Double-blind comparison of etodolac sustained-release tablets and diclofenac sustained-release tablets in patients with rheumatoid arthritis

CURRENT THERAPEUTIC RESEARCH VOL. 53, NO. 2, FEBRUARY 1993

DOUBLE-BLIND COMPARISON OF ETODOLAC SUSTAINED-RELEASE TABLETS AND DICLOFENAC SUSTAINED-RELEASE TABLETS IN PATIENTS WITH RHEUMATOID ARTHRITIS A n I n t e r i m Report F. PORZIO 1 AND M. SCHATTENKIRCHNER 2 lOspedale S. Camillo, Div. di Reumatologia, Rome, Italy, and 2Rheuma-Einheit der Li~dwig-Maximilians Universit~tt, Munich, Germany

ABSTRACT E t o d o l a c SR is the new sustained-release f o r m u l a t i o n of etodolac, a w e l l - e s t a b l i s h e d n o n s t e r o i d a l a n t i - i n f l a m m a t o r y d r u g used in t h e t r e a t m e n t of a r t h r i t i c conditions. This double-blind, r a n d o m i z e d , para l l e l - g r o u p s t u d y was conducted in G e r m a n y and I t a l y to c o m p a r e the efficacy a n d safety of etodolac SR 600 m g and diclofenac S R 100 mg in p a t i e n t s with active r h e u m a t o i d a r t h r i t i s (RA). The p a t i e n t s met at least five o f the A m e r i c a n R h e u m a t i s m A s s o c i a t i o n diagnostic c r i t e r i a a n d were w i t h i n S t e i n b r o k e r progression stage I, II, or I I I a n d funct i o n a l class I, II, or I I I . Active RA was c o n f i r m e d by at l e a s t t h r e e of t h e following f o u r criteria: six or more t e n d e r or p a i n f u l j o i n t s on m o t i o n , t h r e e o r more swollen j o i n t s , m o r n i n g stiffness d u r a t i o n of 45 m i n u t e s or more, and a W e s t e r g r e n e r y t h r o c y t e s e d i m e n t a t i o n r a t e of 28 m m / h r or longer. I n this i n t e r i m report, 50 p a t i e n t s were r a n d o m l y assigned to receive etodolac SR and 41 p a t i e n t s received diclofenac SR. M e a n age was 58 y e a r s (range, 18 to 74 y e a r s ) in t h e etodolac SR group a n d 55 y e a r s (range, 26 to 73 years) in t h e diclofenac group. A t baseline, no differences in t h e d e m o g r a p h i c c h a r a c t e r i s t i c s were observed between groups. The results showed no s t a t i s t i c a l l y s i g n i f i c a n t differences between groups for a n y efficacy assessment. S t a t i s t i c a l l y sign i f i c a n t i m p r o v e m e n t s from baseline at t h e final o n - t h e r a p y visit were observed w i t h i n each t r e a t m e n t group in the p a t i e n t and p h y s i c i a n overall a s s e s s m e n t s o f the p a t i e n t ' s condition, t h e n u m b e r o f p a i n f u l j o i n t s , a n d the n u m b e r of swollen joints. I n addition, p a i n i n t e n s i t y , d u r a t i o n o f m o r n i n g stiffness, average grip strength, t i m e to w a l k 15 meters, a n d a r t i c u l a r index were all s i g n i f i c a n t l y improved. Two pat i e n t s were w i t h d r a w n from the study because o f adverse events, one p a t i e n t in t h e e t o d o l a c SR group because of gastric i n t o l e r a n c e and one in t h e d i c l o f e n a c SR group because of epigastric p o s t p r a n d i a l pain. T h e r e were no c l i n i c a l l y s i g n i f i c a n t changes from baseline in vital signs, l a b o r a t o r y values, or u r i n a l y s i s . The results o f this study i n d i c a t e t h a t both etodolac SR 600 mg and diclofenac SR 100 m g once daily a r e effective and safe for the t r e a t m e n t of RA. Both drugs were well Address correspondenceto: M. Schattenkirchner, RheumatologyUnit, Ludwig-MaximilliansUniversit~it, Munich, Germany. Received for publication on October 13, 1992. Printed in the U.S.A. Reproduction in whole or part is not permitted. 144

