Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritisResults of a multicenter randomized double-blind placebo-controlled trial.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 50, No. 2, February 2004, pp 353–363 DOI 10.1002/art.20019 © 2004, American College of Rheumatology Once-Weekly Administration of 50 mg Etanercept in Patients With Active Rheumatoid Arthritis Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Edward C. Keystone,1 Michael H. Schiff,2 Joel M. Kremer,3 Shelly Kafka,4 Michael Lovy,5 Todd DeVries,6 and Daniel J. Burge6 cept twice weekly, and by 19% of the patients in the placebo group (P < 0.0001 for each etanercept group versus placebo). Similarly, achievement of the ACR50 response was attained by 18% of patients in each of the 2 etanercept groups, compared with 6% of patients in the placebo group (P < 0.03 for each comparison). Pharmacokinetics of the 2 etanercept regimens were similar at steady state. No clinically significant differences in efficacy or safety were observed between the 2 etanercept groups. Conclusion. Safety, efficacy, and pharmacokinetics were comparable between the 2 etanercept dosing regimens. Thus, comparable clinical outcomes are to be expected when patients are treated with etanercept administered either as 50 mg once weekly or as 25 mg twice weekly. Objective. To evaluate the safety, efficacy, and pharmacokinetics of 50 mg etanercept administered subcutaneously once weekly in adult patients with active rheumatoid arthritis (RA). Methods. Four hundred twenty RA patients were randomized to receive, in a blinded manner, the study drug for up to 16 weeks: 214 patients received 50 mg etanercept once weekly, 153 received 25 mg etanercept twice weekly, and 53 received placebo for 8 weeks followed by 25 mg etanercept twice weekly for 8 weeks. Efficacy and safety were assessed at weeks 8 and 16. Pharmacokinetic analyses were performed on serum samples from patients at selected study sites. The primary efficacy end point was achievement of the American College of Rheumatology (ACR) 20% improvement criteria (ACR20 response) at week 8. Results. An ACR20 response was achieved at week 8 by 50% of the patients receiving 50 mg etanercept once weekly, by 49% of the patients receiving 25 mg etaner- Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays an important role in inflammatory disorders such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Etanercept (Enbrel; Immunex Wyeth Research, Seattle, WA) is a soluble receptor TNF antagonist that competitively inhibits the interaction of TNF with cell-surface receptors, preventing TNFmediated cellular responses and modulating the activity of other proinflammatory cytokines and processes that are regulated by TNF. The safety and efficacy of etanercept in patients with RA and PsA have been demonstrated in randomized clinical trials (1–6). In these trials, the only adverse event seen significantly more frequently in etanercepttreated patients was injection-site reactions. Etanercept was consistently and significantly effective, as evaluated using the American College of Rheumatology (ACR) improvement response criteria (7). Clinical responses to Supported by Immunex Corporation, Seattle, Washington, a wholly owned subsidiary of Amgen Inc., Thousand Oaks, California. 1 Edward C. Keystone, MD: Mt. Sinai Hospital, Toronto, Ontario, Canada; 2Michael H. Schiff, MD: Denver Arthritis Clinic, Denver, Colorado; 3Joel M. Kremer, MD: The Center for Rheumatology, Albany, New York; 4Shelly Kafka, MD: Altoona Center for Clinical Research, Duncansville, Pennsylvania; 5Michael Lovy, MD: Radiant Research—Tacoma, Lakewood, Washington; 6Todd DeVries, PhD, Daniel J. Burge, MD: Immunex Corporation, Seattle, Washington. Drs. Keystone and Kremer have received honoraria and consulting fees from Amgen. Dr. Kafka has received honoraria from Amgen. Dr. Lovy holds Amgen stock. Address correspondence and reprint requests to Edward C. Keystone, MD, The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, The Joseph and Wolf Lebovic Building, Mount Sinai Hospital, 60 Murray Street, 2nd Floor, Toronto, Ontario M5G 1X5, Canada. E-mail: email@example.com. Submitted for publication April 8, 2003; accepted in revised form October 1, 2003. 