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Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritisResults of a multicenter randomized double-blind placebo-controlled trial.

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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: edkeystone@mtsinai.on.ca.
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 [14]), 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.
Thus, comparable clinical outcomes are to be expected
when patients are treated with 50 mg etanercept administered once weekly or 25 mg etanercept administered
twice weekly for 16 weeks.
ACKNOWLEDGMENTS
We thank Margaret Summersgill for assistance with
the study protocol, and Roberta Connelly, MS, for assistance
in writing the manuscript.
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