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F. PORZIO AND M. SCHATTENKIRCHNER

tolerated. The new sustained-release formulation of etodolac appears to have good efficacy and tolerability while offering the practical advantage of once-daily dosing. INTRODUCTION

Etodolac SR is the new sustained-released formulation of etodolac, a wellestablished nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of arthritic diseases. 1-9 This new formulation of etodolac was developed to provide once-daily administration, which should improve compliance. Etodolac SR in doses of 400 mg and 600 mg once daily is bioequivalent to the conventional formulation of etodolac in doses of 200 mg and 300 mg twice daily, respectively. 1° Etodolac SR is rapidly absorbed and has a short elimination half-life from plasma (6 to 8 hours), which is comparable, as expected, to that of the conventional formulation. 1° Consistent with sustained-release behavior, etodolac SR has a lower m a x i m u m concentration (Cmax) and a longer time to Cmax (Tmax) compared with the conventional formulation. In patients with rheumatoid arthritis (RA), the conventional formulation of etodolac compares favorably with naproxen 11'12 and piroxic a m . 13'14 It also has an excellent safety profile. 5'6'8'15'16 Microbleeding and endoscopic studies have indicated that etodolac m a y cause significantly less gastrointestinal (GI) injury than naproxen, ibuprofen, or indomethacin. 17 The good efficacy and safety of the new sustained-release formulation of etodolac have recently been documented in patients with osteoarthritis (OA) of the knee; etodolac SR 600 mg given once daily for 4 weeks was shown to compare favorably with diclofenac SR 100 mg once daily, is Another recent comparative study 19 with piroxicam (20 mg once a day) showed that etodolac SR is also effective and safe in the treatment of patients with active RA. In a 52-week study in 158 patients with RA or OA, etodolac SR appeared to be as safe and effective as the conventional formulation for long-term maintenance of the therapeutic effect (personal communication from A. Calin, Wyeth-Ayerst, Philadelphia, Pennsylvania, October 1992). Etodolac SR 600 to 1200 mg once daily, compared with naproxen 500 mg twice daily was also reported to be particularly safe for the GI tract in a microbleeding study in healthy volunteers. 2° Diclofenac is a widely used NSAID for the treatment of patients with RA or OA. The present study was designed to compare the efficacy and safety of recommended daily doses of etodolac SR (600 mg once daily) and diclofenac SR (100 mg once daily) for the relief of RA symptoms. P A T I E N T S AND METHODS