353 354 KEYSTONE ET AL etanercept were rapid, generally measurable within 2 weeks after initiation of therapy, and nearly always occurring within 3 months of treatment initiation. Based on the results of these trials, etanercept was approved for reducing signs and symptoms in patients with moderately to severely active RA and PsA and for inhibiting the progression of structural damage in patients with RA. Etanercept can be used in combination with methotrexate (MTX) and has been administered as a twice-weekly 25-mg subcutaneous injection to the majority of patients. The pharmacokinetics of subcutaneously administered etanercept at 25 mg twice weekly have been characterized in healthy volunteers and in patients with RA. Subcutaneously administered etanercept is slowly absorbed and has a half-life in excess of 4 days (8,9). A comprehensive retrospective analysis of pharmacokinetic data from previous studies was performed using nonlinear mixed-effects modeling. The modeling predicted that steady-state serum concentrations of etanercept should be similar at dosing regimens of 50 mg once weekly and 25 mg twice weekly (10–12). Because projected serum levels of etanercept at 50 mg once weekly were very similar to those observed in patients treated with etanercept at 25 mg twice weekly, it was anticipated that both efficacy and safety would also be comparable. Therefore, it was hypothesized that etanercept 50 mg once weekly would be superior in efficacy to placebo and would be comparable with a twice-weekly 25-mg etanercept dosing regimen. Once-weekly dosing would substantially improve the convenience of use for patients with inflammatory arthritis who self-administer etanercept subcutaneously. Thus, this study was designed to confirm the efficacy and safety of 50 mg etanercept administered once weekly, and to evaluate the pharmacokinetic predictions. PATIENTS AND METHODS Patients. Patients were eligible for the study if, prior to first administration of the study drug, they were at least 18 years of age, met the ACR (formerly, the American Rheumatism Association) 1987 criteria for RA (13), and had active RA as defined by the presence of ⱖ6 tender joints and ⱖ6 swollen joints. Patients were excluded if they had received etanercept or antibodies to TNF previously, cyclophosphamide within 6 months of the first dose of the study drug, investigational agents within 4 weeks of the screening visit, or intraarticular corticosteroids within 2 weeks of the first dose of the study drug. Patients were also excluded from the study if they had serious infections or other significant concurrent medical conditions. Disease-modifying antirheumatic drugs other than MTX must have been discontinued at least 28 days prior to initiation of the study drug. Patients were allowed to receive concomitant MTX (ⱕ25 mg/week), corticosteroids (ⱕ10 mg/ day prednisone or its equivalent), and nonsteroidal antiinflammatory drugs (NSAIDs), provided that the doses were stable prior to the first dose of study drug (1 month for MTX; 2 weeks for corticosteroids and NSAIDs) and maintained at stable doses throughout the study. Study drug. The masked study drug was supplied to patients in syringes that contained the contents of 1 vial of etanercept (25 mg etanercept, mannitol, sucrose, and tromethamine) or placebo (the same constituents but without etanercept), reconstituted with bacteriostatic water. Study design. This 16-week, double-blind, placebocontrolled trial was conducted at 41 sites in the US and 7 sites in Canada. The institutional review boards of all participating medical centers approved the protocol, and all patients gave their written informed consent before any study-related procedures were performed. Randomization was stratified by MTX usage at baseline, and patients were randomized on the basis of a 1:4:3 allocation to receive placebo, etanercept 50 mg once weekly, or etanercept 25 mg twice weekly, respectively. After 8 weeks of treatment, patients in the placebo group began receiving etanercept 25 mg twice weekly in a blinded manner. The unbalanced design was selected to allow the maximum number of patients to receive the active drug rather than the placebo. By enrolling more patients in the active drug groups as compared with the placebo group, we increased the power for the noninferiority comparison of etanercept 50 mg once weekly and 25 mg twice weekly. To maintain blinding, all patients self-administered the injections twice each week, as outlined in Table 1. Patients were instructed to rotate injection sites among the thighs, abdomen, and upper arms. Efficacy evaluation. The primary analysis compared etanercept 50 mg once weekly with placebo with regard to the proportion of patients who met the ACR20 improvement response criteria at week 8. A secondary objective of the study was to evaluate the comparative efficacy of 50 mg etanercept