naproxen, or both were associated with greater mean decreases from baseline scores (indicating improvement)

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Table III. Adverse experiences, including those not related to treatment, occurring in >5% of patients. No. of Patients (%)

Any adverse experience* Digestive system disturbances Dyspepsiat Flatulence Constipation Whole-body disturbances Headache Respiratory system disturbances Nervous system disturbances Urogenital system disturbances

Etodolac (n = 86)

Naproxen (n = 82)

Placebo (n = 86)

48 (56) 29 (34) 15 (17) 5 (6) 2 (2) 13 (15) 7 (8) 6 (7) 4 (5) 6 (7)

50 (61) 20 (24) 9 (11) 1 (1) 7 (9) 22 (27) 6 (7) 8 (10) 6 (7) 6 (7)

42 (49) 15 (17) 9 (10) 0 (0) 1 (1) 19 (22) 11 (13) 3 (3) 5 (6) 2 (2)

"Some patients had more than one adverse experience. *Dyspepsiaincluded gastric distress, heartburn, reflux, epigastric discomfort, indigestion, esophageal reflux, and gastrointestinal upset.

than placebo at week 2 (etodolac, -0.8; naproxen, --0.9; placebo, -0.2; P < 0.001, etodolac vs placebo; P < 0.001, naproxen vs placebo) and week 4 (etodolac, -1.0; naproxen, -1.2; placebo, -0.4; P < 0.001, naproxen vs placebo); there were no differences between the two active treatment groups. Mean nighttime pain scores decreased in all three groups, resulting in a significant overall treatment effect at week 2 (etodolac, -0.9; naproxen, -0.8; placebo, -0.3; P < 0.05) but not at week 4 (etodolac, -0.9; naproxen, -0.9; placebo, -0.6). Nighttime pain scores were lower in the naproxen group than in the placebo group at week 2 (P < 0.01); otherwise there were no between-group differences in this secondary variable. When patients were asked about the quality of sleep, slightly less than half in 662

each treatment group slept well the week before baseline. In the etodolac, naproxen, and placebo groups, respectively, the percentages increased to 71%, 71%, and 59% at week 2 and to 75%, 77%, and 62% at week 4; however, there was neither an overall treatment effect nor were there any significant between-group differences.

Safely All patients were evaluated for adverse experiences. The numbers of patients who had adverse experiences (Table III) and who discontinued treatment because of them (Table I) were similar in the three treatment groups. The most common type of adverse experience was digestive system disturbance, usually manifested by

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dyspepsia, flatulence, or constipation. The next most common was whole-body disturbance such as headache. There were no statistically significant between-group differences in the distribution of adverse experiences. Most adverse experiences were mild to moderate in severity. Only two were severe: one case of treatment-related dyspepsia in the etodolac group and one case of chest pain in the placebo group. Of 26 patients who discontinued treatment because of adverse experiences, 6 had adverse experiences that were not related to treatment (etodolac, 2; naproxen, 1; placebo, 3). Discontinuation for treatmentrelated reasons occurred in 9 etodolactreated patients, in 6 naproxen-treated patients, and 5 placebo-treated patients. Two patients experienced gastrointestinal bleeding (1 in the naproxen group and 1 in the placebo group). Mean changes from baseline in laboratory variables were minimal at weeks 2 and 4 in all treatment groups and comparable between treatments. No significant between-treatment differences were observed in the incidence of laboratory abnormalities (P c 0.05). Only two laboratory abnormalities were classified as adverse experiences by the investigator; both occurred in the placebo group. No clinically relevant findings were observed for the vital-sign evaluation or the physical examination.

DISCUSSION In this study, both etodolac 400 mg twice daily and naproxen 500 mg twice daily were equally effective and both were superior to placebo in the management of symptomatic OA of the knee. Efficacy variables improved progressively over the

4-week treatment period. Between-group differences in primary efficacy variables were significant at 2 weeks and remained significant at the second evaluation at 4 weeks. Comparable findings were observed for secondary efficacy variables, but between-group differences were not always significant. Etodolac has compared favorably with other NSAIDs based on physicians’ and patients’ overall assessments in doubleblind studies of patients with OA of the knee. The reference NSAIDs used were diclofenac, indomethacin, and piroxi~am.‘~-” The dose of etodolac was an important distinction between our study and previous studies. In European or South American studies,4d the daily dose of etodolac was 600 mg. Consistent with prescribing trends in the United States, a higher dose was administered in this study. When the 800-mg dose was used in a recent double-blind comparison,18 etodolac was superior to nabumetone in patient and physician overall assessment. Patients with OA of the knee were randomized to receive etodolac 400 mg twice daily, nabumetone 1500 mg once daily, or placebo for 4 weeks. Interestingly, etodolac had a more rapid onset of action and had significantly higher physicians’ and patients’ overall assessments at end point. Both etodolac and naproxen were well tolerated in our study. There were no statistically significant between-group differences in the numbers of patients who had an adverse experience, serious adverse experience, or adverse experience leading to study discontinuation. As with most NSAID studies,19 the single most common adverse experience was dyspepsia. However, neither this nor the distribution of any other type of adverse experience was statistically significant; dyspepsia was not