This double-blind, randomized, parallel-group study was performed in It145

ETODOLACVERSUSDICLOFENAC

aly and Germany. Arthritic patients were eligible for the study if they exhibited at least five of the American Rheumatism Association (ARA) diagnostic criteria 21 and were within Steinbrocker progression (anatomic) stages I, II, or III and in functional class I, II, or III. Patients at Steinbrocker progression stage IV (ie, cartilage and bone destruction) or functional class IV (ie, largely or wholly incapacitated), or those who met any of the ARA exclusion criteria were not included in the study. Active RA was confirmed by at least three of the following four criteria: six or more tender or painful joints on motion, three or more swollen joints, morning stiffness duration of 45 minutes or more, and a Westergren erythrocyte sedimentation rate (ESR) of 28 mm/hr or longer. Several joint signs and symptoms, such as morning stiffness, pain on motion or tenderness, swelling in at least one joint, and symmetrical joint swelling involvement, had to be present continuously for at least 6 weeks. Patients had to have a history of positive therapeutic response to one or more NSAIDs, including aspirin. Those hypersensitive to NSAIDs, including aspirin, or who had never received NSAIDs for the treatment of RA were excluded from the study. Active peptic ulcer, history of GI ulcer or hemorrhagia, serious symptomatic diseases, or neurologic or psychologic disorders were all exclusion criteria. Women who were pregnant or nursing were not eligible. Patients receiving NSAID therapy underwent a washout period of up to 2 weeks. At the end of this period, a worsening in at least two of the criteria for active RA was required for inclusion. During the washout period and the first 7 days of the study, up to 500 mg of paracetamol four times daily was allowed. Each patient provided written informed consent. Patients received either etodolac SR 600 mg once daily or diclofenac SR 100 mg once daily after the evening meal for 4 weeks. Efficacy and safety assessments were performed after 2 and 4 weeks of treatment. Primary efficacy assessments were the patient and physician overall assessments of the patient's condition, the number of painful or tender joints, and the number of swollen joints. The overall assessments were rated on a five-point categoric scale from 1 (very good) to 5 (very poor). The number of painful or tender and swollen joints was assessed on 69 peripheral joints (34 on each side plus the cervical spine) and 66 joints, respectively. S e c o n d a r y e f f i c a c y a s s e s s m e n t s i n c l u d e d t h e p a t i e n t ' s selfassessments of pain intensity and duration of morning stiffness and the physician's assessments of ARA functional class, average grip strength, time to walk 15 meters, articular index, and ESR. Pain intensity was rated on a five-point categoric scale from 1 (none) to 5 (very severe). The articular index was calculated as the sum of the scores for pain or tenderness and swelling using a four-point categoric scale from 1 (mild) to 4 (very s e v e r e ) . 22

A complete physical examination, hematology and blood chemistry 146

F. PORZIO AND M. SCHATTENKIRCHNER

analysis, and urinalysis were performed at the screening and final visits. Body weight, temperature, sitting blood pressure, heart rate, and adverse events were recorded at all visits.

Statistical Analysis The effectiveness of the randomization for the two treatment groups was tested at baseline using an analysis of variance for continuous variables and the Cochran-Mantel-Haenszel test for categoric variables. Within each t r e a t m e n t group, changes from baseline for all continuous variables except the duration of morning stiffness were tested using the paired t test. Differences between groups with respect to changes from baseline were determined using an analysis of variance that included the effects of treatment, center, and their interaction. Categoric variables and the duration of morning stiffness were analyzed using the Wilcoxon signrank test for within-group changes and the nonparametric CochranMantel-Haenszel test for changes from baseline between groups. P r i m a r y analysis was based on the final on-therapy assessment. The level of statistical significance was 0.05 for all comparisons. RESULTS

Data from 91 patients were available for this interim analysis. Fifty patients received etodolac SR and 41 received diclofenac SR. The difference in the number of patients in each treatment group can be explained by the fact that eight centers recruited patients for the study. At the time of this interim analysis, the recruitment rate at each site into each t r e a t m e n t group differed slightly. The demographic characteristics of the patients are reported in Table I. The mean -+ SD age was 58 +- 13 years (range, 18 to 74 years) in the etodolac group and 55 +- 11 years (range, 26 to 73 years) in the diclofenac group. Sixteen (32%) patients receiving etodolac and six (15%) patients treated with diclofenac were 65 years of age or older. No significant differences between the two treatment groups were observed in the distribution of sex, age, height, or weight at screening. The mean values of the primary efficacy parameters at baseline and at the last visit and the changes from baseline are reported in Table II. At baseline, no statistically significant differences between the two t r e a t m e n t groups were observed for the efficacy assessments. Improvements from baseline at the last visit were observed in all primary efficacy assessments. There were no statistically significant differences between groups. At the last visit, improvement rates (percentage better) in the patient and physician overall assessments were 60% and 58%, respectively, in the etodolac group and 61% and 59%, respectively, in the diclofenac group. 147

ETODOLAC VERSUS DICLOFENAC

Table I. Demographic characteristics. Etodolac SR (n = 50) Sex Male Female Age (yr) Mean -+ SD Range Height (cm) Mean -+ SD Range Weight (k+g) Mean _ SD Range

8 42

16% 84%

58 -+ 13" 18-74

Diclofenac SR (n = 41) 7 34

17% 83%

55 +- 11 26-73

161 -+ 8 148-180

163 -+ 9 149-183

66 -+ 14 40-107

64 +- 11 46-90

*n =49.