given once weekly and 25 mg etanercept given twice weekly with respect to the ACR20 response after 8 weeks of treatment, as assessed by a noninferiority analysis. Supplemental analyses compared the efficacy of the 2 etanercept dosing regimens by using, in addition to the ACR20 response, the ACR50 and ACR70 improvement responses, and by assessing the percentage change from baseline in individual measures of disease activity. The ACR response criteria (7) and duration of morning stiffness were evaluated at baseline and at weeks 8 and 16. Individual components of the ACR response criteria included the tender joint count (71 joints assessed), swollen joint count (68 joints assessed), patient’s assessment of pain (10-cm visual analog scale), patient and physician global assessments of disease activity (Likert scales of 0–10), patient assessment of physical function (Health Assessment Questionnaire Disability Index, scale 0–3 ), and C-reactive protein (CRP) levels. Pharmacokinetics evaluation. Blood samples for pharmacokinetic analyses were collected from patients at designated study sites (those sites most experienced in performing pharmacokinetic sampling) during week 1 (baseline and days 2, 3, 4, and 7) and week 8 (days 49, 50, 52, 54, and 56). Exact ONCE-WEEKLY ADMINISTRATION OF 50 MG ETANERCEPT Table 1. 355 Study drug dosing schedule* Treatment group Dose 1 (2 injections) Dose 2 (1 injection) Placebo† Etanercept 50 mg qw Etanercept 25 mg biw Placebo; placebo 25 mg etanercept; 25 mg etanercept 25 mg etanercept; placebo Placebo Placebo 25 mg etanercept * Study drug was administered on a Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday schedule. qw ⫽ once weekly; biw ⫽ twice weekly. † Patients received in a blinded manner placebo for 8 weeks followed by etanercept 25 mg biw for the remaining 8 weeks of the treatment period. dosing and sampling times were noted and used in the analyses. Serum etanercept concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) with a limit of quantitation of 0.3 g/liter. Noncompartmental analyses were conducted using WinNonlin Professional software, version 4.0 (Pharsight, Mountain View, CA). Safety evaluation. All patients who received at least 1 dose of study drug were evaluated for safety of the treatment. Safety assessments at weeks 8 and 16 included premature discontinuations from the study and treatment-emergent adverse events. Standard laboratory tests at baseline and week 16 were conducted at a central laboratory and included hematologic evaluations (complete blood cell counts with differential and platelet counts), serum chemistry (levels of blood urea nitrogen, creatinine, alanine transaminase, aspartate transaminase, total protein, and albumin), and urinalysis profiles. Sera were analyzed for the presence of antibodies to etanercept by ELISA (1), and antibody-positive samples were tested for neutralizing antibodies. Statistical analysis. All patients who received at least 1 dose of study drug were included in the analyses of efficacy and safety. All statistical tests were 2-sided, and P values of less than 0.05 were considered to denote significant differences in efficacy. Patients who discontinued treatment prematurely were considered nonresponders at all time points subsequent to withdrawal, so that binary end points could be analyzed. A last observation carried forward approach was used to account for missing postbaseline data, so that continuous end points could be analyzed. In accordance with the study protocol, the noninferiority of 50 mg etanercept once weekly compared with 25 mg etanercept twice weekly could be claimed if at least 50% of the benefit of 25 mg etanercept twice weekly, compared with placebo, was preserved with 50 mg etanercept at week 8. The basis for the noninferiority assessment was the lower 1-sided 95% confidence interval (95% CI) for the difference between 50 mg etanercept once weekly and 25 mg etanercept twice weekly, which represents a lower boundary for the difference. A criterion for evaluating the noninferiority of the 2 etanercept treatment groups at week 16 was not specified in the protocol because no placebo group was used. Comparisons of demographics, disease history, and measures of disease activity at baseline were performed using a chi-square test for categorical data and analysis of variance for continuous data. Pairwise analyses of ACR responses were conducted using the Cochran-Mantel-Haenszel test stratified by MTX usage at baseline. The Breslow-Day test was used to assess homogeneity of odds ratios across the