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predictive of more serious gastrointestinal events as there were only two episodes of gastrointestinal bleeding, one each in the naproxen and placebo groups. The results of preclinical studies and endoscopy studies suggest that etodolac may be less likely to cause gastrointestinal bleeding than naproxen. A blinded clinical study was conducted to assess gastrointestinal microbleeding using Vrlabeled erythrocytes. Etodolac 800 mg was associated with one twelfth as much fecal blood loss as naproxen 750 mg (P < O.O5).*OIn addition, endoscopic scores in volunteers after taking etodolac 600 or 1000 mg/d were similar to those of patients taking placebo and better than those of patients taking naproxen 1000 mg/d.9 Between-group differences were confirmed in a 4-week, double-blind studylo in which etodolac 600 mg/d did not cause any single erosions, whereas naproxen 1000 mg/d was associated with frank ulceration and multiple erosions in seven patients (P < 0.05). Interestingly, only one of these patients complained of gastrointestinal symptoms, which underscores the dichotomy between serious gastrointestinal experiences such as ulceration and symptoms such as dyspepsia. NSAID-specific gastrointestinal effects have been attributed to differences in NSAID effects on prostaglandin production. Naproxen 1000 mg/d, but not etodolac 600 mg/d, suppressed gastric prostaglandin E,, duodenal prostaglandin E,, and prostaglandin I, in a 4-week study.” As observed previously,” naproxen induced more endoscopic and histologic abnormalities than etodolac (P c 0.05). Unfortunately, however, there was no correlation between prostaglandin values and the degree of endoscopic damage within individuals.”

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A 4-week, prospective, randomized, double-blind comparison*’ of etodolac, naproxen, and placebo in healthy volunteers demonstrated that endoscopically observed gastric injury associated with 1 month of 400 mg twice-daily etodolac use was comparable to that seen with placebo use and significantly less than the gastric damage associated with 500 mg twicedaily naproxen use. *l The clinical significance of these findings is unclear; more research is needed to determine the mechanism of NSAID-induced gastrointestinal bleeding. Twice-daily dosing is more desirable than dosing four times daily because it is more convenient and may have implications for patient compliance. Not surprisingly, compliance was excellent in this study. Capsule counts confirmed that more than 90% of patients in all three treatment groups were compliant. The ability of twice-daily etodolac to provide efficacy comparable to that of twice-daily naproxen is interesting in view of differences between their pharmacokinetic profiles. The elimination half-life of naproxen is 13 hours, which is clearly consistent with twice-daily dosing.7 In contrast, etodolac has a 7.3-hour half-life.8 Nonetheless, etodolac usually has been administered twice daily in comparative studies of patients with 0A.4-6*‘s There has been no evidence that naproxen or any other NSAID was superior to twice-daily etodolac in previous studies4-6,‘2,‘3,‘5,L7*22 or in our study.

CONCLUSION Etodolac 400 mg twice daily is as effective as naproxen 500 mg twice daily and both are superior to placebo in the management of symptomatic OA of the knee.

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Both regimens are well tolerated and associated with excellent patient compliance. ACKNOWLEDGMENTS This study was supported by a research grant from Wyeth-Aye& Laboratories, Philadelphia, Pennsylvania. We thank the following investigators for enrolling patients: Scott W. Baumgartner, MD, Spokane, Washington; Jane Box, MD, and Patrick Box, MD, Charlotte, North Carolina; Richard A.H. Jimenez, MD, Edmonds, Washington; Alastair C. Kennedy, MD, Vero Beach, Florida; Richard L. Lautzenheizer, MD, Indianapolis, Indiana; Howard W. Marker, MD, Memphis, Tennessee; Raymond Scheetz, Jr., MD, Cleveland, Ohio; James Wild, MD, San Antonio, Texas; and George T. Young, MD, Boulder, Colorado. We also thank Clinical Trials Research. Inc. Address correspondence to: Robin Dore, MD, 1120 West La Palma, Suite 7, Anaheim, CA 9280 1. REFERENCES Boh LE. Osteoarthritis. In: DiPiro JT, Talbert RL, Hayes PE, et al, eds. Pharmucotherapy. A Pathophysiologic Approach. 2nd ed. Norwalk, Conn: Appleton & Lange; 1993:133&1342. Brandt KD, Kovalov-St. John K. Osteoarthritis. In: Wilson JD, Braunwald E, Isselbacher KJ, et al, eds. Harrison’s Principles of Internal Medicine. 12th ed. New York: McGraw-Hill; 1991:1475-1479. Todd PA, Clissold cacy-a reappraisal

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