The m e a n values of the secondary efficacy parameters at baseline and at the last visit and the changes from baseline for the two t r e a t m e n t groups are reported in Table III. Each group showed statistically significant improvements from baseline in pain intensity, duration of morning stiffness, average grip strength, time to walk 15 meters, and articular index. There were no significant differences between groups for changes from baseline at the last visit. With regard to tolerability, only one patient in each t r e a t m e n t group reported adverse events, and both patients were withdrawn from the study. The reason for the discontinuation was gastric intolerance for the patient in the etodolac SR group and epigastric postprandial pain for the patient in the diclofenac SR group. In addition, four (8%) patients in the etodolac SR group were withdrawn from the study because of an unsatisfactory response after 14 to 26 days of treatment. Patient's request was the reason t h a t two further patients in each group discontinued the treatment. Both t r e a t m e n t groups showed small changes from baseline in vital signs and clinical laboratory values, but none were clinically significant. No significant changes occurred in the urinalysis findings. DISCUSSION

In this study, the efficacy of the new sustained-release formulation of etodolac was confirmed by the significant improvements in the signs and symptoms of RA as assessed by both the patients and the physicians. At the last visit, significant improvements were observed in all four primary efficacy parameters, including the patient's overall assessment of his or her condition, possibly the most sensitive variable overall in NSAID trials in RA. 22 Significant improvements in pain intensity, duration of morning 148

2.9 0.8 29.8 16.4

3.6 0.7

35.4 15.3

24.8 13.3

No. of swollen joints Mean SD 9.8* 13.9

5.6* 10.0

0.7* 0.9

0.9* 1.0

Change from Baseline

24.7 13.2 (n = 39)

34.1 14.9 (n = 39)

3.5 0.6

3.6 0.7

Baseline

* Based on a five-point scale: 1 = very good, 2 = good, 3 = fair, 4 = poor, 5 = very poor. * P < 0.001, from paired t test or Wilcoxon sign-rank test for changes from baseline within groups.

15.0 10.6

2.8 0.8

3.7 0.7

Baseline

Patient overall assessment* Mean SD Physician overall assessment* Mean SD No. of painful/ tender joints Mean SD

Primary Assessments

Last Visit

Etodolac SR (n = 50)

15.6 12.8 (n = 39)

27.9 14.9 (n = 39)

2.8 0.6

2.7 0.6

Last Visit

Diclofenac SR (n = 41)

9.2* 12.3 (n = 39)

6.2* 5.4 (n = 39)

0.8* 0.7

0.8

0.9*

Change from Baseline

Table II. Effect of etodolac SR and diclofenac SR on the four primary efficacy assessments in patients with rheumatoid arthritis.

0.64

0.82

0.88

0.77

Difference Between Groups (P value)

2.2 0.4 103.1 91.5 21.7 9.9 65.9 41.1

2,2 0.4 92.2 89.4 23,7 10.7 102.4 54.1 34.0§ 22.5 (n = 33)

78.5 96.4

120.4 73.9

36.4$ 24.4 (n = 38)

2.8 0.8

3.6 0.8

Baseline

3.0 10.7 (n = 27)

36.5* 44.6

2.0* 4.3

-10.9" 21.8

0.0 0.2

41.9* 71.4

0.8* 0.9

Change from Baseline

44.3:~ 23.6 (n = 29)

102.8 59.5 (n = 39)

21.4 9.8

88.2 67.2

2.0 0.6

121.0 76.3

3.7 0.7

Baseline

44.3§ 28.2 (n = 26)