MTX strata. With at least 200 patients in the 50 mg etanercept once weekly group and at least 50 patients in the placebo group, the study had ⬃98% power to declare 50 mg etanercept once weekly superior to placebo, assuming ACR20 responses of 55% and 25% for 50 mg etanercept and placebo, respectively. In addition, assuming a sample size of 150 patients and an ACR20 response of 55% at week 8 in the 25 mg etanercept twice weekly group, the design provided ⬃87% power to demonstrate the noninferiority of 50 mg etanercept once weekly. Individual components of the ACR response and duration of morning stiffness were analyzed as the percentage improvement from baseline, with pairwise comparisons between treatment groups performed under an analysis of variance model that considered treatment group, baseline MTX usage, and the interaction of the 2 parameters as predictors. Analysis of the ranked percentage improvement from baseline values was used for the duration of morning stiffness, which had a decidedly non-normal distribution. Adverse events and abnormal laboratory values were graded on a scale derived from the Common Toxicity Criteria of the National Cancer Institute (see http://ctep.cancer.gov/ forms/ctcv2nom-4-30-99-final3.pdf). The proportions of patients experiencing adverse events were compared between treatment groups using Fisher’s exact test. Laboratory results were compared with the central laboratory’s normal ranges. RESULTS Study population. Of the 476 patients who were screened for entry into the study, 420 were randomized to receive the study drug. All 420 patients were included in the efficacy and safety evaluations. The 3 treatment groups were well matched in demographic characteristics and disease history at baseline (Table 2), and the demographics of the patients in the pharmacokinetics substudy were similar to those of the population as a whole. Approximately half of the patients in each group were receiving concomitant MTX. Similarly, the measures of disease activity were comparable among the 3 treatment groups at baseline (Table 3). No statistically significant differences in baseline characteristics were observed among the treatment groups. Of interest, 59% 356 KEYSTONE ET AL Table 2. Demographic characteristics and disease history at baseline* Etanercept Characteristic Male, no. (%) Age, years, mean (range) Race, no. (%) White Hispanic Black Other Weight, kg, mean (range) Duration of RA, years, mean (range) Rheumatoid factor positive, no. (%) Concomitant MTX, no. (%) Mean (median) dose, mg/week Previous use of DMARDs, no. (%) Placebo (n ⫽ 53) 50 mg qw (n ⫽ 214) 25 mg biw (n ⫽ 153) 15 (28) 54 (24–90) 45 (21) 53 (21–87) 32 (21) 52 (20–84) 47 (89) 2 (4) 3 (6) 1 (2) 81 (48–170) 10.8 (0–46) 28 (54) 29 (55) 13.8 (15.0) 47 (89) 180 (84) 15 (7) 12 (6) 7 (3) 78 (38–164) 9.0 (0–51) 124 (59) 113 (53) 14.3 (15.0) 188 (88) 128 (84) 12 (8) 10 (7) 3 (2) 79 (41–174) 8.2 (0–35) 97 (64) 79 (52) 15.0 (15.0) 137 (90) * qw ⫽ once weekly; biw ⫽ twice weekly; RA ⫽ rheumatoid arthritis; MTX ⫽ methotrexate; DMARDs ⫽ disease-modifying antirheumatic drugs. of patients had a baseline CRP level within normal limits. Treatment compliance, which was monitored at the sites by review of patients’ diaries and assessment of return of used and unused syringes, was comparable among the treatment groups. Eighty percent of patients self-administered all scheduled doses of the study drug, and ⬃10% of patients in each treatment group missed just 1 dose. Overall, 95% of patients completed the first 8 weeks of treatment and 91% completed 16 weeks, with similar proportions of patients within each group completing treatment (Figure 1). Efficacy. The primary efficacy analysis compared the ACR20 response between the etanercept 50 mg once Table 3. weekly group and the placebo group after 8 weeks of treatment. Fifty percent of patients in the etanercept 50 mg once weekly group were classified as ACR20 responders compared with 19% in the placebo group (P ⱕ 0.0001). The impact of demographic characteristics, baseline disease severity, and MTX usage on the primary end point was evaluated. Subgroup analyses of sex, race, body weight, age, and components of the ACR response criteria at baseline revealed no significant treatment– subgroup variable interactions for any of these variables (P ⬎ 0.10). The proportion of patients achieving an ACR20 response among those receiving concomitant MTX were Individual measures of disease activity at baseline* Etanercept Parameter Tender joint count (range 0–71) Swollen joint count (range 0–68) Physician global assessment (scale 0 [best]–10 [worst]) Patient global assessment (scale 0 [best]–10 [worst]) Pain assessment (scale 0 [best]– 10 [worst]) HAQ Disability Index (scale 0 [best]–3 [worst]) CRP, mg/dl† Morning stiffness, minutes/day Placebo (n ⫽ 53) 50 mg qw (n ⫽ 214) 25 mg biw (n ⫽ 153) 24.6 (19.5) 19.2 (18.0) 5.9 (6.0) 26.0 (22.0) 19.2 (16.0) 6.3 (6.0) 29.2 (28.0) 19.2 (17.0) 6.3 (6.0) 6.2 (7.0) 6.0 (6.0) 6.1 (6.0) 5.3 (4.9) 5.3 (5.4) 5.7 (5.9) 1.4 (1.4) 1.4 (1.4) 1.4 (1.5) 1.4 (0.5) 245.8 (120) 1.7 (0.5) 237.8 (90) 1.9 (0.7) 252.9 (120) * Values are the mean (median). qw ⫽ once weekly; biw ⫽ twice weekly; HAQ ⫽ Health Assessment Questionnaire. † Normal range of C-reactive protein (CRP) is 0–0.79 mg/dl. ONCE-WEEKLY ADMINISTRATION OF 50 MG ETANERCEPT 357 Figure 1. Flow diagram of the study. qw ⫽ once weekly; biw ⫽ twice weekly. 17%, 49%, and 51% in the placebo, 50 mg etanercept once weekly, and 25 mg etanercept twice weekly groups, respectively; among patients not receiving concomitant MTX, these proportions achieving an ACR20 response were 21%, 51%, and 47% in the placebo, 50 mg etaner- cept once weekly, and 25 mg etanercept twice weekly groups, respectively. The Breslow-Day test, used to assess the homogeneity of responses, provided no evidence of differences between the MTX and non-MTX strata (P ⬎ 0.56). 358 KEYSTONE ET AL Table 4. ACR20, ACR50, and ACR70 responses* Etanercept Placebo† (n ⫽ 53) 50 mg qw (n ⫽ 214) 25 mg biw (n ⫽ 153) 8 16 10 (19) – 107 (50)‡ 117 (55) 75 (49)‡ 96 (63) 8 16 3 (6) – 38 (18)§ 63 (29) 28 (18)§ 50 (33) 8 16 1 (2) – 5 (2) 17 (8) 7 (5) 12 (8) Parameter ACR20 Week Week ACR50 Week Week ACR70 Week Week * Values are the number (%) of patients. P values represent pairwise comparisons with placebo using the Cochran-Mantel-Haenszel test. Patients with missing data were considered to be nonresponders. qw ⫽ once weekly; biw ⫽ twice weekly; ACR20, ACR50, and ACR70 ⫽ the American College of Rheumatology 20%, 50%, and 70% criteria for improvement, respectively. † Patients received in a blinded manner placebo for 8 weeks followed by 25 mg etanercept biw for the remaining 8 weeks of the treatment period. ‡ P ⱕ 0.0001 compared with placebo. § P ⬍ 0.03 compared with placebo. Table 4 summarizes the ACR20, ACR50, and ACR70 responses observed in the study. At week 8, the proportion of patients in the 25 mg etanercept twice weekly group who achieved an ACR20 response (49%) was nearly identical to that of the 50 mg once weekly group (50%) and significantly better than that of the placebo group (19%) (P ⱕ 0.0001). The secondary end point, in which the comparative efficacy of 50 mg etanercept once weekly and 25 mg etanercept twice weekly was assumed by a noninferiority analysis, was achieved. The observed benefit of 25 mg etanercept twice weekly compared with placebo was represented by a margin of 30 percentage points, with 50% benefit being 15 percentage points. The lower limit of the 1-sided 95% CI for the difference in treatment effect between the 2 etanercept groups was ⫺7.7 percentage points, well within the 15-percentage point limit established per protocol to indicate that the 2 dosing regimens are comparable. The proportion of patients in the placebo group who achieved an ACR50 response at 8 weeks (6%) was significantly lower than the 18% observed in the 50 mg etanercept once weekly and the 25 mg etanercept twice weekly groups (both P ⬍ 0.03 versus placebo). Results for the ACR70 response were not significantly different among the 3 treatment groups. At week 16, ACR responses in the 2 etanercept groups were similar. Fifty-five percent of patients in the etanercept 50 mg once weekly group and 63% of pa- tients in the etanercept 25 mg twice weekly group had achieved an ACR20 response (P ⫽ 0.12). The 95% CI for the difference in ACR20 response was ⫺18.2% to 2.1%. ACR50 responses were achieved by 29% and 33% of patients in the etanercept 50 mg once weekly and 25 mg twice weekly groups, respectively, and 8% of patients in each etanercept group had achieved an ACR70 response at week 16. The percentage improvement in individual components of the ACR response and in duration of morning stiffness were analyzed (Table 5). At week 8, improvements in individual measures of disease activity were significantly better in the etanercept groups compared with the placebo group, with the exception of swollen joint counts (P ⫽ 0.05 and P ⫽ 0.06 for placebo compared with the 50 mg once weekly and 25 mg twice weekly groups, respectively). Improvements in individual disease activity measures were similar