61.7 44.6 (n = 39)

19.4 8.2

99.8 72.5

2.0 0,5

61.2 57.8

2.7 0.7

Last Visit

- 1,9 17.9 (n = 24)

41.1 * 35.6 (n = 39)

2 .or 3.4

-11.6* 16.8

0.1 0.3

59.8* 70.3

1.0" 0.9

Change from Baseline

Diclofenac SR (n = 41)

ARA = American Rheumatism Association; ESR = erythrocyte sedimentation rate. * P < 0,001, JP = 0,002, from paired t test or Wilcoxon sign-rank test for changes from baseline within groups, :~ screening. § week 4.

Mean SD

Patient assessments Pain intensity Mean SD Duration of morning stiffness (rain) Mean SD Physician assessments ARA functional class Mean SD Average grip strength (mmHg) Mean SD Time to walk 15 m (sec) Mean SD Articular index Mean SD ESR (mm/hr)

Secondary Assessments

Last Visit

Etodolac SR (n = 50)

Table III. Effect of etodolac SR and diclofenac SR on the secondary efficacy assessments in patients with rheumatoid arthritis.

0.70

0.67

0.95

0.85

0.19

0.80

0.36

Difference between Groups (P value)

F. P O R Z I O A N D M. S C H A T T E N K I R C H N E R

stiffness, average grip strength, time to walk 15 meters, and the articular index also confirmed the efficacy of etodolac SR. No significant differences were observed in the efficacy assessments when compared with the results from patients treated with diclofenac SR, a widely used NSAID for the treatment of RA or OA. Thus these results, as expected from the already well-documented clinical effectiveness of the conventional formulation of etodolac in RA, confirmed the recently demonstrated efficacy of the new sustained-release formulation of etodolac in patients with arthritic disorders.iS, 19,23 Only two patients, one in each group, reported adverse events. Both events were related to GI complaints and both patients were withdrawn from the study. Gastrointestinal symptoms and upper GI injuries are well known to be among the most frequent consequences of NSAID treatment. Nevertheless, several studies s'15'17'24-29 with the conventional formulation of etodolac and recent results with etodolac SR have demonstrated the particularly good tolerance of etodolac in the GI tract. In a recent microbleeding study 2° with healthy volunteers, etodolac SR in doses of 600 to 1200 mg once daily was shown to cause significantly less GI blood loss t h a n naproxen 500 mg twice daily. The GI tolerance of etodolac m a y result from a selective sparing of cytoprotective prostaglandins by etodolac in the human digestive tract. 3°-32 In conclusion, the results of this study indicate that etodolac SR 600 mg once daily and diclofenac SR 100 mg once daily are effective and safe for the treatment of RA. Both drugs were well tolerated. The new sustained-release formulation of etodolac appears to have good efficacy and tolerability while offering the practical advantage of once-daily dosing.

Acknawledgment This study was supported in part by Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania. References: 1. Bacon PA. An overview of the efficacy of etodolac in arthritic disorders. EurJRheumatol Inflamm 1990; 10:22-34. 2. Ciocci A. Efficacy and tolerabitity of etodolac therapy in the treatment of osteoarthritis. Curr Med Res Opin 1989; 11:471-475. 3. De Figueiredo JG, Paulsen GA, Baigun S, de Freitas GG. Efficacy and safety comparison of etodolac with piroxicam in the treatment of patients with osteoarthritis of the knee. Curr Med Res Opin 1991; 12:401-412. 4. De Freitas GG. A double-blind comparison of etodolac and piroxicam in the treatment of osteoarthritis. Curr Med Res Opin 1990; 12:255-262. 5. Jacob G, Sanda M, Mullane J, et al. Long-term evaluation of the efficacy and safety of etodolac in the treatment of rheumatoid arthritis. Adv Ther 1985; 2:82-95. 6. Karbowski A. A global safety evaluation of etodolac. Clin Rheumatol 1989; 8(Suppl 1):73-79. 151

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