in the etanercept groups at each time point. The 95% CI calculated for the differences in the mean percentage improvement between the etanercept groups included zero for all individual disease activity measures at both week 8 and week 16, indicating that the 2 etanercept dosing regimens were not significantly different (Table 5). For the CRP level to contribute to the ACR20 response, patients must have experienced at least a 20% decrease from baseline in the CRP value. The limit of quantitation for the assay was 0.4 mg/dl; thus, patients with baseline CRP values of ⬍0.5 mg/dl could not achieve a 20% response in this parameter. Approximately half of the patients in this study had baseline CRP values ⬍0.5 mg/dl, of whom 43% had levels below the limit of quantitation. We therefore performed subgroup analyses evaluating those patients whose CRP values exceeded the various thresholds (Table 6). Patients in the 2 etanercept groups whose baseline CRP levels were ⱖ0.5 mg/dl had median improvements ranging from 55% to 62% at weeks 8 and 16. Results were similar between the 2 etanercept groups when various baseline CRP restrictions were applied to the data. Thus, the relatively high number of patients with CRP values below the limit of quantification may explain why the magnitude of improvement in CRP observed in this study was lower than that observed in other studies of etanercept. Pharmacokinetics. Twenty-six patients in the etanercept 50 mg once weekly group and 18 patients in the 25 mg twice weekly group were included in the analyses of pharmacokinetics. The mean dose administration times and blood sampling times indicated good compliance with the protocol. Overall, the observed ONCE-WEEKLY ADMINISTRATION OF 50 MG ETANERCEPT 359 Table 5. Percentage improvement from baseline in individual disease activity measures* Placebo† (n ⫽ 53) 50 mg qw (n ⫽ 214) 25 mg biw (n ⫽ 153) 95% CI for difference in etanercept means percentage improvement 6.7 (26.3) – 46.4 (53.3) 57.4 (68.1) 44.3 (47.2) 58.5 (70.7) ⫺8.1, 12.5 ⫺9.6, 8.1 20.8 (17.4) – 38.0 (42.3) 48.1 (52.2) 38.0 (47.4) 47.6 (58.8) ⫺11.9, 11.5 ⫺9.9, 10.9 33.4 (44.6) 32.3 (54.5) 27.0 (41.9) 40.5 (55.2) ⫺6.7, 19.8 ⫺23.3, 6.5 15.1 (33.3) – 41.1 (50.0) 49.7 (60.0) 39.6 (50.0) 50.7 (57.1) ⫺6.6, 9.3 ⫺8.7, 6.7 0.2 (0.0) – 26.8 (33.3) 31.2 (50.0) 26.7 (33.3) 32.4 (42.9) ⫺12.4, 12.3 ⫺14.9, 11.6 ⫺7.7 (5.9) – 33.0 (26.7) 35.4 (42.9) 29.7 (25.0) 37.3 (33.3) ⫺7.3, 14.1 ⫺14.2, 10.8 ⫺41.0 (0.0) – 21.9 (5.6) 14.5 (9.3) 17.0 (0.0) 27.3 (13.6) ⫺13.8, 23.8 ⫺29.1, 4.2 ⫺23.3 (0.0) – 28.3 (66.7) 41.7 (81.7) 51.4 (77.8) 59.4 (87.5) ⫺9.7, 0.0‡ ⫺6.3, 0.0‡ Etanercept Parameter No. of tender joints Week 8 Week 16 No. of swollen joints Week 8 Week 16 Pain assessment Week 8 Week 16 Physician global assessment Week 8 Week 16 Patient global assessment Week 8 Week 16 HAQ Disability Index Week 8 Week 16 CRP Week 8 Week 16 Duration of morning stiffness Week 8 Week 16 ⫺19.3 (3.9) – * Values are the mean (median) percentage improvement from baseline. A last observation carried forward approach was used to account for missing postbaseline data. qw ⫽ once weekly; biw ⫽ twice weekly; 95% CI ⫽ 95% confidence interval; HAQ ⫽ Health Assessment Questionnaire; CRP ⫽ C-reactive protein. † Patients received in a blinded manner placebo for 8 weeks followed by 25 mg etanercept biw for the remaining 8 weeks of the treatment period. ‡ 95% CI for the difference in median percentage improvement using the Hodges-Lehmann procedure. The mean and standard deviation values were highly influenced by outliers. concentration–time profiles were consistent with those predicted by the pharmacokinetic model. The mean concentration–time profiles resulting from the 2 etaner- cept dosing regimens overlapped extensively at week 1 and week 8, which is an indication of steady state (Figure 2). Subcutaneous administration of etanercept 50 mg Table 6. Subgroup analysis of the percentage improvement in C-reactive protein (CRP) by baseline CRP values* Etanercept 50 mg qw Time point, baseline CRP in mg/dl† Week 8 All patients CRP CRP ⬍ 0.5 CRP ⱖ 0.5 CRP ⱖ 1.0 CRP ⱖ 2.0 Week 16 All patients CRP CRP ⬍ 0.5 CRP ⱖ 0.5 CRP ⱖ 1.0 at baseline CRP ⱖ 2.0 Etanercept 25 mg biw No. of patients Mean (median) No. of patients Mean (median) 213 110 103 74 55 21.9 (5.6) ⫺5.2 (0.0) 50.9 (57.6) 64.1 (73.8) 67.0 (80.5) 151 67 84 63 36 17.0 (0.0) ⫺8.1 (0.0) 37.0 (55.4) 47.7 (64.1) 56.5 (74.2) 213 110 103 74 55 14.5 (9.3) ⫺19.5 (0.0) 50.8 (58.4) 63.2 (75.2) 66.8 (82.6) 151 67 84 63 36 27.3 (13.6) ⫺3.2 (0.0) 51.6 (61.6) 63.1 (73.9) 68.8 (81.5) * Values are the mean (median) percentage improvement from baseline. qw ⫽ once weekly; biw ⫽ twice weekly. † Normal range of CRP is 0–0.79 mg/dl. 360 KEYSTONE ET AL Figure 2. Serum etanercept concentrations (Conc.) at weeks 1 and 8 after treatment with 50 mg etanercept once weekly (Œ) (n ⫽ 26) or 25 mg etanercept twice weekly (u) (n ⫽ 18). Bars show the mean ⫾ 1 SD. ONCE-WEEKLY ADMINISTRATION OF 50 MG ETANERCEPT Table 7. Adverse events occurring in at least 5% of patients in any treatment group* Etanercept Time point, event Week 8 Asthenia Diarrhea Headache Injection/site hemorrhage Injection/site reaction Nausea Rash Upper respiratory infection Week 16 Accidental injury Asthenia Cough increased Diarrhea Headache Injection/site reaction Nausea Pain (not otherwise specified) Rash Sinusitis Upper respiratory infection Vomiting Placebo† (n ⫽ 53) 50 mg qw (n ⫽ 214) 25 mg biw (n ⫽ 153) 3 (6) 2 (4) 5 (9) 3 (6) 3 (6) 8 (15) 5 (9) 7 (13) 5 (2) 12 (6) 27 (13) 6 (3) 38 (18)‡ 13 (6) 14 (7) 6 (3) 8 (5) 9 (6) 19 (12) 6 (4) 27 (18)‡ 19 (12)§ 5 (3) 9 (6) – – – – – – – – – – – – 3 (1) 7 (3) 8 (4) 18 (8) 32 (15) 40 (19) 16 (8) 14 (7) 19 (9) 12 (6) 18 (8) 5 (2) 10 (7)§ 14 (9)§ 8 (5) 11 (7) 22 (14) 29 (19) 24 (16)§ 5 (3) 7 (5) 9 (6) 19 (12) 8 (5) * Values are the number (%) of patients. Adverse events of all intensities are included. qw ⫽ once weekly; biw ⫽ twice weekly. † Patients received in a blinded manner placebo for 8 weeks followed by 25 mg etanercept biw for the remaining 8 weeks of the treatment period. ‡ P ⬍ 0.05 compared with the placebo group. § P ⬍ 0.05 compared with the etanercept 50 mg qw group. once weekly produced smooth serum concentration– time profiles with fairly low peak-to-trough ratios at steady state. Exposure of etanercept to serum during week 8 of the study, measured by the mean partial area under the curve (AUC), was similar in the 2 groups: mean AUCs were 297 mg䡠hours/liter and 317 mg䡠hours/ liter for the etanercept 50 mg once weekly and 25 mg twice weekly groups, respectively. Safety. During the 16-week study, 14 patients discontinued treatment due to adverse events. Four patients (8%) in the placebo group (2 during the placebo phase of treatment), 7 patients (3%) in the etanercept 50 mg once weekly group, and 3 patients (2%) in the etanercept 25 mg twice weekly group discontinued treatment due to adverse events. Safety in the etanercept treatment groups was evaluated in comparison with placebo through the first 8 weeks of treatment, and the 2 etanercept groups were further compared over 16 weeks. Adverse events of any intensity occurring in at least 5% of patients in any treatment group are summarized in Table 7. 361 Comparison of adverse events occurring in the 2 etanercept groups was of primary interest. In terms of adverse events occurring in at least 5% of patients in any treatment group, the 2 etanercept groups were statistically significantly different in the percentage of patients experiencing accidental injury (P ⫽ 0.02 at week 16), asthenia (P ⫽ 0.02 at week 16), and nausea (P ⫽ 0.04 and P ⫽ 0.02 at weeks 8 and 16, respectively). In each case, a higher proportion of patients in the etanercept 25 mg twice weekly group experienced those events. Moreover, at week 8, the highest proportions of patients with asthenia and nausea occurred in the placebo group. Most adverse events during the study were of mild to moderate intensity. Four of 214 patients (2%) in the etanercept 50 mg once weekly group, 8 of 153 patients (5%) in the 25 mg twice weekly group, and no patients in the placebo group (n ⫽ 53) experienced events that were serious, which were defined as lifethreatening events or those requiring hospitalization or intravenous antibiotics. In the etanercept 50 mg once weekly group, 4 hospitalizations were reported (gastroenteritis, hiatal hernia, bronchial infection, and urinary retention). In the etanercept 25 mg twice weekly group, 1 patient was diagnosed as having prostatic adenocarcinoma, and 7 hospitalizations were reported (pneumonia, bronchitis, urinary tract infection, cholecystitis, back pain, stomach ulcer, and confusion). Serious infections occurred at expected rates for the patient population and were not increased in the etanercept 50 mg group relative to the etanercept 25 mg group. No opportunistic infections were observed. No deaths occurred during the study. Thus, administration of 50 mg etanercept once weekly was not associated with an increase in the severity of adverse events. Consistent with the observations in previous studies, the only adverse event observed significantly more frequently in etanercept-treated patients than in the placebo group was injection-site reactions. One patient in the etanercept 50 mg once weekly group discontinued the study due to a mild injection-site reaction. All injection-site reactions were of mild to moderate intensity, and the proportions of patients with injection-site reactions were similar between the etanercept groups (Table 7). Laboratory evaluations were conducted at baseline and at week 16, after all patients had received etanercept. Most laboratory abnormalities were of mild or moderate intensity, and none were considered clinically significant or caused a patient to discontinue the study. Most of the abnormalities were intermittent, and 362 KEYSTONE ET AL these laboratory values returned to normal without intervention. Three percent of patients in each of the etanercept groups tested positive for antibodies to etanercept. However, no patient developed neutralizing antibodies to etanercept during the study. DISCUSSION Etanercept has previously been demonstrated to be safe and effective for the treatment of patients with RA (2–4) and PsA (5). Most patients have been treated with 25 mg etanercept, administered twice weekly. Pharmacokinetic modeling predicted that steady-state etanercept concentrations should be similar with dosing regimens of 50 mg once weekly and 25 mg twice weekly, and consequently, the 2 dosing regimens should provide comparable efficacy and safety profiles. This study was conducted to evaluate the pharmacokinetic predictions and to confirm the efficacy and safety of 50 mg etanercept administered once weekly. The primary efficacy analysis comparing ACR20 responses at week 8 demonstrated that 50 mg etanercept administered once weekly was significantly more effective than placebo (P ⱕ 0.0001). Patients in both etanercept groups achieved statistically significant improvements in the ACR20 and ACR50 scores at week 8 compared with those in the placebo group. Likewise, patients in both etanercept groups showed significantly greater improvements from baseline than did those in the placebo group in all individual components of the ACR criteria except swollen joint counts, which showed a trend toward statistical significance (P ⬍ 0.06). Comparable efficacy results were observed in patients receiving concomitant MTX compared with those not receiving MTX. Similar proportions of patients in the etanercept groups achieved ACR20 responses at each time point. Fifty percent of patients in the etanercept 50 mg once weekly group and 49% of patients in the etanercept 25 mg twice weekly group achieved an ACR20 response at week 8, the prespecified primary end point. At week 16, 55% of patients in the etanercept 50 mg once weekly group and 63% in the etanercept 25 mg twice weekly group achieved an ACR20 response (P ⫽ 0.12). Similarly, ACR50 and ACR70 responses and improvement in individual components of the ACR response criteria were comparable between the 2 etanercept dosing regimens. Administration of 50 mg etanercept once weekly produced smooth serum concentration–time profiles with fairly low peak-to-trough ratios at steady state. These results are consistent with those observed when 25 mg etanercept is administered twice weekly, and are a consequence of the slow absorption and clearance of the drug. At week 8, representing steady state, the mean serum exposures and concentration–time profiles for the 2 etanercept groups were very similar. Safety in the 2 etanercept groups was compared with placebo through the first 8 weeks of treatment, and the 2 etanercept groups were further compared over 16 weeks. Consistent with the results of previous studies (2,3), the only adverse event that occurred significantly more frequently in the etanercept groups relative to the placebo group was injection-site reactions. The proportions of patients with infections were similar among all 3 treatment groups. The proportions of patients who experienced serious adverse events were similar in the 2 etanercept treatment groups, and this was consistent with the findings of previous reports. The results of this 16-week study confirm the predictions of the pharmacokinetic modeling. The efficacy of 50 mg etanercept administered once weekly is comparable with that of the standard regimen of 25 mg etanercept administered twice weekly. The pharmacokinetics of the 2 dosing regimens are similar at steady state. No clinically significant differences in safety are evident between the 2 etanercept treatment groups. 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